SK283744B6 - Benzimidazoles, production thereof and use thereof as medicaments - Google Patents

Abstract

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

Description

Technical field

The present invention relates to benzimidazoles, a process for their preparation, a pharmaceutical composition containing them and their use.

BACKGROUND OF THE INVENTION

WO 98 37075 discloses disubstituted heterocyclic compounds of the general formula Ra-A-Het-B-Ar-E, wherein E is RbNH-C (= NH) - having valuable pharmacological properties, in particular thrombin inhibitory action and prolonging thrombin time and those compounds wherein E is cyano are valuable intermediates for the production of other compounds.

WO 94 08962 discloses fibrinogen receptor antagonists for use in inhibiting the binding of fibrinogen to platelets and inhibiting platelet aggregation.

WO 98 01428 discloses amidinoindoles, amidinoazoles and analogous compounds which are useful as inhibitors of factor Xa or thrombin.

SUMMARY OF THE INVENTION

The present invention provides benzimidazoles of formula (I)

R their tautomers, their stereoisomers, their mixtures, their precursors, their derivatives which contain a negatively charged group at the carboxyl group under physiological conditions, and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases which exhibit valuable properties.

Compounds of formula (I) wherein R ^c is cyano are valuable intermediates for the preparation of other compounds of formula (I) and compounds of formula (I) wherein R ^c is one of the following amidino groups, as well as their tautomers, their stereoisomers, mixtures thereof, their precursors, their derivatives having a negatively charged group in place of the carboxy group and their salts, in particular their physiologically acceptable salts with inorganic or organic acids, and their stereoisomers exhibit valuable pharmacological properties , in particular an antithrombotic effect.

In the above general formula (I), they mean:

Ar is a phenylene or naphthylene group, optionally substituted with a fluorine, chlorine or bromine atom, trifluoromethyl, Cl 2. _3- alkyl or C 1 -alkoxy, optionally in a C 1 -C 3 carbon skeleton. _{A 3-} alkyl-substituted thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,

AC ,. _3- alkylene,

B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C 1-4 -alkyl group in which the alkyl moiety may be mono- or disubstituted by carboxy, R ^and R'-CO-C _3-5 -cycloalkyl, in which

^R1 is

C 1-3 -alkoxy-, amino-, C 1-4 -alkylamino- or di- (C _1-4 -alkyl) -amino, in which the alkyl portion may in each case be substituted by a carboxy group,

A 4- to 7-membered cycloalkyleneimino- or cycloalkenyleneimino group, which may be substituted by one or two C 1-6 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by hydroxy-, C 1-6 -alkyl. _3- alkoxy-, carboxy-, carboxy-C 1-6 alkyl; _3- alkoxy-, carboxy-C 1-6 alkyl; ₃ -alkylamino, • W (Cl. ₃ alkyl) -N- ^{I '-} (carboxy-Ci.3 alkyl) amino, carboxy-C | .3-alkylaminocarbonyl, ^A, - (C | .3- alkyli -. "N- _{(carboxy-C-1J} -alkylj aminocarbonyl, carboxy-C, _ ₃ -alkylaminocarbonylamino-, L (C. _3-alkyl) -3- (carboxy-C |. ₃ alkyl) - aminokarbonylamino-, RCI-S ^ S--alkylj fkarboxy-Cfyí -alkyl is aminocarbonyl or amino-l, 3-di- (C [. ₃ -alkyl) -3- (carboxy-C |. ₃ -alkylj- aminocarbonylamino, hydroxy substituted 4- to 7-membered cycloalkyleneimino, or C 1-4 alkyl substituted by 5- to 7-membered cycloalkylene-imino, to which is fused via two adjacent carbon atoms a phenyl ring, morpholino, piperazino, A'- (C |. ₃ alkyl) -piperazino-, pyrolino-, 3,4-dehydro-piperidino or pyrrol-l-yl radical, R ² -CX-C _{3. 5} -cycloalkyl, wherein

R ² is optionally C 1-4 -alkyl substituted phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally contains C 1. _{A 3-} alkyl-substituted amino, oxygen or sulfur atom, or an optionally C 1-6 -alkyl-substituted amino group, and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted by carboxy-, carboxy-C _1-3 -alkoxy-, carboxy C |. _3- alkylamino- or N 1 -C 6 -alkyl-carboxy-C 1 -alkylamino, and

X is O, C ₁ _ ₃ -alkylimino- C | ₃ -alkoxyimino- C _{first 3-alkyl-hydrazino,} di (C, _ ₃ -alkyl) -hydraiíino-, C ₂ 4-alkanoyIhydrazino-, N- (C j _ ₃ -alkyl) -C _{second A 4-} alkanoylhydrazino- or C _1-3 -alkylidene group, which in each case may be substituted in the alkyl or alkanoyl part or in the alkyl and alkanoyl part by a carboxy, imidazole or imidazolone group substituted by a C _1-3 -alkyl- or a C ₃ . _{A 5-} cycloalkyl group in which the imidazole ring may be substituted with a phenyl or carboxy group and one or two C 1-6 -cycloalkyl groups; _3- alkyl, or one, two or three C 1-6 alkyl; _3- alkyl groups, wherein the substituents may be the same or different and one of the above-mentioned alkyl substituents may be simultaneously substituted by carboxy or in the 2 or 3 position of amino, C ₂₄ -alkanoylamino-, C 1-4 -alkylamino-, Λ- (C ₂ . ₄ alkanoyl) _{-C1. 3-} alkylamino- or di- (C ₁₃ -alkyl) -amino, and the imidazolone ring may be substituted by C. ₃ -alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C _{2nd 4} -alkanoylamino-, _{C] t} alkylamino-, N - _{(C2. 4} -alkanoyl) -C |. _; -alkylamino- or di-t-alkyl-amino, and in addition to the aforementioned imidazole and imidazolone ring, a phenyl or pyridine ring, an imidazolidin-2,4-dione-5-yl group, which can be fused via two adjacent carbon atoms be substituted by one or two C ₁₃ -alkyl groups, wherein at the same time one alkyl substituent may be substituted by carboxy, C 1-6 alkyl. _4- alkyl which is substituted

C 1-6 -alkyl-Y'-Cu-alkyl-, HOOC-Cu-alkyl-Y-Cu-alkyl-, tetrazolyl-Cu-alkyl-Y ² -, R ³ NR ⁴ -, or R'NR 1 'Cu-alkyl and optionally C 1. _3- alkyl substituted with isoxazolidinylcarbonyl, pyrolinocarbonyl-, 3,4-dicydro-piperidinocarbonyl-, pyrrol-1-ylcarbonylcarboxy-, aminocarbonyl-, C1-6alkyloxycarbonyl-, C1-6alkyloxycarbonyl-, C1-6alkyloxycarbonyl-, C1-6alkyloxycarbonyl-, C1-6alkyloxycarbonyl-, C1-6alkylamino; _3- alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl- or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkylimino moiety may be substituted by one or two C 1-6 -alkyl groups and at the same time may be alkyl a portion or an alkyl substituent of the aforementioned C 1-6 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-carbonyl- or cycloalkyleneiminocarbonyl substituted with a carboxy group and the remaining hydrogen atoms of C ₁ . _{The 4-} alkyl groups may be wholly or partially replaced by the fluorine atoms in which the

R ³ is hydrogen or an optionally carboxy substituted C _{first 3-} alkyl; and

R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y'-C 1-3 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ -C 1-3 -alkyl-Y ² -, Cpj -alkyl-Y ² -, or carboxy-alkyl Cl.j -Y ² -group or

R ³ and R ⁴ together with the intervening nitrogen atom represent optionally carboxy-, C 1 -. _3- alkyl- or carboxyC 1-6 alkyl; _{A 3-} alkyl substituted 4- to 7-membered cycloalkyleneimino group in which

Y ¹ represents a carbon-carbon bond, O, sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH- group, and

Y ² represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO-group, wherein the carbonyl group of the -NH-CO-group is bonded to the nitrogen atom of the R ³ NR ⁴ -groups and the imino groups which occur in the definition residues Y ¹ and Y ² may in each case be additionally substituted by C 1-6 -alkyl- or carboxy-C 1-3 -alkyl, R ⁵ NR ⁶ -substituted by C 1-3 -alkyl- or C ₃₅ -cycloalkyl, in which:

R ⁵ represents a hydrogen atom, a C _3-3 -alkyl-, a C 5-7 -cycloalkyl-, a phenylcarbonyl-, a phenylsulfonyl- or a pyridinyl group and

R ⁶ represents C 1-6 alkyl, carboxy-C 1-6 alkyl or carboxy-C ₁ . ₃ -alkylcarbonyl,

C 1-6 alkyl which is substituted with C ₂ . ₄ -alkanoyl- or C ₅ . _7- cycloalkanoyl; ₃ -alkyl substituted by Cl, Br or I, R ^b is H or C |. _3- alkyl; and

R ^c is cyano or optionally one or two C 1-6 groups. _3- alkylsubstituted amidino.

In addition, the carboxy groups mentioned in the definition of the abovementioned residues may be replaced by a group which can be converted in vivo to the carboxy group or under physiological conditions with a negatively charged group, or in the definition of the abovementioned residues the amino and imino groups may additionally be substituted in in vivo cleavable residue. For example, such groups are described in WO 98/46576 and N. M. Nielson et al. in Intemational Joumal of Pharmaceutics 39, 75-85, 1987.

Group which can be converted in vivo into a carboxy group, it should be understood, for example, hydroxymethyl, carboxy esterified with an alcohol wherein the alcoholic moiety is preferably a C ^ -alkanol, _{phenyl-C. 3} -alkanol, C 9 are _{3-cycloalkanol,} wherein the C _{5. 8} cycloalkanol may additionally be substituted by one or two C |., - alkyl groups, C _{5. g} -cycloalkanol, in which the methylene group in the 3 or 4 position is replaced by an oxygen atom or optionally C1-C4-alkyl-, phenyl-C1-C4. _3- alkyl-, phenyl-C 1-6 alkyl; ₃ -alkoxycarbonyl or C _{2nd The 6-} alkanoyl group substituted with an imino group and the cycloalkanol moiety may additionally be substituted with one or two C 1-6 alkyl groups, C ₄ . ₇ -cycloalkenol, C ₃ . ₅ -alkenes, phenyl-C _{3. 5} -alkenol, C ₃ . ₅ -alkinol or phenyl-C _{3. 5-} alkinol with the proviso that there is no bond to the oxygen atom from a carbon atom having a double or triple bond, C ₃ . ₈ -cycloalkyl-C ₁ . ₃ -alkanol, bicycloalkanol having 8 to 10 carbon atoms in total, which may additionally be substituted in the bicycloalkyl moiety with one or two C 1-6 alkyl groups, 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

R ^d -CO-O- (R ^e CR ^f ) -OH in which

R ^d is C. ₈ -alkyl-, C _{5. 7} -cycloalkyl-, phenyl- or phenyl-C ₁ . _3- alkyl,

R ^e represents a hydrogen atom, C 1-6. ₃ alkyl-, C _{5. 7} -cycloalkyl- or phenyl; and

R ^f represents a hydrogen atom or C ₁ . _{A 3-} alkyl group, under physiological conditions a negatively charged group such as tetrazol-5-yl-, phenylcarbonylaminocarbonyl-, trifluoromethylcarbonylaminocarbonyl-alkylsulfonylamino, phenylsulfonylamino-, benzylsulfonylamino-, trifluoromethylsulfonylamino-, C ₁ . _6- alkylsulfonylaminocarbonyl-, phenylsulfonylaminocarbonyl-, benzylsulfonylaminocarbonyl or p-fluoro-C 1-6 -alkylsulfonylaminocarbonyl, and in vivo leaving the imino or amino group is understood to be, for example, hydroxy, fluoro, C, acyl, acyl ]. Alkyl- or _3-wire alkoxy mono- or disubstituted benzoyl wherein the substituents are the same or different, or C pyridinoylskupina _W i6-alkanoyl, such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoylskupina 3 , 3,3-trichloropropionyl- or allyloxycarbonyl, C 1-6 -alkoxycarbonyl- or C 1-6 -alkyloxycarbonyl; _6- alkylcarbonyl-oxy, in which the hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, , octyloxycarbonyl-, nonyloxycarbonyl-, decyloxycarbonyl-, undecyloxycarbonyl-, dodecyloxycarbonyl-, hexadecyloxycarbonyl-, methylcarbonyloxy-, ethylcarbonyloxy-, 2,2,2-trichloroethylcarbonyloxy-, isopropylcarbonyl-oxy-, propylcarbonyl-oxy- butylcarbonyloxy-, pentylcarbonyloxy-, hexylcarbonyloxy-, octylcarbonyloxy-, nonylcarbonyloxy-, decylcarbonyloxy-, undecylcarbonyloxy-, dodecylcarbonyloxy- or hexadecylcarbonyloxy-, phenyl-C 1-6. _6- alkoxycarbonyl, such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl, 3-aminopropionyl, in which the amino group may be mono- or disubstituted by C _1-6 -alkoxycarbonyl; _6- alkyl- or C ₃ . ₇ -cycloalkyl, and the substituents may be the same or different, C | _ _{(C2-alkylsulfonyl. 4} alkoxycarbonyl-, _{C1. 3 -alkoxy-C2. 4 -alkoxy-C2. 4} -alkoxycarbonyl-, ^Rd - CO-O- (R ^d CR ^f ) -O-CO-, C 1-6 -alkyl-CO-NH- (R ⁸ CR ^h ) -O-CO- or C 1-6 -alkyl-CO-O ^with CR ^h ) - (R ⁸ CR ^h ) -O-CO-group in which R ^d and R ^f are as defined above,

R ⁸ and R ^h , which may be the same or different, are hydrogen or C 1. _3- alkyl.

Furthermore, in the definition, the aforementioned saturated alkyl and alkoxy moieties containing more than 2 carbon atoms also include their branched isomers such as isopropyl, tert-butyl, isobutyl and the like.

Preferred compounds are those having the general formula (Ia)

R ^b in which

A represents a C 1-6 -alkylene group,

B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, optionally C. _{A 3-} alkyl-substituted amino group in which the alkyl moiety may be mono- or disubstituted with a carboxy group,

R ^a represents

R ¹ -CO-C _{3. 5-} cycloalkyl wherein:

^R1 is

C 1 -alkoxy-, amino-, C 1-6 alkoxy- _4- alkylamino- or di-C 1-6 -alkyl-amino, in which the alkyl portion may in each case be substituted by a carboxy group,

A 4- to 7-membered cycloalkyleneimino- or cycloalkenyleneimino group which may be substituted by one or two C 1-6 -alkyls; ₃ -alkyl, wherein the alkyl substituent may simultaneously be substituted by hydroxy, C |. _3- alkoxy-, carboxy-, carboxy-C 1-6 alkyl; _3- Alkoxy-, carboxy-C1-4 -alkyl. ₃ -alkylammo-. ^A - (C | .3 alkyl) -N ^/ - (carboxy ARTICLE 3 alkyl) amino. carboxy-C |. ₃ alkylaminocarbonyl, 7V- _(C1 .3 alkyl) -7V- (carboxy-C _first -alkylj _{3-aminocarbonyl,} carboxy-C ^ alkylaminocarbonylamino, 1 - (Ci-alkyli-S-íkarboxy- Cb.j aminokarbonylamino--alkylamino, 3- (C _{first 3} -alkyl) -3- (carboxy-C _{first 3-alkyl)} -amino-carbonylamino, or l, 3-di- (C _{first 3} - alkyl) -3- (carboxy-C ₁ _3-alkyli-aminocarbonylamino, hydroxy-substituted 4- to 7-membered cycloalkyl -alkylénimino radical, or _a C. ₃ -alkyl substituted with a 5- to 7-membered cycloalkylene-imino group, , which is connected via two adjacent carbon atoms fused with a phenyl ring, morpholino, piperazino, N - _(C.! alkyl) -piperazino-. pyrolino-, 3,4-dehydro-piperidino or pyrrol-l-yl- R ² -CX-C ₃ - ₅ -cycloalkyl;

R ² is optionally C 1. _{A 3-} alkyl substituted phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally contains a C 1-4 -alkyl substituted amino, oxygen or sulfur or optionally C 1-6 alkyl substituted amino and oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted by carboxy-, carboxy-C 1-6 -alkoxy-, carboxy-C 1-6. ₃ alkylamino- or N- _{(C]. 3} alkyl) _{carboxy-C1. 3-} alkylamino, and

X represents an oxygen atom, a C 1-6 alkylimino-, a C 1-6 alkyl group; _3- alkoxyimino-, C ₁ -C ₃ . _3- alkyl-hydrazino-, di- (C _1-3 -alkyl) -hydrazino-, C2. -Alkanoylhydrazino- _4, ^A, - (C _{first 3} -alkyl) -C _{second 4-} alkanoylhydrazino- or C ₁ . ₃ alkylidene group which each of the alkyl or alkanoyl and the alkanoyl and the alkyl may be substituted by carboxy, an imidazole or an imidazolone-substituted Cj-3 alkyl or C _{3. 5} cycloalkyl group, wherein the imidazole ring may be substituted by phenyl or carboxyl, and one or two C _K3-alkyl groups or by one, two or three C _{first 3} -alkyl, the substituents can be the same or different and one of the previously mentioned alkyl substituents may simultaneously be substituted by a carboxy group or in the 2 or 3 amino, C _{2nd 4} alkanoyl amino, alkylamino C'u-M _{(C2. 4} alkanoyl) _M-C -alkylamino or di- (C |. -Alkyljaminoskupinou _3, and the imidazolone ring may be substituted with C]. ₃ - alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C _{2. 4} -alkanoylamino-, _{C1. 3} alkylamino-, TV- (C _{2. 4} -alkanoyl) -C |. ₃ -alkylamino - or di (C _{first 3} alkyl) amino, and in addition to the previously mentioned imidazole and imidazolone ring may be via two adjacent carbon atoms of the phenyl or fused pyridine ring, imidazolidin-2,4-dion-5-yl group, which may be substituted by one or two C |. ₃ -alkyl, while the alkyl substituent may be the one substituted by carboxy, C _{l. 4} -alkyl which is substituted by C _{l. ^3-alkyl-Y1-C} | .3-alkyl- , HOOC-C 1-4 -alkyl-Y'-C 1-4 -alkyl-, tetrazolyl-C 1-3 -alkyl-Y ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C _1-3 -alkyl and optionally C _1-3 - alkyl subs substituted-isoxazolidin-1-ylcarbonyl, pyrolinocarbonyl-, 2,3-dehydro-piperidinocarbonyl-, pyrrol-1-yl-carbonyl-, carboxy-, aminocarbonyl-, C 1-4 -alkylaminocarbonyl-, di- (C 1-6 -carbonyl) -carbonyl- _3- alkyl) -aminocarbonyl- or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkyleneimine moiety may be substituted with one or two C 1-6 -alkyl groups and at the same time may be an alkyl moiety or an alkyl substituent of the aforementioned C _1J -alkylaminocarbonyl- carboxy-substituted di- (C _1-3 -alkyl) aminocarbonyl- or cycloalkyleneiminocarbonyl groups and the remaining hydrogen atoms of the C _1-4 -alkyl group may be wholly or partially replaced by fluorine atoms in which:

R ³ is hydrogen or an optionally carboxy substituted C _{first 3-} alkyl; and

R ⁴ represents a hydrogen atom, C 1-4 -alkyl-Y'-C 1 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ -C 1. _3- alkyl-Y ² -, C 1-6 -alkyl-Y ² - or carboxy-C ₁ . -Alkyl-Y ₃ -group or ^J

R ³ and R ⁴ together with the intervening nitrogen atom represent optionally carboxy-, C 1-4 -alkyl- or carboxyC _1-3 -alkyl substituted 4- to 7-membered cycloalkyleneimino groups in which

Y ¹ represents a carbon-carbon bond, O, sulphenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NHskupinu and

Y ² represents a carbon-nitrogen bond or a carbonyl-, sulfonyl-, imino- or -NH-CO- group, wherein the carbonyl group of the -NH-CO-group is bonded to the nitrogen atom of the R ³ NR ⁴ -group and in the definition of Y ¹ and Y ² occurring imino groups can in each case be additionally substituted by C 1-3 -alkyl- or carboxy-C 1-3 -alkyl, R ^with NR ⁶ -substituted by C 1-3 -alkyl- or C ₃ . _5- cycloalkyl wherein:

R ⁵ is H, Cl alkyl, _C, _ ₇ -cycloalkyl-, fcnylkarbonyl-, sulfonyl, or phenyl-pyridinyl, and

R ⁶ represents a C _1-3 -alkyl-, carboxy-C 1-3 -alkyl- or carboxy-C 1-6 -alkyl-carbonyl group,

C 1-3 -alkyl, which is substituted with C _2-6 . ₄ -alkanoylalebo _C5 _7 cycloalkyl-alkanoyl and C ^ -alkyl substituted by Cl, Br or I, R ^b is H or Ci.3-alkyl and R ^c represents a cyano or amidino, which is optionally substituted by hydroxy, one or two C 1-4 -alkyl groups, one or two C 3-3 -alkoxycarbonyl groups, wherein, in the definition of the abovementioned residues, said carboxy-, amino- and imino-groups may additionally be substituted by an in vivo leaving group, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of formula (Ia) are those in which

A represents a C 1-4 -alkylene group,

B is an oxygen atom, a methylene, imino- or N-t-alkyl-amino group in which the alkyl moiety may be substituted by carboxy,

R ^a represents in the 1-position R * -CO- the radical substituted with C ₃ . _5- cycloalkyl wherein:

^R1 is

C ^ -alkoxy, amino, C _M -alkylamino or di- (C] _ ₄ alkyl) amino group in which each alkyl may be substituted with carboxy,

A 4- to 7-membered cycloalkyleneimino group which may be substituted by hydroxy or by one or two C ₁ . ₃ -alkyl, wherein alkylsubstitucnt may be simultaneously substituted with hydroxy, C |. _3- alkoxy-, carboxy-, carboxy-C 1-3 -alkoxy-, carboxy-C 1-3. ₃ -alkylamino, N- (C |. ₃ alkyl) -N- (carboxy-Ci. ₃ alkyl) amino, carboxy-Cu-alkylaminocarbonyl, ^N - (C | .3 alkyl) - A ^I - (carboxy-C1. ₃ alkyl) aminocarbonyl-, _{carboxy-C1. 3-} alkylaminocarbonylamino-, 1- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonylamino-, S-C 1-6 -alkyl-5-carboxy-C 1-6 -alkyl-amino -carbonylamino- or 1,3-di- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) aminocarbonylamino, optionally C 1. _{A 3-} alkyl substituted 5- to 7-membered cycloalkylene-imino group to which a phenyl ring, morpholino-, piperazino-, N-C 1-6 -alkyl- piperazino-, pyrrolino-, 3,4-dehydro-, fused phenyl is fused via two adjacent carbon atoms piperidino- or pyrrol-1-yl-group, in the 1-position of the R ² -CX- radical substituted by a C _3-5 -cycloalkyl group in which:

R ² is optionally C _1-3 -alkyl substituted phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally contains C 1. ₃ -alkyl substituted NH, O, S and optionally C, _ ₃ -alkyl-substituted imino group and the oxygen or sulfur atom or one or two nitrogen atoms and the previously mentioned alkyl substituent may be substituted by carboxy, carboxy-C ^ -alkoxy- , carboxy-C _1-3 -alkylamino- or N-C 1-6 -alkyl-carboxy-C 1-6 -alkylamino, and

