SK82001A3 - 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

Benzimidazoles, process for their preparation, pharmaceutical composition containing them and their use

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

(I) their tautomers, their stereoisomers, their mixtures, their precursors, their derivatives which, on the carboxy site, contain negatively charged under physiological conditions

-2, and their salts, especially their salts. physiologically acceptable salts with inorganic or organic acids or bases which exhibit valuable properties.

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

In the above general formula I, they mean:

Ar is a phenylene or naphthylene group, optionally substituted by a fluorine, chlorine or bromine atom, a trifluoromethyl, a C 1-3 -alkyl or a C 1-3 -alkoxy group, optionally in a C 1-3 -alkyl-carbon backbone substituted by thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrimidinylene group

A C 1-3 -alkylene group,

B an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C 1-3 -alkyl group in which the alkyl moiety may be mono- or disubstituted by a carboxy group,

R 1 ^and R ¹ -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 moiety 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 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy-, carboxy-, carboxy- C 1-3 -alkoxy-, carboxy-C 1-3 -alkylamino-, N- (C 1-3 -alkyl) -N- (carboxy-C 1-3 -alkyl) amino-, carboxy-C 1-3 -alkylaminocarbonyl- - (C 1-3 -alkyl) - N - (carboxy-C _1-3 -alkyl) aminocarbonyl-, carboxy-C 1-3 -alkylaminocarbonylamino-, 1- (C 1-3 -alkyl) -3- (carboxyC 1-3) alkyl) -aminocarbonylamino-, 3- (C 1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonyl-3 ··· ·········· 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, or a C 1-3 alkyl substituted by a 5- to 7-membered cycloalkyleneimino group to which is fused via two adjacent carbon atoms phenyl ring, morpholino-, piperazino-, N - (C 1-3 -alkyl) -piperazino-, pyrrolino-, 3,4-dehydropiperidino- or pyrrol-1-yl-group, R ² -CX-C3-5 a 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 1-6 -alkyl group substituted amino, oxygen or sulfur atom or optionally C1-3-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-C1-3-alkoxy-, carboxy-C1-3- alkylamino- or N-C 1-6 -alkyl-1-carboxy-C 1-6 alkylamino, and

X represents an oxygen atom, a C 1-3 -alkylimino-, a C 1-6 -alkylimino- or a C 1-6 -alkylimino-; -Alkoxyimino- _3, C ₃ -alkylhydrazino-, di- (Ci-3-alkyl) -hydrazino-, C ₂ 4-alkanoylhydrazino-, A / - (Ci_3 alkyl) or C -C2-4alkanoylhydrazino- 3 an alkylidene group which in each of the alkyl or alkanoyl portions or in the alkyl and alkanoyl portions may be substituted by a carboxy, imidazole or imidazolone group substituted by a C 1-3 -alkyl- or C 3-5 -cycloalkyl group, in which the imidazole ring may be substituted by a phenyl- or carboxy group and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -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, C2-4-alkanoylamino-, Ci-3-alkylamino, N (C ₂ -4 -alkanoyl) -Ci.3-alkylamino or di (C ₃ 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 ₃ -alkylamino, A / - (4-C ₂ alkanoyl ) -C. _{The 3-} alkylamino or di- (C _1-3 -alkyl) amino group, and in addition to the above imidazole and imidazolone ring, a phenyl or pyridine ring, an imidazolidin-2,4-dione-5-yl group, may be fused via two adjacent carbon atoms. , which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time one alkyl substituent may be substituted by carboxy, C 1-4 -alkyl which is substituted

Ci. _3- alkyl-Y ¹ -C 1-3 -alkyl-, HOOC-C 1-3 -alkyl-Y ¹ -C 1-3 -alkyl-, tetrazolyl-C 1-6 alkyl; _3- alkylY ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C 1. _3- alkyl and optionally C _1-3 -alkyl substituted with isoxazolidinylcarbonyl, pyrolinocarbonyl-, 3,4-dehydro-piperidinocarbonyl-, pyrrol-1-ylcarbonylcarboxy-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, di- (C _1-3) -alkyl) -aminocarbonylamino or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkyleneimine moiety may be substituted by one or two C 1-6 alkylsubstituted or substituted by 1 to 2 carbon atoms. _3-alkyl groups and at the same time can be alkyl or alkyl substituent of the aforementioned Ci. _3- alkylaminocarbonyl- "di- (C _1-3 -alkyl) -aminocarbonyl- or cycloalkyleneiminocarbonyl substituted with 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 is hydrogen or an optionally substituted carboxyl group and a C ₃ -alkyl

R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ¹ -C 1-3 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ C 1-3 -alkyl-Y ² -, C 1-3 -alkyl-Y ^2- or carboxy-C 1-3 -alkyl-Y ² -group;

R ³ and R ⁴ together with the intervening nitrogen atom represent optionally carboxy-, C _1-3 -alkyl- or carboxy-C 1. _{A 3-} alkyl substituted 4- to 7-membered cycloalkyleneimino group in which

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

• · • e • ·· • ··· • · • · • e ···· • • ·· • · • · • • · • ···· • · • · · · · · • ···

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 in each case be additionally substituted by C 1-3 -alkyl- or carboxy-C _1-3 -alkyl,

R ⁵ NR ⁶ -substituted by C _1-3 -alkyl- or C 3-5 -cycloalkyl in which:

R ⁵ represents a hydrogen atom, C 1-6 alkyl; _3- alkyl-, C 3-7 -cycloalkyl-, phenylcarbonyl-, phenylsulfonyl- or pyridinyl; and

R ⁶ represents C _1-3 -alkyl-, carboxy-C 1-6 alkyl; _3- alkyl- or carboxy-C 1-6 alkyl; ₃ -alkylcarbonyl,

Ci. _{A 3-} alkyl group which is substituted with a C 2-4 -alkanoyl- or a C 3-7 -cycloalkanoyl group and a C 1-6 alkyl group; _3- alkyl substituted with chlorine, bromine or iodine;

R ^b represents a hydrogen atom or C 1-6 alkyl; _3- alkyl; and

R ^c represents a cyano group or an optionally substituted amidino group with one or two C _1-3 -alkyl groups.

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 International Journal 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 Ci_6-alkanol, a phenyl-C ₃ -alkanol, C ₃ .g-cycloalkanol, wherein 05-8- the cycloalkanol may additionally be substituted with one or two C 1-6 alkyl. ₃ alkyl groups, C p-cycloalkanol wherein a methylene group in the 3- or 4 replaced by O, or C ₃ optionally alkyl-, phenyl-C ₃ alkyl-, phenyl-C ₃ or C 2-6 alkoxycarbonyl the amino-substituted alkanoyl and cycloalkanol moiety may additionally be substituted by one or two C _1-3 alkyl groups, C 4. ₇ -cycloalkenyl, C ₃ -5-alkenol, a phenyl-C 3-5 -alkenyl, C _{3. 5} -alkinol or phenyl-C _{3. 5} -alkinol with the proviso that the oxygen atom is not based on any bond from a carbon atom having a double or triple bond, _C3 8-cycloalkyl-C ₃ -alkanol, bicycloalkanes a total of 8 to 10 carbon atoms which may additionally be in the bicycloalkyl moiety substituted with one or two C 1-6 alkyl; _3- alkyl, 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

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

R ^d is C 1-8 -alkyl-, C 5-7 -cycloalkyl-, phenyl- or phenyl-C 1-3 -alkyl, R 8 is hydrogen, C 1-3 -alkyl-, C 5-7 -cycloalkyl- or phenyl and R ^f is a hydrogen atom or a C 1-3 -alkyl group, under physiological conditions a negatively charged group such as tetrazol-5-yl-, phenylcarbonylaminocarbonyl-, trifluoromethylcarbonylaminocarbonyl-, C 1-6 -alkylsulfonylamino-, phenylsulfonylamino-, benzylsulfonylamino-, trifluoromethylsulfonylamino- alkylsulfonylaminocarbonyl-, phenylsulfonylaminocarbonyl-, benzylsulfonylaminocarbonyl- or perfluoro-C 1-6 -alkylsulfonylaminocarbonyl, and in vivo removable from the imino- or amino-group means, for example, hydroxy, Cl, acyl, acyl, acyl, acyl, acyl, acyl or acyl; . _3- alkyl- or C _1-3 -alkoxy mono- or disubstituted benzoyl, wherein the substituents may be the same or different, pyridinoyl or C 1-6 -alkanoyl, such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl, 3,3,3-trichloropropionylamino or allyloxycarbonyl, C _1-6 -alkoxycarbonyl- or C _1-6 -alkylcarbonyloxy in which the hydrogen atoms may be completely or partially replaced by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl-, isopropoxycarbonyl-, propoxycarbonyl-, propoxycarbonyl-, propoxycarbonyl-, propoxycarbonyl- butoxycarbonyl-, tert-butoxycarbonyl-, pentoxycarbonyl-, hexoxycarbonyl-, octyloxycarbonyl-, nonyloxycarbonyl-, decyloxycarbonyl-, undecyloxycarbonyl-, dodecyloxycarbonyl-, hexadecyloxycarbonyl-, methylcarbonyloxy-, methylcarbonyloxy-, methylcarbonyloxy-, methylcarbonyloxy- isopropylcarbonyloxy-, butylcarbonyloxy-, tert-butylcarbonyloxy-, pentylcarbonyloxy-, hexylcarbonyloxy-, octylcarbonyloxy-, nonylcarbonyloxy- , decylcarbonyl-7, oxy-, undecylcarbonyloxy-, dodecylcarbonyloxy- or hexadecylcarbonyloxy, phenyl-C 1-6 -alkoxycarbonyl, such as benzyloxycarbonyl-, phenylethoxycarbonyl- or phenylpropoxycarbonyl, 3-amino-propionyl, in which the amino group may be mono- or disubstituted by C1-6-alkyl- or C3-7cycloalkyl groups and the substituents may be the same or different, C1-3alkylsulfonyl-C2- 4-alkoxycarbonyl-, C 1-3 -alkoxy-C 2-4 -alkoxy-C 2-4 -alkoxycarbonyl-, R ^d CO-O- (R ^d CR ^f ) -O-CO-, C 1 -C 4 -alkoxycarbonyl; _6- alkyl-CO-NH- (R ⁹ CR ^h ) -O-CO- or C 7 -alkyl-CO-O (R ⁹ CR ^h ) - (R ⁹ CR ^h ) -O-CO- group in which R ^d and ^Rf are defined as mentioned before,

R ⁹ and R ^h, which may be the same or different, are H or C 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, etc.

Preferred compounds are those having formula la

in which

A represents a C 1-3 -alkylene group,

B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, or a C 1-6 alkyl group; _{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 is} -CO-C 3-5 -cycloalkyl wherein:

^R1 is

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

· · é · • · • ·· · ·· · • · • • · • • · ·· • · · · • · • • · · ···· · · · · · · ·· ···

A 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy-, carboxy-, carboxy-C 1-3 -alkoxy -, carboxy-Ci. _3- alkylamino-, N - (C 1-3 -alkyl) - N - (carboxy-C _1-3 -alkyl) amino-, carboxy-C 1-6 alkyl; _3- alkylaminocarbonyl-, N- (C _1-3 -alkyl) -N- (carboxy-C 1-3 -alkyl) aminocarbonyl-, carboxy-C 1-3 -alkylaminocarbonylamino-, 1- (C _1-3 -alkyl) -3 - (carboxyC 1-3 -alkyl) -aminocarbonylamino-, 3- (C 1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) -amino-carbonylamino- or 1,3-di- (C 1-3 -alkyl) alkyl) -3- (carboxy-C 1-3 -alkyl) aminocarbonylamino, hydroxy substituted 4- to 7-membered cycloalkyleneimino, or C 1-3 -alkyl substituted by 5- to 7-membered cycloalkyleneimino to which it is two adjacent carbon atoms fused phenyl ring, morpholino-, piperazino-, N - (C 1-3 -alkyl) -piperazino-, pyrrolino-, 3,4-dehydropiperidino- or pyrrol-1-yl group,

R ² -CX-C 3-5 -cycloalkyl, wherein

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- an alkyl-substituted amino, oxygen or sulfur atom, or an optionally C1-3-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-C1-3-alkoxy-, carboxy-C1- . _3- alkylamino- or N - (C _1-3 -alkyl) carboxy-C 1-3 alkylamino, and

X is O, C1-3-alkylimino-, C1-3-alkoxyimino-, C1-3-alkylhydrazino-, di- (C1-3-alkyl) -hydrazino-, C2-4-alkanoylhydrazino-, N - (C1-8-alkyl) -hydrazino- 3-alkyl) -C 2-4 alkanoylhydrazino- or C 1-6 alkyl; _{A 3-} alkylidene group which in each case may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety by a carboxy, imidazole or imidazolone group substituted by a C 1-3 -alkyl- or C 3-5 -cycloalkyl group in which:

• · • · • • · • ··· • · • · • · ···· • • ·· • · • · • · ···· · · · · · · • · · · ·

the imidazole ring may be substituted with phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C 1-6 alkyl groups. ₃ alkyl groups, wherein the substituents may 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 ^ ₂ -alkanoylamino-, C ₃ alkylamino, / N (C 2 ^ - alkanoyl) -C _1-3 -alkylamino- or di- (C _1-3 -alkyl) amino, and the imidazolone ring may be substituted with C 1-6 -alkanoyl). ₃ -alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C 2-4 alkanoylamino, C ₃ -alkylamino, A / - (C 2-4 -alkanoyl) -C. _{A 3-} alkylamino or di- (C _1-3 -alkyl) amino group, and in addition to the aforementioned imidazole and imidazolone ring, a phenyl or pyridine ring, an imidazolidin-2,4-dione-5-yl group, may be fused via two adjacent carbon atoms, which may be substituted with one or two C 1-6 alkyl. _3- alkyl, wherein at the same time one alkyl substituent may be substituted by carboxy,

Ci_4-alkyl group substituted by a C ₃ -alkyl-Y ¹ -Ci_3-alkyl, ^{HOOC-Ci.3-alkyl-Y1} -Ci.3-alkyl, tetrazolyl-Ci_3-alkyl-Y ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C 1. _3- alkyl and optionally C 1-6 alkyl; _3- alkyl substituted with isoxazolidin-1-ylcarbonyl, pyrolinocarbonyl-, 2,3-dehydro-piperidinocarbonyl-, pyrrol-1-yl-carbonyl-, carboxy-, aminocarbonyl-, C 1 -C 3 -alkyl; _3- alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonylamino or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein in the above-mentioned groups the cycloalkyleneimine moiety may be substituted by one or two C _1-3 -alkyl groups and at the same time may be an alkyl moiety or an alkyl moiety a substituent of the aforementioned C1. _3- alkylaminocarbonyl-, di-C 1-6 -alkyl-4-aminocarbonyl- or cycloalkyleneiminocarbonyl substituted with 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 an optionally substituted carboxy group. _3- alkyl; and

R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ¹ -C 1-3 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ C 1-3 -alkyl-Y ² -, C 1-3 -alkyl -Y ² - or carboxy-C 1-3 -alkyl-Y ^{2 -} or;

-10 ··· · · · · · · · · ·

R ³ and R ⁴ together with the intervening nitrogen atom are optionally carboxy-, C _1-3 -alkyl- or carboxy-C 1-3 -alkyl substituted by a 4- to 7-membered cycloalkyleneimino group in which

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

Y ² represents a carbon-nitrogen bond or a carbonyl-, sulfonyl-, imino- or -NHCO- 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 the occurring imino groups can in each case be additionally substituted by C 1-3 -alkyl- or carboxy-C 1-3 -alkyl, R ⁵ NR ⁶ -substituted by C _1-3 -alkyl- or C _3-5 -cycloalkyl, in which

R ⁵ is H, C ₃ alkyl-, _C5-.7 cycloalkyl, phenylcarbonyl-, phenylsulfonyl, or pyridinyl, and

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

Ci-3 alkyl-substituted C ₂ -4-C ₅ alkanoyl, or 7-cykloalkanoylskupinou and C-3-alkyl substituted by Cl, Br or I,

R ^b is hydrogen or C 1-3 -alkyl a

R ^c is cyano or amidino which may be substituted by hydroxy, by one or two C 1-3 -alkyl, by one or two C 1-8 -alkoxycarbonyl, wherein, in the definition of the abovementioned residues, said carboxy, amino and imino groups may additionally be substituted in vivo cleavable residues, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of formula Ia above are those in which

A represents a C 1-3 -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 in the 1-position of R ^{1 a} -CO- radical substituted C 3-5 -cycloalkyl group in which

^R1 is

-11 ··· ·· ···· · ··· · · · · ·

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

A 4- to 7-membered cycloalkyleneimino group which may be substituted by hydroxy or by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy-, carboxy-, carboxy-C 1-3 -alkoxy- , carboxy-C 1. ₃ -alkylamino-, N - (C _1-3 -alkyl) - N - (carboxy- C _1-3 -alkyl) amino-, carboxy-C 1-3 -alkylaminocarbonyl-, N - (C _1-3 -alkyl) - N - (carboxy-C _1-3 -alkyl) aminocarbonyl-, carboxy-C 1-3 -alkylaminocarbonylamino-, 1- (C 1-3 -alkyl) -3- (carboxyC 1-3 -alkyl) aminocarbonylamino-, 3- (C 1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -amino-carbonylamino- or 1,3-di- (C _1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) aminocarbonylamino, optionally C 1-3 -alkyl substituted by a 5- to 7-membered cycloalkyleneimino group to which the phenyl ring, morpholino-, piperazino-, N- (C 1-3 -alkyl) -piperazino- is fused via two adjacent carbon atoms , pyrolino-, 3,4-dehydropiperidino- or pyrrol-1-yl group in the 1 R ² -CX- residue substituted C _3-5 -cycloalkyl, wherein

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 contains an optionally C 1-3 -alkyl substituted amino group, an oxygen or sulfur atom or an optionally C 1-3 -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 1-3 -alkylamino- or N- (Ci.3 alkyl) carboxy-C. _3- alkylamino, and

X represents an oxygen atom, a C 1-3 -alkylimino-, a C 1-3 -alkoxyimino- or a C 1-3 alkylidene group which in each case may be substituted by a carboxy group in the alkyl or alkoxy part, in the 1-position by an imidazole or imidazolone substituted C 1-3 alkyl group; which ································································ ·· ·· ·· ···

The -12-imidazole ring may be substituted by phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, the substituents may be the same or different and one of the aforementioned alkyl substituents may be simultaneously substituted by carboxy or in the 2-position or 3 amino-, C 2-4 -alkanoylamino-, C 1-3 -alkylamino-, N (C 2-4 -alkanoyl) -C 1-3 -alkylamino- or di- (C _1-3 -alkyl) amino, and an imidazolone ring it may be substituted with a C 1-3 -alkyl group, wherein the alkyl substituent may be substituted with a carboxy group or in the 2 or 3 position of amino, C 2-4 -alkanoylamino-, C 1-3 -alkylamino-, N- (C 2-4 -alkanoyl) -C ₁ . _{A 3-} alkylamino or di- (C _1-3 -alkyl) amino group, and in addition to the aforementioned imidazole and imidazolone ring, a phenyl or pyridine ring, an imidazolidin-2,4-dione-5-yl group, may be fused via two adjacent carbon atoms, which may be substituted by one or two C 1-3 -alkyl groups, wherein at the same time one alkyl substituent may be substituted by a carboxy group,

C 1-4 alkyl substituted in 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 a 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkylene imine moiety may be substituted with one or two C 1-3 -alkyl groups and at the same time, one alkyl moiety or alkyl substituent of the aforementioned C 1-3 alkylaminocarbonyl-, di- (C 1-3 -alkyl) amino-carbonyl- or cycloalkyleneimino-carbonyl groups may be substituted by carboxy and the remaining hydrogen atoms of the C 1-6 alkyl group may be wholly or partially replaced by fluorine atoms, In which

R ³ is hydrogen or an optionally substituted carboxy-Ci_3 alkyl, and

R ⁴ represents a hydrogen atom, a C 1-3 -alkyl-Y ² - or a carboxy-C 1-3 -alkyl-Y ² -group, or

· · • · • · · • · · · ·· • • • • ···· • • • e · · • • • • • • · • • • · • • ···· · · · · · · · · · ·

R ³ and R ⁴ together with the intervening nitrogen atom, optionally in the 1-position, represent a carboxy, C 1-3 -alkyl or carboxy-C 1-3 -alkyl substituted by a 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 with C 1-3 -alkyl- or carboxy-C 1-3 -alkyl, in the 1-position of R ⁵ NR ⁶ -substituted with C _1-3 -alkyl- or C ₃ . ₅ -cycloalkyl wherein:

R ⁵ represents a hydrogen atom, a C 1-3 -alkyl-, a C 5-7 -cycloalkyl-, a phenylcarbonyl-, a phenylsulfonyl- or a pyridinyl group and

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

Ci-3 alkyl-substituted C ₂ or C ^ -alkanoyl- ₅ cykloalkanoylskupinou _7-3 and C-alkyl substituted by Cl, Br or I,

R ^b is C 1-6. _3- alkyl; and

R ^c is optionally 2,2,2-trichloroethoxycarbonyl-, C 1-6 -alkoxycarbonyl, acetoxymethyloxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino, wherein the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, alkyl- or C 1-3 -alkoxy groups and substituents may be the same or different, their C 1-3 -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 R 1 at position ¹ -CO- radical substituted cyclopropyl group, wherein

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 1-3 -alkoxy-, carboxy-C 1-6 -alkyl. _3- alkylamino or N - (C 1-3 -alkyl) -carboxy- C _1-3 -alkylamino,

-14 in the 1-position of R ² -CX- by a substituted cyclopropyl group in which

^R2 is an optionally Ci-3-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 imidazole substituted by a C 1-2 -alkyl group in which the imidazole ring may be substituted by phenyl or a carboxy group and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, wherein the substituents may be the same or different and one of the aforementioned alkyl substituents may be simultaneously substituted by a carboxy group or in the 2 or 3 position of amino, C ₂ 4-alkanoylamino, C1-3alkylamino-, A / - _(C2 _4-alkanoyl) -Ci_3-alkylamino or di- (Ci-3-alkyl) amino, the addition may be prior to the imidazole ring via two adjacent carbon atoms fused to a phenyl or pyridine ring, substituted in the 1-position by a benzimidazolon-1-yl-substituted C _1-2 -alkyl group, wherein the imidazolone ring may be optionally substituted with k methyl or ethyl substituted with arboxy, methyl or ethyl which may be substituted in the 1-position

R ³ NR ⁴ - or R ³ NR ⁴ -C 1-3 -alkyl and di- (C 1-3 -alkyl) aminocarbonyl, isoxazolidin-1-yl-carbonyl, optionally substituted with pyrrolidinocarbonyl or C 1-3 -alkyl, or piperidinocarbonyl, 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 a hydrogen atom or an optionally C 1-3 -alkyl substituted by a carboxy group a

R ⁴ is H, Ci-3-alkyl-Y ² -, or carboxy-Ci-3-alkyl-Y ² -group or

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

Y ² represents a carbon-nitrogen bond, a carbonyl group or an optionally C 1-3 alkyl-substituted amino group, in the 1-position of R ⁵ NR ⁶ -substituted C 1-6 alkyl; _{A 2-} alkyl group in which they are

· · • · • ·· • ··· ·· • · • · ···· • • · · • · • · • · ···· • · • · · · · · · · ·

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

R ^{6 is} C 1-3 -alkyl- or carboxy-C 1-6 -alkyl; _3- alkyl, n-propyl substituted at the 3-position with n-propyl substituted by cyclopentylcarbonyl at the 1-position, cyclopropyl-substituted cyclopentyl at the 1-position, substituted by carboxy-C 1-3 -alkylcarbonyl at the nitrogen atom,

R ^b represents a methyl group a

R ^{c is} optionally C 1-6 -alkoxycarbonyl-, acetoxymethyloxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino, especially those compounds of formula Ia in which they represent

And a methylene group,

B imino,

R ^and R 1 at position ¹ -CO- radical substituted cyclopropyl group, wherein

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 1-3 -alkoxy-, carboxy-C 1-6 -alkyl. _3- alkylamino or N - (C _1-3 -alkyl) -carboxy-C 1-3 -alkylamino, in the 1-position of R ² -CX- with a radically substituted cyclopropyl group in which

^R2 is an optionally Ci-3-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 -alkyl; _{A 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, wherein in addition one of the aforementioned methyl or ethyl substituents may be simultaneously substituted by carboxy, methyl or ethyl 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 1-3 -alkyl substituted by pyrrolidinocarbonyl or piperidinocarbonyl,

· · · · · · ···· • · • • • • • • · · • · · · • • • • • • • · • • • · • • ···· · · · · · · · · · ·

wherein in the above groups 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 an optionally C 1-3 -alkyl substituted by a carboxy group a

R ⁴ 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 optionally substituted C 1-3 alkyl substituted amino group,

R ^b represents a methyl group a

R ^c or C much alkoxycarbonyl, acetoxymetyloxykarbonyl-, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl substituted by amidino being preferred, in particular the previously mentioned compounds of formula I in which R is in ^the 5-position , their C 1-3 -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-dimethylimidazol-1-ylmethyl] - benzimidazole, (f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-

(g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin-1-yl) -ylcarbonyl) ethyl] benzimidazole; (carbonyl) -ethyl] -benzimidazole, as well as their C 1-6 -benzimidazole. ₃ -alkanol esters, their N - (C 1-8 -alkoxycarbonyl) -, N -benzyloxycarbonyl- and N -benzoylamidines, their tautomers, their stereoisomers and their salts.

According to the present invention, these 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 cyano:

optionally cyclizing the compound of formula II formed in the reaction mixture

Z ¹ Z ²

R ^b 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 an excess of acyium compound. 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 condensation 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, Ndicyclohexylcarbodiimide, or optionally in the presence of a base such as ethylan

-18 potassium 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 the formula II is prepared in the reaction mixture by reduction of the corresponding onitro compound, optionally in the presence of a carboxylic acid of the formula

HO-CO-A-B-Ar-CN (III) wherein

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

b) For a compound of formula I, wherein R ^a is R ² -C -CX' -5cykloalkylénovú ₃ group wherein R ² is as defined in the preamble and X represents one of the iminozvyškov listed in the Introduction to X, a compound of formula IV

(IV) in which

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

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

H ₂ X '(V) wherein

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 19-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 the formula I in which R ^a represents R ² -CX 1 - C 3 - 5 cycloalkylene, in which R ² is defined as at the beginning and X "represents one of the alkylidene residues mentioned at the beginning for X: the compound of formula IV is reacted

R ^b (IV) wherein

R ^b , R ^c , Ar, A and B are as defined above and R ^a 'represents R ² -CO-C3. _{5 a} cycloalkylene group, wherein

R ² is defined as in the introduction, with a phosphonate of the formula

Z ³ -HX '(VI) wherein

X 1 represents one of the alkylidene radicals mentioned at the outset for X, and Z 3 represents 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 dimethyl sulfoxide 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 the formula I in which R ^c is an amidino group which may be substituted by one or two C 1-3 -alkyl groups: a compound of the formula VII, if any, reacts in the reaction mixture

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, η-propoxy, isopropoxy or benzyloxy, or alkylthio or arylalkylthio such as methylthio-, ethylthio-, n-propylthio- or benzylthio, 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, each represent a hydrogen atom or a C 1-3 -alkyl group, or with salts thereof.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, npropanol, 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 a corresponding acid addition salt, such as ammonium carbonate or ammonium acetate.

The compound of formula VII is obtained, for example, by reacting the corresponding cyano compound with a 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 such as triethyloxonium tetrafluoroborate, 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

-21 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 is imidazolidine-

A 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 a carboxy- or C 1-3 -alkoxycarbonyl group:

cyclizes an optionally formed compound of formula IX in the reaction mixture

(IX) in which

R ^b , Ar, A and B are as defined above and R ^a is an aminocarbonylamino group which is substituted at the 3-position with C 1-3 -alkoxycarbonyl-C 1-3 -alkyl.