X represents an oxygen atom; _3- alkylimino-, C 1-6 alkyl; _3- alkoxyimino or C 1-6 alkylidene, which in each alkyl or alkoxy part may be substituted by carboxy, in the 1-position by imidazole or imidazolone substituted C 1-6 -alkyl, in which the imidazole ring may be substituted by phenyl or carboxy and one or two C 1-3 alkyl or one, two or three C 1-6 alkyl; ₃ -alkyl, the substituents can be the same or different and one of the previously mentioned alkyl substituents may simultaneously be substituted by carboxyl group or in the 2 or 3 amino, C ₂₄ -alkanoylamino-, C |. ₃ -alkylamino, N- (C _{2nd 4} -alkanoyl) -C _{first A 3-} alkylamino- or di- (C 1-6 -alkyl) amino group, and the imidazolone ring may be substituted with a C 1-6 alkyl group; ₃ -alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C _{2nd 4} -alkanoylamino-, Cj. ₃ -alkylamino, N- _{(C2. 4} alkanoyl) -Cjj-alkylamino or di-ICU-alkvIjaminoskupinou, in addition to the previously mentioned imidazole and imidazolone ring may be through two adjacent carbon atoms, fused phenyl or pyridine ring.

an imidazolidin-2,4-dione-5-yl group which may be substituted with one or two C 1-6 groups. _3- alkyl, wherein at the same time one alkyl substituent may be substituted by carboxy,

C 1-6 -alkyl which is substituted at the 1-position

R ³ NR ⁴ - or R ³ NR ⁴ -C ₁ . _3- alkyl and pyrolinocarbonyl-, 2,3-dehydro-piperidinocarbonyl-, imidazol-1-yl-carbonyl-, carboxy-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) aminocarbonyl- , isoxazolidin-1-yl-carbonyl- or 4- to 7-membered cycloalkyleneiminocarbonyl, wherein in the above groups the cycloalkyleneimino moiety may be substituted by one or two C _1-3 -alkyl groups and at the same time may be one alkyl moiety or alkyl substituent of the foregoing. C]. _3- alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-carbonyl- or cycloalkyleneiminocarbonyl substituted with carboxy and the remaining hydrogen atoms C ₁ . _{The 4-} alkyl groups may be wholly or partially replaced by the fluorine atoms in which the

R ³ represents a hydrogen atom or an optionally substituted carboxy group. _3- alkyl; and

R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ² - or carboxyCl. Or _3- alkyl-Y- ² ;

R ³ and R ⁴ together with the intervening nitrogen atom are optionally in the 1-position of carboxy-, C 1 -. _3- alkyl- or carboxy-C 1. _{A 3-} alkyl substituted 4- to 7-membered cycloalkyleneimino group in which

Y ² represents a carbon-nitrogen bond or a carbonyl-, imino or -NH-CO-group, wherein the carbonyl group of the -NH-CO-group is bonded to the nitrogen atom of the R ³ NR ⁴ -group and in the definition of Y ² the imino group present may be substituted C _{H 3} alkyl- or carboxy-C. _3- alkyl, in position 1 of R ⁵ NR ⁶ -substituted with C 1. _3- alkyl- or C ₃ . ₅ -cycloalkyl wherein:

R ⁵ represents a hydrogen atom, C 1-6. ₃ alkyl-, C _{5. 7} -cycloalkyl-, phenylcarbonyl-, phenylsulfonyl- or pyridinyl; and

R ⁶ represents a C _1-3 -alkyl-, carboxy-C _1-3 -alkyl- or carboxy-C 1-6 -alkyl-carbonyl group,

Ci. ₃ -alkyl, substituted C _{2nd 4} -alkanoyl- or C ₅ . ₇ -cycloalkanoyl and C 1-6 -alkyl substituted by chlorine, bromine or iodine, R ^b is C _1-3 -alkyl and

R ^c is optionally 2,2,2-trichloroethoxycarbonyl-, C 1-4 -alkoxycarbonyl-, acetoxymethyloxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino, wherein the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or bromine atoms _{The 1-3-} alkyl- or C _1-3 -alkoxy groups and substituents may be the same or different, their C _1-3 . ₃ -alkanol esters, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of formula (I) are those in which they are

And a methylene group,

B an oxygen atom or an imino group,

R ^and in the 1-position the R'-CO- radical substituted cyclopropyl group in which

R ¹ represents an optionally methyl or ethyl substituted pyrrolidino- or piperidino group, in which the methyl or ethyl moiety may in each case be substituted by carboxy-, carboxy-C 1-4 -alkoxy-, carboxy-C 1-6 -alkyl. _3- alkylamino- or N'-N, N-alkyl-1-carboxy-γ-alkylamino, in the 1-position of the R ² -CX- radical substituted cyclopropyl group in which

R ² represents an optionally C _b3 -alkyl substituted phenyl, pyridyl or pyrazolyl, and

X is an oxygen atom, a C _1-3 -alkoxyimino or a C _1-3 -alkylidene group, which in each case is substituted by a carboxy group in the alkyl or alkoxy part, in the 1-position by an imidazole group substituted by C 1-6. _{A 2-} alkyl group in which the imidazole ring may be substituted by phenyl or carboxy and one or two C ₁ . _3- alkyl, or one, two or three C 1. ₃ -alkyl, the substituents can be identical or different and one of the previously mentioned alkyl substituents may simultaneously be substituted by a carboxy group or in the 2 or 3 amino, C -, - alkanoylamino, C _{first 3} -alkylamino, N- (C ₂ .4 alkanoyl) _{C]. A 3-} alkylamino or di- (C _1-3 -alkyl) amino group, wherein in addition to the above imidazole rings, a phenyl or pyridine ring substituted in the 1-position by a benzimidazolon-1-yl-substituted C 1-2- group can be fused via two adjacent carbon atoms alkyl, wherein the imidazolone ring may be substituted with an optionally carboxy substituted methyl or ethyl group, a methyl or ethyl group which may be substituted in the 1-position

R ³ NR ⁴ - or R ³ NR ⁴ -C ₁ . _{A 3-} alkyl group and a di- (C _1-3 -alkyl) aminocarbonyl group, an isoxazolidin-1-yl-carbonyl group, or a C 1-6 alkyl group; _{A 3-} alkyl-substituted pyrrolidinocarbonyl or piperidinocarbonyl group, in which case the alkyl moieties or alkyl substituents may in each case be substituted by a carboxy group in which they represent

R ³ is hydrogen or optionally carboxy substituted C 1-6 alkyl; _{A 3-} alkyl group; and

R ⁴ is H, C, .3 alkyl-Y ² -, or carboxy-Cb3-alkyl-Y ² -group or

R ³ and R ⁴ together with an intervening nitrogen atom or a carboxy substituted 4- to 7-membered cycloalkyleneimino group in which:

Y ² denotes a carbon-nitrogen bond, a carbonyl group or optionally substituted C ₁₃ -alkyl imino group, at the 1 R ⁵ NR ⁶ group joining substituted with C ,. _{A 2-} alkyl group in which they are

R ^{5 is} pyridinyl, phenylcarbonyl or phenylsulfonyl; and

R ⁵ CJJ-alkyl or carboxy-C _l _ ₃ -alkyl, in the 3-position with chloro-substituted n-propyl, which is substituted in the 1-cyclopentylcarbonyl group, at the 1-cyclopentylamino-substituted cyclopropyl, that is the nitrogen atom substituted with carboxy- C]. _3- alkylcarbonyl,

R ^b represents a methyl group a

R ^c or C _bg -alkoxycarbonyl-, acetoxymetyloxykarbonyl-, 2,2,2-trichloroethoxy-carbonyl, benzyloxycarbonyl or benzoyl substituted amidino group, in particular those compounds of formula (Ia), in which are

And a methylene group,

B imino,

R ^and in the 1-position the R'-CO- radical substituted cyclopropyl group in which

R ¹ represents an optionally methyl or ethyl-substituted pyrrolidino or piperidino, where each part of a methyl or ethyl may be substituted by carboxy, carboxy-C _b3 -alkoxy, carboxy-C _B3

alkylamino-, or, -N (C _{first 3} alkyl) carboxy-C _{first A 3-} alkylamino group, in the 1-position of the R ² -CX- radical substituted cyclopropyl group in which

R ² represents an optionally C. _{A 3-} alkyl-substituted phenyl, pyridyl or pyrazolyl group; and

X is oxygen; _3- alkoxyimino- or C 1-6 -alkyloxyimino-; _{A 3-} alkylidene group which in each case is substituted by a carboxy group in the alkyl or alkoxy moiety, in the 1-position by an imidazole group substituted by a C _2-2 -alkyl group in which the imidazole ring may be substituted by 1 to 3 methyl groups or substituted by two methyl groups and one ethyl group; in addition, one of the aforementioned methyl or ethyl substituents may be simultaneously substituted by a carboxy, methyl or ethyl group which may be substituted at the 1-position

R ³ NR ⁴ - or R ³ NR ⁴ -CH ₂ - and di- (C _1-3 -alkyl) -aminocarbonyl or C 1-6 -alkyl substituted by pyrrolidinocarbonyl or piperidinocarbonyl, each of which in each case is an alkyl moiety; or the alkyl substituent may be substituted with the carboxy group in which it represents

R ³ is H or optionally substituted by carboxy C _b3 alkyl group, and

R ^{4 is} Cb 3 -alkyl-Y ² - or carboxy-C 1. _3- alkyl-Y ² -group in which

Y ² represents a carbon-nitrogen bond, a carbonyl group or optionally C 1. _{A 3-} alkyl-substituted amino group,

R ^b represents a methyl group a

R ^c or C 1. _8- alkoxycarbonyl-, acetoxymethyloxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino, with preference given above to those compounds of formula I in which the radical R ^a is in the position 5, their Ci. ₃ -alkanol esters, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds include:

(a) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole;

(b) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] benzimidazole,

(c) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole;

d) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) -pyrrolidin-1-ylcarbonyl] -cyclopropyl] -benzimidazole,

(e) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole;

f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole; and

g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonyl-aminomethyl) -1-methyl-1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole, such as as well as their C _1-3 -alkanol esters, their N-N (S-alkoxycarbonyl) -, N-benzyloxycarbonyl- and N'-benzoylamidines, their tautomers, their stereoisomers and their salts.

According to the present invention, the compounds of formula (I) are obtained by methods known per se, for example by the following methods:

(a) For the preparation of a compound of formula (I) in which R ^c is a cyano group:

is cyclized in the reaction mixture or form a compound of formula (II) of ^'the!

R in which

R ^a , R ^b , Ar, A and B are defined in the introduction,

Z ¹ and Z ² , which may be the same or different, optionally represent C 1 -C 6 alkyl groups, substituted amino, hydroxy or mercapto groups, or Z ¹ and Z ² together represent an oxygen or sulfur atom or an C 1 -C 3 alkyl group imino, alkylenedioxy- or alkylenedithio having 2 or 3 carbon atoms.

The cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin, or in excess of the acylate used. of the formula (II), e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250 ° C, preferably at the boiling point of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N, N-dicyclohexylcarbodiimide, or optionally in the presence of a base such as potassium ethylate or potassium tert-butylate. However, the cyclization can also be carried out without solvents and / or condensation agents.

However, the reaction is particularly preferably carried out in such a way that the compound of formula (II) is prepared in the reaction mixture by reduction of the corresponding o-nitro compound, optionally in the presence of a carboxylic acid of formula

HO-CO-A-B-Ar-CN (III) in which

Ar, A and B are defined as initially, by the acylation optionally in the reaction mixture of the corresponding amino compound.

b) For the preparation of a compound of formula (I) wherein R ^a is R ² -CX'-C ₃ . _{A 5-} cycloalkylene group wherein R ^{2 is} as defined in the introduction and X 'is one of the imino radicals mentioned in the introduction for X:

the compound of formula (IV) is reacted

R 'in which

R ^b , R ^c , Ar, A and B are as defined in the introduction and R ^a 'represents R ² -CO-C ₃ . _{A 5-} cycloalkylene group, wherein

R ² defined in the introduction, with an amine of formula

H ₂ X '(V) in which

X 'is one of the imbalances listed in the introduction for X.

The reaction is preferably carried out in a solvent such as methanol / toluene, ethanol, isopropanol or xylene and suitably in the presence of a dehydrating agent such as a molecular sieve, sodium sulfate or calcium chloride, optionally in the presence of a base such as triethylamine at temperatures between 50 and 100 ° C, preferably at the boiling point of the reaction mixture.

c) For the preparation of a compound of formula (I) wherein R ^a represents R ² -CX "-C _3-5 cycloalkylene group, wherein R ² is as defined in the introduction and X" represents one of the alkylidene residues mentioned in the introduction for X: the compound of formula (IV) is reacted

R 'in which

R ^b , R ^c , Ar, A and B are as defined in the introduction and R 1 'is R ² -CO-C ₃ . _{A 5-} cycloalkylene group, wherein

R 'is defined as above, with a phosphone of formula

Z ³ -HX ”(VI), in which

X 'represents one of the alkylidene residues mentioned at the outset for X, and

Z ₃ is triphenylphosphono- or di- (C _1-3 -alkoxy) phosphono, such as triethoxyphosphono.

The reaction is preferably carried out under a protective atmosphere in a solvent such as tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or dimethylsulfoxide in the presence of a base such as potassium tert-butylate, sodium ethylate or sodium hydride at temperatures between -25 ° C and 50 ° C. preferably at temperatures between -15 ° C and room temperature.

d) For the preparation of a compound of formula (1) in which R ^c is an amidino group which may be substituted by one or two C 1-6 -alkyl groups:

optionally reacting the compound of formula (VII) formed in the reaction mixture

(VII) ₍ in which:

R ^a , R ^b , Ar, A and B are as defined in the introduction and Z ⁴ is alkoxy or arylalkoxy, such as methoxy, ethoxy, npropoxy, isopropoxy or benzyloxy, or alkylthio or arylalkylthio such as methylthio-, ethylthio-, n-propylthio- or benzylthio, with an amine of the formula

H-R'NR ⁸ (VIII) wherein

R ⁷ and R ⁸ , which may be the same or different, each represent a hydrogen atom or a C 1-6 -alkyl group, or with salts thereof.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, α-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, with an amine of formula (VIII) or the corresponding an acid addition salt such as ammonium carbonate or ammonium acetate.

A compound of formula (VII) is obtained, for example, by reacting the corresponding cyano compound with the corresponding alcohol, such as methanol, ethanol, n-propanol, isopropanol or banzylalcohol, in the presence of an acid such as hydrochloric acid, or by reacting the corresponding amide with a trialkyloxonium salt. triethyloxonium tetrafluoroborate, in a solvent such as methylene chloride, tetrahydrofuran or dioxane, at temperatures between 0 and 50 ° C, preferably at 20 ° C, or the corresponding nitrile with hydrogen sulfide, suitably in a solvent such as pyridine or dimethylformamide, and in the presence of a base , such as triethylamine, followed by alkylation of the formed thioamide with the corresponding alkyl or arylalkyl halide.

e) For the preparation of a compound of formula (I) wherein R ^a represents an imidazolidin-2,4-dione-5-yl group which may be substituted by one or two C ₁ . _3- alkyl groups, wherein at the same time the alkyl substituent may be substituted by carboxy- or C _1-3 -alkoxycarbonyl: the compound of formula (IX) optionally formed in the reaction mixture cyclizes

R 'in which

R ^b, Ar, A and B are as defined at the outset and R ^a 'is aminocarbonyl the amino group in the 3-substituted C _b3 ykarbonyl alkoxy-C, _ ₃ alkyl group.

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

f) To prepare a compound of formula (I) wherein R ^c is a hydroxyamidino group: a nitrile of formula (X) is reacted

R 'in which

R ^a , R ^b , Ar, A and B are defined at the beginning, with hydroxylamine or its salts.

The reaction is conveniently 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 150 ° C. 80 ° C.

g) For the preparation of a compound of formula (I) wherein R ^a contains a carboxy group and R ^c is as defined at the outset, or R 1 is as defined at the beginning and R ^c is optionally hydroxy or one or two C 1. _3- alkyl-substituted amidino: the compound of formula (XI) is converted

R 'in which

R ^b , Ar, A and B are as defined in the introduction and R ^a '' and R ^c 'have the meanings given for R ^a and R' in the introduction, provided that R ^a contains an acid-hydrolysable group or a base, thermolysis or hydrogenolysis to convert to a carboxy group, and R ^c is as defined above, or R ^c is a group which can be converted by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to an optionally hydroxy or one or two C 1. _{A 3-} alkyl-substituted amidino group, and R ^a is as defined initially, by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to a compound of formula (I) wherein R ^a contains a carboxy group and R ^c is as defined above or R a ^a is as defined above and R ^c is an optionally substituted hydroxy or one or two C 1-4 -alkyl substituted amidino groups.

Suitable carboxyl groups include, for example, a carboxyl protecting group as well as functional derivatives thereof, such as unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters, which are conveniently converted to a carboxyl group. by hydrolysis, its esters with tertiary alcohols, for example the tert-butyl ester, which are conveniently converted to the carboxyl group by treatment with acid or thermolysis, and their esters with aralkanols, for example the benzyl ester, which are conveniently converted to the carboxyl group by hydrogenolysis.

The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable a solvent such as water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and temperature boiling the reaction mixture.

If the compound of formula (XI) contains, for example, a tert-butyl or tert-butylcarbonyl group, these can also be cleaved by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid. optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or even thermally or in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used. , for example at temperatures between 40 and 12 Low: 14 ° C.

If the compound of formula (XI) contains, for example, benzyloxy or benzyloxycarbonyl, these can also be cleaved by hydrolysis in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, acetic acid, ethyl ester acetic acid, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, for example at room temperature, and at a hydrogen pressure of 1 to 5 bar.

h) For the preparation of a compound of formula (I) wherein R ^c is an amidino group which is substituted by one or two C ₁ . _g -alkoxycarbonyl groups or an in vivo cleavable residue:

reacting a compound of formula (XII)

R in which

R ^a , R ^b , Ar, A and B are as defined in the introduction and R ^c "represents an amidino group, with a compound of the general formula

From ⁵ - R ⁹ (XIII), in which

R ⁹ represents a C 1-4 -alkoxycarbonyl group or an acyl residue of one of the in vivo cleavable residues mentioned at the outset, and

Z ⁵ is a nucleophilic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a p-nitrophenyl group.

The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 ° C and the boiling point of the solvent used.

With a compound of formula (XIII) wherein Z ⁵ is a nucleophilic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as hydride sodium, potassium carbonate, potassium tert-butylate or N-ethyl-diisopropylamine, at temperatures between 0 and 60 ° C.

If according to the invention a compound of formula (I) is obtained which contains (R ³ NR ⁴ ) -C ₁ . _{A 3-} alkyl group in which at least one of the radicals R ³ or R ⁴ represents a hydrogen atom can then be subsequently converted with the corresponding isocyanate or carbamoyl halide into the corresponding urea compound of formula (1) and / or a compound of formula (I) containing NH ₂ -Ci. _{The 3-} alkyl group can then be converted by the corresponding acrylic acid ester into the corresponding 2- ( _1,3- alkoxycarbonyl) -ethyl compound of formula (I) or a compound of formula (I) containing (R ^3). NR ⁴ ) -C ₁ . _{The 3-} alkyl group in which R ³ and R ⁴ each represent a hydrogen atom may then be converted by the corresponding dihaloalkanes into the corresponding compound of formula (I) wherein R ³ and R ⁴ together with the intervening nitrogen atom represent a corresponding 4-alkyl group. an up to 7-membered cycloalkyleneimino group and / or a compound of formula (I) wherein R ^c is an amidino group, which may then be converted by reaction with a haloacetic acid derivative as well as subsequent hydrolysis and decarboxylation to the corresponding amidino compound substituted with one or two and / or a compound of formula (I) in which R ^c is a hydroxyamidino group, which can then be converted by catalytic hydrogenation to the corresponding amidino compound and / or a compound of formula (I) in which R ^a is a carboxy group then this can then be converted into a response by csterification esterifying ester.

The subsequent preparation of the corresponding urea compound of formula (I) is conveniently carried out with the corresponding isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50 ° C, preferably at room temperature.

Subsequent preparation of the corresponding 2- (C _1-3 -alkoxycarbonyl) -ethyl compound is carried out with the corresponding acrylic ester, preferably in a solvent such as methanol, ethanol or isopropanol, at temperatures between 50 and 100 ° C, preferably at the boiling point of the reaction mixture.

The subsequent preparation of the corresponding 4- to 7-membered cycloalkylene-imino compound of formula (I) is conveniently carried out with the corresponding dihaloalkane, preferably in a solvent such as methanol, ethanol or isopropanol, in the presence of a base such as sodium carbonate at at temperatures between 50 and 100 ° C, preferably at the boiling point of the reaction mixture.

The subsequent alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, 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 Λ-ethyl-diisopropylamine or N-methylmorpholine, which may simultaneously serve as solvents, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, preferably at temperatures between - 10 and 80 ° C.

The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. 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 described above, at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.

Subsequent esterification is carried out with the corresponding alcohol, suitably in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, preferably in excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid, or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroethanoate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N-dicyclohexylcarbodiimide, N-hydroxysuccinimide, N, N'-carbonyldiiridazole or N, N'-thionyl diimidazole, triphenylphosphine (carbon tetrachloride or triphenylphosphine) - diethyl azodicarboxylic acid ester, optionally in the presence of a base such as potassium carbonate or diisopropylamide; V./V dimethylaminopyridine. conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, or with the corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as iodide sodium or potassium, 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, which may also serve as solvents at the same time; 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.

In the reactions described above, optionally reactive groups such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, trimethylsilyl-, acetyl-, benzoyl-, tert-butyl-, triethyl-, benzyl- or tetrahydropyranyl-protecting groups for the hydroxy group are trimethylsilyl-, methyl-, ethyl-, tert- butyl, benzyl or tetrahydropyranyl and as the protecting group for the amino, alkylamino or imino groups acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4- dimethoxybenzyl and, for amino, phthalyl.

Optional subsequent cleavage of the protecting moiety used is carried out, for example, hydrolytically in an aqueous solvent, for example water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or alkaline base. , such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

However, the cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide, acetic acid or glacial acid. optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably 0, 3 to 0.5 MPa (3 to 5 bar).

Cleavage of the methoxybenzyl group can also be carried out in the presence of an oxidizing agent such as cerium ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C, preferably at room temperature.

However, the cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl radical is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

The cleavage of the phthalyl residue is preferably carried out 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 dioxane at temperatures between 20 and 50 ° C.

Cleavage of the allyloxycarbonyl moiety is accomplished by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), preferably in a solvent such as tetrahydrofuran, and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 °. C, preferably at room temperature and under an inert atmosphere, or by treating with a catalytic amount of tris (triphenylphosphine) iodine 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.

The compounds of formulas (II) to (XIII), which were used as starting materials and which are partly known from the literature, are obtained by methods known from the literature and, in addition, the preparation thereof in the examples.

The chemistry of compounds of formula (III) has been described, for example, by Jack Robinson in J. Chem. Soc. 1941, 744, imidazoles of Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Pergamon Press, Oxford 1984, Schaumann in Hetaren III, Methoden der organischen Chemie (Heteroarenes III, Organic Chemistry Methods) (Houben-Weyl), 4. edition, Verlag Thieme, Stuttgart 1993.