The reaction is preferably carried out in a solvent such as methanol, ethanol, npropanol, 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) For the preparation of a compound of formula I in which R ^c is a hydroxyamino group:

a nitrile of formula X is reacted

(X) in which

-22 ·····································

R ^a , R ^b , Ar, A and B are as defined in the introduction, with hydroxylamine or its salts.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, npropanol, water, methanol / water, tetrahydrofuran, tetrahydrofuran / water, dioxane or dioxane / water at temperatures between 0 and 150 ° C, preferably between 0 and 80 ° C.

g) For the preparation of a compound of the formula I in which R ^a contains a carboxy group and R ^c is as defined at the outset, or R ^a is as defined at the beginning and R ^c is optionally a hydroxy group or one or two C 1-3 alkyl substituted amidino groups:

the compound of formula XI is converted

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 ^c in the introduction, provided that R ^a contains a group which can be hydrolyzed, treated with acid or by 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 an hydrolysis, acid or base treatment, by thermolysis or hydrogenolysis to an optionally substituted amino group or one or two C 1-6 alkyl groups , and R ^a is defined as above by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis of a compound of formula I wherein R ^a contains a carboxy group and R ^c is as defined at the beginning or R ^a is as defined at the beginning and R ^c is an optionally substituted hydroxy or one or two C 1-3 -alkyl substituted amidino groups.

Suitable carboxyl groups include, for example, a carboxyl protecting group protected by a protecting group, as well as functional derivatives thereof, such as unsubstituted or substituted amides, esters, thioesters,

-23 · trimethylsilyl esters. orthoesters or iminoesters which are conveniently converted to the carboxyl group by hydrolysis, their esters with tertiary alcohols, e.g. to a 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 the boiling point of the reaction mixture.

If the compound of the 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. 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 is 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, at temperatures between 40 and 120 C.

If the compound of formula XI contains, for example, benzyloxy or benzyloxycarbonyl, these can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, acetic acid, ethyl acetate, 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.

-24 ·· ······················ Next 9 · 9 9 9 9

h) For the preparation of a compound of formula I in which R ^c is an amidino group which is substituted with one or two C 1-6 -alkoxycarbonyl groups or an in vivo leaving group: a compound of formula XII is reacted

in which

R ^a , R ^b , Ar, A and B are as defined in the introduction and R ^c is an amidino group with a compound of the general 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 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 the compound of formula XIII in which 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 sodium hydride, potassium carbonate, potassium tert-butylate or N-ethyl-diisopropylamine, at temperatures between 0 and 60 ° C.

··· ·· ···· · ··· · · · · ·

-25 • ··· ·········································

If according to the invention a compound of the formula I is obtained which contains a (R ³ NR ⁴ ) -C 1-3 alkyl group in which at least one of the radicals R ³ or R ⁴ is a hydrogen atom, this can subsequently be converted with the corresponding isocyanate or carbamoyl halide to the corresponding urea compound of formula (I) and / or a compound of formula (I) containing an NH ₂ -C 1-3 -alkyl group, which can then be converted by the corresponding acrylic ester into the corresponding 2- (C 1-3 -alkoxycarbonyl) -ethyl compound of formula (I) and / or a compound of formula (I) which contains a (R ³ NR ⁴ ) -C 1-3 alkyl group in which R ³ and R ⁴ each represent a hydrogen atom, which can then be converted by the corresponding dihaloalkanes into the corresponding compound of the formula of formula I wherein R ³ and R ⁴ together with the intervening nitrogen atom represent a corresponding 4- to 7-membered cycloalk and then a compound of formula I in which R ^c is an amidino group, which can 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 methyl groups, and / or of formula I, wherein R ^c is a hydroxyamidino group, then this may be subsequently converted by catalytic hydrogenation into a corresponding amidino compound and / or a compound of formula I, wherein R ^a is carboxy, then this may be subsequently converted by esterification to the ester.

The subsequent preparation of the corresponding urea compound of the 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 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 N-ethyl-diisopropylamine or N-methylmorpholm 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, Λ /, / '-dicyclohexylcarbodi dicyclohexylcarbodiimide (N) -hydroxysuccinimide, N, N '-carbonyldiimidazole or N, N -thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylic acid ester, optionally in the presence of a base such as • ··· · · · · ·

-27 potassium carbonate, N-ethyl diisopropylamine or N, N-dimethylaminopyridine, suitably 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 sodium or potassium iodide, and preferably in the presence of a base such as sodium carbonate or potassium carbonate, or in the presence of a tertiary organic base such as N-ethyl- diisopropylamine or N-methylmorpholine, which can also serve as solvents at the same time, 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.

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 a protecting group for amino, alkylamino or imino, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl and amino in addition to phthalyl.

Optional subsequent cleavage of the protecting moiety used is carried out, for example, hydrolytically in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an 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, by hydrogenolysis, for example with hydrogen, in the presence of a catalyst such as palladium / carbon in a solvent such as methanol,

-28 ····································································· ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 0.1 to 50 ° C 0.7 MPa (1 to 7 bar), preferably 0.3 to 0.5 MPa (3 to 5 bar).

Cleavage of the methoxybenzyl group may 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) -odium 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 have been used as starting materials and which are known in the literature are obtained by methods known in the literature and, moreover, in the preparation of the examples.

The chemistry of compounds of formula III has been described, for example, by Jack Robinson in J. Chem. Soc. 1941, 744, the imidazoles of Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Pergamon Press, Oxford 1984, Schaumann in Hetarene III, Methoden der Organischen Chemie (Heteroarenes III, · Heteroarenes III, · · · · · ·

-29 Organic Chemistry Methods) (Houben-Weyl), 4th 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 by cyclizing the corresponding substituted compound according to a) and subsequent reduction nitro groups 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 the formula I which exhibit in the 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 I having at least 2 asymmetric carbon atoms by virtue of their physico-chemical differences by methods known per se, for example by chromatography and / or fractional crystallization, to their diastereomers which, if they can be separated into their enantiomers as described above.

The separation of the 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, 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 pure antipodes can be released from the pure diastereomeric salts or derivatives by the action of suitable means. Particularly used optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Suitable optically active alcohol is, for example, (+) - or (-) - 30 menthol and, as optically active acyl residue in amides, for example, (+) - or a (-) mentyloxycarbonyl radical.

In addition, the compounds of the 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 the formula I thus obtained, if they contain a carboxy group, can, if desired, subsequently be 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 the formula I and their salts have valuable properties. For example, compounds of formula I in which R ^c is cyano form valuable intermediates for the preparation of other compounds of formula I and compounds of formula I in which R ^c is one of the aforementioned amidino groups, as well as their tautomers, their stereoisomers and their physiologically acceptable salts exhibit valuable pharmacological properties, in particular an antithrombotic effect, which preferably consists of an action affecting thrombin or factor Xa, for example a thrombin inhibiting or factor Xa inhibiting effect, an aPTT-prolonging effect and an 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) -1-methyl-5- [1 - [(pyridin-2-yl) (carboxymethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride,

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

• · • · • • · • ··· • · • 9 • · ···· 9 • • · · • 9 9 9 • · · ···· · · · · 99 99 999

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 as follows:

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 B10 coagulometer, 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. The precipitation reaction was initiated by the addition of 0.1 ml of calcium solution. 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 the dose-effect curve.

The following table shows the values found:

substance aPTT-time (ED200 in 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.

Because of 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 reoclusion following 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 fibrosis.

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, for oral administration. up to 30 mg / kg, 1 to 4 times daily. For this purpose, the compounds of the formula I prepared according to the invention may optionally be combined with other active substances, together with one or more inert, customary carriers and / or diluents, for example corn starch, milk sugar, cane sugar, microcrystalline cellulose,

-33 Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin , water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fat-containing substances such as hardened fat or suitable mixtures thereof may be incorporated into conventional galenic formulations such as tablets, dragees, capsules, powders, suspensions or suspensions.

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 was added portionwise at -25 ° C 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-nitro-phenyl) -1-cyclopropanecarboxylic acid and 100 ml of methylamine solution (40% in H ₂ O) are heated in a pressure vessel for five hours to 80 ° C. The contents were evaporated to dryness, dissolved in water and acidified 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) - N, N, N, N ', N-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) pyrrolidine and 1.1 g (0.01 mol) N-methylmorpholine is stirred at room temperature for 20 hours. 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% of theory), Rf 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-methylaniline are dissolved in 40 ml of methanol and 40 ml of methylene chloride and after the 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), Rf: 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- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] -2-amino-N-methyl-aniline, O-benzotriazol-1-yl] -N./V. N-tetramethyluroniumtetrafluoroborate, 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 2 hours. 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 evaporated

· · • · • • · • ··· • · • · • · ···· • • • · · • · · · • · · ···· · · · · · · ·· ·· ·

Chromatography on silica gel, eluting with methylene chloride + 2 to 3% methanol.

Yield: 1.0 g (62% of theory), Rf 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 hydrochloric acid and Stir for 5 hours at room temperature. 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), Rf value: 0.61 (silica gel, methylene chloride / methanol = 4: 1) ₂ C ₆ H 4H28N x HCl (416.54 / 453.0)

Mass Spectrum: (M + H) ⁺ = 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 theory, Rf value: 0.25 (silica gel; methylene chloride / methanol = 4: 1) C26H32N6O x HCl (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) ············· ···· ·· ·· ····

-36C2 ₅ H ₃ oN ₆ 0 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)

C25H 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;

Rf value: 0.34 (silica gel; methylene chloride / methanol = 4: 1)

C ₂₈ H ₂₈ N ₆ O x HCl (464,58 / 501,04)

Mass Spectrum: (M + H) ⁺ = 465 (5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) piperidin-1-ylcarbonyl) cyclopropyl] hydrochloride ] benzimidazole

Yield: 85% of the theoretical yield;

Rf value: 0.57 (silica gel; methylene chloride / methanol = 4: 1)

C ₃ o ₃₈ N ₆ 0 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

Yield: 60% of the theoretical yield;

C2 ₉ 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-ethoxycarbonylethyl) -N-methyl-aminomethyl) pyrrolidin-1-ylcarbonyl] cyclopropyl] -benzimidazole Yield: 65% of theory,

C31H41N7O3 x HCl (559.72 / 596.18)

Mass Spectrum: (M + H) ⁺ = 560 (M + 2H) ⁺⁺ = 280.6 (8) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(2-ethoxycarbonylmethyloxymethyl) hydrochloride - pyrrolidin-1-yl-carbonyl] cyclopropyl] benzimidazole

Yield: 61% of the theoretical yield;

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

C29H36N6O4 x HCl (532.66 / 569.11)

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 is 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, Rt value: 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 addition of 1.0 g of Raney nickel was 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], [V ',] V-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide. Yield: 96% of theory.

Rf value: 0.54 (silica gel; methylene chloride / methanol = 19: 1)

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

· · • · • ·· • ··· • · é ··· • • • · • • • • • · • • • • • • · • • • · • • ···· · · · · · · · · · ·

Prepared in analogy to Example 1f from 4- [1- (cyclopentylcarbonyl) cyclopropyl] -2- (4-cyanophenylaminomethylcarbonylamino) - N -methyl-aniline in glacial acetic acid.

Yield: 53% of the theoretical yield;

Rf value: 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%, C 5 H _{3 2 5} 0 The active x HCl (452.00 / 488.56) Mass spectrum: (M + H = 452/4 (C)

Example 3 (E * Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride

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

To a 100 ml butyllithium (1.6 M in hexane) solution is added dropwise at -40 to -50 ° C.

21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether 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 is adjusted to 8 with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were dried and evaporated. The residue was chromatographed on alumina eluting with petroleum ether / ethyl acetate (9: 1).

Yield: 14.0 g (46% of theory), Yield: 0.27 (alumina; petroleum ether / ethyl acetate = 9: 1)

-40 ··· · ···· · ··· · · · · ·

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

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

Yield: 53.7% of theory, Rf: 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 is dissolved in 100 ml of chlorobenzene and after addition of 15 ml of trifluoroacetic anhydride it is stirred for two hours at 110 ml. 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 chloride / 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 -trifluoroacetyl- N -methyl-aniline

· · • · • ·· • ··· ·· • · • · ···· • • ·· · • · ·· • · · ···· • · · · • · ·· ···

1.15 g (3.0 mmol) of 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-trifluoroacetylaniline are dissolved in 50 ml of acetone and after addition of 2.0 g of potassium carbonate and 0.8 ml of methyl iodide was 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), Rf: 0.38 (silica gel; petroleum ether / ethyl acetate = 1: 1)

9) 4- [1 - [(Pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro- N -methyl-ariilin

7.4 g (18.8 mmol) of 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro- N -trifluoroacetyl- N -methyl-aniline was stirred for one hour at 30 ° C. ° C 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),

Rf 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 the theoretical yield;

Rf value: 0.51 (silica gel; methylene chloride / ethanol = 19: 1)

i) 4- [1 - [(Pyridin-3-yl) carbonyl] cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino-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-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide. Yield: 97% of the theoretical yield;

Rf value: 0.48 (silica gel; methylene chloride / methanol = 19: 1)

-42 · · ···········································

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.

Rf value: 0.52 (silica gel; methylene chloride / methanol = 19: 1)

l) (E / Z) -2- (4-Cyanophenylaminomethyl) -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) of carboxymethoxyamine hemihydrate, 0.84 ml of triethylamine, 12 g of molecular sieve 3A and 12 g of molecular sieve 4A are heated in 80 ml of methanol and 40 ml of 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), Rf 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 hydrochloric acid] ammonium carbonate in ethanol.

Yield: 60% of theory, Rf value: 0.28 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2) C29H31N7O3 * HCl (525.62 / 562.09) Mass spectrum: (M + H) ⁺ = 526

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

· · • · • · · • • • e · · • · • · · * ·· • • • · • · • · • · • • · • · • · • · ···· · · · · · · · · · · ·

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

Yield: 52% of theory.