Thus, for example, a compound of formula (II) is obtained by acylating the corresponding o-diamino compound with a corresponding reaction-capable derivative of a compound of formula (III), a compound of formula (IV), (VII), (IX), (X), (XI) and (XII) cyclization of the corresponding substituted compound according to process a) and, if necessary, subsequent reduction of the nitro group present in the phenyl moiety as well as subsequent acylation, amidation and / or halogenation.

Furthermore, the compounds of the formula I obtained can be separated into their enantiomers and / or diastereomers.

Thus, for example, the obtained compounds of formula (I) which appear in racemates can be resolved by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), to their optical antipodes, and compounds of formula (1) with at least 2 asymmetric carbon atoms by virtue of their physicochemical differences by methods known per se, for example by chromatography and / or fractional crystallization, to their diastereomers , which, when formed in racemic form, can then be resolved into their enantiomers in the above manner.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active compound which forms salts or derivatives, such as esters or amides, in particular esters or amides thereof, in particular acids and their activated derivatives or alcohols, and by separating the diastereomeric mixture of salts or derivatives thus obtained, for example on the basis of different solubilities, whereby free antipodes can be released from the pure diastereomeric salts or derivatives by means of suitable means. Particularly used optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-otolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Suitable optically active alcohol is, for example, (+) - or (-) - menthol and, as optically active acyl radical in amides, for example, (+) - or (-) - mentyloxycarbonyl radical.

In addition, the compounds of formula (I) obtained can be converted into their salts, in particular for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids here are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the novel compounds of formula (I) thus obtained, if they contain a carboxy group, can, if desired, be subsequently converted into their salts with inorganic or organic bases, in particular for pharmaceutical use, into their physiologically acceptable salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As mentioned above, the novel compounds of formula (I) and their salts have valuable properties. For example, compounds of formula (I) wherein R ^c is cyano are valuable intermediates for the preparation of other compounds of formula (1) and compounds of formula (I) in which R ^c is one of the amidino groups mentioned above, as well as their the tautomers, their stereoisomers and their physiologically acceptable salts exhibit valuable pharmacological properties, in particular an antithrombotic effect which consists preferably in a thrombin or factor Xa-acting action, for example in a thrombin-inhibiting or factor Xa-inhibiting action, aPTT-prolonging action av inhibiting effect on related serine proteases such as trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the effect of the following compounds on the prolongation of the aPTT-time was investigated:

A = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride, B = (E / Z) -2- (4-amidinophenylaminomethyl) hydrochloride - l-methyl-5- [l - [(pyridin-2-yl) - (karboxymetyloxyimino) metylénjcyklopropylj-benzimidazole,

C = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride,

D = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) -pyrrolidin-1-ylcarbonyl] cyclopropyl] -benzimidazole hydrochloride,

E = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole hydrochloride,

F = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride and

G = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylaminoethyl) -1-methyl-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole dihydrochloride way:

material:

-plasma, from human citrate blood,

-PTT reagent, Boehringer Mannheim (524298),

- calcium solution (0,025 mol / l), Behring Werke, Marburg (ORH 056/57),

-diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61),

-Biomatic Bio Koagulometer, Desaga, Wiesloch.

make:

Determination of aPTT-time was performed with a Biomatic B10 Coagulometer from Desaga.

The test substance was placed in test vials prescribed by the manufacturer with 0.1 ml human citrate plasma and 0.1 ml PTT reagent. The batch was incubated at 37 ° C for three minutes. Addition of 0.1 ml calcium solution triggered a precipitation reaction. Conditionally with the apparatus, the addition of the calcium solution is performed to measure the time up to the precipitation of the batch. Batches in which 0.1 ml of DBA buffer was added were used as controls.

By definition, the effective concentration of the substance at which the aPTT-time was doubled relative to the control was determined through a dose-effect curve.

The following table shows the values found:

substance aPTT-time (ED _2O ov μΜ) 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 because no toxic side effects were observed at therapeutic doses.

Due to their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep leg vein thromboses, the prevention of reocclusion after bypass surgery or angioplasty (PT (C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, in disseminated intravascular coagulation, for the prophylaxis of coronary thrombosis, for the prophylaxis of stroke and for preventing shunt occlusion. In addition, the compounds of the invention are useful for antithrombotic support in thrombolytic treatment, such as rt-PA or streptokinase, to prevent long-term restenosis after PT (C) A, to prevent metastasis and growth from coagulation-dependent tumors and fibrin-dependent inflammatory processes, e.g. in the treatment of pulmonary ftbrosis.

Suitably, the dose required to achieve a corresponding effect is 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, for intravenous administration, and 0.1 to 50 mg / kg, preferably 0.3 to 30 mg, for oral administration. mg / kg, 1 to 4 times daily. For this purpose, the compounds of formula (I) prepared according to the invention may optionally be combined with other active substances, together with one or more inert, conventional carriers and / or diluents, for example, corn starch, milk sugar, cane sugar , microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose containing fat or carboxymethylcellulose with stearate, or a suitable mixture thereof may be incorporated into conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The following examples are intended to explain the invention in more detail.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

a) 1- (4-Chloro-3-nitrophenyl) -1-cyclopropanecarboxylic acid

To 350 ml of fuming nitric acid at -25 ° C was added portionwise 50.0 g (0.21 mol) of 1- (4-chlorophenyl) -1-cyclopropanecarboxylic acid. The solution was stirred at -25 ° C for 15 minutes and then poured into ice water. The precipitated product is filtered off with suction, washed with water and dried.

Yield: 58.5 g (95% of theory), Rf value: 0.45 (silica gel; methylene chloride / methanol = 9.5: 0.5)

b) 1- (4-methylamino-3-nitrophenyl) -1-cyclopropanecarboxylic acid

20.0 g (0.083 mol) of 1- (4-chloro-3-nitrophenyl) -1-cyclopropanecarboxylic acid and 100 ml of methylamine solution (40% in H ₂ O) are heated in a pressure vessel at 80 ° C for five hours. . Evaporate to dryness, dissolve in water and oxygen with glacial acetic acid. The precipitated product is filtered off with suction, washed with water and dried.

Yield: 16.9 g (93% of theory), Rf value: 0.58 (silica gel; methylene chloride / methanol = 9: 1)

c) 4- [1- (Pyrrolidin-1-yl-carbonyl) cyclopropyl] -2-nitro- N -methyl-aniline

2.4 g (0.01 mol) of 1- (4-methylamino-3-nitro-phenyl) -1-cyclopropanecarboxylic acid are dissolved in 50 ml of dimethylformamide and after addition of 3.2 g (0.01 mol) of O - (benzotriazol-1-yl) -Y, N, N ', N'-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) pyrrolidine and 1.1 g (0.01 mol) N-methyl-morpholine were hours at room temperature. The solvent was distilled off and the residue was chromatographed on silica gel, eluting with methylene chloride. The desired fractions were evaporated, triturated with ether, filtered off with suction and dried. Yield: 1.8 g (61%), _{R f} value: 0.58 (silica gel, methylene chloride / methanol = 9: 1)

d) 4- [1- (Pyrrolidin-1-ylcarbonyl) cyclopropyl] -2-amino- N -methyl-aniline

1.8 g (6.2 mmol) of 4- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] -2-nitro-N-methyl-aniline are dissolved in 40 ml of methanol and 40 ml of methylene chloride and after addition of 0 4 g of palladium on charcoal (10%) were hydrogenated at room temperature for 4 hours. It is then filtered off from the catalyst and evaporated. Yield: 1.6 g (100% of theory), _{R f} value: 0.26 (silica gel, methylene chloride / methanol = 9: 1)

e) 4- [1- (Pyrrolidin-1-ylcarbonyl) cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino- N -methylaniline

Prepared in analogy to Example 1c from 4- [1- (pyrrolidine-

-yl-carbonyl) -cyclopropyl] -2-amino-N-methyl-aniline, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4- cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 66% of theory, Rf value: 0.51 (silica gel; methylene chloride / methanol = 9: 1)

f) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] -benzimidazole

1.7 g (0.004 mol) of 4- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline were heated in 7 ml of glacial acetic acid for one hour. reflux. The solvent was distilled off, the residue was dissolved in water and extracted with methylene chloride. The organic phase is dried, evaporated and subsequently chromatographed on silica gel, eluting with methylene chloride from +2 to% methanol.

Yield: 1.0 g (62% of theory), _{R f} value: 0.49 (silica gel, methylene chloride / methanol = 9: 1)

(g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -cyclopropyl] benzimidazole hydrochloride

Dissolve 1.0 g (2.5 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole in 50 ml of saturated ethanolic acid solution The mixture was stirred at room temperature for 5 hours. The solvent was distilled off, the residue was dissolved in 50 ml of absolute ethanol and treated with 2.3 g (25 mmol) of ammonium carbonate. After 60 hours at room temperature, it is evaporated to dryness. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol (7: 1). Yield: 700 mg (62% of theory), _{R f} value: 0.61 (silica gel, methylene chloride / methanol = 4: 1) C ₂₄ H ₂₈ N ₆ O x HC1 (416.54 / 453.0) Mass spectrum: (M + H) < ^{+ &gt}; = 417

In analogy to Example 1, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-methylpiperidin-1-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride

Yield: 45% of the theoretical yield;

_{R f} value: 0.25 (silica gel; methylene chloride / methanol = 4: 1) C ₂₆ H ₃₂ N ₆ O x HC1 (444.59 / 481.05)

Mass Spectrum: (M + H) ⁺ = 445

2. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (piperidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride Yield: 57% of theory;

Rf value: 0.23 (silica gel; methylene chloride / methanol = 4: 1) C ₂₅ H ₃₀ N ₆ O x HCl (430.56 / 467.93)

Mass Spectrum: (M + H) ⁺ = 431

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (4-methyl-piperazin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 32% of the theoretical yield,

Rf value: 0.26 (silica gel; methylene chloride / methanol / ammonia = 2: 1: 0.25)

C ₂₅ H ₃₂ N ₇ O x HCl (445.58 / 482.04)

Mass Spectrum: (M + H) ⁺ = 446

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2,3-dihydroindolin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 60% of the theoretical yield;

_{R f} value: 0.34 (silica gel, methylene chloride / methanol = 4: 1) C _{2 B} H ₂₈ N ₆ O x HC1 (464.58 / 501.04)

Mass Spectrum: (M + H) ⁺ = 465

5. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) -piperidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 85% of the theoretical yield;

_{R f} value: 0.57 (silica gel, methylene chloride / methanol = 4: 1) C ₃₀ H ₃₈ N ₆ O ₃ x HCl (530.67 / 567.13)

Mass Spectrum: (M + H) ⁺ = 531

6. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) -pyrrolidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 60% of the theoretical yield;

C ₂₉ H ₃₆ N ₆ O ₃ x HCl (516.64 / 553.10)

Mass Spectrum: (M + H) ⁺ = 517 (M + 2H) @ ⁺ = 259

7. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(N - (2-ethoxycarbonyl-ethyl) - N -methyl-aminomethyl) -pyrrolidin-1-ylcarbonyl] -cyclopropyl] -benzimidazole hydrochloride

Yield: 65% of the theoretical yield;

C ₃₁ H ₄₁ N ₇ O ₃ x HCl (559.72 / 596.18)

Mass Spectrum: (M + H) ⁺ = 560 (M + 2H) @ ⁺ = 280.6

8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(2-ethoxycarbonylmethyl-oxymethyl) -pyrrolidin-1-ylcarbonyl] -cyclopropyl] -benzimidazole hydrochloride

Yield: 61% of the theoretical yield;

_{R f} value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)

C ₂₉ H ₃₆ N ₆ O ₄ x HCl (532.66 / 569.11)

SK 283744 Β6

Mass Spectrum: (M + H) ⁺ = 533 (M + 2H) @ ⁺ = 267

Example 2

2- (4-amidinophenylaminomethyl) -1-methyl-5- (1-cyclopentylcarbonyl-3-chloro-n-propyl) -benzimidazole hydrochloride

a) 4- [1- (Cyclopentylcarbonyl) cyclopropyl] chlorobenzene

2.4 g (0.1 mol) of magnesium sawdust are suspended in 10 ml of ether. After addition of iodine to the tip of a spatula, 14.9 g (0.1 mol) of bromocyclopentane in 40 ml of ether is slowly added dropwise, starting with gentle heating at the beginning of the reaction. After completion of the addition, it is heated under reflux for a further 30 minutes. A solution of 14.0 g (0.08 mol) of 1- (4-chlorophenyl) -1-cyclopropanecarbonitrile in 75 ml of ether was then added and heated under reflux for a further 3 hours. The reaction solution was poured into ice water, adjusted to pH 3 with hydrochloric acid, and extracted with ether. The organic extracts were dried and evaporated. The residue is chromatographed on silica gel, eluting 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)

b) 4- [1- (Cyclopentylcarbonyl) cyclopropyl] -2-nitro-chlorobenzene

Prepared in analogy to Example 1a from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -chlorobenzene and fuming nitric acid.

Yield: 87% of theory, Yield: 0.60 (silica gel; petroleum ether / ethyl acetate = 9: 1)

c) 4- [1- (Cyclopentylcarbonyl) cyclopropyl] -2-nitro-N-methyl-aniline

Prepared in analogy to Example 1b from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2-nitro-chlorobenzene and an aqueous solution of methylamine.

Yield: 18% of theory, Yield: 0.54 (silica gel; methylene chloride / methanol = 19: 1)

d) 4- [1- (Cyclopentylcarbonyl) cyclopropyl] -2-amino-N-methyl-aniline

2.3 g (7.9 mmol) of 4- [1- (cyclopentylcarbonyl) cyclopropyl] -2-nitro-N-methyl-aniline are dissolved in 125 ml of ethyl acetate and 25 ml of ethanol and, after the addition of 1.0 g of Raney nickel, Hydrogenated at room temperature for 1.5 hours. It is then filtered off from the catalyst and evaporated.

Yield: 2.0 g (98% of theory), Yield: 0.15 (silica gel; methylene chloride / methanol = 19: 1)

e) 4- [1- (Cyclopentylcarbonyl) cyclopropyl] -2- (4-cyanophenylaminomethylcarbonylamino) -N-methyl-aniline

Prepared in analogy to Example 1c from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2-amino-N-methyl-aniline, O-benzotriazol-1-yl-N, N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 96% of theory, Rf: 0.54 (silica gel; methylene chloride / methanol = 19: 1)

f) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (cyclopentylcarbonyl) -cyclopropyl] -benzimidazole

Prepared in analogy to Example 1f from 4- [1- (cyclopentylcarbonyl) cyclopropyl] -2- (4-cyanophenylaminomethylcarbonylamino) - N -methyl-aniline in glacial acetic acid. Yield: 53% of theory, Yield: 0.46 (silica gel; methylene chloride / methanol = 19: 1)

(g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (1-cyclopentylcarbonyl-3-chloro-n-propyl) -benzimidazole hydrochloride

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- (1-cyclopentylcarbonyl-3-chloro-n-propyl) -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 61% of theory, C ₂₅ H ₃₀ ClN ₅ O x HCl (452.00 / 488.56) Mass spectrum: (M + H) ⁺ = 452/4 (Cl)

Example 3

(& Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride

a) 1 - [(Pyridin-3-yl) carbonyl] cyclopropyl-benzene

A solution of 21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether was added dropwise at -40 to -50 ° C to 100 ml of butyllithium (1.6 M in hexane) and then stirred at -40 ° C for 20 minutes. . It is then cooled to -60 ° C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropane-carbonitrile in 125 ml of ether is added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 5 hours. The suspension was mixed with 20% hydrochloric acid and heated to 100 ° C for 30 minutes. After cooling, the pH was adjusted to 8 with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were dried and evaporated. The residue is chromatographed on alumina eluting with petroleum ether / ethyl acetate (9: 1).

Yield: 14.0 g (46%), _{R f} value: 0.27 (aluminum oxide, petroleum ether / ethyl acetate = 9: 1)

b) 4- [1 - [(Pyridin-3-yl) carbonyl] cyclopropyl] nitrobenzene

Prepared in analogy to Example 1a from 1 - [(pyridin-3-yl) carbonyl] cyclopropyl-benzene and fuming nitric acid.

Yield: 53.7% of theory, Yield: 0.29 (alumina; petroleum · ether / ethyl acetate = 4: 1)

c) 4- [1 - [(Pyridin-3-yl) -carbonyl] cyclopropyl] -aniline

Prepared in analogy to Example 2d from 4- [1 - [(pyridin-3-yl) -carbonyl] -cyclopropyl] -nitrobenzene and Raney nickel in ethyl acetate / ethanol.

Yield: 94% of theory, Yield: 0.51 (silica gel; methylene chloride / ethanol = 19: 1)

d) 4- [1 - [(Pyridin-3-yl) -carbonyl] cyclopropyl] -trifluoroacetyl-aniline

8.0 g (33.5 mmol) of 4- [1 - [(pyridin-3-yl) -carbonyl] cyclopropyl] -aniline are dissolved in 100 ml of chlorobenzene and after addition of 15 ml of trifluoroacetic anhydride it is stirred for two hours at 110 ° C. The solvent was distilled off, the residue was stirred with petroleum ether / ether (9: 1), filtered off with suction and dried.

Yield: 10.0 g (88% of theory), Rf value: 0.54 (silica gel; methylene chloride / ethanol = 19: 1)

e) 4- [1 - [(Pyridin-3-yl) -carbonyl] cyclopropyl] -2-nitro-trifluoroacetyl-aniline ml of concentrated sulfuric acid and 16 ml of 65% nitric acid are mixed in portions at -5 ° C with 1.7 g (5 mmol) of 4- [1 - [(pyridin-3-yl) -carbonyl] -cyclopropyl] -trifluoroacetylaniline. It was then stirred for 30 minutes without cooling, poured into ice water and extracted with ethyl acetate. The organic extracts were dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride13

Household / ethanol (50: 1 and 25: 1). The desired fractions were evaporated, triturated with ether / petroleum ether, filtered off with suction and dried. 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 -fluoroacetyl- N -methyl-aniline

1.15 g (3.0 mmol) of 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-trifluoro-acetylaniline are dissolved in 50 ml of acetone and after addition of 2.0 g of carbonate of potassium iodide and 0.8 ml of methyl iodide were heated under reflux for two hours. The insoluble material was filtered off and the solution was concentrated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (1: 1 and 1: 4).

Yield: 0.88 g (75% of theory), _{R f} value: 0.38 (silica gel; petroleum ether / ethyl acetate = 1: 1)

g) 4- [1 - [(Pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro- N -methyl-aniline

7.4 g (18.8 mmol) of 4-11-L (pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-N-trifluoro-acetyl-N-methyl-aniline were stirred at 30 ° C for one hour. in 200 ml of 20% potassium hydroxide solution. Subsequently, it is diluted with isopropanol, the organic phase is separated, mixed with 10.0 g of aluminum oxide and evaporated to dryness. The residue was chromatographed on alumina eluting with petroleum ether / ethyl acetate (4: 1 and 1: 1). Yield: 2.6 g (47% of theory), _{R f} value: 0.50 (silica gel, petroleum ether / ethyl acetate = 1: 1)

h) 4- [1 - [(Pyridin-3-yl) carbonyl] cyclopropyl] -2-amino-N-methyl-aniline

Prepared in analogy 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 f} value: 0.51 (silica gel, methylene chloride / ethanol = 19: 1)

i) 4- [1 - [(Pyridin-3-yl) carbonyl] cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonyl-amino-N-methyl-aniline

Prepared in analogy to Example 1c from 4- [1 - [(pyridin-3-yl) -carbonyl] -cyclopropyl] -2-amino-N-methyl-aniline, O- (benzotriazol-1-yl) - N, N , N ', N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 97% of theory, _{R f} value: 0.48 (silica gel; methylene chloride / methanol = 19: 1)

k) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -benzimidazole

Prepared in analogy to Example 1f from 4- (pyridin-3-yl-carbonyl) -cyclopropyl-2- (4-cyanophenyl) -aminomethylcarbonylamino-N-methylaniline in glacial acetic acid. Yield: 76% of theory, _{R f} value: 0.52 (silica gel; methylene chloride / methanol = 19: 1)

l) (E / Z) -2- (4-Cyanophenylammomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) (carboxymethyloxyimino) -methylene] -cyclopropyl] -benzimidazole

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) Carboxymethoxyamine hemihydrate, 0.84 ml triethylamine, 12 g molecular sieve 3A and 12 g molecular sieve 4A are heated in 80 ml methanol and 40 ml toluene for 12 hours under reflux. It is then filtered off from the molecular sieve and evaporated. The residue is mixed with water, filtered off with suction 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),

_{R f} value: 0.34 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)

(m) (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (ethoxycarbonylmethyloxyimino) methylene] -cyclopropyl] -benzimidazole hydrochloride

Prepared in analogy to Example 1g from (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (ethoxycarbonylmethyloxyimino) methylene] -cyclopropyl] -benzimidazole and acid sodium / ammonium carbonate in ethanol. Yield: 60% of the theoretical yield;

Rf value: 0.28 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)

C ₂₉ H ₃₁ N ₇ O ₃ x HCl (525.62 / 562.09) Mass Spectrum: (M + H) ⁺ = 526

In analogy to Example 3, the following compounds are obtained:

(E7Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) - (ethoxycarbonylmethyloxyimino) methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 52% of theory.

_{R f} value: 0.21 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)

C ₂₉ H ₃₁ N ₇ O ₃ x HCl (525.62 / 562.09) Mass Spectrum: (M + H) ⁺ = 526

(E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (ethoxycarbonyl-methyloxyimino) methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 18% of the theoretical yield,

C ₃₀ H ₃₂ N ₆ O ₃ x HCl (524.63 / 561.09) Mass Spectrum: (M + H) ⁺ = 525 (M-H + HCl) + = 559/61 (Cl)

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (1-methyl-pyrazol-5-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 10% of the theoretical yield;

C ₂₄ H ₂₅ N ₇ O x HCl (427.51 / 463.97) Mass Spectrum: (M + H) ⁺ = 428 (M + H + HCl) + = 464/6 (Cl)

4. (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(1-methyl-pyrazol-5-yl) - (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride Yield: 80% of the theoretical yield,

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2 + + 1% glacial acetic acid)

C ₂ H ₃₂ N ₈ O ₃ x HCl (528.63 / 565.08) Mass Spectrum: (M + H) ⁺ = 529

5. (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (3-ethoxycarbonyl-n-propyloxyimino) methylene] cyclopropyl] -benzimidazole dihydrochloride

Yield: 47% of the theoretical yield;

_{R f} value: 0.06 (silica gel, methylene chloride / methanol = 9: 1) C ₃₂ H ₃₆ N ₆ O ₃ x 2 HCl (552.69 / 625.60)

Mass Spectrum: (M + H) ⁺ = 553

Example 4

(E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl- (carboxymethyl-oxyimino) methylene] cyclopropyl] benzimidazole hydrochloride

150 mg of (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) - (ethoxycarbonylmethyloxyimino) methylene] -cyclopropyl] -benzimidazole hydrochloride and 2.5 ml of 2N sodium The reaction mixture was stirred at room temperature for 5 hours in 10 ml of ethanol. The alcohol is distilled off and the residue is adjusted to pH 5 with hydrochloric acid. The crystalline product is filtered off with suction, washed with water and dried.

Yield: 46% of the theoretical yield;

Rf: 0.10 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.1)

C ₂₇ H ₂₇ N ₇ O ₃ x HCl (497.58 / 534.05) Mass Spectrum: (M + H) ⁺ = 498 (M + Na) ⁺ = 520

In analogy to Example 4, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) -piperidin-1-ylcarbonyl] cyclopropyl] -benzimidazole hydrochloride

Yield: 94% of theory, Rf value: 0.57 (reverse phase RP 18; methanol / 5% sodium chloride solution = 3: 2)

C ₂₈ H ₃₄ N ₆ O ₃ x HCl (502.62 / 539.08) Mass Spectrum: (M + II) ⁺ = 503 (M + Na) ⁺ = 525

2. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Yield: 98% of theory, Yield: 0.73 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 2)

C ₂₆ H ₃₃ N ₇ O ₃ x HCl (491.60 / 564.54) Mass Spectrum: (M + H) ⁺ = 492 (M + 2H) ⁺⁺ = 247

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-carboxypropionylamino) -1- (ethoxycarbonyl) ethyl] -benzimidazole hydrochloride

Yield: 98% of the theoretical yield;

Rf value: 0.70 (RP 8; methanol / 5% sodium chloride solution = 1: 2)

C ₂₅ H ₃ N ₆ 0 ₅ x HCl (494.55 / 531.05) Mass Spectrum: (M + H) ⁺ = 495 (2M + H) ⁺⁺ = 989

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) methyl] benzimidazole hydrochloride

Yield: 87% of theory, C ₂₄ H ₂₉ N ₇ O ₃ x HCl (463.54 / 500.04) Mass spectrum: (M + H) ⁺ = 464 (M + 2H) ⁺⁺ = 232.6

5. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) -pyrrolidin-1-ylcarbonyl] cyclopropyl] -benzimidazole hydrochloride

Yield: 94% of theory, C ₂₇ H ₃₂ N ₆ O ₃ x HCl (488.59 / 525.05) Mass spectrum: (M + II) + = 489 (M + Na) ⁺ = 511

6. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) methyl] benzimidazole hydrochloride

Yield: 49% of theory.

C ₂₅ H ₂₉ N ₇ O ₄ x HCl (491.55 / 528.01)

Mass Spectrum: (M + H) ⁺ = 492 (M + H + Na) + = 257.7

7. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Yield: 92% of the theoretical yield;

C ₂₆ H ₃₁ N ₇ O ₄ x HCl (505.58 / 542.04)

Mass Spectrum: [M + H] + = 506 (M + H + Na) ⁺⁺ = 264.7

8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-carboxymethyl-imidazoline-2,4-dione-5-yl) -benzimidazole hydrochloride

Yield: 88% of the theoretical yield;

C ₂₂ H ₂₃ N ₇ O ₄ x HCl (449.47 / 485.94)

Mass Spectrum: (M + H) ⁺ = 450 (M-2Na) = 247.7

9. (E / Z) -2- (4-Aminidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] benzimidazole hydrochloride

Yield: 54% of the theoretical yield,

C ₂₇ H ₂₇ N ₇ O ₃ x HCl (497.56 / 534.09)

Mass Spectrum: (M + H) ⁺ = 498 (M + Na) ⁺ = 520

10. 2- (4-Amino-phenylaminomethyl) -1-methyl-5- [1- [2- (N- (2-carboxyethyl) -N-methyl-aminomethyl) -pyrrolidin-1-yl-carbonyl] -cyclopropyl] hydrochloride -benzimidazole u Yield: 100% of the theoretical yield,

C ₂₉ H ₃₇ N ₇ O ₃ x HCl (531.66 / 568.12)

Mass Spectrum: (M + H) < ^{+ &gt}; = 532 ([delta] -H) - = 530

11. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [[N- (2-carboxyethyl) -N- (2-pyridyl) aminomethyl] benzimidazole hydrochloride

Yield: 91% of the theoretical yield;

C ₂₅ H ₂₇ N ₇ O ₂ x HCl (457.54 / 493.96)

Mass Spectrum: (M + H) ⁺ = 458

12. 2- (4-amidinophenylaminomethyl) -1-methyl-5 - (; N-benzenesulfonyl-N-carboxymethylaminomethyl] -benzimidazole hydrochloride

Yield: 84% of theory.

C ₂₅ H ₂₆ N ₆ O ₄ S x HCl (506.59 / 543.06)

Mass Spectrum: (M + H) ⁺ = 507

13. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) benzimidazol-1-ylmethyl] benzimidazole hydrochloride

Yield: 76% of theory.

C ₂₇ H ₂₇ N ₇ O ₂ x HCl (481.56 / 518.05)

Mass Spectrum: (M + H) ⁺ = 482 (M + 2H) ²⁺ = 242 (M + Na) ⁺ = 504 (M + H + Na) ²⁺ = 253 (M-H + 2Na) ⁺ = 526 ( M + 2Na ¹² '= 264

14. 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2-methyl-4-carboxyimidazol-1-ylmethyl) benzimidazole hydrochloride Yield: 61% of theory;

C ₂₂ H ₂₃ N ₇ O ₂ x HCl (417.47 / 453.92)

Mass Spectrum: (M + H) ⁺ = 418

15. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [3- (3-carboxy-n-propyl) -benzimidazole-2-one-1-ylmethyl] -benzimidazole hydrochloride

Yield: 86% of theory.

C ₂₈ H ₂₉ N ₇ O ₃ 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

16. 2- (4-amidinophenylammomethyl) -1-methyl-5- [3- (2-carboxyethyl) imidazo [4,5-b] pyridin-2-one-1-ylmethyl] hydrochloride - benzimidazole

Yield: 83% of theory.

C ₂₆ H ₂₆ N ₈ O ₃ x HCl (498.55 / 535)

Mass Spectrum: (M + H) < ^{+ &gt}; = 499 (M + Na) < ^{+ &gt}; = 521 ([delta] -H) < ⁺ > = 497 (2M-H) = 995

17. 2- (4-Amidinophenylammomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethylimidazol-1-ylmethyl] benzimidazole hydrochloride

Yield: 68% of the theoretical yield;

Rf value: 0.70 (reverse phase RP 8: methanol / 5% sodium chloride solution = 6: 4)

C ₂₅ H ₂₉ N ₇ O ₂ x HCl (459.56 / 496.01)

Mass Spectrum: (M + H) ⁺ = 460 (M + Na) ⁺ = 482 (M + H + Na) ²⁺ = 241

18. (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (carboxymethyloxyimino) methylene] cyclopropyl] benzimidazole dihydrochloride

Yield: 70% of the theoretical yield;

C ₂₈ H _2g N ₆ O ₃ x 2 HCl (496.57 / 569.5)

Mass Spectrum: (M + H) < ^{+ &gt}; = 497 ([delta] -H) - = 495

19. (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyridin-3-yl) - (carboxymethylidene) methylene] cyclopropyl] benzimidazole hydrochloride

Yield: 37% of the theoretical yield;

Rf value: 0.45 (reverse phase RP 8; methanol / 5% sodium chloride solution = 6: 4)

C ₂₇ H ₂₆ N ₆ O ₂ x HCl (466.55 / 503.0)

Mass Spectrum: (M + H) ⁺ = 467

20. (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(1-methyl-pyrazol-5-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride

Yield: 30% of the theoretical yield;

Rf value: 0.25 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1)

C ₂₆ H ₂₈ N ₈ O ₃ x HCl (500.58 / 537.03)

Mass Spectrum: (M + H) < ^{+ &gt}; = 501 ([delta] -H) < - >

(E7Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (3-carboxy-n-propyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride

Yield: 37% of theory, _{R f} value: 0.35 (reversed phase RP 8, 5% saline solution / methanol = 3: 2)

C ₃₀ H ₃₂ N ₆ O ₃ x 2 HCl (524.64 / 597.55) Mass Spectrum: (M + H) ⁺ = 525

Example 5

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl)] - benzimidazole hydrochloride

a) 5- (4-Chloro-phenyl) -imidazolidine-2,4-dione

15.0 g (0.11 mol) of 4-chlorobenzaldehyde, 51.3 g (0.53 mol) of ammonium carbonate and 7.6 g (0.12 mol) of potassium cyanate are stirred in 150 ml of water and 150 ml of methanol 18. hours at 55 ° C. The solvent was distilled off, the residue was dissolved in water and extracted with ethyl acetate. The combined organic extracts were dried and evaporated.

Yield: 8.6 g (38% of theory)

b) 5- (4-Chloro-3-nitro-phenyl) -imidazolidine-2,4-dione

Prepared in analogy to Example 1a from 5- (4-chlorophenyl) -imidazolidine-2,4-dione and fuming nitric acid. Yield: 52% of theory.

Rf value: 0.63 (silica gel; methylene chloride / methanol = 9: 1)

c) 4-Chloro-3-nitro-phenylalanine hydrochloride

560 mg (2.2 mmol) of 5- (4-chloro-3-nitro-phenyl) -imidazolidine-2,4-dione was heated to reflux for 24 hours in 20 ml of semi-concentrated hydrochloric acid. The solvent was distilled off, the residue was dissolved in water, filtered off from the insoluble fraction and evaporated. The residue was dissolved in ethanol three times, evaporated to dryness, triturated with ether, filtered off with suction and dried.

Yield: 380 mg (65% of theory)

d) 4-Chloro-3-nitro-N-tert-butyloxycarbonyl-phenylalanine

5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine hydrochloride are dissolved in 50 ml of dioxane and 25 ml of water and after addition of 5.5 ml (39.1 mmol) of triethylamine and 4.8 g. (21.3 mmol) of di-tert-butyl bicarbonate was stirred at room temperature for 18 hours. It is then diluted with 0.5 M potassium hydrogen sulphate solution and extracted with ethyl acetate. The combined organic extracts were dried and evaporated.

Yield: 6.3 g (100% of theory), Rf: 0.20 (silica gel; methylene chloride / methanol = 9: 1)

e) 2- (4-Chloro-3-nitro-phenyl) -2- tert -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone

Prepared in analogy to Example 1c from 4-chloro-3-nitro-N-tert-butyloxycarbonyl-phenylalanine, O- (benzotriazol-1-yl) -, -, -, -, -, -. tetramethyluronium tetrafluoroborate, pyrrolidine and N'-ethyl-diisopropylamine in tetrahydrofuran. Yield: 68% of the theoretical yield;

Melting point: 203 ° C

f) 2- (4-Methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone

Prepared in analogy to Example 1b from 2- (4-chloro-3-nitro-phenyl) -2- tert -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone and methylamine solution.

Yield: 76% of theory, Rf: 0.33 (silica gel; cyclohexane / ethyl acetate = 1: 1)

g) 2- (4-Methylamino-3-amino-phenyl) -2- tert -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone

Prepared in analogy to Example 1d from 2- (4-methylamino-3-nitro-phenyl) -2- tert -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone and palladium on activated carbon in methylene chloride / ethanol.

Yield: 100% of theory, _{R f} value: 0.12 (silica gel; cyclohexane / ethyl acetate = 1: 1)

h) 2- [4-Methylamino-3- (4-cyanophenylaminomethylcarbonylamino) phenyl] -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone

Prepared in analogy to Example 1c from 2- (4-methylamino-3-amino-phenyl) -2- tert -butyloxycarbonylamino-1 (pyrrolidin-1-yl) ethanone, O- (benzotriazol-1-yl) -N, N , N ', N-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in tetrahydrofuran.

Yield: 100% of the theoretical yield;

_{R f} value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)

i) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) amino-methyl] -benzimidazole

Prepared in analogy to Example 1f from 2- [4-methylamino-3- (4-cyanophenylaminomethylcarbonylamino) -phenyl] -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone in glacial acetic acid.

Yield: 30% of the theoretical yield;

Rf value: 0.19 (silica gel; methylene chloride / methanol = 9.5: 0.5)

(k) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) aminomethyl] -benzimidazole hydrochloride

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) amino-methyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 27% of the theoretical yield,

C22H27N7O x HCl (405.50 / 441.96) Mass Spectrum: (M + H) ⁺ = 406

In analogy to Example 5, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N-acetyl-aminomethyl] -benzimidazole hydrochloride

Yield: 29% of theory, C ₂₄ H ₂₉ N ₇ O ₂ x HCl (447.54 / 484.54) Mass spectrum: (M + H) ⁺ = 448

2. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) - N - (2-ethoxycarbonylethyl) - N ¹ -methyl-aminomethyl] benzimidazole hydrochloride

Yield: 74% of theory, C ₂ H ₃₇ N ₇ O ₃ x HCl (519.65 / 556.11) Mass spectrum: (M + H) ⁺ = 520

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (ethoxycarbonylmethyl) aminomethyl] benzimidazole hydrochloride

Yield: 76% of theory. C ₂₆ H ₃₃ N ₇ O ₃ x HCl (491.59 / 528.05) Mass spectrum: (M + H) ⁺ = 492 (M + 2H) ⁺⁺ = 246.7

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N, N'-di- (ethoxycarbonylmethyl) aminomethyl] -benzimidazole hydrochloride

Yield: 51% of theory, C ₃₀ H ₃₉ N ₇ O ₅ x HCl (577.68 / 614.14) Mass spectrum: (M + H) ⁺ = 578 (M + Na) ⁺ = 600

5. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (ethoxycarbonylmethylcarbonyl) aminomethyl] -benzimidazole hydrochloride

Yield: 29% of theory, C ₂₇ H ₃ N ₇ O ₄ x HCl (519.60 / 556.06) Mass spectrum: (M + H) ⁺ = 520 (M + 2H) ⁺⁺ = 260.7

6. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (2-ethoxycarbonylethyl) aminomethyl] benzimidazole hydrochloride

Yield: 84% of theory, C ₂₇ H ₃₅ N ₇ O ₃ x HCl (505.62 / 542.62) Mass spectrum: (M + H) ⁺ = 506 (M + 2H) ⁺⁺ = 253.7

Example 6

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N - (2-ethoxycarbonylethyl) amino] -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

a) 5- (4-Chloro-3-nitro-phenyl) -5-methyl-imidazolidine-2,4-dione

To 50 ml of fuming nitric acid is added portionwise at -25 ° C to -35 ° C 10.0 g (4.45 mmol) of 5- (4-chloro-phenyl) -5-methyl-imidazolidine-2,4- dione. After 45 minutes, the reaction mixture is poured into ice water at -25 ° C to -20 ° C. The crystalline product is filtered off with suction, washed with water and dried. Yield: 10.5 g (100% of theory), Melting point: 173-178 ° C _r value: 0.30 (silica gel; cyclohexane / ethyl acetate = 1: 1)

b) 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid

10.5 g (0.044 mol) of 5- (4-chloro-3-nitro-phenyl) -5-methyl-imidazolidine-2,4-dione were heated in 200 ml of dioxane and 700 ml of 6N hydrochloric acid under reflux for 5 days. The solution was evaporated, the residue was taken up in water and extracted with ethyl acetate. The aqueous phase is evaporated, mixed with toluene and evaporated to dryness. The residue is triturated with ether, filtered off with suction and dried. Yield: 6.8 g (63% of theory), _{R f} value: 0.24 (reversed phase RP 8, 5% saline solution / methanol = 1: 1)

c) 2- tert -Butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid

Prepared in analogy to Example 5d from 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid, pyrocarbonate-di- tert -butyl bicarbonate and triethylamine in dioxane.

Yield: 9.6 g (100% of theory), Rf value: 0.31 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 2)

d) 2- (4-Chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone

Prepared in analogy to Example 1c from 2-tert-butyloxycarbonylamino-2- (4-chloro-3-nitrophenyl) propionic acid, O- (benzotriazol-1-yl) -N, N, N ', N-tetramethyluronium tetrafluoroborate, pyrrolidine and N- methyl morpholine 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 -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone

Prepared in analogy to Example 1b from 2- (4-chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone and a solution of methylamine in dimethylformamide at 160 ° C.

_{R f} value: 0.79 (silica gel, ethyl acetate / ethanol = 9: 1)

f) 2- (4-Methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone

Prepared in analogy to Example 1d from 2- (4-methylamino-3-nitro-phenyl) -2- tert -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone and palladium on charcoal / hydrogen in methanol.

Yield: 100% of theory, Rf value: 0.63 (silica gel; ethyl acetate / ethanol = 9: 1)

g) 2- [4-Methylamino-3- (4-cyanophenylaminomethylcarbonylamino) phenyl] -2- tert -butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone

Prepared in analogy to Example 1c from 2- (4-methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and Λ'-methylmorpholine in dimethylformamide. Yield: 37% of theory, _{R f} value: 0.47 (silica gel, ethyl acetate)

h) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole

Prepared in analogy to Example 1f from 2- [4-methylamino-3- (4-cyanophenylaminomethylcarbonylamino) -phenyl] -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone and glacial acetic acid.

Yield: 60% of theory, _{R f} value: 0.37 (silica gel, ethyl acetate)

i) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole

1.3 g (2.3 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyl-oxycarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) 1-Ethyl-1-benzimidazole is dissolved in 20 ml of dioxane and, after addition of 40 ml of semi-concentrated hydrochloric acid, is stirred at room temperature for two hours. The solution was mixed with ice, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts were dried and evaporated.

Yield: 0.9 g (98% of theory), _{R f} value: 0.14 (silica gel, ethyl acetate / ethanol = 9: 1)

k) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- [N - (2-ethoxycarbonylethyl) amino] -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole

Dissolve 0.4 g (1.04 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole in 10 ml ethanol, and after addition of 0.3 ml (2.7 mmol) of ethyl acrylate, it is stirred at 95 ° C for 24 hours. The solvent was distilled off, and the residue was chromatographed on silica gel, eluting with methylene chloride / ethanol (20: 1 and 4: 1).

Yield: 0.16 g (31% of theory), Rf: 0.26 (silica gel; ethyl acetate / ethanol = 9: 1)

(l) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N - (2-ethoxycarbonylethyl) amino] -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Prepared in analogy to Example g of 2- (4-kyanofenylaminometyl) -l-methyl-5- [l- [7V ^N - (2-ethoxycarbonylethyl) -amino-1 - (pyrrolidin-1-yl-carbonyl) ethyl] - benzimidazole and hydrochloric acid / ammonium carbonate in ethanol. Yield: 96% of theory, C ₂₈ H ₃₇ N ₇ O ₃ x HCl (519.65 / 556.11) Mass spectrum: (M + H) ⁺ = 520 (M + Na) ⁺ = 542

In analogy to Example 6, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonyl-propionylamino) -1-ethoxycarbonyl-ethyl] -benzimidazole hydrochloride

Yield: 69% of theory, C ₂₇ H ₃₄ N ₆ O ₅ x HCl (522.62 / 555.08) Mass spectrum: (M + H) ⁺ = 523 (M + H + Na) ⁺⁺ = 273

2. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylcarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Yield: 95% of theory, C ₂₈ H ₃₅ N ₇ O ₄ x HCl (533.64 / 570.10) Mass spectrum: (M + H) ⁺ = 534 (M + Na) ⁺ = 556

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonylpropionyl-amino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 20% of the theoretical yield;

C ₂₉ H ₃₇ N ₇ O ₄ x HCl (547.66 / 584.12) Mass Spectrum: (M + H) ⁺ = 548 (M + H + Na) = 285.7

4. 2- [4-Aminophenyl-N- (2-ethoxycarbonylethyl) aminomethyl] -1-methyl-5- [1-dimethylamino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Yield: 91% of theory, C ₃₀ H ₄₁ N ₇ O ₃ x HCl (547.71 / 584.17) Mass spectrum: (M + H) ⁺ = 548 (Μ-H) - = 546

5. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-ethyl-amino) -1- (dimethylaminocarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 40% of the theoretical yield;

_{R f} value: 0.60 (reversed phase RP 8, 5% saline solution / methanol = 1: 1)

C ₂₆ H ₃₅ N ₇ O ₃ x HCl (493.63 / 530.08) Mass Spectrum: (M + H) ⁺ = 494 (M-H + 2HCl) + = 564/566/568 (Cl ₂ )

6. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl-amino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 77% of the theoretical yield;

_{R f} value: 0.40 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C ₂₇ H ₃₅ N ₇ O ₃ x HCl (505.63 / 542.08) Mass Spectrum: (M + H) ⁺ = 506

7. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -1-N-ethyl-N '-methylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 85% of theory, _{R f} value: 0.44 (silica gel, methylene chloride / CTAN = 9: 1)

C ₂₇ H ₃₇ N ₇ O ₃ x HCl (507.64 / 544.14)

Mass Spectrum: (M + H) ⁺ = 508 (M + Cl) + = 542/4 (Cl)

8. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (methoxycarbonylethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole hydrochloride

Yield: 99% of the theoretical yield;

_{R f} value: 0.21 (silica gel, methylene chloride / ethanol 4: 1 + 1% glacial acetic acid)

C ₂₆ H ₃₃ N ₇ O ₃ x HC1 (491.60 / 528.05)

Mass Spectrum: (M + H) ⁺ = 492 (M-H + HCl) · = 526/8 (Cl) (M-H + 2HCl) - = 562/4/8 (Cl ₂ )

9. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N, N'-bis (ethoxycarbonylmethyl) amino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 65% of the theoretical yield;

Rf value: 0.35 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C ₃₁ H ₄₁ N ₇ O ₅ x HCl (591.72 / 628.17)

Mass Spectrum: (M + H) ⁺ = 592 (M-H + HCl) - = 626/8 (Cl) (M-H + 2HCl) - = 662/4/6 (Cl ₂ )

10. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl-amino) -1- (isoxazolidin-1-ylcarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 9% of the theoretical yield;

Value: 0.50 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C ₂₆ H ₃₃ N ₇ O ₄ x HCl (507.60 / 544.05)

Mass Spectrum: (M + H) ⁺ = 508

11. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -1- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

12. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl-amino) -1- (N-methyl-N-ethylaminocarbonyl) ethyl] benzimidazole dihydrochloride

Yield: 58% of theory.

R value: 0.70 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C ₂₆ H ₃₅ N ₇ O ₃ x 2HCl (493.62 / 566.52)

Mass Spectrum: (M + H) ⁺ = 494 (M + HCl-H) · = 528/30 (Cl)

13. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - ((N, N-di (ethoxycarbonylmethyl) amino) -1- (N'-methyl-N ^, -ethylaminocarbonyl) dihydrochloride - ethyl] benzimidazole

Yield: 30% of the theoretical yield;

Value: 0.40 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C ₃₀ H ₄₁ N ₇ O ₅ x 2HCl (579.71 / 652.62)

Mass Spectrum: (M + H) < ^{+ &gt}; = 580 ([delta] -H) - = 578

14. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (piperidinocarbonyl) ethyl] benzimidazole dihydrochloride

Yield: 82% of theory.