Rf value: 0.21 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)

C ₂ 9H ₃ N ₇ O ₃ x HCl (525.62 / 562.09)

Mass Spectrum: (M + H) ⁺ = 526 (2) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (ethoxycarbonylmethyloxyimino) methylene] hydrochloride] cyclopropyl] benzimidazole

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

Yield: 10% of the theoretical yield;

C ₂ 4H 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-pyrazole-

5-yl) - (etoxykarbonylmetyloxyimino) methylene] cyclopropyl] -benzimidazole

Yield: 80% of the theoretical yield;

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

C ₂₈ 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)] dihydrochloride methylene] cyclopropyl] -benzimidazole

Yield: 47% of the theoretical yield;

· · • · • • 4 • ··· ·· • · • · ···· • • ·· • · • · · · • • · • · • · e · ···· · · · · · · · · · · ·

Rf: 0.06 (silica gel; methylene chloride / methanol = 9: 1) C32H36N6O3 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 hydroxide solution in 10 ml of ethanol were stirred at room temperature for 5 hours. 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 theory, Rf value: 0.10 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.1) C27H27N7O3 * 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)

C28H34N6O3 x HCl (502.62 / 539.08)

Mass Spectrum: (M + H) ⁺ = 503 (M + Na) ⁺ = 525 (2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1 (pyrrolidine-) hydrochloride 1-yl-carbonyl) -ethyl] -benzimidazole ··········

Yield: 98% of the theoretical yield;

R value: 0.73 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 2)

C ₂ 6H 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

Yield: 98% of the theoretical yield;

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

C ₂₅ H ₃₀ 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-pyrrolidine-1 hydrochloride yl-carbonyl) methyl] benzimidazole

Yield: 87% of the theoretical yield;

C ₂ 4H 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) hydrochloride ) pyrrolidin-1-yl-carbonyl] cyclopropyl] benzimidazole

Yield: 94% of the theoretical yield;

C ₂₇ H ₃₂ N ₆ O ₃ x HCl (488.59 / 525.05)

Mass Spectrum: (M + H) ⁺ = 489 (M + Na) ⁺ = 511 (6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -1- (pyrrolidine) hydrochloride (n-1-ylcarbonyl) methyl] benzimidazole

Yield: 49% of theory.

-46 ···························

C25H29N7O4 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- - (pyrrolidine-1-yl-carbonyl) -ethyl] benzimidazole

Yield: 92% of the theoretical yield;

C26H31N7O4 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-carboxymethylimidazoline) hydrochloride 2,4-dione-5-yl) benzimidazole

Yield: 88% of the theoretical yield;

C22H23N7O4 x HCl (449.47 / 485.94)

Mass Spectrum: (M + H) ⁺ = 450 (M + 2Na) ⁺⁺ = 247.7 (9) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [ (pyridin-3-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] -benzimidazole

Yield: 54% of the theoretical yield,

C27H27N7O3 x HCl (497.56 / 534.09)

Mass Spectrum: (M + H) ⁺ = 498 (M + Na) ⁺ = 520 (10) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (N - (2-) -] hydrochloride carboxyethyl) -

A / N-methyl-aminomethyl) pyrrolidin-1-yl-carbonyl] cyclopropyl] benzimidazole

Yield: 100% of the theoretical yield;

C29H37N7O3 x HCl (531.66 / 568.12)

Mass Spectrum: (M + H) ⁺ = 532 (MH +) = 530

· · • · • * · • ··· • · • · • · ··· · • • ·· · • • · · · · · · · · · ·· ···

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

Yield: 91% of the theoretical yield;

C25H27N7O2 x HCl (457.54 / 493.96)

Mass Spectrum: (M + H) ⁺ = 458 (12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (N-benzenesulfonyl- N -carboxmethylaminomethyl) benzimidazole hydrochloride

Yield: 84% of theory.

C25H26N6O4S 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.

C27H27N7O2 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) ²⁺ = 264 (14) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2-methyl-4-carboxyimidazol-1-ylmethyl) benzimidazole hydrochloride

Yield: 61% of the theoretical yield;

C22H23N7O2 x HCl (417.47 / 453.92)

Mass Spectrum: (M + H) ⁺ = 418 (15) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [3- (3-carboxy-n-propyl) benzimidazol-2-one-1-yl hydrochloride methyl] benzimidazole

Yield: 86% of the theoretical yield, ______________________________________________________________________ ·, · · 86 86 86 86 86 86 86 86 86 86 86 86 86 86 86 86 86 86 ··· ·· ·· ·· ·· _ββΒ

-48C28H29N7O3 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-amidinophenylaminomethyl) -1-methyl-5- [3- (2-carboxy-ethyl) -imidazo [4,5-b] pyridin-2-one-1-ylmethyl] -benzimidazole

Yield: 83% of theory.

CzeHzeNsOa x HCl (498.55 / 535)

Mass Spectrum: (M + H) ⁺ = 499 (M + Na) ⁺ = 521 (MH) + = 497 (2M-H) + = 995 (17) 2- (4-amidinophenylaminomethyl) -1-methyl-5 hydrochloride - [2- (2-carboxyethyl) -4,5dimetyl-imidazol-1-yl-methyl] benzimidazole

Yield: 68% of the theoretical yield;

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

C25H29N7O2 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- (carboxymethyl-oxyimino) methylene] cyclopropyl] -benzimidazole

Yield: 70% of the theoretical yield;

C28H28N6O3 x 2 HCl (496.57 / 569.5)

Mass Spectrum: (M + H) ⁺ = 497 (MH) + = 495 (19) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyridine-3-) hydrochloride yl) (carboxy-methylidene) methylene] cyclopropyl] -benzimidazole

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)] hydrochloride - (karboxymetyloxyimino) methylene] cyclopropyl] -benzimidazole

Yield: 30% of the theoretical yield;

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

Cae ^ eNaOa x HCl (500.58 / 537.03)

Mass Spectrum: (M + H) ⁺ = 501 (.delta.-H) @ - = 499 (M + Cl) ^{@ +} = 535/537 (Cl) (21) (E / Z) -2- (4-amidinophenylaminomethyl) - 1-methyl-5- [1- [phenyl- (3-carboxy-n-propyl oxyimino) methylene] cyclopropyl] -benzimidazole

Yield: 37% of the theoretical yield;

R value: 0.35 (reverse phase RP 8; 5% sodium chloride / methanol = 3: 2)

C30H32N6O3 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),

Melting point: 215 ° C

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),

Melting point: 186 ° C

d) 4-Chloro-3-nitro- N -t-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 value: 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) - N, N, N, N, N -tetramethyluronium-tetra- fluoroborate, 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 value: 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 the theoretical yield;

Rf: 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) - (V, A) Ar, N, tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in tetrahydrofuran.

Yield: 100% of the theoretical yield;

Rf 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 the theoretical yield;

C24H29N7O2 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) hydrochloride - / V-methyl-aminomethyl] benzimidazole

Yield: 74% of theory.

C28H37N7O3 x HCl (519.65 / 556.11) Mass Spectrum: (M + H) ⁺ = 520 (3) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl) hydrochloride carbonyl) - / V- (ethoxycarbonylmethyl) aminomethyl] benzimidazole

Yield: 76% of theoretical yield, ·· ····

-53C26H33N7O3 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-yl) hydrochloride yl-carbonyl) - / \ /, / \ / - di (ethoxycarbonylmethyl) aminomethyl] benzimidazole

Yield: 51% of the theoretical yield;

C30H39N7O5 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) hydrochloride - / N (etoxykarbonylmetylkarbonyl) aminomethyl] benzimidazole

Yield: 29% of the theoretical yield;

C27H33N7O4 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-yl) hydrochloride yl-carbonyl) -N- (2-ethoxycarbonylethyl) aminomethyl] benzimidazole

Yield: 84% of theory.

C27H35N7O3 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 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

Rf 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),

Rf value: 0.24 (reverse phase RP 8; 5% saline / 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-nitrophenyl) -propionic acid, pyrocarbonic acid-di-tert-butyl bicarbonate and triethylamine in dioxane.

Yield: 9.6 g (100% of theory),

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-methylmorpholine in dimethylformamide. Yield: 94% of the theoretical yield;

Rf: 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.

Rf 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 the theoretical yield;

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' -tetramethyluroniumtetrafluoroborate, 4-cyanophenylglycine and N -methylmorpholine in dimethylformamide.

Yield: 37% of the theoretical yield;

Rf 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, Rf value: 0.37 (silica gel; ethyl acetate)

Φ · • é · • ··· ·· • · • · ···· • • · · • · • · • · ···· · · · · · · «· ·· ·

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-ylcarbonyl) - Ethyl] -benzimidazole is dissolved in 20 ml of dioxane and stirred at room temperature for two hours after addition of 40 ml of semi-concentrated hydrochloric acid. 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), Rf: 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 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- [N - (2-ethoxycarbonylethyl) amino] -1- (pyrrolidin-1-ylcarbonyl) ethyl] - benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 96% of theory, C28H37N7O3 x HCl (519.65 / 556.11) Mass spectrum: (M + H) ⁺ = 520 (M + Na) ⁺ = 542

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

·· • · • ·· • ··· ·· • · • · ···· • • ·· • · • · • 9 • ···· • · • · • · • · • · ·· • · ·· · · ·

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

Yield: 69% of theory.

C27H34N6O5 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- (pyrrolidine) hydrochloride 1-yl-carbonyl) -ethyl] benzimidazole

Yield: 95% of the theoretical yield;

C28H35N7O4 x HCl (533.64 / 570.10)

Mass Spectrum: (M + H) ⁺ = 534 (M + Na) ⁺ = 556 (3) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonylpropionylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole

Yield: 20% of the theoretical yield;

C29H37N7O4 x HCl (547.66 / 584.12)

Mass Spectrum: (M + H) ⁺ = 548 (M + H + Na) ⁺⁺ = 285.7 (4) 2- [4-amidinophenyl- N - (2-ethoxycarbonylethyl) aminomethyl] -1-methyl hydrochloride -5 [1-Dimethylamino-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole

Yield: 91% of the theoretical yield;

C30H41N7O3 x HCl (547.71 / 584.17)

Mass Spectrum: (M + H) ⁺ = 548 (Μ-H) - = 546 (5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-ethylamino) -1- (dimethylaminocarbonyl) ethyl] benzimidazole

Yield: 40% of the theoretical yield;

· · • · • ·· • ··· ·· • · • · ···· • • ·· · • · ·· • · · ···· · · · · · · ·· ·· ·

Rf value: 0.60 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1)

C26H35N7O3 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- (ethoxycarbonylmethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole

Yield: 77% of the theoretical yield;

Rf value: 0.40 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C27H35N7O3 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) hydrochloride ) ethyl] benzimidazole

Yield: 85% of the theoretical yield;

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

C27H37N7O3 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] hydrochloride - (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 99% of the theoretical yield;

Rf value: 0.21 (silica gel; methylene chloride / ethanol = 4: 1 + 1% glacial acetic acid)

C26H33N7O3 x HCl (491,60 / 528,05)

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

-59 ···············································

(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)

C31H41N7O5 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- (ethoxycarbonylmethylamino) -1- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole

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) hydrochloride - ethyl] -benzimidazole (12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -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 - ((/ V, / V-di (ethoxycarbonylmethyl) amino) -1 - (/ V-methyl- / V-ethylaminocarbonyl) ethyl] benzimidazole

· · • · • • ··· ·· • · • · ···· • • ·· · • · ·· • · · ···· · · · · · · ·· ···

Yield: 30% of the theoretical yield;

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

C30H41N7O5 x 2HCI (579.71 / 652.62)

Mass Spectrum: (M + H) ⁺ = 580 (Μ-H) - = 578 (14) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (piperidinocarbonyl) dihydrochloride - ethyl] benzimidazole

Yield: 82% of theory.

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

C28H37N7O3 x 2HCI (519.65 / 592.75)

Mass Spectrum: (M + H) ⁺ = 520 (M-H + HCl) · = 534/6 (Cl) (M-H + 2HCl) · = 590/2/4 (Cl ₂ ) (15) Dihydrochloride 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl-methylamino) -1- (diethylaminocarbonyl) ethyl] -benzimidazole

Yield: 88% of the theoretical yield;

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

C27H37N7O3 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- (etoxykarbonylmetylmetyl-amino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] benzimidazole

Yield: 46% of the theoretical yield;

Rf value: 0.43 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C28H37N7O3 x 2 HCl (519.65 / 592.56) ······················ ···················

-61 Mass Spectrum: (M + H) ⁺ = 520 (M + Cl = 554/6 (Cl) (17) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazole-5-) dihydrochloride yl-methylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole (18) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonylpropyl-amino) -hydrochloride - 1- (Pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole

Yield: 95% of the theoretical yield;

Rf value: 0.50 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C29H39N7O3 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 mixed with 8.3 g (76 mmol) of ethyl chloromethanate. After one hour at room temperature, 0.75 g of tetrabutylammonium bromide is added. The solution is then added dropwise

6.3 g (96 mmol) of sodium azide in 20 ml of water. 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

· · • · • ·· • ··· ·· • · • · ···· • • • · • · e · • · ···· · · · · · · · · ·· ·

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 stirred for 7 hours at room temperature. The solvent was distilled off, the residue was triturated with ether, filtered off with suction and dried.

Yield: 98% of theory, Rf: 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 -methylaniline 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, eluting 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) triethylamine was mixed 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 value: 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 the theoretical yield;

Rf value: 0.18 (silica gel; ethyl acetate / cyclohexane = 1: 1)

f) 4- [1- (N - (3-Ethoxycarbonylpropionyl) - N -cyclopentyl-amino) cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino- N -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 ', N-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 96% of theory.

Rf value: 0.54 (silica gel; methylene chloride / methanol = 9.5: 0.5)

g) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- [N-cyclopentyl-N- (3-ethoxycarbonylpropionyl) amino] cyclopropyl] benzimidazole

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

Yield: 52% of theory.