Value: 0.60 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C ₂₈ H ₃₇ N ₇ O ₃ x 2HCl (519.65 / 592.75)

Mass Spectrum: (M + H) ⁺ = 520 (M-H + HCl) - = 534/6 (Cl) (M-H + 2HCl) - = 590/2/4 (Cl ₂ )

15. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (diethylaminocarbonyl) ethyl] benzimidazole dihydrochloride

Yield: 88% of theory, Yield: 0.60 (reverse phase RP 8; methanol / 5% sodium salt solution = 3: 2)

C ₂₇ H ₃₇ N ₇ O ₃ x 2 HCl (507.64 / 580.56) Mass spectrum: (M + H) ⁺ = 508 (M-H + 2HCl) + = 578/580/582 (Cl ₂ )

16. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl-methyl-amino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 46% of theory, Rf: 0.43 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C ₂₈ H ₃₇ N ₇ O ₃ x 2 HCl (519.65 / 592.56) Mass spectrum: (M + H) ⁺ = 520 (M + Cl) + = 554/6 (Cl)

17. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol-5-yl-methyl-amino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole dihydrochloride at

18. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonyl-propylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 95% of theory, Rf: 0.50 (reverse phase RP 8; methanol / 5% sodium salt solution = 1: 1)

C ₂₉ H ₃₉ N ₇ O ₃ x 2 HCl (533.68 / 606.58) Mass Spectrum: (M + H) ⁺ = 534

Example 7

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N-cyclopentyl-N- (3-ethoxycarbonyl-propionyl) -amino] cyclopropyl] benzimidazole hydrochloride

a) 4 - ((1-tert-Butyloxycarbonylamino) cyclopropyl) -2-nitro-N-methyl-aniline

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 at 0 ° C was treated with 8.3 g (76 mmol) of ethyl chloromethanate. After one hour at room temperature, 0.75 g of tetrabutylammonium bromide is added. A solution of 6.3 g (96 mmol) of sodium azide in 20 ml of water is then added dropwise. After one hour at 0 ° C, the solution was diluted with water and extracted with ethyl acetate. The organic extracts were dried and evaporated. The residue was dissolved in 200 ml of tert-butanol and heated at reflux for two hours. The solvent was evaporated, the residue was chromatographed on silica gel and eluted with methylene chloride.

Yield: 15.5 g (77% of theory), Rf value: 0.83 (silica gel; methylene chloride / methanol = 9.5: 0.5)

b) 4 - ((1-Amino) cyclopropyl) -2-nitro-N-methyl-aniline hydrochloride

15.5 g (0.05 mmol) of 4 - [(1-tert-butyloxycarbonylamino) cyclopropyl] -2-nitro-N-methyl-aniline are dissolved in 50 ml of ethanol and 50 ml of ethanolic hydrochloric acid solution and Stir at room temperature. The solvent was distilled off, the residue was triturated with ether, filtered off with suction and dried. Yield: 98% of the theoretical yield;

Rf value: 0.44 (silica gel; methylene chloride / methanol = 9.5: 0.5)

c) 4- [N- (1-Cyclopentylamino) cyclopropyl] -2-nitro-N-methyl-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 addition of 4.1 g (0.05 mol) of cyclopentanone and 3.2 ml of glacial acetic acid under nitrogen are mixed portionwise with 13.6 g (0.064 mol) of sodium triacetoxyborohydride. After 16 hours at room temperature, it was diluted with sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried and evaporated. 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 = 9.5: 0.5)

d) 4- [1- (N - (3-Ethoxycarbonylpropionyl) -N'-cyclopentyl-amino) cyclopropyl] -2-nitro-N-methyl-aniline

1.0 g (3.6 mmol) of 4 - [(1-cyclopentylamino) cyclopropyl] -2-nitro-N-methyl-aniline is dissolved in 30 ml of tetrahydrofuran and after addition of 0.45 g (4.4 mmol) of triethylamine This was treated with 0.65 g (4.4 mmol) of ethyl succinate chloride and stirred at room temperature for four hours. It is then diluted with ethyl acetate and sodium bicarbonate solution, the organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with ethyl acetate / cyclohexane (1: 1).

Yield: 1.3 g (90% of theory), Rf: 0.46 (silica gel; ethyl acetate / cyclohexane = 1: 1)

e) 4- [1- (N - (3-Ethoxycarbonylpropionyl) -N-cyclopentyl-amino) cyclopropyl] -2-amino-N-methyl-aniline

Prepared in analogy to Example 1d from 4- [1- (N - (3-ethoxycarbonylpropionyl) - N -cyclopentyl-amino) cyclopropyl] -2-nitro- N -methyl-aniline and palladium on activated carbon (hydrogen in methylene chloride) ethanol.

Yield: 100% of theory. Yield: 0.18 (silica gel; ethyl acetate / cyclohexane = 1: 1)

f) 4- [1- (N- (3-Ethoxycarbonylpropionyl) -N-cyclopentyl-amino) cyclopropyl] -2- (4-cyano-phenyl) -aminomethylcarbonylamino-N-methyl-aniline

Prepared in analogy to Example 1c from 4- [1- (N - (3-ethoxycarbonylpropionyl) - N -cyclopentyl-amino) cyclopropyl] -2-amino- N -methyl-aniline, O- (benzotriazol-1-yl) - N, N, N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 96% of theory. Yield: 0.54 (silica gel; methylene chloride / methanol = 9.5: 0.5)

g) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- [N-cyclopetyl-N- (3-ethoxycarbonyl-propionyl) -amino] cyclopropyl] -benzimidazole

Prepared in analogy to Example If from 4- [1- (N - (3-ethoxycarbonylpropionyl) - N -cyclopentyl-amino) cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino- N -methyl-aniline in glacial acetic acid.

Yield: 52% of theory, Rf: 0.81 (silica gel; methylene chloride / methanol = 9: 1)

h) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N-cyclopentyl-N- (3-ethoxycarbonylpropionyl) amino] cyclopropyl] benzimidazole hydrochloride

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- [N-cyclopentyl-N- (3-ethoxycarbonylpropionyl) amino] cyclopropyl] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 36% of theory, C ₃₁₎ H ₃₈ N ₆ O ₃ x HCl (530.68 / 567.14) Mass spectrum: (M + H) ⁺ = 531

Example 8

2- (4-amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-methoxycarbonylmethyl-imidazolin-2,4-dione-5-yl) benzimidazole hydrochloride

a) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino-carbonyl-amino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole

Dissolve 1.0 g (2.5 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole in 10 ml of dimethylformamide and after addition of 0.9 ml (7.9 mmol) of ethyl isocyanatoacetate, it was stirred at room temperature for 45 minutes. The solution is poured into ice water, the crystalline product is filtered off with suction 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: 0.0i)

b) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-methoxycarbonylmethyl-imidazoline-2,4-dione-5-yl) benzimidazole hydrochloride

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylaminocarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol. Yield: 68% of theory, C ₂₄ H ₂₇ N ₇ O ₄ x HCl (477.52 / 513.99) Mass spectrum: (M + H) ⁺ = 478

Example 9

2- (4-amidinophenylaminomethyl) -1-methyl-5 - [N - (2-pyridyl) -N- (2-ethoxycarbonylethyl) aminomethyl] benzimidazole hydrochloride

a) 4- (2- tert -Butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-chlorobenzene

13.4 g (0.053 mol) of 4-chloro-3-nitrobenzyl bromide and 11.8 g (0.053 mol) of 2-tert-butyloxycarbonylatylaminopyridine are stirred at 90 DEG C. for 3 hours in 80 ml of N-ethyl-diisopropylamine. The solution is evaporated, the residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (8: 2 and 7: 3).

Yield: 8.2 g (40% of theory), Rf: 0.64 (silica gel; petroleum ether / ethyl acetate = 8: 2)

b) 4- (2-tert-Butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-N-methyl-aniline

Prepared in analogy to Example 1b from 4- (2- tert -butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-chlorobenzene and methylamine solution.

Yield: 20% of theory, Yield: 0.65 (silica gel; methylene chloride / ethanol = 9: 1)

c) 4- (2-tert-Butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-amino-N-methyl-aniline

1.6 g (4 mmol) of 4- (2- tert -butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-N-methyl-aniline are dissolved in 200 ml of methanol and, after addition of 2 g of Raney nickel, mixed with 1 ml hydrazine hydrate. The solution was stirred at room temperature for 30 minutes and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (95: 5). Yield: 1.2 g (82% of theory), _{R f} value: 0.33 (silica gel, methylene chloride / ethanol = 9: 1)

d) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [N - (2-pyridyl) -N- (2-ethoxycarbonylethyl) aminomethyl] benzimidazole

Prepared in analogy to Example 1c from 4- (2-tert-butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-amino-N-methyl-aniline, O- (benzotriazol-1-yl) - N, N, N, N N '-tetra-methyluronium tetrafluoroborate, 4-cyanophenylglycine in tetrahydrofuran and glacial acetic acid.

Yield: 72% of theory, Rf: 0.36 (silica gel; methylene chloride / ethanol = 9: 1)

e) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [N - (2-pyridyl) - N - (2-ethoxycarbonyl-ethyl) -aminomethyl] -benzimidazole hydrochloride

Prepared in analogy to Example 1g from 4- [5- (2-tert-butyloxycarbonylethyl) -2-pyridylaminomethyl-1-methyl-benzimidazol-2-yl) -methyl-amino] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 59% of theory.

C ₂₇ H ₃₁ N ₇ O ₂ x HCl (485.59 / 522.1) Mass Spectrum: (M + H) ⁺ = 486

In analogy to Example 9, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N - (ethoxycarbonylmethyl) -benzenesulfonylaminomethyl] -benzimidazole hydrochloride

Yield: 53% of theory.

C ₂₇ H ₃₀ N ₆ O ₄ S x HCl (534.64 / 571.1) Mass Spectrum: (M + H) ⁺ = 535

2. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [N - (methylphenylcarbonylamino-methyl)] - benzimidazole hydrochloride Yield: 42% of theory;

C ₂₅ H ₂₆ N ₆ O x HCl (426.53 / 462.96) Mass Spectrum: (M + H) ⁺ = 427

Example 10

2- (4-amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-benzimidazol-1-yl) methyl]] - benzimidazole hydrochloride

a) 1- (4-Chloro-3-nitrobenzyl) -2-methylbenzimidazole

Prepared in analogy to Example 9a from 2-methyl-benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulfoxide.

Yield: 78% of theory, C ₁₅ H ₁₂ ClN ₃ O ₂ (301.7)

Mass Spectrum: M ⁺ = 301/303

b) 1- (4-Methylamino-3-nitrobenzyl) -2-methylbenzimidazole

Prepared in analogy to Example 1b from 1- (4-chloro-3-nitrobenzyl) -2-methylbenzimidazole and methylamine. Yield: 96% of theory.

Rf value: 0.56 (silica gel; methylene chloride / ethanol = 19: 1)

c) 1- (4-Methylamino-3-aminobenzyl) -2-methylbenzimidazole

Prepared in analogy to Example 1c from 1- (4-methylamino-3-nitrobenzyl) -2-methylbenzimidazole and hydrogen ^from Raney nickel.

Yield: 100% of theory, Rf: 0.34 (silica gel; methylene chloride / ethanol = 19: 1)

d) 2- (4-Cyanophenylaminomethyl) -1-methyl-5 - [(2-methylbenzimidazol-1-yl) methyl)] benzimidazole

A mixture of 1.94 g (11.0 mmol) of N- (4-cyanophenyl) -glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole was heated in 80 ml of absolute tetrahydrofuran under reflux for 15 min. After addition of 2.7 g (10.46 mmol) of 1- (4-methylamino-3-aminobenzyl) -2-methylbenzimidazole, the mixture was heated under reflux for a further 16 hours. Subsequently, the solution is evaporated to dryness, the residue is treated with 80 ml of glacial acetic acid and heated under reflux for 1 hour. It is then evaporated again to dryness, the residue thus obtained is mixed with 50 ml of water and adjusted to alkaline with concentrated ammonia (about pH 10). The crystallized product is filtered off with suction, washed with a little water and dried.

Yield: 4.1 g (96% of theory), Rf: 0.30 (silica gel; methylene chloride / ethanol = 19: 1) C ₂₅ H ₂₂ N ₆ (406.5)

Mass Spectrum: M ⁺ = 406

e) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-methylbenzimidazol-1-yl) methyl]] benzimidazole hydrochloride

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5 - [(2-methyl-benzimidazol-1-yl) methyl] -benzimidazole and hydrochloric acid / ammonium carbonate. Yield: 59% of theory, C ₂₅ H ₂₅ N ₇ x HCl (423.5 / 459.9) Mass spectrum: (M + H) ⁺ = 424 (M + 2H) ²⁺ = 217.7

In analogy to Example 10, the following compounds are obtained:

1. 2- (4-Amidinophenyloxymethyl) -1-methyl-5 - [(imidazol-1-yl) methyl]] benzimidazole hydrochloride

Yield: 30% of theory, C ₂₀ H ₂₀ N ₆ O x HCl (360.4 / 396.9) Mass spectrum: (M + H) ⁺ = 361 (M + 2H) ²⁺ = 181

2. 2- (4-Amino-phenylammomethyl) -1-methyl-5- [1- (imidazol-1-yl) -ethyl] -benzimidazole hydrochloride

Yield: 70% of theory, C ₂₁ H ₂₃ N ₇ x HCl (373.46 / 410) Mass spectrum: (M + H) ⁺ = 374 (M + 2H) ²⁺ = 187.6

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethyl-4-methyl-imidazol-1-yl) -ethyl] -benzimidazole dihydrochloride

Yield: 18% of theory, C ₂₄ H ₂₉ N ₇ x 2 HCl (415.55 / 488.46) Mass spectrum: (M + H) ⁺ = 416 (M + 2H) ²⁺ = 208.7

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-ethyl-4-methyl-imidazol-1-yl) -methyl] -benzimidazole dihydrochloride Yield: 36% of theory;

C ₂₃ H ₂₇ N ₇ x 2 HCl (401.52 / 437.97) Mass Spectrum: (M + H) ⁺ = 402 (M + 2H) ²⁺ = 201.7

5. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [N- (pyridin-2-yl) -N-methyl-amino-methyl] -benzimidazole dihydrochloride Yield: 78% of theory.

C ₂₃ H ₂₅ N ₇ x 2 HCl (399.5 / 435.95) Mass Spectrum: (M + H) ⁺ = 400 (M + 2H) ²⁺ = 200.6

6. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-ethoxycarbonyl-ethyl) -benzimidazol-1-yl) -methyl] -benzimidazole dihydrochloride

Yield: 61% of the theoretical yield;

C ₂₉ H ₃₁ N ₇ O ₂ x HCl (509.62 / 546.07)

Mass Spectrum: (M + H) ⁺ - 510 (M + 2H) ²⁺ = 255.7 (M + H + Na) ²⁺ = 266.7

7. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(imidazol-1-yl) methyl] benzimidazole hydrochloride

Yield: 35% of the theoretical yield,

C ₂₀ H ₂₁ N ₇ x HCl (359.44 / 395.89)

Mass Spectrum: (M + H) ⁺ = 360 (M + 2H) ²⁺ = 180.6

8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-acetyl-amino-ethyl) -4,5-dimethyl-imidazol-1-yl) -methyl] -benzimidazole dihydrochloride

Yield: 42% of theory.

C ₂₆ H ₃₂ N ₈ O x 2 HCl (472.6 / 545.51)

Mass Spectrum: (M + H) ⁺ = 473 (M + 2H) ²⁺ = 237 (M + H + Na) ²⁺ = 248

9. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-aminocarbonyl-ethyl) -4,5-dimethyl-imidazol-1-yl) -methyl] -benzimidazole dihydrochloride

Yield: 68% of the theoretical yield;

CjjHjoNgO x 2 HCl (458.6 / 531.51)

Mass Spectrum: (M + H) ⁺ = 459 (M + 2H) ²⁺ = 230

10. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-4-ethoxycarbonyl-imidazol-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 34% of the theoretical yield;

C ₂₄ H ₂₇ N ₇ O ₂ x HCl (445.53 / 481.98)

Mass Spectrum: (M + H) ⁺ = 446 (M + 2H) ²⁺ = 223.5 (M + H + Na) ² '= 234.5

11. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(3- (3-ethoxycarbonyl-n-propyl) -benzimidazol-2-on-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 58% of theory.

C ₃₀ H ₃₃ N ₇ O ₃ x HCl (539.64 / 576.09)

Mass Spectrum: (M + H) ⁺ = 540 (M + H + Na) ²⁺ = 281.7

12. 2- (4-amidinophenylaminomethyl) -1-methyl-5 - ((3- (2-ethoxycarbonyl-ethyl)) imidazo [4,5-b] pyridin-2-one-

-1-yl) -methyl] -benzimidazole

Yield: 29% of the theoretical yield;

C ₂₈ H ₃₀ N ₈ O ₃ x HCl (526.6 / 563.05)

Mass Spectrum: (M + H) ⁺ = 527 (M + 2H) ²⁺ = 264 (M + H + Na) ²⁺ = 275

13. 2- (4-amidinophenylaminomethyl) -1-methyl-5 - [(2-phenyl-imidazol-1-yl) -methyl] -benzimidazole hydrochloride Yield: 58% of theory;

C ₂₆ H ₂₅ N ₇ x HCl (435.54 / 472)

Mass Spectrum: (M + H) ⁺ = 436 (M + Na) ⁺ = 218.6

14. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(4,5-dimethyl-2- (2-ethoxycarbonylethyl) imidazol-1-yl) methyl] benzimidazole dihydrochloride

Yield: 52% of theory, C ₂₇ H ₃₃ N ₇ O ₂ x 2 HCl (487.61 / 560.52) Mass spectrum: (M + H) ⁺ = 488 (M + 2H) ²⁺ = 244.6

Example 11

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl) -carbonyl] -ethyl] -benzimidazole hydrochloride

a) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (2-tert-butyloxycarbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl) -carbonyl) -ethyl] benzimidazole

0.8 g (1.86 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole and 1.65 g (5.5 mmol) of 2,4-dibromobutyric acid tert-butyl ester was dissolved in 5 ml of ethanol, treated with 0.2 g (1.86 mmol) of sodium carbonate and stirred at 55 ° C for 30 hours under nitrogen. After cooling, the white precipitate was filtered off and the solution was washed with ethanol. The filtrate is evaporated, the residue is chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate / ethanol / ammonia (20: 1: 0.01). The desired fractions were combined and evaporated. Yield: 0.44 g (44% of theory), C ₃₁ H ₃₈ N ₆ O ₃ (542.69) Mass spectrum: (M + H) = 543

b) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylazetidin-1-yl) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride (mixture of diastereomers)

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (2-tert-butyloxycarbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl) -carbonyl) - ethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol. Yield: 12% of the theoretical yield;

C ₂₉ H ₃₇ N ₇ O ₃ x HCl (531.66 / 568.12) Mass Spectrum: (M + H) ⁺ = 532 (M-H + HCl) ² '= 568/70 (Cl)

Example 12

(E '/ Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) -ethoxycarbonylmethylidene) -methylene] cyclopropyl] -benzimidazole hydrochloride

a) (E / Z) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) -ethoxycarbonylmethylidene-methylene] cyclopropyl] -benzimidazole

897 mg (4.0 mmol) of phosphonoacetic acid triethyl ester are dissolved under argon in 30 ml of tetrahydrofuran. Potassium tert-butylate (449 mg, 4.0 mmol) was added at -15 ° C. After 30 minutes, 815 mg (2.0 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyridin-3-ylcarbonyl) cyclopropyl] benzimidazole was added portionwise and stirred overnight at room temperature. The solution was then heated at reflux for 6 hours and concentrated. The residue was treated with brine and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel, eluting with dichloromethane with 5% ethanol. The desired fractions are concentrated, the residue is triturated with ether, filtered off with suction and dried.

Yield: 365 mg (38% of theory).

SK 283744 Β6

(b) ((E / Z) -2- (4-Aminophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) ethoxycarbonylmethylidene) methylene] cyclopropyl] benzimidazole hydrochloride

Prepared in analogy to Example 1g from ((E / 2) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) -ethoxycarbonylmethylidene) methylene] cyclopropyl] benzimidazole and acid sodium / ammonium carbonate in ethanol. Yield: 58% of theory.

C ₂₉ H ₃₀ N ₆ O ₂ x HCl (494.60 / 531.05) Mass Spectrum: (M + H) ⁺ = 495

In analogy to Example 12, the following compound is obtained:

((E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) -ethoxycarbonylmethylidene) -methylene] cyclopropyl] -benzimidazole hydrochloride

Yield: 72% of theory. C ₂₉ H ₃₀ N ₆ O ₂ x HCl (494.60 / 531.05) Mass spectrum: (M + H) ⁺ = 495

Example 13

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyazetidin-1-yl) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride (mixture of diastereomers)

200 mg (0.35 mmol) of 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) hydrochloride -ethyl] -benzimidazole is dissolved in 30 ml of 6N hydrochloric acid and stirred at room temperature for 13 hours. The reaction mixture was evaporated with the addition of toluene, the residue was triturated with acetone / ether, filtered off with suction, washed with ether and dried.

Yield: 200 mg (> 100% of theory, containing ammonium chloride)

C ₂₇ H ₃₃ N ₇ O ₃ x HCl (503.62 / 540.07)

Mass Spectrum: (M + H) ⁺ = 504

In analogy to Example 13, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (dimethylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 91% of the theoretical yield;

Rf value: 0.75 (reverse phase; 5% sodium chloride / methanol = 1: 1)

C ₂₄ H ₃₁ N ₇ O ₃ x HCl (465.56 / 502.01)

Mass Spectrum: (M + H) ⁺ = 466 (M-H + 2HCl) - = 537/539 (Cl ₂ )

2. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole dihydrochloride

Yield: 70% of the theoretical yield;

_{R f} value: 0.51 (reversed phase, 5% saline solution / methanol = 3: 2)

C ₂₅ H ₃₁ N ₇ O ₃ x 2 HCl (477.57 / 550.48) Mass Spectrum: (M + H) ⁺ = 478

3. (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) -carboxymethylidene) -methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 65% of theory, C ₂₇ H ₂₆ N ₆ O ₂ x HCl (466.55 / 503.0) Mass spectrum: (M + H) ⁺ = 467 (M + C1) ⁺ = 501/503 (Cl)

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methyl-carboxymethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride

Yield: 99% of theory, Rf value: 0.55 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C ₂₈ H ₃₅ N ₇ O ₄ x 2 HCl (533.64 / 606.64) Mass Spectrum: (M + H) ⁺ = 534 (M-H) - = 532 (M-H + HCl) - = 568 / 70 (Cl)

5. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethyl-amino) -1- (N-ethyl-N-methyl-aminocarbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 75% of theory, _{R f} value: 0.54 (reversed phase RP 8; methanol / 5% saline solution = 1: 1)

C ₂₅ H ₃₃ N ₇ O ₃ x 2 HCl (479.59 / 552.59) Mass Spectrum: (M + H) ⁺ = 480

Example 14 2- [4- (N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2-ethoxycarbonyl-ethylamino) -1- (dimethylaminocarbonyl) -ethyl] -benzimidazole

1.5 g (2.8 mmol) of 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -1- (dimethylaminocarbonyl) ethyl] benzimidazole dihydrochloride are dissolved in 14 ml of water and ml of tetrahydrofuran, treated with 2.0 g of potassium carbonate and 1.0 ml (6 mmol) of hexyl chloroformate and stirred at room temperature for 4 hours. After removal of the solvent in vacuo, the residue was mixed with brine and extracted three times with methylene chloride. The combined organic phases are washed with a little water, dried over magnesium sulphate and evaporated. The crude product is purified on silica gel, eluting with methylene chloride plus 2 to 7.5% ethanol. The individual fractions were combined, evaporated, dissolved in a small amount of ethyl acetate and mixed with petroleum ether. The solid formed is filtered off with suction, washed with petroleum ether and dried.

Yield: 0.8 g (43% of theory), C ₃₃ H ₄₇ N ₇ O ₅ (621.79)

_{R f} value: 0.50 (silica gel, methylene chloride / ethanol = 19: 1) Mass spectrum: (M + H) ⁺ = 622 (M + Na) ⁺ = 644

Example 15

2- (4-amidmofenylaminometyl) -1-methyl-5- [1 - ^{(In--etoxykarbonyhnetyl} karbonylmetylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole

a) 2- (4-Chloro-phenyl) -3-hydroxy-2-methyl-propionic acid methyl ester

To a solution of 8.1 mL of diisopropylamine (85 mmol) in 20 mL of tetrahydrofuran at -78 ° C was added dropwise 35 mL of a 1.6 molar solution of n-butyllithium in hexane (61 mmol). Subsequently, a solution of 10.0 g (50 mmol) of methyl 2- (4-chloro-phenyl) -propionate in 30 ml of tetrahydrofuran was added dropwise at -78 ° C. Formaldehyde gas is then introduced into the reaction mixture at -20 ° C for 30 minutes. After addition of 5% citric acid and glacial acetic acid, it is extracted with ethyl acetate. The organic phases are washed with 1N sulfuric acid, water, saturated sodium bicarbonate solution and brine and dried over magnesium sulphate. The crude product is purified on silica gel, eluting with cyclohexane / ethyl acetate (19: 1.9: 1.4: 1.1: 1 and 0: 1). The individual fractions were combined and evaporated.

Yield: 9.7 g (84% of theory) of a yellow oil,

Rf value: 0.25 (silica gel; petroleum ether / ethyl acetate = 4: 1)

b) 2- (4-Chloro-phenyl) -3-hydroxy-2-methyl-propionic acid

Prepared in analogy to Example 4 from 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid methyl ester and sodium hydroxide in ethanol.

Yield: 83% of theory.

Rf value: 0.55 (silica gel; ethyl acetate / cyclohexane 2: 1 + + glacial acetic acid)

c) 2- (4-Chloro-3-nitro-phenyl) -2-methyl-3-nitrooxy-propionic acid

Prepared in analogy to Example 1a from 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid and nitric acid.

Yield: 90% of theory. Melting point: 129-132 ° C. ₁₀ H ₉ ClN ₂ O ₇ (304.64)

d) 2- (4-Chloro-3-nitro-phenyl) -2-methyl-3-hydroxy-propionic acid

Prepared in analogy to Example 6 from 2- (4-chloro-3-nitro-phenyl) -3-nitrooxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxane.

Yield: 98% of theory, C ₁₀ H ₁₀ ClNO ₅ (259.65)

Mass Spectrum: (MH) - = 258/60 (Cl) (2M-H) · = 517/9 (Cl ₂ )

e) 2- [4- (N-Benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-propionic acid

Prepared in analogy to Example 1b from 2- (4-chloro-3-nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.

Yield: 81% of theory, C ₁₈ H ₂₀ ClN ₂ O ₅ (344.37) Mass spectrum: M ⁺ = 344

f) 2- [4- (N-Benzylmethylamino) -3-nitrophenyl] -2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one

Prepared in analogy to Example 1c from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine, Yield: 96% of theory. .

C ₂₂ H ₂₇ N ₃ O ₄ (397.48) Mass Spectrum: M ⁺ = 398 (M + Na) ⁺ = 420

g) 2- [4- (N-Benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-methanesulfonyloxy-1-pyrrolidin-1-yl-propan-1-one

A solution of 1.2 g (3.0 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1 -one in 20 ml of tetrahydrofuran was treated with 1.3 ml (9.3 mmol) of triethylamine at room temperature. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonyl chloride is added dropwise at 2-5 ° C. After 2 hours at room temperature, the precipitate formed is filtered off with suction and the filtrate is evaporated. The crude product was used without further purification.

Yield: 1.4 g (98% of theory),

h) 2- [4- (N-Benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one

A solution of 1.4 g (2.9 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-methanesulfonyloxy-1-pyrrolidin-1-yl-propane- of 1-one in 10 ml of DMF was mixed with 20 ml of a 40% aqueous methylamine solution and heated at 100 ° C for 70 minutes. After cooling, the reaction mixture was treated with ice water and extracted with ethyl acetate. The organic phases are washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified on silica gel using ethyl acetate / ethanol (10: 1, 9: 1, 4: 1 1% concentrated ammonia) as the eluent. The individual fractions were combined and evaporated. Yield: 740 mg (61%), _{R f} value: 0.45 (silica gel; methylene chloride / ethanol 9: 1 + 1% conc. Ammonia)

i) 2- [4- (Benzylmethylamino) -3-nitrophenyl] -2-methyl-3- (N-methoxycarbonylmethylcarbonylmethylamino) -1-pyrrolidin-1-yl-propan-1-one

Prepared in analogy to Example 7d from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one and methyl ester malonic acid chloride.

Yield: 84% of theory.

Rf value: 0.65 (silica gel; ethyl acetate / ethanol 9: 1 + ammonia)

C ₂₇ H ₃₄ N ₄ O ₆ (510.60)

Mass Spectrum: (MH +) = 509 (M + Na) ⁺ = 533

j) 2- (4-Methylamino-3-aminophenyl) -2-methyl-3- (N-methoxycarbonylmethylcarbonylmethyl-amino) -1-pyrrolidin-1-yl-propan-1-one

Prepared in analogy to Example 1d from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3- (N-methoxycarbonylmethyl-carbonyl-methylamino) -1-pyrrolidin-1-yl -propan-1-one and hydrogen / palladium on activated carbon.

Yield: 100% of theory, _{R f} value: 0.40 (silica gel; ethyl acetate / ethanol 9: 1 + 1% conc. Ammonia)

C ₂₀ H ₃₀ N ₄ O ₄ (390.49) Mass spectrum: M ⁺ = 390

k) 4- [2- (3- (N-Methoxycarbonylmethylcarbonyl-methylamino)) -2-methyl-1-pyrrolidin-1-yl-propan-1-one-2-yl] -2- (4-cyanophenyl) - aminometylkarbonylamino- / V-methyl-aniline

Prepared in analogy to Example 1e from 2- (4-methylamino-3-amino-phenyl) -2-methyl-3- (N-methoxycarbonylmethylcarbonyl-methylamino) -1-pyrrolidin-1-yl-propan-1-one and O- (benzotriazol-1-yl) -, N, N, N ', N' - tetra-methyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 95% of the theoretical yield;

Rf value: 0.35 (silica gel; ethyl acetate / ethanol 9: 1 + 1% horse, ammonia)

l) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methyl-amino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Prepared in analogy to Example 1f of 4- [2- (3- (N-methoxycarbonylmethyl-carbonyl-methylamino)) - 2-methyl-1-pyrrolidin-1-yl-propan-1-one-2-yl] -2- (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.

Yield: 47% of the theoretical yield;

R f value: 0.20 (silica gel; ethyl acetate / ethanol 9: 1) C ₂₉ H ₃₄ N ₆ O ₄ (530.63)

Mass Spectrum: (M + H) ⁺ = 531 (M + Na) ⁺ = 553

(m) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N'-ethoxycarbonylmethylcarbonylmethyl amino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole hydrochloride

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole and hydrochloric acid / carbonate ammonium in ethanol.

Yield: 65% of theory, _{R f} value: 0.30 (silica gel; methylene chloride / methanol = 4: 1 + glacial acetic acid)

C ₃₀ H ₃₉ N ₇ O ₄ x HCl (561.69 / 598.19) Mass Spectrum: (M + H) ⁺ = 562 (M + CI + = 596/8 (Cl)

In analogy to Example 15, the following compounds are obtained:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methoxycarbonylmethylmethylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride

Yield: 89% of theory, _{R f} value: 0.35 (reversed phase RP 8; methanol / 5% saline solution = 3: 2)

C ₂₈ H ₃₇ N ₇ O ₃ x HCl (519.66 / 556.11) Mass Spectrum: (M + H) ⁺ = 520 (M-H + HCl) + = 554/6 (Cl)

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole acetate

Yield: 45% of theory, Rf: 0.20 (silica gel; methylene chloride / methanol = 8: 2 + 1% ethyl acetate)

C ₂₉ H ₃₇ N ₇ O ₄ x CH ₃ COOH (547.66 / 607.71) Mass spectrum: (M + H) ⁺ = 548 (Μ-H) - = 546 (M-H + CH ₃ COOH) - = 606

3. 2- (4-amidinofenylaminometyl) -l-methyl-5- [1 - (/ V-etoxykarbonylmctyl-carbonyl-amino) -2- ^(methyl-L and ethylaminocarbonyl) prop-2-yl] benzimidazole

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethyl-methylamino) -2- (N-methyl-N-ethylaminocarbonyl) -prop-2-yl] -benzimidazole

5. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (piperidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride

6. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylsulfonylmethylamino) -2- (piperidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride

7. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methoxycarbonylmethyl-carbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole acetate

Yield: 72% of the theoretical yield;

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2 + + 1% glacial acetic acid)

C ₂₉ H ₃₇ N ₇ O ₄ x CH ₃ COOH (547.66 / 607.71) Mass Spectrum: (M + H) ⁺ = 548 (MH) + = 546

8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-ethylcarbonyl-amino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride

9. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylsulfonylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride

Yield: 14% of the theoretical yield,

_{R f} value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2) _{2 S} C H ₃₇ N ₇ O ₅ S x HC1 (583.65 / 620.17)

Mass Spectrum: (M + H) ⁺ = 584 (M + Na) ⁺ = 606

10. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol-5-yl) methylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride

11. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride

Yield: 40% of the theoretical yield;

C ₂₈ H ₃₇ N ₇ O ₃ x 2 HCl (519.65 / 592.56) Mass Spectrum: (M + H) ⁺ = 520 (M + Na) ⁺ = 542 (M + HCOO) = 564 (M + Cl) ) = 554

Example 16

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Prepared by hydrolyzing 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -2- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride with sodium hydroxide in ethanol.

Yield: 90% of theory, Rf value: 0.65 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

CmHmN4 * HCl (479.54 / 515.99)

Mass Spectrum: (M + H) ⁺ = 480

In analogy to Example 16, the following compounds were prepared:

1. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

2. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (N-methyl-N-ethylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 93% of theory.

Value: 0.40 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C ₂₄ H ₃₁ N ₇ O ₃ x HCl (465.57 / 502.02) Mass spectrum: (M + H) ⁺ = 466 (M + Cl-Η) - = 500/2 (Cl)

3. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethyl-methyl amino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride

Yield: 89% of theory.

Rf value: 0.57 (reverse phase RP 8; methanol / 5% sodium chloride solution = 4: 3)

C ₂₇ H ₃₅ N ₇ O ₃ x 2 HCl (505.63 / 578.54)

Mass Spectrum: (M + H) ⁺ = 506 (M + 2H) ⁺⁺ = 253 (M-H + Na) ⁺⁺ = 264.5

4. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride

Yield: 90% of the theoretical yield;

_{R f} value: 0.55 (reversed phase RP 8; methanol / 5% saline solution = 6: 4)

C ₂₇ H ₃₃ N ₇ O ₄ x HCl (519.61 / 556.06)

Mass Spectrum: (M + H) ⁺ = 520 (MH +) = 518

5. 2- (4-amidinofenylaminometyl) -l-methyl-5- [1 - ^(A, carboxymethyl-methyl-amino) -2-ethyl-GV-methylaminocarbonyl) prop-2-yl] benzimidazole

6. 2- (4-amidinofenylaminometyl) -l-methyl-5- [1 - (A-karboxymetylkarb-benzenesulfonyl-amino) -2 ^(f A-methylaminocarbonyl-ethyl) -prop-2-yl] benzimidazole

7. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylcarbonylmethylamino) -2 (piperidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride

8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylsulfonyl-methylamino) -2- (piperidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride

9. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1-N-carboxymethylamino) -1- (piperidinocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 81% of theory.

Rf value: 0.40 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C ₂₆ H ₃₃ N ₇ O ₃ (491.60 / 528.05)

Mass Spectrum: (M + H) ⁺ = 492 (MH) - = 490

10. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride

11. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylsulfonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride

12. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (diethylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 70% of the theoretical yield;

_{R f} value: 0.50 (reversed phase RP 8; methanol / 5% saline solution -nv = 1: 1)

C ₂₃ H ₃₃ N ₇ O ₃ x HCl (479.59 / 516.05)

Mass Spectrum: (M + H) ⁺ = 480 (MH +) = 478 (M-H + HCl) = 514/516 (CI)

13. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyl-amino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride

Yield: 22% of the theoretical yield,

_{R f} value: 0.50 (reversed phase RP 8, 5% saline solution / methanol = 1: 1)

C ₂₆ H ₃₃ N ₇ O ₃ x 2 HC1 (491.60 / 564.51)

Mass Spectrum: (M + H) ⁺ = 492 (MH) - = 490

14. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethyl-methyl-amino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole dihydrochloride

_{R f} value: 0.48 (reversed phase RP 8, 5% saline solution / methanol = 3: 2)

C ₂₆ H ₃₃ N ₇ O ₃ x 2 HCl (491.60 / 564.51) Mass Spectrum: (M + H) ⁺ = 492 (MH) + = 490

15. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (3-carboxy-propylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 82% of theory, Rf value: 0.73 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1)

C ₂₇ H ₃₅ N ₇ O ₃ x 2 HCl (505.63 / 578.54) Mass Spectrum: (M + H) ⁺ = 506

Example 17 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonyl-methylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

A suspension of 1.4 g of 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride (2.4 mmol) in 5 ml of N-ethyl- of diisopropylamine and 2 ml of dimethylformamide were combined with 1.5 g (6 mmol) of 4-nitrophenyl benzoate to give a clear solution upon heating. After 2 hours at 120 ° C, the solution was evaporated in vacuo, the residue dissolved in dichloromethane after cooling and purified on silica gel, eluting first with dichloromethane, then with dichloromethane / ethanol (50: 1, 25: 1, 18: 1). The individual fractions were combined, evaporated, triturated with water, filtered off with suction and dried. Yield: 0.7 g (49% of theory), _{R f} value: 0.40 (silica gel; methylene chloride / ethanol = 19: 1) ₃ C 4 H ₃₉ N ₇ O ₄ (609.73) Mass spectrum: (M + H) ⁺ = 610 (M + Na) ⁺ = 632 (MH) - = 608

In analogy to Examples 14 and 17, the following compounds are obtained:

2- [4- (N'-n-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 53% of theory, Rf value: 0.35 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₄ H ₄₇ N ₇ O ₅ (633.79)

Mass Spectrum: (M + Na) ⁺ = 656 (MH) + = 632

2. 2- [4- ^{(N-n-octyloxycarbonylamidino)} phenylaminomethyl] -1-methyl-5- [l - (ethoxycarbonylmethyl) -1 - (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 46% of the theoretical yield;

_{R f} value: 0.43 (silica gel, methylene chloride / ethanol = 9: 1) C ₃₆ H _5I N ₇ O ₅ (661.84)

Mass Spectrum: (M + Na) ⁺ = 684 (MH) + = 660

3. 2- [4- (N-N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

4. 2- [4- (N-Octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 32% of the theoretical yield,

Rf value: 0.27 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₅ H ₄₉ N ₇ O ₅ (647.82)

Mass Spectrum: (M + Na) = 670 (M-H) = 646

5. 2- [4- (N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield 52% of the theoretical yield,

Rf value: 0.60 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₇ H ₅₁ N ₇ O ₆ (689.85)

Mass Spectrum: (M + H) ⁺ = 690 (MH) + = 688 (M + Na) ⁺ = 712 (M + HCl-H) + = 724/26 (CI)

6. 2- [4- (N-N-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] - benzimidazole

7. 2- [4- (N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] - benzimidazole Yield: 21% of theory,

Rf value: 0.55 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₆ H ₄₉ N ₇ O ₆ (675.83)

Mass Spectrum: (M + H) ⁺ = 676 (M + Na) ⁺ = 698 (M + HCl-H) · = 724/26 (Cl)

8. 2- [4- (N-N-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2- yl] benzimidazole

9. 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonyl-methylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 34% of the theoretical yield;

Rf value: 0.55 (silica gel; methylene chloride / ethanol = 9: 1 + + 1% ammonia)

C ₃₃ H ₇ N ₇ O ₄ (595.70)

Mass Spectrum: (MH +) = 594 (M + Na) ⁺ = 618

10. 2- [4- (N-Isopropyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 66% of theory.

_{R f} value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₄ H ₄₅ N ₇ O ₆ (647.77)

Mass Spectrum: (M + H) ⁺ = 648 (MH) + = 646 (M + Na) ⁺ = 670

11. 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield : 23% of the theoretical yield,

_{R f} value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₇ H ₄₃ N ₇ O ₅ (665.79)

Mass Spectrum: (M + H) ⁺ = 666 (MH) + = 664 (M + Na) ⁺ = 688 (M + H + Cl) = 700/2 (Cl)

12. 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonylmethyl-amino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 67% of the theoretical yield,

R f value: 0.60 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₆ H ₄ fN ₇ O ₅ (651.76)

Mass Spectrum: (M + H) ⁺ = 652 (MH) + = 650 (M + Na) ⁺ = 674

13. 2- [4- (N-Butyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2 -yl] -benzimidazole Yield: 45% of the theoretical yield,

R f value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₄ H ₄₅ N ₇ O ₆ (647.77)

Mass Spectrum: (M + H) ⁺ = 648 (MH) + = 646 (M + Na) ⁺ = 670 (M-H + Cl) · = 682/4 (Cl)

14. 2- [4- (N-Ethyloxycarbonylamidinoyl-phenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 54% of the theoretical yield,

R f value: 0.40 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₃ H ₄₃ N ₇ O ₆ (633.75)

Mass Spectrum: (M + H) ⁺ = 634 (MH) + = 632 (M + Na) ⁺ = 656

15. 2- [4- (N-Ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield : 53% of the theoretical yield,

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₂ H ₄₁ N ₇ O ₆ (619.72)

Mass Spectrum: (M + H) ⁺ = 620 (MH) + = 618 (M + Na) ⁺ = 642

16. 2- [4- (N-Pyridin-3-yl-carbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop- 2-yl] -benzimidazole Yield: 16% of theory,

R f value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₆ H ₄₂ N ₈ O ₅ (666.78)

Mass Spectrum: (M + H) ⁺ = 665 (M + Na) ⁺ = 689

17. 2- [4- (N-Butyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 52% of theory.

Rf value: 0.42 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₂ H ₄₃ N ₇ O ₅ (605.74)

Mass Spectrum: (M + H) ⁺ = 606 (M + Na) ⁺ = 628 (MH) + = 604

18. 2- [4- (N-Ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 30% of the theoretical yield;

Rf value: 0.44 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₀ H ₃₉ N ₇ O ₅ (577.68)

Mass Spectrum: (M + H) ⁺ = 578 (M + Na) ⁺ = 600 (MH) + = 576

19. 2- [4- (N-Benzyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 51% of theory, Yield: 0.50 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₅ H ₄₁ N ₇ O ₅ (639.75)

Mass Spectrum: (M + Na) ⁺ = 662 (MH) + = 638

20. 2- [4- (N-Pyridin-3-yl-carbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 84% of theory, Rf value: 0.20 (silica gel; ethyl acetate / ethanol = 4: 1) C ₃₃ H ₃₈ N ₈ O ₄ (610.72)

Mass Spectrum: (M + H) ⁺ = 611 (MH) - = 609 (M-HCOO) - = 611

21. 2- [4- (N-Acetoxymethyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 42% of theory, _{R f} value: 0.44 (silica gel, methylene chloride / ethanol = 9: 1) C ₃₁ H ₃₉ N ₇ O ₅ (621.09)

Mass Spectrum: (M + Na) ⁺ = 644 (MH) + = 620

22. 2- [4- (N - (2,2,2-Trichlorethyloxycarbonyl) -amino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 73% of theory, _{R f} value: 0.54 (silica gel, methylene chloride / ethanol = 9: 1) C ₃₀ H ₃₆ Cl ₃ N ₇ O ₅ (681)

Mass Spectrum: M ⁺ = 679/81/3 (Cl ₃ ) (M + Na) ⁺ = 702/4/6 (Cl ₃ ) (MH +) = 678/80/2 (Cl ₃ )

Example 18 2- [4- (N-n-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

A solution of 0.2 g (0.3 mmol) of 2- [4- (N-octyloxycarbonylamidino) -phenylamino-methyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole in 3 ml of tetrahydrofuran and 2.5 ml of ethanol was mixed with 1.1 ml of 1N sodium hydroxide solution and stirred at room temperature for 4 hours. The reaction mixture was evaporated and treated with 1 ml of 1N hydrochloric acid. After 12 hours at room temperature (pH 4), 2 drops of ammonia (33%) are added, whereupon a pale yellow precipitate precipitates. After suctioning off the solid formed, the filtrate is treated with 1 ml of 1N hydrochloric acid and evaporated with the addition of toluene. The residue is triturated with acetone, filtered off with suction, washed with diethyl ether and dried.

Yield: 0.1 g (50% of theory), _{R f} value: 0.35 (reversed phase RP 8; methanol / 5% saline solution = 2: 1)

C ₃₄ H ₄₇ N ₇ O ₅ (633.79) Mass Spectrum: (M + H) ⁺ = 634 (M + H + Na) ⁺ = 328.5

Example 19 2- [4- (N-Hydroxyamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

A suspension of 0.6 g (1.2 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole in 50 ml of ethanol was mixed with hydroxylamine hydrochloride (0.47 g, 7.8 mmol) and sodium carbonate (0.35 g, 3.5 mmol) and heated under reflux for 17 hours. After cooling, the residue was filtered off, the filtrate was evaporated and taken up in water. After extraction twice with dichloromethane, the combined organic phases are dried and evaporated. The crude product was purified on silica gel, eluting with dichloromethane / ethanol (19: 1 and 7: 1). The individual fractions were combined, evaporated, triturated with diisopropyl ether and dried. Yield: 0.025 g (4% of theory), _{R f} value: 0.68 (silica gel, methylene chloride / ethanol = 4: 1) C ₂₇ H ₃₅ N ₇ O ₄ (521.62)

Mass Spectrum: (MH +) = 520 (M + Na) ⁺ = 544

Example 20 2- [4- ^{(I '-Fenylkarbonylamidino)} -fenylaminomctyl] -l-methyl-5- [1 - (isopropyloxycarbonyl-methylamino) -1 - (pyrrolidinocarbonyl) -ethyl] -benzimidazole

a) 4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylamino-acetic acid ethyl ester

Prepared in analogy to Example 9a from 4- (5-methyl-1,2,4-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 = 1: 1)

b) 4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylaminoacetic acid

Prepared in analogy to Example 4 from 4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylamino-acetic acid ethyl ester and sodium hydroxide in ethanol.

Yield: 75% of theory, _{R f} value: 0.15 (silica gel, methylene chloride / ethanol = 9: 1)

c) 2- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- [1-amino- (pyrrolidin-1-yl-carbonyl) -ethyl ] benzimidazole

Prepared in analogy to example 1e / f from 2- (4-methylamino-3-aminophenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidin-1-yl-propanone, 4- (5-methyl-1,2,4-oxadioic acid) -zol-3-yl) -phenylamino-acetic acid and carbonyldiimidazole in tetrahydrofuran and subsequent treatment with glacial acetic acid.

Yield: 34% of theory, Rf: 0.10 (silica gel; methylene chloride / ethanol = 9: 1)

d) 2- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Prepared in analogy to Example 11 from 2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole, isopropyl bromoacetate and potassium carbonate in isopropanol / methylene chloride.

Yield: 42% of theory, Yield: 0.60 (silica gel; methylene chloride / ethanol = 9: 1)

e) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (isopropyloxycarbonyl-methyl-amino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole acetate

Prepared in analogy to Example 1d from 2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidino- carbonyl) -ethyl] -benzimidazole and hydrogen / palladium (10% on activated carbon) 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) -phenylammomethyl] -1-methyl-5- [1- (isopropyl-oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Prepared in analogy to Example 17 from 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole acetate and 4-nitrophenyl benzoate in N-ethyl -diizopropylamíne / dimethylformamide.