Rf value: 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 the theoretical yield,

CaoHaeNeOs x HCl (530.68 / 567.14) Mass Spectrum: (M + H) ⁺ = 531 ·· ····

-64Example 8

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

a) 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylaminocarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) 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: 0.01)

b) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-ethoxycarbonylmethyl-imidazolin-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 80 DEG C. for 3 hours in 80 ml of ety-ethyldiisopropylamine. 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 value: 0.64 (silica gel; petroleum ether / ethyl acetate = 8: 2)

b) 4- (2-tert-Butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-1H-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, Rf value: 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 of hydrate hydrazine. 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), Rf 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) - (1 H, 1 H), N, N -tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine in tetrahydrofuran and glacial acetic acid.

Yield: 72% of the theoretical yield;

Rf value: 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.

·· ·· ····

-67 • «··

Yield: 59% of theory.

C27H31N7O2 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 the theoretical yield;

C27H30N6O4S 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.

C25H26N6O 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 the theoretical yield;

C ₁₅ Hi ₂ CIN ₃ O2 (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.

-67 ·································· ·· ·· ·· ·· ···

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 / 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 N - (4-cyanophenyl) glycine (1.94 g, 11.0 mmol) and carbonyldiimidazole (1.78 g, 11.0 mmol) was heated in refluxing absolute tetrahydrofuran (80 ml) for 15 min. After addition of 2.7 g (10.46 mmol) of 1- (4-methylamino-3-aminobenzyl) -2-methylbenzimidazole, the mixture was heated at 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 value: 0.30 (silica gel; methylene chloride / ethanol = 19: 1) C ₂₅ H22N ₆ (406.5)

Mass Spectrum: M ⁺ = 406

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

Prepared in analogy to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5 - [(2-methylbenzimidazol-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 the theoretical yield;

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-amidinophenylaminomethyl) -1-methyl-5- [1- (imidazol-1-yl) hydrochloride] - ethyl)] - benzimidazole

Yield: 70% of the theoretical yield;

C ₂ 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-) dihydrochloride methyl-imidazol-1-yl) -ethyl] -benzimidazole

Yield: 18% of the theoretical yield,

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-) - dihydrochloride imidazole

yl) methyl] benzimidazole

Yield: 36% of the theoretical yield,

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) dihydrochloride] N- (N-Methylamino-methyl) -benzimidazole

Yield: 78% of the theoretical yield;

C23H25N7 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) dihydrochloride) ) benzimidazole-1-yl) methyl] benzimidazole

Yield: 61% of the theoretical yield;

C29H31N7O2 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 hydrochloride -5 - [(imidazol-1-yl) methyl] benzimidazole

Yield: 35% of the theoretical yield,

C20H21N7 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) dihydrochloride) ethyl) -

4,5-dimethyl-imidazol-1-yl) methyl] benzimidazole

Yield: 42% of theory.

C26H32N8O 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-aminocarbonylethyl) -4,5-dimethyl-imidazol-1-yl) methyl] benzimidazole

• · • · • • ··· • · • · • · ···· • • ·· · • · · ···· · · · · é · • · ···

Yield: 68% of the theoretical yield;

C25H30N8O 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-imidazole) hydrochloride 1-yl) methyl] benzimidazole

Yield: 34% of the theoretical yield;

C24H27N7O2 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 hydrochloride - [(3- (3-ethoxycarbonyl-propyl) -benzimidazole-2-one-1-yl) methyl] benzimidazole

Yield: 58% of theory.

C30H33N7O3 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-ethoxycarbonylethyl) hydrochloride) ) -imidazo [4,5-b] pyridin-2-on-1-yl) methyl] benzimidazole

Yield: 29% of the theoretical yield;

C28H30N8O3 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

Yield: 58% of theory.

C26H25N7 x HCl (435,54 / 472) ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-71 Mass Spectrum: (M + H) ⁺ = 436 (M + Na) ⁺ = 218.6 (14) 2- (4-amidinophenylaminomethyl) -1-methyl-5 - [(4,5-dimethyl-2) dihydrochloride - (2-ethoxy-carbonylethyl) -imidazol-1-yl) methyl] benzimidazole

Yield: 52% of theory, C27H33N7O2 * 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 tert-butyl ester

The 2,4-dibromobutyrate is 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 ₃ H ₃₈ N ₆ O3 (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 1-benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

e · • · • ·· • ··· · · • • • • ···· • • · · • · • • • • • • · • • • · • • ···· · · · · · · · · · · ·

Yield: 12% of theory, C29H37N7O3 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 3 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).

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

Prepared in analogy to Example 1g from ((E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) -ethoxycarbonylmethylidene) methylene] cyclopropyl] benzimidazole and hydrochloric acid] ammonium carbonate in ethanol.

Yield: 58% of theory, C29H30N6O2 x HCl (494.60 / 531.05) Mass spectrum: (M + H) ⁺ = 495

• · • · • ·· • ··· ·· • · • e ···· • • ·· · • · ·· • · · ···· · · · · · · ·· ···

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

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

Yield: 72% of theory, C29H30N6O2 x HCl (494.60 / 531.05) Mass spectrum: (M + H) ⁺ = 495

Example 13

2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxy-azetidin-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) -ethyl] hydrochloride 1-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) C27H33N7O3 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 theory, Yield: 0.75 (reverse phase; 5% sodium chloride / methanol = 1: 1) C24H31N7O3 x HCl (465.56 / 502.01)

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

e · • · • • · • ··· • · • · • · ···· • • • · · • · · · • t · ···· · · · · · · ·· ···

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

Yield: 70% of the theoretical yield;

R value: 0.51 (reverse phase; 5% sodium chloride / methanol = 3: 2)

C25H31N7O3 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] hydrochloride methylene] cyclopropyl] benzimidazole

Yield: 65% of the theoretical yield;

C27H26N6O2 x HCl (466.55 / 503.0)

Mass Spectrum: (M + H) ⁺ = 467 (M + Cl) ⁺ = 501/503 (Cl) (4) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methyl) dihydrochloride carboxymethyl-carbonylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole

Yield: 99% of the theoretical yield;

Rf value: 0.55 (reverse phase RP 8; methanol / 5% saline = 1: 1)

C28H35N7O4 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-carboxyethylamino) -1- (N-ethyl- N -methylaminocarbonyl) -ethyl] -benzimidazole

Yield: 75% of the theoretical yield;

Rf value: 0.54 (reverse phase RP 8; methanol / 5% saline = 1: 1)

C25H33N7O3 x 2 HCl (479.59 / 552.59)

Mass Spectrum: (M + H) ⁺ = 480

· · • · • ·· • ··· ·· ···· · · · · · · ·· · • · · · • · · ···· · · ·· ·· ·· ···

Example 14 2- [4- (N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -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 55 ml of tetrahydrofuran, It is mixed 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 2

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) Rf value: 0.50 (silica gel; methylene chloride / ethanol = 19: 1) Mass spectrum: (M + H) ⁺ = 622 (M + Na) ⁺ = 644

Example 15 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride

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-chlorophenyl) -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: · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Wash with 1N sulfuric acid, water, saturated sodium bicarbonate solution and brine, and dry over magnesium sulfate. The crude product was 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 the theoretical yield;

Melting point: 129-132 ° C

C10H9CIN2O7 (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, C10H10CINO5 (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.

·· ·· • · · • ♦ · • · • · • · ···· • • ·· · • · ·· • · · ···· ·· · · · · ·· ···

-77C18H20CIN2O5 (344.37)

Mass Spectrum: MH + = 344

f) 2- [4- (N-Benzylmethylamino) -3-nitrophenyl] -2-methyl-3-hydroxy-1-pyrrolidin-1-ylpropan-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.

C22H27N3O4 (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-propane-1- In 20 ml of tetrahydrofuran, at room temperature, 1.3 ml (9.3 mmol) of triethylamine are added. 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-1- The reaction mixture was stirred at room temperature for 1 hour in 10 ml of dimethylformamide and treated 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 was purified on silica gel, eluting with ethyl acetate / ethanol (10: 1, 9: 1, 4: 1 1% concentrated ammonia). The individual fractions were combined and evaporated.

-78 ··································

Yield: 740 mg (61% of theory),

Rf value: 0.45 (silica gel; methylene chloride / ethanol 9: 1 + 1% horse, 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-nitrophenyl] -2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one and acid chloride methyl ester malonate.

Yield: 84% of theory.

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

C27H34N4O6 (510.60)

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

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

Prepared in analogy to Example 1d from 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3- (N-methoxycarbonylmethylcarbonylmethylamino) -1-pyrrolidin-1-ylpropane- 1-one and hydrogen / palladium on activated carbon.

Yield: 100% of the theoretical yield;

Rf value: 0.40 (silica gel; ethyl acetate / ethanol 9: 1 + 1% horse, ammonia)

C20H30N4O4 (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-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 95% of theory, Yield: 0.35 (silica gel; ethyl acetate / ethanol 9: 1 + 1% of horse, ammonia)

· · • · • ·· • ··· ·· ···· · · · · · · ·· • · • · • · ···· · · ·· ·· · · · · ·

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

Prepared in analogy to Example 1f of 4- [2- (3- (N-methoxycarbonylmethylcarbonyl-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;

Rf value: 0.20 (silica gel; ethyl acetate / ethanol 9: 1)

C ₂ 9H34N ₆ O ₄ (530.63)

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

(m) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -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 / ammonium carbonate in ethanol.

Yield: 65% of the theoretical yield;

Rf value: 0.30 (silica gel; methylene chloride / methanol = 4: 1 + glacial acetic acid)

C ₃ H 39 N ₇ 0 ₄ x HCl (561,69 / 598,19)

Mass Spectrum: (M + H) ⁺ = 562 (M + Cl) + = 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-value: 0.35 (reverse phase RP 8; methanol / 5% sodium chloride 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) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxycarbonylmethylcarbonylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] -benzimidazole acetate

Yield: 45% of the theoretical yield;

Rf value: 0.20 (silica gel; methylene chloride / methanol = 8: 2 + 1% ethyl acetate)

C29H37N7O4 x CH3COOH (547.66 / 607.71)

Mass Spectrum: (M + H) ⁺ = 548 (Μ-H) - = 546 (M-H + CH 3 COOH) · = 606 (3) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2 - (N-methyl-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-ethoxycarbonylmethylcarbonyl-methylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazole (6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylsulfonyl-methylamino) -hydrochloride (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazole 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)

C29H37N7O4 x CH3COOH (547.66 / 607.71)

Mass Spectrum: (M + H) ⁺ = 548 (Μ-H) - = 546 (8) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-ethylcarbonyl-amino) - hydrochloride - 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole • • • • • • • • • • • • ·· ·· · _Μ (9) 2- (4-amidinofenylaminometyl) -1-methyl-5- [1- (ethoxycarbonylmethyl- sulfonyl-amino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole

Yield: 14% of the theoretical yield,

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2)

C28H37N7O5S x HCl (583.65 / 620.17)

Mass Spectrum: (M + H) ⁺ = 584 (M + Na) ⁺ = 606 (10) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol-5-yl) hydrochloride] - methylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -2- (pyrrolidinocarbonyl) dihydrochloride prop-2-yl] benzimidazole

Yield: 40% of the theoretical yield;

C28H37N7O3 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 hydrolysis of 2- (4-amidinophenylaminomethyl) -1-methyl-

Of 5- [1- (ethoxy-carbonylmethylamino) -2- (isoxazolidin-1-yl-carbonyl) -ethyl] -benzimidazole with sodium hydroxide in ethanol.

Yield: 90% of the theoretical yield;

Rf value: 0.65 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2) C24H29N7O4 x HCl (479.54 / 515.99)

Mass Spectrum: (M + H) ⁺ = 480

· · • · • • e • ··· · · • · • · ···· • • ·· • · • · • · • ···· · · · · · · · · ·· ·

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) hydrochloride -amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1 (N-methyl- N -ethylaminocarbonyl) -ethyl] -benzimidazole

Yield: 93% of theory.

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

C24H31N7O3 x HCl (465.57 / 502.02)

Mass Spectrum: (M + H) ⁺ = 466 (M + Cl-H) · = 500/2 (Cl) (3) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (V) dihydrochloride -karboxymetylmetylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole

Yield: 89% of theory.

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

C27H 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 hydrochloride - [1- (carboxymethyl-carbonylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole

Yield: 90% of the theoretical yield;

Rf value: 0.55 (reverse phase RP 8; methanol / 5% saline = 4: 6)

C27H33N7O4 x HCl (519.61 / 556.06)

Mass Spectrum: (M + H) ⁺ = 520 (Μ-H) - = 518 (5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethyl-methylamino) -2-hydrochloride - (N-Ethyl-methylaminocarbonyl) -prop-2-yl] -benzimidazole ··· ··· ··········· • · · · · · · · · · ···

(6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylcarbonyl-methylamino) -2- (N-ethyl-methylaminocarbonyl) -prop-2-yl hydrochloride yl] -benzimidazole (7) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylcarbonyl-methylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride (8) ) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylsulfonylmethylamino) -2- (piperidinocarbonyl) prop-2-yl] benzimidazole hydrochloride (9) 2- (4) hydrochloride -amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylamino) 1- (piperidinocarbonyl) ethyl] benzimidazole

Yield: 81% of theory.