Yield: 26% of the theoretical yield;

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₅ H ₄₁ N ₇ O ₄ (623.75)

Mass Spectrum: (M + Na) ⁺ = 646 (MH) + = 622

In analogy to Example 20, the following compounds were prepared:

2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2-phenylethyloxycarbonylmethylamino) -1 (pyrrolidinocarbonyl) ethyl] benzimidazole

3. 2- [4- (N-n-Hexyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 40% of theory, _{R f} value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₅ H ₄₉ N ₇ O ₅ (647.82)

Mass Spectrum: (M + H) ⁺ = 648 (M-H) - = 646 (M + Na) ⁺ = 670

4. 2- [4- (N-N-octyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (isopropyl-oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 31% of theory.

_{R f} value: 0.48 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₇ H ₃₃ N ₇ 0j (675.88)

Mass Spectrum: (M + H) ⁺ = 674 (M + Na) ⁺ = 698

5. 2- [4- (N - (2,2,2-Trichlorethyloxycarbonyl) amidino) phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 43 % of the theoretical yield,

R f value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1) C ₃₁ H ₃₈ Cl ₃ N ₇ O, (695.05)

Mass Spectrum: (MH) - = 692/694/696/698 (Cl ₃ )

6. 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyl-oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 79% of the theoretical yield;

R f value: 0.35 (silica gel; ethyl acetate / ethanol = 9: 1) C ₃₅ H ₄₁ N ₇ O ₄ (623.76)

Mass Spectrum: (M + H) = 624 (M-H) = 622 (M + HCOO) = 668

7. 2- [4- (N-n-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 53% of theory,

R f value: 0.39 (silica gel; ethyl acetate / ethanol = 9: 1) C ₃₇ H ₅₃ N ₇ O ₅ (675.88)

Mass Spectrum: (M + H) ⁺ = 676 (M + Na) ⁺ = 698 (MH) + = 674

Example 21

(R) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidino-carbonyl) -ethyl] -benzimidazole hydrochloride

a) 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid ethyl ester

A mixture of 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid (28 g, 0.11 mol) in 200 ml of 5.6N ethanolic hydrochloric acid was heated under reflux for 36 hours. After evaporation of the solvent, the residue is taken up in 300 ml of ethyl acetate and mixed with 300 ml of saturated sodium bicarbonate solution. The organic phase is washed twice with saturated sodium bicarbonate solution and once with water, dried over sodium sulphate and evaporated.

(b) (R) - (+) - 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid ethyl ester

17.33 g (63.6 mmol) of 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid ethyl ester are dissolved in 247 ml of isopropanol and 207 ml of methanol and mixed with 9.54 g ( 63.6 mmol) of (L) - (+) - tartaric acid. The reaction mixture was heated to 100 ° C to give a clear solution. The solution is cooled to 27 ° C over 3 hours, the precipitate formed is filtered off with suction, washed with ethanol and dried. Subsequently, the solid formed (21.5 g) was dissolved in 400 ml of ethyl acetate and treated with 400 ml of saturated sodium bicarbonate solution. After extraction and phase separation, the organic phase is washed with water, dried and evaporated.

Yield: 7.68 g (44.4% of theory) of a pale yellow oil, [.alpha.] D @ ²⁰ = + 4.38 DEG (ethyl acetate) HPLC analysis: ee-value> 98.6%

(c) (R) - (-) - 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid

Prepared in analogy to Example 4 from (R) - (+) - 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid ethyl ester and sodium hydroxide in tetrahydrofuran.

Yield: 63% of theory, [.alpha.] D @ ²⁰ = - 59.6 DEG (methanol / water 1: 1)

(d) (R) -2-tert-Butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid

Prepared in analogy to Example 5d from (R) - (-) - 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid and di-tert-butyl-bicarbonate and triethylamine in dioxane.

Yield: 100% of theory.

(e) (R) -2-tert-Butyloxycarbonylamino-2- (4-methylamino-3-nitrophenyl) propionic acid

Prepared in analogy to Example 1b from (R) -2-tert-butyloxycarbonyl-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid and methylamine.

Yield: 69% of theory.

f) (R) -2- (4-Methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone

Prepared in analogy to Example 1c from (R) -2- tert -butyloxycarbonylamino-2- (4-methylamino-3-nitro-phenyl) -propionic acid, pyrrolidine and carbonyldiimidazole in tetrahydrofuran.

Yield: 96% of theory.

g) (R) -2- (4-Methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone

Prepared in analogy to Example lez (R) -2- (4-methylamino-3-nitro-phenyl) -2- tert -butyloxycarbonylamino-1-pyrrolidino-propanone and hydrogen / palladium on activated carbon in methanol.

Yield: 99% of theory.

h) (R) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Prepared in analogy to Example 1c / 1f from (R) -2- (4-methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidinopropanone, 4-cyanophenylglycine, carbonyldiimidazole in tetrahydrofuran and subsequent ring closure in ice acetic acid. Yield: 100% of theory.

(i) (R) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Prepared in analogy to Example 6i from (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and 6N hydrochloric acid in dioxane.

Yield: 76%.

k) (R) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Prepared in analogy to Example 6k from (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole and ethyl iodoacetate / potassium carbonate in acetone. Yield: 75% of theory.

(l) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride

Prepared in analogy to Example 1 g of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol . Yield: 95% of theory.

(m) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride

Prepared in analogy to Example 4 from (K) -2- (4-amidinophenylammomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and sodium hydroxide in ethanol.

Yield: 100% of theory.

C ₂₅ H ₃₁ N ₇ O ₃ x HCl (477.57 / 550.5)

Mass Spectrum: (M + H) ⁺ = 478 (M-H + HCl) = 512/514 (Cl) (M-H + 2HCl) - = 448/550/552 (Cl ₂ )

Example 22

Dry ampoule with 75 mg of active substance per 10 ml

Ingredients:

Active Substance 75.0mg

Manitol 50,0mg

Water for injections ad 10.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. Dissolve to a ready-to-use solution with water for injection purposes.

Example 23

Dry ampoule with 35 mg of active substance per 2 ml

Ingredients:

Active Substance 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. Dissolve to a ready-to-use solution with water for injection purposes.

Example 24

Tablet with 50 mg of the active substance

Ingredients:

First Active substance 50.0 mg Second Milk sugar 98.0 mg Third Maize starch 50.0 mg 4th polyvinylpyrrolidone 15.0 mg 5th Magnesium stearate 2.0 mg 215.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dry granulate is admixed with (5). Tablets are compressed from this mixture, bilaterally planar and with a bevel veneer and a one-sided slit. Tablet diameter: 9 mm.

Example 25

Tablet with 350 mg of the active substance

Ingredients:

First Active substance 350.0 mg Second Milk sugar 136.0 mg Third Maize starch 80.0 mg 4th polyvinylpyrrolidone 30.0 mg 5th Magnesium stearate 4.0 mg 600.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dry granulate is admixed with (5). Tablets are compressed from this mixture, bilaterally planar and with a bevel veneer and a one-sided slit.

Tablet diameter: 12 mm.

Example 26 Capsules containing 50 mg of the active substance Ingredients: 1. Active substance 50.0 mg 2. Dried corn starch 58.0 mg 3. Milk sugar powder 50.0 mg 4. Magnesium stearate 2.0 mg 160.0 mg

Preparation:

(1) is rubbed with (3). This ground material is added with vigorous stirring to mixtures (2) and (4). This powder mixture is filled on a capsule filling machine into hard gelatine insert capsules, size 3.

Example 27

Capsules with 350 mg of the active substance

Ingredients:

First Active substance 350.0 mg Second Corn starch, dried 46.0 mg Third Powdered milk sugar 30.0 mg 4th Magnesium stearate 4.0 mg 430.0 mg

Preparation:

(1) is rubbed with (3). This triturated material is added under vigorous stirring to mixtures (2) and (4). This powder mixture is filled on a capsule filling machine into hard gelatine insert capsules, size 0.

Example 28

Suppositories with 100 mg of the active ingredient suppository contains:

Active Substance 100.0mg

Polyethylene glycol (molecular weight 1,500) 600.0mg

Polyethylene glycol (MW 6,000) 460.0mg

Polyethylene sorbitan monostearate 840.0mg

000.0 mg

Preparation:

The polyethylene glycol is melted together with the polyethylene sorbitan monostearate. At 40 ° C, the milled active ingredient is dispersed homogeneously in the melt. Cool to 38 ° C and pour into slightly pre-cooled suppository forms.

Claims (12)

PATENT CLAIMS 1. Benzimidazoles of formula (I) Where R is Ar is a phenylene or naphthylene group, optionally substituted with a fluorine, chlorine or bromine atom, trifluoromethyl, C 1-3 -alkyl or C 1-6 alkyl. _{A 3-} alkoxy, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted with a C 1 -C 1 carbon skeleton. _3- alkyl. AC |. _3- alkylene, B an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C 1-6 alkyl group, which may be mono- or disubstituted by a carboxy group, R ^a represents R 1 -CO-C 1-6 -cycloalkyl wherein ^R1 is _B3 C -alkoxy, amino, C _{first 4} -alkylamino or di- (C _M alkyl) amino group in which each alkyl may be substituted with carboxy, A 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group, which may be substituted with one or two C 1. ₃ -alkyl, wherein the alkyl substituent may simultaneously be substituted by hydroxy, C _b3 -alkoxy, carboxy, carboxy-C _b3 -alkoxy, carboxy-C |. ₃ -alkylamino, ^A, - _{(C1. 3} alkyl) -N- (carboxy-C |. ₃ alkyl) amino, carboxy-Cu-alkylaminocarbonyl, N- (C]. ₃ alkyl) -. 'N- (carboxy-C _1.> - alkyl) aminocarbonyl-, karboxy' -C ₁₃ alkylaminocarbonylamino, 1 - (Ci.a -alkyl is-S-tkarboxyChí -alkyl is aminokarbonylamino--3- (C |. ₃ -alkyl) -3- _{(carboxy-C1. 3} alkyl) aminocarbonyl-amino or di-SS-alkyl is jCi.j fkarboxy-CH-alkyl) aminocarbonylamino-alkyl, hydroxy-substituted 4- a 7-membered cycloalkylenimino group, A 5- to 7-membered cykloalkyléniminoskupinu an unsubstituted _B3 -alkyl, which is connected to two adjacent carbon atoms a fused phenyl ring, morpholino, piperazino, N- (C _{first 3} alkyl) -piperazino-, pyrolino-, 3 , 4-dehydro-piperidino- or pyrrol-1-yl, R ² -CX-C ₃ . _5- cycloalkyl wherein: R ² is phenyl, naphthyl or a monocyclic 5- or 6-membered heteroaryl group optionally substituted with C _{1st 3} -alkyl, 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 Cu alkyl, O, S, NH, or an optionally substituted C |. _{The 3-} alkyl group and the oxygen or sulfur atom, or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted by carboxy-, carboxy-C 1. _3- alkoxy-, carboxy-C 1-6 alkyl; Alkylamino- or _3, N- _{(C]. 3} alkyl) carboxy-C. _1- alkylamino, and X represents an oxygen atom; ₃ -alkylimino-, C _b3 -alkoxyimino-, CJJ-alkyl-hydrazino, di-IC -alkylj-hydrazino, C ^ -alkanoylhydrazino- _2, N- (C t _ ₃ -alkyl) -C _{second 4} -alkanoylhydrazino- or C _b3 alkylidene group which each of the alkyl or alkanoyl and the alkanoyl and the alkyl may be substituted by carboxy, an imidazole or an imidazolone-substituted C _b3 -alkyl- or C _{3. A 5-} cycloalkyl group in which the imidazole ring may be substituted by a phenyl or carboxy group and one or two C 1-6 alkyl groups, or one, two or three C 1-6 groups. ₃ -alkyl, the substituents can be the same or different and one of the previously mentioned alkyl substituents may simultaneously be substituted by carboxyl group or in the 2 or 3 amino, C _{2nd 4} -alkanoylamino-, C ^ -alkylamino, N- _{(C2. 4} -alkanoyl) -C |. _{The 3-} alkylamino- or di- (C _1-3 -alkyl) amino group, and the imidazolone ring may be substituted by a C ₁₃ -alkyl group, wherein the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position of the amino-, C ₂ -alkyl. _4- alkanoylamino-, C 1-6 -alkanoylamino-; ₃ alkylamino-, TV- _{(C2. 4} -alkanoyl) -C |. _3- alkylamino- or di- (C _1-3 -alkyl) -amino, and in addition to the aforementioned imidazole and imidazolone ring, a phenyl or pyridine ring, imidazolidine-2,4-dione-5-, may be fused via two adjacent carbon atoms. a yl group which may be substituted by one or two C 1-6 groups. _3- alkyl, wherein at the same time one alkyl substituent may be substituted by carboxy, C 1-6 -alkyl which is substituted C 1-6 -alkyl-Y'-C 1-6 -alkyl-, HOOC-C ₁ . _3- alkyl-Y ¹ -C 1-3 -alkyl-, tetrazolyl-C 1-6 -alkyl-Y ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C 1. _3- alkyl and isoxazolidinylcarbonyl optionally substituted with C ₁ . _3- alkyl, pyrolinocarbonyl-, 3,4-dehydropiperidinocarbonyl-, pyrrol-1-ylcarbonylcarboxy-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) aminocarbonyl- or 4- to 7 a membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkyleneimine moiety may be substituted by one or two C 1-6 -alkyleneimino-carbonyl groups. _3-alkyl groups and at the same time can be alkyl or alkyl substituent of the aforementioned C | _, - alkylaminocarbonyl, di- (C _{first 3} -alkyl) aminocarbonyl- and cykloalkyléniminokarbonylových group substituted by carboxy, and the remaining hydrogen atoms of C | _ ₄ -alkyl they may be wholly or partially replaced by fluorine atoms in which R ³ is H or C _b3 -alkyl optionally substituted by carboxy, and R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ¹ -C 1. _3-alkyl-Y ² -, carboxy-C1., - ^alkyl-Y-I -Ci.3 alkyl-Y ² -, C ₃ -alkyl-Y ² -, or carboxy-Cj_3 alkyl-Y ² -group or R ³ and R ⁴ together with the intervening nitrogen atom represent a 4- to 7-membered cycloalkyleneimino group optionally substituted by carboxy-, C 1-6 -alkyl. _3- alkyl- or carboxyC1. _3- alkyl; Y ¹ represents a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfmyl, sulfonyl, -NH-, -NH-CO- or -NII-CO-NH-group and Y ² represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO-group, wherein the carbonyl group of the -NH-CO-group is bonded to the nitrogen atom of the R ³ NR ⁴ -groups and the imino groups which occur in the definition the radicals Y ¹ and Y ² may each additionally be substituted by a C ^ alkyl- or carboxy-Ci.3 alkyl, NR ⁶ R ⁵ group joining substituted C | _3-alkyl or C _{3. 5-} cycloalkyl wherein: R ⁵ represents a hydrogen atom, C ₁ . ₃ alkyl-, _C5-.7 cycloalkyl, phenylcarbonyl-, phenyl-sulfonyl, or pyridinyl, and R ⁶ represents C 1-6 -alkyl-, carboxy-C _1-4 -alkyl- or carboxy-C _1-4 . ₃ -alkylcarbonyl, C ₁ . ₃ -alkyl, substituted C _{2nd 4} or C ₅ -alkanoyl- _7 -cycloalkyl-C noylskupinou a _{first 3} -alkyl substituted by Cl, Br or I, R ^b is H or C. _3- alkyl; and R ^c represents a cyano or amidino group optionally substituted by one or two C 1-6 -alkyl groups, wherein the carboxy groups mentioned in the definitions of said groups may be replaced by a group which may be converted in vivo to a carboxy group or a group negatively charged under physiological conditions; the imino groups mentioned in the definitions of said groups may also be substituted with a residue that is cleaved in vivo, where a hydroxymethyl group may be defined below a group that can be converted in vivo to a carboxy group, a carboxyl group esterified with an alcohol, wherein the alcohol group is preferably C 1. ₆ -alkanol, phenyl-Ci. ₃ alkanol, C ₃ . ₉ -cycloalkanol, wherein C ₅ . _{The 8-} cycloalkanol may additionally be substituted with one or two C 1-6 -alkyl groups, C _5-6 . ₈ -cycioalkanol in which the methylene group at the 3 or 4 position is replaced by an oxygen atom or an amino group optionally substituted by C 1-6 alkyl, phenyl-C 1-6. _3- alkyl, phenyl-C 1. ₃ -alkoxycarbonyl or C _{2nd The 6-} alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C _1-6 groups. _3- alkyl, C ₄ . ₇ -cycloalkenyl, C ₅ -alkenes _{3, phenyl-C? 5} -alkenol, C ₃ . ₅ -alkinol or phenyl-C _{3. 5-} alkinol with the proviso that there is no bond to the oxygen atom from a carbon atom having a double or triple bond, C 1-4 -cycloalkyl-C 1-4 -alkanol, bicycloalkanol having 8 to 10 carbon atoms in total, which may additionally be substituted in the bicycloalkyl moiety one or two C | _3- alkyl, 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula R ^d -CO-O- (R ^e CR ^f ) -OH in which R ^d is C _ls -alkyl-, C _{5. A 7-} cycloalkyl-, phenyl- or phenyl-C 1-6 -alkyl group, R ^e represents a hydrogen atom, C 1-6 -alkyl-, C ₅ . ₇ -cycloalkyl- or phenyl; and R ^f is hydrogen or C 13 -alkyl, the group which is negatively charged under physiological conditions can be tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C _1-6 -alkyl; _C 1-6 alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C 1-6 alkylsulfonylamino; _6- alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoro-C _1-6 alkylsulfonylaminocarbonyl; _{The 6-} alkylsulfonylaminocarbonyl group, and the residue which may be cleaved from the imino or amino group in vivo, may be a hydroxy group, an acyl group such as a benzoyl group optionally mono- or disubstituted with fluorine, chlorine, bromine or iodine atoms, Cj. _3- alkyl or C 1-6 alkyl. _3- alkoxy, wherein the substituents may be the same or different, pyridinoyl or C 1-6 -alkoxy; ₍₁₎ -alkanoyl, such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl, 3,3,3-trichloropropionyl or allyloxycarbonyl; ( _{l )} -alkoxycarbonyl or C1. ₁₆ alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partly replaced by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-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, dodecylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy, dodecylcarbonyloxy, dodecylcarbonyloxy, dodecylcarbonyloxy, dodecylcarbonyloxy, dodecylcarbonyloxy; _6- alkoxycarbonyl, such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl, 3-aminopropionyl, in which the amino group may be mono- or disubstituted (C _1-6 -alkyl or C ₇ -cycloalkyl and the substituents may be the same or different, C |. ₃ -C 2 -alkylsulfonyl. ₄ -alkoxycarbonyl, C |. _{3 -alkoxy-C2. 4-alkoxy-C2-4-alkoxycarbonyl,} R ^d-CO-O- (R ^d CR ^f) -O-CO- , Cw-alkyl-CO-NH- (R ^g CR ^h) -O-CO- or alkyl-Cb6-CO-O- (R ^g CR ^h) - (R ^g CR ^h) -O-CO- group in wherein R ^d and R ^f are as defined above, R ^g and R ^h , which may be the same or different, represent hydrogen atoms or C _1-3 -alkyl groups, their tautomers, their stereoisomers, mixtures thereof, and salts thereof. 2. Benzimidazoles of formula (Ia) (.3). R 'in which A represents a C _1-3 -alkylene group, B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C 1-4 alkyl group in which the alkyl moiety may be mono- or disubstituted by carboxy, R ^a represents R ¹ -CO-C _3-5 -cycloalkyl wherein: ^R1 is C |. ₃ -alkoxy, amino, C _b4 -aJkylamino- or di- (Cj_ ₄ -alkyl) amino group in which each alkyl may be substituted with carboxy, A 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted with one or two C 1-6 alkyl groups. ₃ -alkyl, wherein one alkyl substituent may simultaneously be substituted by hydroxy, C _b3 -alkoxy, carboxy, carboxy-C _b3 -alkoxy, carboxy-C _b3 alkylamino-, LV- (C _b3 alkyl) - / in - ('carboxy-C _1-3 -alkyl) -amino-, carboxy-C 1-6 -alkyl; ₃ alkylaminocarbonyl,, N- (C | _, - Alkyl) - N- (carboxy-C _l3 -alkyl) aminocarbonyl-, carboxy-C ^ alkylaminocarbonylamino, 1 - (C ₁ _ _J -alkyl) 3- (carboxy-C_ ₃ -alkyl) aminokarbonylamino-, 3- _{(C]. 3} -alkyl) -3- (carboxy-C |. ₃ alkyl) aminocarbonyl-amino or 1,3-di- (C 1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) aminocarbonylamino, a hydroxy substituted 4- to 7-membered cycloalkyleneimino group, A 5- to 7-membered cykloalkyléniminoskupinu an unsubstituted | .3-alkyl, which is connected to two adjacent carbon atoms a fused phenyl ring, morpholino, piperazino, N- (C _t _ ₃ alkyl) -piperazino-, pyrolino- , 3,4-dehydro-piperidino- or pyrrol-1-yl, R ² -CX-C ₃ . _5- cycloalkyl wherein: R ² represents a phenyl, naphthyl or monocyclic 5 or 6-membered heteroaryl group optionally substituted with C 1-6. _{A 3-} alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an amino group optionally substituted with C ₁ . _{A 3-} alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted with a C 1-6 alkyl group; _{The 3-} alkyl group and the oxygen or sulfur atom, or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted by carboxy-, carboxy-C 1-6 -alkyl. _3- alkoxy-, carboxy-C 1-6 alkyl; ₃ alkylamino- or N- (C _{first 3} alkyl) carboxy-C _{first 3-} alkylamino, and X is O, C _{first 3} -alkylimino-, _b3 -alkoxyimino- C, C ₃ alkyl-hydrazino, di-JCU-hydrazino -alkyl is C _{2nd 4-} alkanoylhydrazino-, X- (C _1-3 -alkyl) -C ₂ . _4- alkanoylhydrazino- or C 1-6 -alkanoylhydrazino-; ₃ alkylidene group which each of the alkyl or alkanoyl and the alkanoyl and the alkyl may be substituted by carboxy, an imidazole or an imidazolone-substituted C _b3 -alkyl- or C _{3. 5} cycloalkyl group, wherein the imidazole ring is substituted by a phenyl or carboxy group and by one or two C _b3-alkyl groups or by one, two or three C _b3 -alkyl, the substituents can be the same or different and one of the previously mentioned alkyl substituents may simultaneously be a substituted carboxyl group or in the 2 or 3 amino, C ₂₄ -alkanoylamino-, C ₃ -alkylamino,? (C-i-alkanoylj-Cu-alkylamino or di- (C _b3 alkyl) amino, and imidazolone ring may be substituted by Ci. ₃ -alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C _{2. 4} -alkanoylamino-, C ₁₃ alkylamino-,, N _{(C. 4} alkanoyl ) C |. ₃ -alkylamino or di- _{(C1. 3} alkyl) amino, and in addition to the previously mentioned imidazole and imidazolone ring is via two adjacent carbon atoms a fused phenyl ring or a pyridine, imidazolidine-2,4- di on-5-yl group which may be substituted by one or two wire-alkyl groups, while simultaneously an alkyl substituent may be one substituted with carboxy, C _B4 -alkyl, substituted C _{first 3} -alkyl-Y ¹ -C 1-3 -alkyl-, HOOC-C, .3-alkyl-Y'-C i-j-alkyl, tetrazolyl-C), 3-alkyl-Y ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C 1. _3- alkyl and isoxazolidin-1-ylcarbonyl optionally substituted with C 1-6 alkyl; _3- alkyl, pyrolinocarbonyl-, 2,3-dehydro-piperidinocarbonyl-, pyrrol-1-yl-carbonyl-, carboxy-, aminocarbonyl-, C 1-6 -alkyl; _3- alkylaminocarbonyl-, di- (C1-C4-alkyl) -aminocarbonyl- or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkyleneimine moiety may be substituted by one or two C1-7. _3-alkyl groups and at the same time can be alkyl or alkyl substituent, the aforementioned C. _3- alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl- or cycloalkyleneiminocarbonyl substituted with carboxy and the remaining hydrogen atoms of C 1-6; _{The 4-} alkyl groups may be wholly or partially replaced by the fluorine atoms in which the R ³ represents a hydrogen atom or a C _1-3 -alkyl group optionally substituted by a carboxy group a R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ¹ -Cl 3 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ -C 1. _3-alkyl-Y ² -, C-alkyl-Y ² -, or carboxy-C ₃ _ ₃ -alkyl-Y ² -group or R ³ and R ⁴ together with the nitrogen atom they are lying 4- to 7-membered optionally substituted cykloalkyléniminoskupinu carboxy, C alkyl- or carboxyC _{c3 <3} -alkyl, in which Y ¹ represents a carbon-carbon bond, an oxygen atom, a sulfenyl-, a sulfrnyl-, a sulfonyl-, -NH-, -NH-CO- or -NH-CO-NH- group and Y ² represents a carbon-nitrogen bond or a carbonyl-, sulfonyl-, imino- or -NH-CO-group, wherein the carbonyl group of the -NH-CO-group is bonded to the nitrogen atom of the R ³ NR ⁴ group and in the definition of Y ¹ and Y ² occurring imino groups may each additionally substituted by C _{first 3} -alkyl or carboxy-C 1-6 alkyl, R ⁵ NR ⁶ -substituted with C ₁ . _3- alkyl- or C ₃ . _5- cycloalkyl wherein: R ⁵ represents a hydrogen atom; _3- alkyl-, C ₃ . ₇ -cycloalkyl-, phenylcarbonyl-, phenylsulfonyl- or pyridinyl; and R ⁶ is Cf ^ alkyl-, carboxy-C _c3 alkyl- or carboxy-C j. ₃ -alkylcarbonyl, C _B3 -alkyl, substituted C _{2nd 4} -alkanoyl- or C ₅ . ₇ cyclo alkanoyl group and C _b3 -alkyl substituted by Cl, Br or I, R ^b is H or alkyl, and Cb3-R ^c represents a cyano or amidino, which is optionally substituted by hydroxy, one or two C |. 3-alkyl groups, one or two C _bs -alkoxycarbonyl, wherein the definition of the aforementioned radicals mentioned carboxy, amino and imino groups may also be substituted by an in vivo cleavable radical according to claim 1, the tautomers, stereoisomers and salts thereof. The benzimidazoles of formula (Ia) according to claim 2, wherein A represents a C _b3 -alkylene group, B is an oxygen atom, a methylene, imino- or N - (C _1-3 -alkyl) amino group in which the alkyl moiety may be substituted by a carboxy group, R ^a represents the 1-position of R 1 -CO- by a radical substituted with C ₃ . _5- cycloalkyl wherein: ^R1 is Cj. ₃ -alkoxy, amino, C _l4 alkylamino- or di- (C ₁ _ ₄ alkyl) amino group in which each alkyl may be substituted with carboxy, A 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group with one or two or two C1-C1 groups. _3- alkyl groups, wherein one alkyl substituent may be simultaneously substituted with hydroxy-, C1-alkyl. ₃ -alkoxy, carboxy, carboxy-C _b3 -alkoxy, carboxy-C. _3- alkylamino-, N '- (C _1-3 -alkyl) - N' - (carboxy-C _1-3 -alkyl) -amino-, carboxy-C _1-3 -alkylaminocarbonyl-, N - (C _1-3 -alkyl) -A- (carboxy-C _1-3 -alkyl) -amino-carbonyl-, carboxy-C ₁ . ₃ -alkylaminocarbonylamino-, 1 - (C |. ₃ -alkyl) -3- (carboxy-C _{1. 3} alkyl) -aminokarbonylamino-, 3- (C | _ ₃ -alkyl) -3- (carboxy-C _B3 -alkyl-1-amino-carbonyl-amino- or 1S-di- (C 1-6 -alkyl) - (S -carboxy-C 1-6 -alkyl) aminocarbonylamino-group, A 5- to 7-membered cycloalkylene-C = NH optionally substituted -alkyl _b3 to which the via two adjacent carbon atoms a fused phenyl ring, morpholino, piperazino, Y- (C _{first 3} alkyl) -piperazino-, pyrolino- 3,4-dehydro-piperidino- or pyrrol-1-yl-group, in the 1-position of R ² -CX- is substituted by C ₃ . _5- cycloalkyl wherein: R ² represents a phenyl, naphthyl or monocyclic 5 or 6-membered heteroaryl group optionally substituted with a C 1-6 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 with C 1-6. ₃ -alkyl, O, S or NH _b3 an unsubstituted alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the previously mentioned alkyl substituent may be substituted by carboxy, carboxy-C _b3 -alkoxy, carboxy-C. ₃ alkylamino- or cis- _{(C. 3} alkyl) carboxy-C |.? - alkylamino, and X represents an oxygen atom, C1-6. _3- alkylimino-, C 1-6 -alkoxyimino- or C 1. ₃ alkylidene group which each of the alkyl or alkoxy portion may be substituted by carboxy, in the 1-imidazole or imidazolone-substituted C _{first 3-} alkyl wherein the imidazole ring may be substituted by phenyl or carboxy and one or two C 1-6 -alkyl or one, two or three C 1-6 -alkyl groups, wherein the substituents may be the same or different and one of the aforementioned alkyl substituents may be simultaneously substituted by carboxy group joining or in the 2 or 3 amino, C _{2nd 4} -alkanoylamino-, C ^ -alkylamino, N- _{(C2. 4} -alkanoyl) -C. ₃ -alkylamino or di- (C _b3 alkyl) amino, and the imidazolone ring may be substituted by C _B3 -alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C _{2nd 4-} alkanoylamino-, Ci. ₃ alkylamino-, TV- (C _{2nd 4} -alkanoyl) -C _b3 alkylamino- or di-jCj.j alkyljaminoskupinou, in addition to the previously mentioned imidazole and imidazolone ring is via two adjacent carbon atoms a fused phenyl or pyridine a ring, an imidazolidin-2,4-dione-5-yl group which may be substituted with one or two C 1-6 rings. _3- alkyl, wherein at the same time one alkyl substituent may be substituted by carboxy, C1-alkyl. _{A 4-} alkyl group which is substituted at the 1-position R ³ NR ⁴ - or R ³ NR ⁴ -Ci_ pyrolinokarbonyl- ₃ -alkyl, and, 2,3-dehydro-piperidinocarbonyl-, imidazol-l-yl-carbonyl, carboxy, aminocarbonyl, C _b3 alkylaminocarbonyl, di - (C _1-3 -alkyl) -aminocarbonyl-, isoxazolidin-1-yl-carbonyl- or a 4- to 7-membered cycloalkyleneiminocarbonyl group, in which case the cycloalkyleneimine moiety may be substituted by one or two C 1-6 alkyl groups and at the same time may always be one alkyl moiety or alkyl substituent of the aforementioned C 1. _3- alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-carbonyl- or cycloalkylene-iminocarbonyl substituted by carboxy and the remaining hydrogen atoms of the C _1-4 -alkyl group may be wholly or partially replaced by fluorine atoms in which R ³ represents a hydrogen atom or a C 1-6 alkyl group optionally substituted by carboxy group a R ⁴ is H, Cb3-alkyl-Y ² - or karboxyCi.3 alkyl-Y ² -group or R ³ and R ⁴ together with the intervening nitrogen atom represent a 4- to 7-membered cycloalkyleneimino group optionally substituted at the 1-position of carboxy-, C 1-6 -alkyl. _3- alkyl- or carboxy-C 1-6 alkyl; _3- alkyl; Y ² represents a carbon-nitrogen bond or a carbonyl-, imino or -NH-CO-group, wherein the carbonyl group -NHCO-group is bonded to the nitrogen atom of the R ³ NR ⁴ -group and in the definition of the Y ² residue the amino group may additionally be substituted by C _{β 3} -alkyl- or carboxy-C _1-6 alkyl; _3- alkyl, in the 1-position of R ⁵ NR ⁶ -substituted with C ^1-6 -alkyl; _3- alkyl- or C ₃ . _5- cycloalkyl wherein: R ⁵ represents a hydrogen atom, C 1-6 -alkyl-, C ₅ . ₇ -cycloalkyl-, phenylcarbonyl-, phenylsulfonyl- or pyridinyl; and R ⁶ represents C 13 -alkyl-, carboxy-C _1-4 -alkyl- or carboxy-C 1-4. ₃ -alkylcarbonyl, C. ₃ -alk_vlskupinu substituted C _{2nd 4-} alkanoyl or C _5-7 -cycloalkanoyl; ₃ -alkyl substituted by Cl, Br or I, R ^b is C |. _3- alkyl; and R 1 is an amidino group optionally substituted with 2,2,2-trichloroethoxycarbonyl, C 1-8 alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl, wherein the benzoyl moiety may be mono- or disubstituted with fluorine, chlorine, bromine or iodine atoms _{; <C} i-j-alkyl or alkoxy groups and the substituents may be the same or different, the C _b3 -alkanolcstery. their tautomers, their stereoisomers and their salts. The benzimidazoles of formula (Ia) according to claim 2, wherein A represents a methylene group, B an oxygen atom or an imino group, R ^a represents in the 1-position R'-CO- a radically substituted cyclopropyl group in which R ¹ represents a pyrrolidino- or piperidino group optionally substituted by a methyl or ethyl group, in which the methyl or ethyl moiety may in each case be substituted by carboxy-, carboxy-C 1-6. _3- alkoxy, carboxy-C _b3 -alkylamino- or N - (C 1-6 -alkyl) -carboxy- C 1-6 -alkylamino, in the 1-position of R ² -CX- with a radically substituted cyclopropyl group in which: R ² represents a phenyl, pyridyl or pyrazolyl group optionally substituted with a C 1-6 alkyl group and X is oxygen, C 1 -alkoxyimino or C 1-6. ₃ alkylidene group, as each of the alkyl or alkoxy moieties substituted with carboxy, in the 1-substituted imidazole of the C _{b 2} -alkyl, in which the imidazole ring may be substituted by a phenyl or carboxy group and one or two C _{first 3-alkyl} groups or by one, two or three C .j-alkyl groups, wherein the substituents are the same or different and one of the previously mentioned alkyl substituents may simultaneously be substituted by a carboxy group or in the 2 or 3 amino, C _{2nd 4} -alkanoylamino-, C _{first 3} alkylamino-, TV- (C _{2nd 4} -alkanoyl) -C _{first A 3-} alkylamino- or di- (C _1-3 -alkyl) -amino group, wherein in addition to the above imidazole rings, a phenyl or pyridine ring substituted in the 1-position by a benzimidazolon-1-yl-substituted C group can be fused via two adjacent carbon atoms ). _{The 2-} alkyl group, wherein the imidazolone ring may be substituted with a methyl or ethyl group optionally substituted with a carboxy group, a methyl or ethyl group which may be substituted in the 1-position R ³ NR ⁴ - or R ³ NR ⁴ -C ₁ . _{A 3-} alkyl group and a di-N, N-alkyl-aminocarbonyl, isoxazolidin-1-yl-carbonyl, pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted with a C 1-6 alkyl group; _{A 3-} alkyl group, in which case the alkyl moiety or alkyl substituent may in each case be substituted by a carboxy group in which they represent R ³ is a hydrogen atom or a C 1-6 -alkyl group optionally substituted with a carboxy group a R ⁴ is H, C | .3 alkyl-Y ² -, or carboxy-C | _3-alkyl-Y ² -group or R ³ and R ⁴ together with the intervening nitrogen atom a 4- to 7-membered cycloalkyleneimino group optionally substituted by carboxy, in which: Y ² represents a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted with C ₁ . _3- alkyl, in the 1-position of R ⁵ NR ^{with a} substituted-C _1-2 -alkyl group in which they represent R ^{5 is} pyridinyl, phenylcarbonyl or phenylsulfonyl; and R ^{6 is} C 1-3 -alkyl or carboxy-C 1-4 -alkyl, in the 3-position of the chlorine-substituted n-propyl group which is substituted in the 1-position by a cyclopentylcarbonyl group, in the 1-position a cyclopentylamino substituted cyclopropyl group -C 1-4 alkylcarbonyl, R ^b represents a methyl group a R ^{c is an} amidino group optionally substituted with C 1-6. ₈ alkoxycarbonyl-, acetoxymetyloxykarbonyl-, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl, C _b3 -alkanolestery thereof, the tautomers, stereoisomers and salts thereof. The benzimidazoles of formula (Ia) according to claim 2, wherein A represents a methylene group, B imino, R ^a represents a 1-position in the R 1 -CO- radical substituted cyclopropyl group in which R ¹ represents a pyrrolidino- or piperidino group optionally substituted by a methyl or ethyl group, in which the methyl or ethyl moiety may in each case be substituted by carboxy-, carboxy-C ₁ . _3- Alkoxy-, carboxy-C1-4 -alkyl. ₃ -alkylamino and / or N- _{(C1. 3} alkyl) carboxy-C _l., - alkyl amino, R 1 at position ² --CX-- substituted cyclopropyl moiety, wherein R ² is phenyl, pyridyl or pyrazolyl group optionally substituted with C ,. _3- alkyl; and X is oxygen; -Alkoxyimino- _3-wire or alkylidene group, as each of the alkyl or alkoxy moieties substituted with carboxy, in the 1-substituted imidazole of the C _{b 2} -alkyl, in which the imidazole ring may be substituted by 1 to 3 methyl groups, or substituted with two methyl groups and one ethyl group, wherein in addition one of the aforementioned methyl or ethyl substituents may be simultaneously substituted by a carboxy, methyl or ethyl group which may be substituted in the 1-position R ³ NR ⁴ - or R ³ NR ⁴ -CH ₂ - group and a di _{(C1. 3} alkyl) -aminokarbonylovou group, a pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted with C |. _3- alkyl, wherein in the above-mentioned groups the alkyl moiety or alkyl substituent may in each case be substituted by a carboxy group in which they represent R ³ is hydrogen or C ₁ . _{A 3-} alkyl group optionally substituted with a carboxy group; and R ^{4 is} C 1-3 -alkyl-Y ² - or carboxy-C ₁ . _3- alkyl-Y ² -group in which Y ² represents a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted with a C 1-4 -alkyl group, R ^b represents a methyl group a R ^{c is an} amido group optionally substituted with C 1-6 alkyl; _8- alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl, their C. ₃ -alkanol esters, their tautomers, their stereoisomers and their salts. The benzimidazoles of formula (I) according to at least one of claims 1 to 5, wherein the radical R ^a is in the 5-position, their tautomers, their stereoisomers and their salts. 7. The following compounds of formula (Ia) (a) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] benzimidazole; (b) (E7Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] -benzimidazole, c) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1H-2-yl] -2- (4-amidinophenylaminomethyl) -1-methyl-5- - (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole, (d) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) pyrrolidin-1-ylcarbonyl] cyclopropyl] benzimidazole; (e) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole; f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole and (g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonyl-aminomethyl) -1-methyl-1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole, as well as their C 1-4 -alkanol esters, their N (C 1-8 -alkoxycarbonyl) -, N -benzyloxycarbonyl- and N -benzoylamides, their tautomers, their stereoisomers and their salts. 8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole, its N-alkanol esters and their AJCs.g (alkoxycarbonyl) -, N -benzyloxycarbonyl- and N'-benzoylamidines, their tautomers, stereoisomers and salts thereof. Physiologically acceptable salts of the compounds according to claims 1 to 8, wherein R ^c is one of the amidino groups mentioned in claims 1 to 8. Process for the preparation of benzimidazoles according to claims 1 to 9, characterized in that (a) for the preparation of a benzimidazole of the general formula (I) in which R ^c represents a cyano group, a compound of the general formula (II) optionally formed in the reaction mixture R ”in which R ^a , R ^b , Ar, A and B are as defined in claims 1 to 8, Z ¹ and Z ² , which may be the same or different, represent amino, hydroxy or mercapto groups optionally substituted with C 1 -C 6 alkyl groups, or Z ¹ and Z ² together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy- or alkylenedithio-group having in each case 2 or 3 carbon atoms, cyclizes or b) for the preparation of a benzimidazole of formula (I) wherein R ^a is R ² -CX'-C ₃ . _{A 5-} cycloalkylene group wherein R ² is as defined in claims 1 to 8 and X 'is one of the imino radicals mentioned in claims 1 to 8 for X, a compound of formula (IV) R ”in which R ^b , R ^c , Ar, A and B are as defined in claims 1 to 8 a R ^a 'represents R ² -CO-C ₃ . ₅ -cycloalkylene group, wherein ^R2 is defined as in claims 1 to 8, is reacted with an amine of formula H ₂ X '(V) in which X 'represents one of the imino radicals mentioned in claims 1 to 8 for X, or c) for the preparation of a benzimidazole of formula (I) wherein R ^a is R ² -CX 1 -C ₃ . _{A 5-} cycloalkylene group wherein R ² is as defined in claims 1 to 8 and X "is one of the alkylidene residues mentioned in claims 1 to 8 for X, with a compound of formula (IV) R in which R ^b , R ^c , Ar, A and B are as defined in claims 1 to 8 a R '' represents R ² -CO-C ₃ . _{A 5-} cycloalkylene group, wherein R ² is specified in claims 1 to 8, is reacted with a phosphonate of the formula Z ³ -HX ”(VI), in which X 'represents one of the alkylidene residues mentioned in claims 1 to 8 for X, and Z ₃ is triphenylphosphono- or di- (C _1-3 -alkoxy) phosphono, or d) for the preparation of the benzimidazole of the general formula (I) in which R ^c represents an amidino group which may be substituted by one or two C 1-6 -alkyl groups, a compound of the general formula (VII) formed optionally in the reaction mixture R in which R ^a , R ^b , Ar, A and B are as defined in claims 1 to 8 a Z ⁴ is alkoxy, aralkoxy, alkylthio or aralkylthio, reacted with an amine of the formula HR ⁷ NR ⁸ (VIII), in which R ⁷ and R ⁸ , which may be the same or different, are each hydrogen or C 1-6. _{A 3-} alkyl group or a salt thereof; or e) for the preparation of a benzimidazole of general formula (I) in which R ^a represents an imidazolidin-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein the alkyl substituent may be substituted by carboxy- or C |. _{A 3-} alkoxycarbonyl group optionally forming a compound of formula (IX) formed in the reaction mixture R in which R ^b , Ar, A and B are as defined in claims 1 to 8 a ^And R 'represents aminocarbonylamino, which is in the 3-substituted C _{first 3} -alkoxycarbonyl-C ₁ _ ₃ -alkyl, or scyklizuje (i) for the preparation of a benzimidazole of formula (I) in which R ^c is a hydroxyamido group, a nitrile of formula (X) R ^b in which R ^a , R ^b , Ar, A and B are as defined in claims 1 to 8, reacted with hydroxylamine or its salts, or g) for the preparation of the benzimidazoles of formula (I) wherein R ^a contains a carboxy group and R ^c is as defined in claims 1 to 8, or R ^a is defined as in claims 1 to 8 and R ^c is an amidino group optionally substituted by hydroxy or one or two C 1-6 alkyl groups, a compound of formula (XI) R 'in which R ^b , Ar, A and B are as defined in claims 1 to 8 a R ,,, _{and R, So is} the meanings given for R ^a and R ^c in Claims 1 to 8, with the proviso that R ^a comprises a group which may be hydrolysis, with acid or base, thermolysis or hydrogenolysis zou converted to or R ^c is as defined in claims 1 to 8, or R ^c is a group which can be converted by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to an amidino group optionally substituted by hydroxy or one or two C 1-6 alkyl groups, and R ^{c and} set out in claims 1 to 8, by hydrolysis with an acid or base, thermolysis or hydrogenolysis into a compound of formula (I), wherein R ^a contains a carboxy group and ^Rc is defined as in claims 1 to 8, or R ^and as defined in claims 1 to 8 and R ^c is an amidino group optionally substituted by hydroxy or one or two C 1-3 -alkyl groups, or h) for the preparation of a benzimidazole of the general formula (I) in which R ^c is an amidino group which is substituted by one or two C ₁ . _{With 3-} alkoxycarbonyl groups or an in vivo leaving group, the compound of formula (XII) is converted into a salt thereof, in particular for pharmaceutical use, into a physiologically acceptable salt thereof with an inorganic or organic acid or base. A pharmaceutical composition comprising benzimidazole according to at least one of claims 1 to 8, wherein R ^c is one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, in addition to one or more inert carriers and and / or diluents. The use of benzimidazole according to at least one of claims 1 to 8, wherein R ^c is one of the amidino groups according to claims 1 to 8, or the salt according to claim 9, for the manufacture of a pharmaceutical composition for the treatment and / or prophylaxis of vascular and arterial thrombotic diseases. End of document (XII) in which R ^a , R ^b , Ar, A and B are as defined in claims 1 to 8 a R _c 'is an amidino group, reacted with a compound of formula From ⁵ - R ⁹ (XIII), in which R ⁹ represents a C 1-6 -alkoxycarbonyl group or an acyl residue of one of the in vivo cleavable moieties mentioned in the introduction, and Z ⁵ is a nucleophilic leaving group, and optionally the compound of formula (1) thus obtained, which contains (R ³ NR ⁴ ) -C ₁ . _{A 3-} alkyl group in which at least one of the radicals R ³ or R ⁴ is a hydrogen atom is subsequently converted by the corresponding isocyanate or carbamoyl halide into the corresponding urea compound of formula (I) and / or the compound of formula (I) thus obtained NH ₂ -C 1. ₃ -alkyl, then converted to the corresponding acrylic acid ester into a corresponding 2- (C _{first 3-alkoxycarbonyl)} -ethyl compound of general formula (I), and / or the resulting compound of formula (I) containing the ⁽³ R NR ⁴ ) -C ₁ . _{A 3-} alkyl group in which R ³ and R ⁴ each represent a hydrogen atom will convert the corresponding dihaloalkanes into the corresponding compound of formula (I) wherein R ³ and R ⁴ together with the intervening nitrogen atom represent a corresponding 4- to 7-membered cycloalkyleneimino group, and / or converting a compound of formula (1) in which R ^c is an amidino group with a haloacetic acid derivative as well as subsequent hydrolysis and decarboxylation to the corresponding amidine compound substituted with one or two methyl groups, and / or a compound of the formula (I) in which R ^c is a hydroxyamino group is converted by catalytic hydrogenation to the corresponding amidino compound and / or the compound of formula (I) in which R ^a is a carboxy group thus obtained is esterified to the corresponding ester by esterification and / or a protecting group used during these re reactive groups, cleaved, and / or the compound of formula (I) thus obtained is separated into its stereoisomers, and / or