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

C26H33N7O3 (491.60 / 528.05)

Mass Spectrum: (M + H) ⁺ = 492 (Μ-H) - = 490 (10) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylsulfonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] - benzimidazole (12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) 1- (diethylaminocarbonyl) ethyl] -benzimidazole hydrochloride

Yield: 70% of the theoretical yield;

Rf value: 0.50 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1) C25H33N7O3 x HCl (479.59 / 516.05)

Mass Spectrum: (M + H) ⁺ = 480 (Μ-H) - = 478 (M-H + HCl) · = 514/516 (Cl) (13) 2- (4-amidinophenylaminomethyl) -1-methyl- 5- [1- (Carboxymethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 22% of theory, Yield: 0.50 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1) C26H33N7O3 x 2 HCl (491.60 / 564.51)

Mass Spectrum: (M + H) ⁺ = 492 (Μ-H) - = 490 (14) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylmethylamino) dihydrochloride - 1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Rf value: 0.48 (reverse phase RP 8; 5% sodium chloride / methanol = 3: 2) C26H33N7O3 x 2 HCl (491.60 / 564.51)

Mass Spectrum: (M + H) ⁺ = 492 (MH) + = 490 (15) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (3-carboxypropylamino) -1- (pyrrolidinocarbonyl) dihydrochloride - ethyl] benzimidazole

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

C27H35N7O3 x 2 HCl (505.63 / 578.54)

Mass Spectrum: (M + H) ⁺ = 506

Example 17

2- [4- (N-Fenylkarbonylamidino) -fenylaminometyl] -1-methyl-5- [1- (ethoxycarbonylmethyl) -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-diisopropylamine and 2 ml of dimethylformamide were mixed 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 is evaporated in vacuo, the residue dissolved in water after cooling

-85 dichloromethane 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),

Rf value: 0.40 (silica gel: methylene chloride / ethanol = 19: 1)

C34H39N7O4 (609.73)

Mass Spectrum: (M + H) ⁺ = 610 (M + Na) ⁺ = 632 (.delta.-H) @ - = 608

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

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

Yield: 53% of the theoretical yield;

Rf value: 0.35 (silica gel; methylene chloride / ethanol = 9: 1)

C34H47N7O5 (633.79)

Mass Spectrum: (M + Na) ⁺ = 656 (Μ-H) - = 632 (2) 2- [4- (N, N-octyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1 - (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 46% of the theoretical yield;

Rf value: 0.43 (silica gel; methylene chloride / ethanol = 9: 1)

C36H51N7O5 (661.84)

Mass Spectrum: (M + Na) ⁺ = 684 (Μ-H) - = 660 (3) 2- [4- (N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonylmethylamino) - 1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

· · • · • ·· • ··· ·· ···· · · · • · · ·· t • · ·· • · · ···· · · ·· ·· ·· ···

(4) 2- [4- (N-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 H49N ₇ O ₅ (647.82)

Mass Spectrum: (M + Na) ⁺ = 670 ([delta] -H) &lt; - &gt; = 646 (5) 2- [4- (N-n-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1 - (/ N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 52% of theory.

Rf value: 0.60 (silica gel; methylene chloride / ethanol = 9: 1)

C37H51N7O6 (689.85)

Mass Spectrum: (M + H) ⁺ = 690 (MH) + = 688 (M + Na) ⁺ = 712 (M + HCl-H) + = 724/26 (CI) (6) 2- [4 - (/ N- (R-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 H49N ₇ O6 (675.83)

Mass Spectrum: (M + H + = 676 (M + Na) ⁺ = 698 (M + HCl-H) - = 724/26 (Cl) (8) 2- [4- (N-octyloxycarbonylamidino) -phenylaminomethyl ] -1-Methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole ·············· (9) 2- [4- (N-Phenylcarbonylamidino) · · 9 9 9 9 9 9 9 9 9 9 9 9 9 -phenylaminomethyl] -1-methyl-5- [1- (methoxy-carbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 34% of the theoretical yield;

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

C33H37N7O4 (595.70)

Mass Spectrum: (MH) - = 594 (M + Na) ⁺ = 618 (10) 2- [4- (N-isopropyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ΛΖ-ethoxycarbonylmethylcarbonyl-methylamino)] -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 66% of theory,

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C34H45N7O6 (647.77) Mass Spectrum: (M + H) ⁺ = 648 (M-H) = 646 (M + Na) ⁺ = 670

(11) 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonyl-methylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2- yl] -benzimidazole Yield: 23% of theory,

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C37H43N7O5 (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-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 67% of theory .

Rf value: 0.60 (silica gel; methylene chloride / ethanol = 9: 1)

C36H41N7O5 (651.76)

• · • · • «· • ··· · · • · • · ···· • • • · · · · · · · · • · · ···· · · · · · ·· ···

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

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

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C34H45N7O6 (647.77)

Mass Spectrum: (M + H) ⁺ = 648 (M-H) - = 646 (M + Na) ⁺ = 670 (M-H + Cl) · = 682/4 (Cl) (14) 2- [4- (N-Ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 54% of theory .

Rf value: 0.40 (silica gel; methylene chloride / ethanol = 9: 1)

C33H43N7O6 (633.75)

Mass Spectrum: (M + H) ⁺ = 634 (M-H) = 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)

C32H41N7O6 (619.72)

Mass Spectrum: (M + H) ⁺ = 620 (.delta. -H) @ - = 618 (M + Na) ^{@ +} = 642

· · • · • ·· • ··· 9 9 • · · • · ·· • · · ···· · · ·· ·· ·· ···

(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.

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C36H42N8O5 (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)

C32H43N7O5 (605.74)

Mass Spectrum: (M + H) ⁺ = 606 (M + Na) ⁺ = 628 (.delta. -H) @ - = 604 (18) 2- [4 - ((VEYloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [ 1- (ethoxy-carbonyl-methylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 30% of the theoretical yield;

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

C30H39N7O5 (577.68)

Mass Spectrum: (M + H) ⁺ = 578 (M + Na) ⁺ = 600 (MH) + = 576 (19) 2- [4- (N-Benzyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [ 1- (ethoxycarbonylmethyl) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 51% of the theoretical yield;

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C35H41N7O5 (639.75)

· · • · • • · • ··· ·· ···· · · · · · · ·· · • · · ···· · · ·· ·· ·· ···

Mass Spectrum: (M + Na) ⁺ = 662 (MH) + = 638 (20) 2- [4- (N-Pyridin-3-ylcarbonylamidino) -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)

CasHsaNeCU (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.

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

C31H39N7O5 (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.

Rf value: 0.54 (silica gel; methylene chloride / ethanol = 9: 1)

C30H36C13N7O5 (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-R-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) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole in 3 ml of tetrahydrofuran and 2.5 ml of ethanol are 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),

Rf value: 0.35 (reverse phase RP 8; methanol / 5% sodium chloride solution = 2: 1) C34H47N7O5 (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 is mixed with 0 , 47 g (7.8 mmol) of hydroxylamine hydrochloride and 0.35 g (3.5 mmol) of sodium carbonate were heated under reflux for 17 hours. After cooling, the residue is filtered, the filtrate is 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), Rf: 0.68 (silica gel; methylene chloride / ethanol = 4: 1)

C27H35N7O4 (521.62)

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

·· ·· • · · • ··· · · • · • · ···· • • ·· · • · ·· • · · ···· ·· · · · · ·· ···

Example 20

2- [4 - (/ V-Fenylkarbonylamidino) -fenylaminometyl] -1-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 the theoretical yield;

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 the theoretical yield;

Rf: 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) 2- (4-methylamino-3-aminophenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidin-1-yl-propanone, 4- (5-methyl-1,2,4-oxadiazole-) 3-yl) -phenylamino-acetic acid and carbonyldiimidazole in tetrahydrofuran and subsequent treatment with glacial acetic acid.

Yield: 34% of the theoretical yield;

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- (iso-propyloxycarbonylmethylamino) -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 the theoretical yield, · · * * * * * · • • · · · · · · · · · · · · · · · ···· ·· ·· ·· ··

-93Value: 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) phenylamino-triethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) - 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) -phenylaminomethyl] -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] -benzimidazoacetate and 4-nitrophenyl benzoate in N-ethyl-diisopropylamine / dimethylformamide .

Yield: 26% of the theoretical yield;

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C35H41N7O4 (623.75)

Mass Spectrum: (M + Na) ⁺ = 646 ([delta] -H) - = 622

In analogy to Example 20, the following compounds were prepared:

(1) 2- [4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole (2) 2- [ 4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2-phenylethyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

· · • · • ·· • ··· · · • e • · ···· • • ·· · • · ·· • · · ···· • · · · · · ·· ···

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

Yield: 40% of the theoretical yield;

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C35H49N7O5 (647.82)

Mass Spectrum: (M + H) ⁺ = 648 (MH) + = 646 (M + Na) ⁺ = 670 (4) 2- [4- (N-N-octyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5 - [1- (i-propyloxykarbonylmetylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 31% of theory.

Rf value: 0.48 (silica gel; methylene chloride / ethanol = 9: 1)

C37H53N7O5 (675.88)

Mass Spectrum: (M + H) ⁺ = 674 (M + Na) ⁺ = 698 (5) 2- [4- (R / - (2,2,2-Trichlorethyloxycarbonyl) amidino) phenylaminomethyl] -1-methyl- 5- [1- (Isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole Yield: 43% of theory.

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C31H38Cl3N7O5 (695.05)

Mass Spectrum: (MH) - = 692/694/696/698 (CI3) (6) 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyl- oxykarbonylmetylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 79% of the theoretical yield;

Rf value: 0.35 (silica gel; ethyl acetate / ethanol = 9: 1)

C35H41N7O4 (623.76)

Mass Spectrum: (M + H) ⁺ = 624 (MH) + = 622 (M + HCOO) · = 668

·· ·· • · · • ··· · · • · • · ···· • • ·· · • · ·· • · · ···· ·· · · · · ·· ···

(7) 2- [4- (N-n-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 53% of the theoretical yield;

Rf value: 0.39 (silica gel; ethyl acetate / ethanol = 9: 1)

C37H53N7O5 (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 of (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).

-96HPLC 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 -butyloxycarbonylamino-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-pyrrolidinopropanone

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-pyrrolidinopropanone

Prepared in analogy to Example 1c from (R) -2- (4-methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone and hydrogen / palladium on activated carbon in methanol.

·····························

-97 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 glacial 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.

(I) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride

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

Yield: 95% of theory.

· · • · • • e •·· ·· • · • · ···· • • • · · • · ·· • · · ···· • · · · · · ·· ···

(m) (R) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride

Prepared in analogy to Example 4 from (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and sodium hydroxide in ethanol.

Yield: 100% of theory.

C25H31N7O3 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 75.0 mg

Mannitol 50.0 mg

Water for injections ad 10.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. Dissolution to a ready-to-use solution is performed with water for injection purposes.

Example 23

Dry ampoule with 35 mg of active substance per 2 ml

Ingredients:

Active substance

mannitol

Water for injection purposes

35.0 mg 100.0 mg ad 2.0 ml

· · • · • ·· • ··· ·· • · • · ···· • • ·· · • · ·· • · · ···· · · · · · · ·· ···

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. Dissolution to a ready-to-use solution is done with water for injection purposes.

Example 24

Tablet with 50 mg of the active substance

Ingredients:

(1) Active substance

50,0 mg (2) Milk sugar

98,0 mg (3) Corn starch

50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) 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: (1) Active substance 350.0 mg (2) Milk sugar 136.0 mg (3) Maize starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 ma

600.0 mg

-100 -

· · • · • ·· • ··· ·· • · • · ···· • • ·· · • · ·· • · · ···· · · · · · · ·· ···

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) Corn starch, dried 58.0 mg (3) Powdered milk sugar 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg

Preparation:

(1) is rubbed with (3). This triturated 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:

(1) Active substance

350,0 mg (2) Corn starch dried

46,0 mg (3) Milk sugar powder

30,0 mg (4) Magnesium stearate

4.0 mg

430.0 mg

-101 -

·· • · • • · · • ··· • · ♦ · ···· · · · • · · • · · · · ·· • · • · • · • ·· • • ···· · · ·· ·· · · · · ·

Preparation:

(1) is rubbed with (3). This triturated 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 0.

Example 28

Suppositories with 100 mg of the active ingredient suppository contains:

Active substance 100.0 mg Polyethylene glycol (molecular weight 1 500) 600.0 mg Polyethylene glycol (molecular weight 6,000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg 2 000.0 mg

Preparation:

The polyethylene glycol is melted together with the polyethylene sorbitan monostearate. At ° C, the milled active ingredient is dispersed homogeneously in the melt. Cool to 38 ° C and pour into slightly pre-cooled suppository forms.

Claims (13)

1. Benzimidazoles of the formula I in which: Ar is a phenylene or naphthylene group, optionally substituted with a fluorine, chlorine or bromine atom, trifluoromethyl, C 1-6 alkyl; _3- alkyl or C 1-6 alkyl; _3- alkoxy, optionally in a carbon skeleton of C 1-6; _{A 3-} alkyl-substituted thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group, A C _1-3 -alkylene group, B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, or a C 1-6 alkyl group; _{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-3, 5-cycloalkyl, wherein ^R1 is Ci. _3- alkoxy-, amino-, C 1-4 -alkylamino- or di- (C 1-4 -alkyl) amino, in which the alkyl moiety may in each case be substituted by a carboxy group, A 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted with one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy-, carboxy-, carboxy-C _1-3 -alkoxy-, carboxy-C1-6alkyl; _3- alkylamino-, N - (C _1-3 -alkyl) - N - (carboxy-C _1-3 -alkyl) amino-, carboxy-C _1-3 -alkylaminocarbonyl-, N - (C _1-3 -alkyl) - N - (carboxy-C _1-3 -alkyl) aminocarbonyl-, carboxy-C 1-6 alkyl; _3- alkylaminocarbonylamino-, 1- (C _1-3 -alkyl) -3- (carboxyC _1-3 -alkyl) -aminocarbonylamino-, S-C 1-8 -alkyl-C 5-6 -carboxy-C 5-6 -alkyl-4-aminocarbonyl · · ··· · -103 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Amino- or 1,3-di- ( C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonylamino, hydroxy substituted with 4- to 7-membered cycloalkyleneimino, optionally C 1-3 -alkyl substituted with 5- to 7-membered cycloalkyleneimino, to which the phenyl ring, morpholino-, piperazino-, N - (C _1-3 -alkyl) -piperazino-, pyrrolino-, 3,4-dehydropiperidino- or pyrrol-1-yl-group is fused via two adjacent carbon atoms, R ² -CX-C ₃ -5-cycloalkyl wherein R ² is optionally C 1-6. _{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 C 1-6 alkyl; _{A 3-} alkyl-substituted amino, oxygen or sulfur atom, or optionally a C 1-6 alkyl group; _{The 3-} 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 1-3 -alkoxy, carboxy-C 1. _3- alkylamino- or N - (C _1-3 -alkyl) -carboxy-C 1-6 alkyl; ₃ alkylamino, and X represents an oxygen atom; _3- alkylimino-, Ci. -Alkoxyimino- _3, C ₃ -alkylhydrazino-, di-ÍCKj hydrazino-alkylene, C 2-4 alkanoylhydrazino-, A / - (C ₃ -alkyl) ₂ C or C -4alkanoylhydrazino-. 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 group substituted by a C ₃ alkyl- or C _{3. A} cycloalkyl group in which the imidazole ring may be substituted by phenyl or carboxy and one or two C _1-3 -alkyl groups, or one, two or three C 1-6 alkyl groups; ₃ alkyl groups, wherein the substituents may be the same or different and one of the above alkyl substituents may be simultaneously substituted with a carboxy group or in the 2 or 3 position of amino, C2-4-alkanoylamino-, C1-3alkyloxy; _3- alkylamino-, N (C 2-4 -alkanoyl) -C 1. _3- alkylamino- or di- (C _1-3 -alkyl) amino, and • · · · ·· · • · • • • • • · · · • · · · • • • • · · ···· • · • · • · ·· ··· The -104 imidazolone ring may be substituted with C 1-6 alkyl. ₃ -alkyl, wherein the alkyl substituent is optionally substituted with carboxy, or in the 2 or 3 amino, C 2-4 alkanoylamino, C 3-amino- / V- (C ₂ -4 -alkanoyl) -C. _{The 3-} alkylamino or di- (C _1-3 -alkyl) amino group, and in addition to the above imidazole and imidazolone ring, a phenyl or pyridine ring, an imidazolidin-2,4-dione-5-yl group, may be fused via two adjacent carbon atoms. , which may be substituted with one or two C 1-6 alkyl. _3- alkyl, wherein at the same time one alkyl substituent may be substituted by carboxy, C 1-4 -alkyl which is substituted A C ₃ -alkyl-Y ¹ -Ci_3-alkyl, HOOC-C 3 -C ¹ alkyl, 3-alkyl, tetrazolyl-Ci.3 alkyl ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C 1-3 alkyl and optionally C 1-6 alkyl; _3- alkyl substituted with isoxazolidinylcarbonyl, pyrolinocarbonyl-, 3,4-dehydro-piperidinocarbonyl-, pyrrol-1-ylcarbonylcarboxy-, aminocarbonyl-, C 1 -C 3 -alkyl; _{A 3-} alkylaminocarbonyl-, di- (C _1-3 -alkyl) aminocarbonyl- or 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein for the above groups the cycloalkyleneimine moiety may be substituted by one or two C 1-3 -alkyl groups and at the same time may be an alkyl moiety or an alkyl substituent of the aforementioned C 1-6 alkyl. _3- alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-carbonyl- or cycloalkyleneiminocarbonyl 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 an optionally C 1-3 -alkyl substituted by a carboxy group and R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ¹ -C 1-3 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ C 1-3 -alkyl-Y ² -, C 1-3 -alkyl-Y ² - or carboxy-C 1-3 -alkyl-Y ² -group or R ³ and R ⁴ together with the intervening nitrogen atom represent optionally carboxy-, C _1-3 -alkyl- or carboxy-C 1. _{A 3-} alkyl substituted 4- to 7-membered cycloalkyleneimino group in which Y ¹ represents a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH-group, and ··· -105Y 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 occurring in the the definitions of Y ¹ and Y ² may in each case be additionally substituted by C 1-3 -alkyl- or carboxy-C 1-3 -alkyl, R ⁵ NR ⁶ -substituted by C _1-3 -alkyl- or C 3-5 -cycloalkyl in which: R ⁵ represents a hydrogen atom, a C _1-3 -alkyl-, a C 3-7 -cycloalkyl-, a phenylcarbonyl-, a phenylsulfonyl- or a pyridinyl group and R ⁶ represents C _1-3 -alkyl-, carboxy-C 1-3 -alkyl- or carboxy-C 1-3 -alkyl-carbonyl, C 1-3 -alkyl which is substituted by C ₂ . _4- alkanoyl- or C 3-8 -cycloalkanoyl and C 1-3 -alkyl substituted by a chlorine, bromine or iodine atom, R ^b is hydrogen or C 1-3 -alkyl a R ^c is cyano or optionally one or two C 1-3 -alkyl substituted amidino groups, their tautomers, their stereoisomers, mixtures thereof, their precursors, their derivatives which contain a negatively charged group at the carboxyl group under physiological conditions, and their salts. Benzimidazoles of the general formula Ia (Ia) in which A represents a C 1-3 -alkylene group, B an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, or a C 1-3 -alkyl-substituted amino group in which the alkyl moiety may be mono- or disubstituted by a carboxy group, · * ··· é · · · ············ -106R ^and means R ^{1 is} -CO-C 3-5 -cycloalkyl wherein: ^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, 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by one or two C 1-3 -alkyl groups, wherein one alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy-, carboxy-, carboxy-C 1-3- alkoxy-, carboxy-C 1-6 alkyl; _3- alkylamino-, N- (C1-3-alkyl) -N- (carboxy-C1-3-alkyl) amino-, carboxy-C1-3-alkylaminocarbonyl-, N- (C1-3-alkyl) - N - (carboxy-C 1-3 -alkyl) -aminocarbonyl-, carboxy-C 1-3 -alkylaminocarbonylamino-, 1- (C 1-3 -alkyl) -3- (carboxy-C 1-3 alkyl) aminocarbonylamino-, 3- (C 1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) aminocarbonylamino- or 1,3-di- (C 1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) - aminocarbonylamino, hydroxy substituted 4- to 7-membered cycloalkyleneimino, or C 1-3 -alkyl substituted by 5- to 7-membered cycloalkyleneimino, to which the phenyl ring, morpholino, piperazino, is fused via two adjacent carbon atoms. N - (C _1-3 -alkyl) -piperazino-, pyrrolino-, 3,4-dehydropiperidino- or pyrrol-1-yl-group, R ² -CX-C 3-5 -cycloalkyl, 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 1-6 alkyl; _{A 3-} alkyl-substituted amino, oxygen or sulfur atom, or an optionally C 1-3 -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 1-3 -alkylamino- or N - (C 1-3 -alkyl) carboxy-C 1-3 alkylamino, and X represents an oxygen atom; -Alkylimino- _3, C-3-alkoxyimino-, Ci_3-alkylhydrazino-, di- (Ci-3-alkyl) -hydrazino-, C 2-4 alkanoylhydrazino-, / N (Ci_3 alkyl) _2, -C -4alkanoylhydrazino or a C 1-3 -alkylidene group, which is always in the alkyl or alkyl group The alkanoyl moiety or in the alkyl and alkanoyl moiety may be substituted by a carboxy, imidazole or imidazolone group substituted with a C 1-3 -alkyl- or C 3-5 -cycloalkyl group, wherein the imidazole ring may be substituted with phenyl or carboxy and one or two C 1-3 -alkyl or one, two or three C 1-3 -alkyl groups, wherein the substituents may be the same or different and one of the aforementioned alkyl substituents may be simultaneously substituted with carboxy or in the 2-position; 3 amino-, C2-4-alkanoylamino-, C1-4alkylamino; _3- alkylamino-, N (C 2-4 -alkanoyl) -C 1-3 -alkylamino- or di- (C 1-3 -alkyl) amino, and the imidazolone ring may be substituted with C 1-6 -alkyl; _3- alkyl, wherein the alkyl substituent may be substituted by carboxy or in the 2 or 3 position of amino, C2-4-alkanoylamino-, C1-3-alkylamino-, N- (C2-4-alkanoyl) - C1-3-alkylamino or di - (C 1-3 -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 may be substituted via two adjacent carbon atoms, may be fused one or two Ci. _3- alkyl, wherein at the same time one alkyl substituent may be substituted by carboxy, C 1-4 -alkyl which is substituted by C 1-8 -alkyl. ₃ -alkyl-Y ¹ -C 3 -alkyl-, ^{HOOC-Ci.3-alkyl-Y1} -Ci.3-alkyl, tetrazolyl-Ci-3-alkyl-Y ² -, R ³ NR ⁴ - or R ³ NR ⁴ -C 1-3 -alkyl and optionally C 1-3 -alkyl substituted by isoxazolidin-1-ylcarbonyl, pyrolinocarbonyl-, 2,3-dehydro-piperidinocarbonyl-, pyrrol-1-yl-carbonyl-, carboxy-, aminocarbonyl- , C 1-3 -alkylaminocarbonyl-, di- (C 1-3 -alkyl) -aminocarbonylamino or 4- to 7-membered cycloalkyleneiminocarbonyl, wherein for the above-mentioned groups the cycloalkyleneimine moiety may be substituted by one or two C 1-3 -alkyl groups simultaneously the alkyl or alkyl substituent of the aforementioned C 1-3 -alkylaminocarbonyl-, di- (C 1-3 -alkyl) -aminocarbonyl- or cycloalkyleneiminocarbonyl 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 · · · · · · ···· • · · • • • · · • · · · • · · · • · • • · · • · · · · • · · ·· ·· -108 R @ ³ represents a hydrogen atom or an optionally C1-3 -alkyl-substituted carboxy group; R ⁴ represents a hydrogen atom, C 1-3 -alkyl-Y ¹ -C 1-3 -alkyl-Y ² -, carboxy-C 1-3 -alkyl-Y ¹ C 1-3 -alkyl-Y ² -, C 1-3 -alkyl -Y ² -, or carboxy-Ci-3-alkyl-Y ² -group or R ³ and R ⁴ together with the intervening nitrogen atom represent optionally a carboxy, C 1-3 -alkyl or carboxy-C 1-3 -alkyl substituted 4- to 7-membered cycloalkyleneimino group in which Y ¹ represents a carbon-carbon bond, O, sulphenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH- group, and Y ² represents a carbon-nitrogen bond or a carbonyl-, sulfonyl-, imino- or -NHCO- 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 the occurring imino groups can in each case be additionally substituted by a C 1-3 -alkyl- or carboxy-C 1-3 -alkyl group, R ⁵ NR ⁶ -substituted by a C 1-3 -alkyl- or a C 3-5 -cycloalkyl group in which R ⁵ represents a hydrogen atom, a C 1-3 -alkyl-, a C 5-7 -cycloalkyl-, a phenylcarbonyl-, a phenylsulfonyl- or a pyridinyl group and R ⁶ represents C _1-3 -alkyl-, carboxy-C 1-6 alkyl; _3- alkyl- or carboxy-C 1-6 alkyl; ₃ -alkylcarbonyl, C 1-3 -alkyl which is substituted by C 2-4 -alkanoyl- or C 1-4 -cycloalkanoyl and C 1-3 -alkyl substituted by a chlorine, bromine or iodine atom, R ^b is hydrogen or C 1-3 -alkyl a R ^c is cyano or amidino which may be substituted by hydroxy, by one or two C 1-3 -alkyl groups, by one or two C 1-8 -alkoxycarbonyl groups, wherein, in the definition of the abovementioned radicals, said carboxy, amino and imino groups may additionally be substituted in vivo cleavable residues, their tautomers, their stereoisomers and their salts. The benzimidazoles of formula Ia according to claim 2, wherein A represents a C 1-3 -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, · · • · · · ···· ·· · • · • • · • • · · · • · · · • · • • · e ···· • · • · · · ·· ··· -109 R ^a represents in the 1-position of R ¹ -CO- radical substituted with C ₃ . _5- cycloalkyl wherein: ^R1 is C 1-3 -alkoxy-, amino-, C 1-4 -alkylamino- or di- (C 1-4 -alkyl) amino, in which the alkyl moiety can in each case be substituted by carboxy, A 4- to 7-membered cycloalkyleneimino group which may be substituted by hydroxy or by one or two C _1-3 -alkyl groups, wherein one alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy-, carboxy-, carboxy-C _1-3 -alkoxy -, carboxy-C 1-3 -alkylamino-, N - (C _1-3 -alkyl) - N - (carboxy-C 1-3 -alkyl) amino-, carboxy-C 1-6 -alkyl- _3- alkylaminocarbonyl-, N - (C _1-3 -alkyl) - N - (carboxy-C 1-3 -alkyl) aminocarbonyl-, carboxy-C 1-6 alkyl; _3- alkylaminocarbonylamino-, 1- (C _1-3 -alkyl) -3- (carboxy-C 1-3 alkyl) -aminocarbonylamino-, 3- (C 1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) - amino-carbonylamino- or 1,3-di- (C _1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) aminocarbonylamino or C 1-3 -alkyl substituted by a 5- to 7-membered cycloalkyleneimino group, to which the phenyl ring, morpholino-, piperazino-, N - (C _1-3 -alkyl) -piperazino-, pyrrolino-, 3,4-dehydropiperidino- or pyrrol-1-yl-group is fused via two adjacent carbon atoms, at the 1-position, R ² -CX- is substituted by C ₃ . _5- cycloalkyl wherein: R ² is optionally C 1-6. _{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 _1-3 -alkyl substituted amino group, an oxygen atom or sulfur; _{The 3-} alkyl-substituted amino 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. _3- alkylamino- or N - (C _1-3 -alkyl) -carboxy-C 1-6 alkyl; ₃ alkylamino, and X represents an oxygen atom; _3- alkylimino-, Ci. _{A 3-} alkoxyimino or C 1-3 alkylidene group, which in each case may be substituted by a carboxy group in the alkyl or alkoxy moiety, -110 substituted C 1-3 alkyl in the 1-position by imidazole or imidazolone, 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 groups, wherein the substituents may be the same or different and one of the above alkyl substituents may be simultaneously substituted by carboxy or in the 2 or 3 position of amino, C 2-4 -alkanoylamino-, C 1-3 -alkylamino -, N (C 2-4 -alkanoyl) -C 1-3 -alkylamino- or di-C 1-8 -alkyl-amino, and the imidazolone ring may be substituted by C 1-3 -alkyl, wherein the alkyl substituent may be substituted by carboxy or in the 2 or 3 position amino-, C 1-4 -alkanoylamino-, C 1-3 -alkylamino-, N- (C 2-4 -alkanoyl) -C 1-3 -alkylamino or di- (C 1-3 -alkyl) amino, and in addition to the above imidazole and imidazolone ring can be through two adjacent and so on We atoms a fused phenyl ring or a pyridine, imidazolidine-2,4-dione-5-yl group which may be substituted by one or two Ci-3-alkyl groups, while simultaneously an alkyl substituent may be one substituted with carboxy, C 1-4 -alkyl which is substituted in 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 group, wherein for the above groups the cycloalkyleneimine moiety may be substituted with one or two C 1-3 -alkyl groups and at the same time one alkyl moiety or alkyl substituent of the aforementioned C 1-3 alkylaminocarbonyl-, di- (C 1-3 -alkyl) amino-carbonyl- or cycloalkylene-iminocarbonyl groups may be substituted by carboxy and the remaining hydrogen atoms of the alkyl group may be wholly or partially replaced fluorine atoms in which R ³ is hydrogen or an optionally substituted carboxy-Ci_3 alkyl, and R ⁴ represents a hydrogen atom, a C 1-3 -alkyl-Y ² - or a carboxy-C 1-3 -alkyl-Y ² -group, or 99 • 9 • 9 · 999 • 9 • · • · · ·> · • • 99 • · 9 · • · • ·· 9 · · 99 • e · · • · e -111 R ³ and R ⁴ together with the intervening nitrogen atom, optionally in the 1-position, represent a carboxy-, C _1-3 -alkyl- or carboxy-C 1-3 -alkyl substituted by a 4-7-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 with C 1-3 -alkyl- or carboxy-C 1-3 -alkyl, in the 1-position of R ⁵ NR ⁶ -substituted C 1-3 -alkyl- or C 3-5 -cycloalkyl in which: R ⁵ is hydrogen, Ci_3-alkyl, _{C5-7-cycloalkyl,} phenylcarbonyl-, phenylsulfonyl, or pyridinyl, and R ⁶ represents C 1-3 -alkyl-, carboxy-C 1-3 -alkyl- or carboxy-C 1-3 -alkylcarbonyl, C 1-3 -alkyl which is substituted by C 2-4 -alkanoyl- or C 1-4 -cycloalkanoyl and C _1-3 -alkyl substituted by a chlorine, bromine or iodine atom, R ^b is C 1-6. _3- alkyl; and R ^c is optionally 2,2,2-trichloroethoxycarbonyl-, C 1-6 -alkoxycarbonyl-, acetoxymethyloxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino, wherein the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, C- The _1-3- alkyl- or C 1-3 -alkoxy groups and substituents may be the same or different, their C 1-3 -alkanol esters, 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 in the 1-position of R ^{1 is a} -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 is in each case -112 may be substituted with carboxy-, carboxy-C 1-3 -alkoxy-, carboxy-C 1. _3- alkylamino or N - (C 1-3 -alkyl) -carboxy-C _1-3 -alkylamino, in the 1-position of R ² -CX- with a radically substituted cyclopropyl group in which: ^R2 is an optionally Ci-3-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 moiety, in the 1-position imidazole substituted by a C 1-2 alkyl group in which the imidazole ring may be substituted by phenyl or carboxy and one or two Ci. _3- alkyl or one, two or three C 1-3 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, C2-4-alkanoylamino-, C1-3alkylamino -, N - (C 2-4 -alkanoyl) -C 1-3 -alkylamino- or di- (C 1-3 -alkyl) amino, wherein in addition to the aforementioned imidazole rings, phenyl or pyridine may be fused via two adjacent carbon atoms a ring, in the 1-position, a benzimidazolon-1-yl-substituted C 1-2 -alkyl group, wherein the imidazolone ring may be optionally substituted by a carboxy group substituted by a methyl or ethyl group, a methyl or ethyl group which may be substituted at the 1-position R ³ NR ⁴ - or R ³ NR ⁴ -C 1-3 -alkyl and di- (C 1-3 -alkyl) aminocarbonyl, isoxazolidin-1-yl-carbonyl, optionally substituted with pyrrolidinocarbonyl or C 1-3 -alkyl, or piperidinocarbonyl, 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 a hydrogen atom or an optionally C 1-3 -alkyl-substituted carboxy group a R ⁴ is H, Ci-3-alkyl-Y ² -, or carboxy-Ci-3-alkyl-Y ² -group or R ³ and R ⁴ together with the intervening nitrogen atom or a carboxy substituted 4- to 7-membered cycloalkyleneimino group in which -113 ··· ·· ···· · ··· · · · · · Y ² represents a carbon-nitrogen bond, a carbonyl group or an optionally C 1-3 alkyl-substituted amino group, in the 1-position of the R ⁵ NR ⁶ -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 1-3 -alkyl, in the 3-position of the chlorine-substituted n-propyl which is substituted in the 1-position by cyclopentylcarbonyl, in the 1-position a cyclopentylamino substituted cyclopropyl group substituted by carboxy-C 1 A _3- alkylcarbonyl group, R ^b represents a methyl group a R ^{c is} optionally C 1-6 -alkoxycarbonyl-, acetoxymethyloxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino; ₃ -alkanol esters, their tautomers, their stereoisomers and their salts. The benzimidazoles of formula Ia according to claim 2, wherein A represents a methylene group, B represents an imino group, R ^a in the 1-position of R ¹ -CO- is a 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 1-6 -alkyl. _3- alkoxy-, carboxy-C 1-6 alkyl; _3- alkylamino or N - (C _1-3 -alkyl) carboxy-C 1-6 alkyl; _3- alkylamino, in the 1-position of R ² -CX- is a substituted cyclopropyl group in which: R ² is a C ₃ -alkyl, optionally 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 imidazole substituted by a C 1-2 -alkyl group in which the imidazole ring may be substituted or methyl -114 - «· • · • ·· • ··· • e • · • 9 ···· • • ·· · • · ·· • · · ···· · · • · 9 · ·· ··· substituted by two methyl groups and one ethyl group, wherein in addition one of the aforementioned methyl or ethyl substituent may be simultaneously substituted by carboxy, methyl or ethyl, which may be substituted in the 1-position R ³ NR ⁴ - or R ³ NR ⁴ -CH ₂ - and di- (C 1-3 -alkyl) aminocarbonyl or C 1-3 -alkyl substituted by pyrrolidinocarbonyl or piperidinocarbonyl, in which case the alkyl moiety or alkyl substituent may in each case be an alkyl moiety or an alkyl substituent be substituted with the carboxy group in which they represent R ³ is hydrogen or optionally C ₁ -C ₃ -alkyl substituted by carboxy; and R ^{4 is} C 1-3 -alkyl-Y ² - or carboxy-C 1-6 alkyl; _3- alkyl-Y ² -group in which Y ² represents a carbon-nitrogen bond, a carbonyl group, or an optionally C 1-3 alkyl substituted amino group, R ^b represents a methyl group a R ^{c is} optionally C 1-6 -alkoxycarbonyl-, acetoxymethyloxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, benzyloxycarbonyl- or benzoyl-substituted amidino, their C 1-3 -alkanol esters, their tautomers, their stereoisomers and their salts. 6. A compound of the formula I as claimed in claim 1 5, wherein the residue 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) (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) (d) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) pyrrolidine] -carboxyethylamino] -1- (pyrrolidin-1-ylcarbonyl) ethyl] -benzimidazole; 1-ylcarbonyl-cyclopropyl-benzimidazole, -115- · · · · · · ···· • e · • · • • · • • · · · • · · · • · • • · · ··· · · · · · · · ·· ··· (e) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethylimidazol-1-ylmethyl] benzimidazole, (f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidine- 1-yl-carbonyl) -ethyl] -benzimidazole and (g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidine-1) -yl-carbonyl) -ethyl] -benzimidazole as well as their C 1-3 -alkanol esters, their N - (C 1-4 -alkoxycarbonyl) -, N -benzyloxycarbonyl- and N-benzoylamidines, their tautomers, their stereoisomers and their salts . 8. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole, its C1-3-alkanol esters and their N / - (C 1-8 -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. A process for the preparation of benzimidazoles according to claims 1 to 9, characterized in that a) for the preparation of the benzimidazole of the general formula I, in which R ^c represents a cyano group, optionally a compound of the general formula II formed in the reaction mixture Z ¹ Z ² R ^b in which R ^a , R ^b , Ar, A and B are as defined in claims 1 to 8, -116 - · · · · ·· ···· ·· · • · • • · • • · ·· • · · · • · • • · · ···· · · · · · · ·· · · · Z ¹ and Z ² , which may be the same or different, optionally represent C 1 -C 6 alkyl substituted amino, hydroxy or mercapto groups, or Z ¹ and Z ² together represent an oxygen or sulfur atom, or an alkyl group having 1 to 3 carbon atoms, a substituted amino group, an alkylenedioxy- or alkylenedithio group each having 2 or 3 carbon atoms, cyclizes or b) for the preparation of a benzimidazole of the general formula I in which R ^a represents a R ² -CX'C ³ -5-cycloalkylene group in which R ² is as defined in claims 1 to 8 and X 'represents one of the imino radicals mentioned in claims 1 to 8 8 for X, the compound of formula IV R ^b (IV) wherein 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, wherein R ² is defined as in claims 1 to 8, is reacted with an amine of formula H ₂ X '(V) wherein X 'is one of the imino residues listed in claims 1 to 8 for X, or c) for the preparation of a benzimidazole of the general formula I in which R ^a represents R ² -CX "C ₃ -5-cycloalkylene group, wherein R ² is as defined in claims 1 to 8 and X" represents one of the alkylidene residues mentioned in the claims 1-8 for X, the compound of formula IV -117 - • e · · · · ···· 99 • · • • • 9 9 • 9 • · · · • • 9 9 9 • • · • 9 • · • 9 ···· · · · · · · · · 9 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, wherein R ² is specified in claims 1 to 8, is reacted with a phosphonate of the formula Z ³ -HX '(VI) wherein X 1 represents one of the alkylidene radicals mentioned in claims 1 to 8 for X, and Z 3 represents 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 is an amidino group which may be substituted by one or two C 1-3 -alkyl groups, optionally a compound of the general formula VII is formed in the reaction mixture 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 general formula HR ⁷ NR ⁸ (VIII) ··· ··············· -118 in which R ⁷ and R ⁰ , which may be the same or different, each represent a hydrogen atom or a hydrogen atom C 1-3 alkyl, or salts thereof, or e) for the preparation of a benzimidazole of the 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, at the same time being an alkyl substituent substituted by carboxy- or A C 1-3 -alkoxycarbonyl group is optionally a compound of formula IX formed in the reaction mixture R ¹ CK (IX) in which R ^b , Ar, A and B are as defined in claims 1 to 8 a R ^a 'represents an aminocarbonylamino group, which is substituted at the 3-position by a C 1-3 alkoxycarbonyl-C 1-3 -alkyl group, is cyclized or (f) for the preparation of a benzimidazole of the general formula I in which R ^c is a hydroxyamino group, a nitrile of the general formula X R ' B Ar CN 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 (X) -119 - · · • · • · · • · · · · · • • ···· ·· • · • · • · • • • • • • · • • • · • · ···· · · · · • · · · · · g) for the preparation of benzimidazoles of the general formula I, in which R ^a contains a carboxy group and R ^c is as defined in claims 1 to 8, or R ^a is as defined in claims 1 to 8 and R ^c is optionally hydroxy or one or two C 1-3- an alkyl-substituted amidino group, a compound of the general Formula XI (XI) wherein: R ^b , Ar, A and B are as defined in claims 1 to 8 a R ^a '''and R ^c ' have the meanings given for R ^a and R ^c in claims 1 to 8, with the proviso that R ^a contains a group which can be converted to hydrolysis, acid or base treatment, thermolysis or hydrogenolysis into carboxy, and R ^c is as defined in claims 1 to 8, or R ^c is a group which can be converted by an hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to an optionally substituted amino group or one or two C 1-3 -alkyl groups, and R ^a is as defined in claims 1 to 8, 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 in claims 1 to 8, or R ^a is as defined in claims 1 to 8 and R ^c is optionally an hydroxy or one or two C _1-3 -alkyl substituted amidino groups, or (h) for the preparation of a benzimidazole of the formula I in which R ^c is an amidino group which is substituted by one or two C 1-6 -alkoxycarbonyl groups or an in vivo cleavable residue, a compound of the formula XII ·············································· -120- 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) wherein 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 I thus obtained, which contains a (R ³ NR ⁴ ) -C _1-3 -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 to the corresponding urea compound of formula I, and / or the compound of formula I containing NH 2 -C 1-3 alkyl is then converted to the corresponding 2- (C 1-3 -alkoxycarbonyl) -ethyl- by the corresponding acrylic ester. the compound of formula I, and / or the compound of formula I thus obtained, which contains a (R ³ NR ⁴ ) C 1-3 alkyl group in which R ³ and R ⁴ each represent a hydrogen atom, is converted by the corresponding dihaloalkanes into the corresponding compound of the formula I, wherein R ³ and R ⁴ together with the intervening nitrogen atom represent the corresponding 4- to 7-membered a cycloalkyleneimino group and / or a compound of the formula I in which R ^c is an amidino group is thus converted with a haloacetic acid derivative as well as a subsequent haloacetic acid derivative. -121 by hydrolysis and decarboxylation to the corresponding amidino compound substituted with one or two methyl groups and / or the compound of formula I in which R ^c is hydroxyamido is converted by catalytic hydrogenation to the corresponding amidino compound and / or the compound of formula I thus obtained, wherein R ^a is a carboxy group, converted by esterification to the corresponding ester, and / or the protecting group used during these reactions for protecting the reactive groups is cleaved, and / or the compound of formula I thus obtained is separated into its stereoisomers, and / or the compound of formula I thus obtained is converted into its salts, in particular for pharmaceutical use, into its physiologically acceptable salts 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. A process for the preparation of a pharmaceutical composition according to claim 10, characterized in that the benzimidazole according to at least one of claims 1 to 8, wherein R ^c represents one of the amidino groups mentioned in claims 1 to 8, or the salt according to claim 9, by a non-chemical route. incorporated into one or more inert carriers and / or diluents. Use of benzimidazole according to at least one of Claims 1 to 8, in which R ^c is one of the amidino groups according to Claims 1 to 8, or of the salt according to Claim 9, for the manufacture of a medicament with thrombin prolongation, thrombin inhibitory and related serine proteases.