DE19912690A1 - New benzimidazolyl amidine or nitrile compounds, useful as thrombin inhibitors or antithrombotic agents, for treating deep leg vein thrombosis - Google Patents

Abstract

Benzimidazolyl-substituted (hetero)aromatic amidine or nitrile derivatives (I) are new. Benzimidazoles of formula (I) and their tautomers, stereoisomers, mixtures, prodrugs, derivatives (having a group which is negatively charged instead of COOH) and salts are new. Ar = phenylene or naphthylene (both optionally substituted by F, Cl, Br, CF3, T or OT); or thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene (all optionally substituted on C by T); T = 1-3C alkyl; A = 1-3C alkylene; B' = O, S, CF2, CO, SO, SO2, NH or NT (optionally substituted on T by 1 or 2 of COOH); Ra = R1-CO-(3-5C) cycloalkylene; R2-C(X)-(3-5C) cycloalkylene; T or 3-5C cycloalkyl, (both substituted by (a) imidazolyl, optionally substituted by one Ph or COOH and 1 or 2 T or by 1-3 T, where T moieties are optionally substituted by COOH or in the 2- or 3-position by NH2, NHCOT, NHT, N(T)COT or N(T)2, (b) imidazolonyl, optionally substituted by T (optionally substituted by COOH or in the 2- or 3-position by NH2, NHCOT, NHT, N(T)COT or N(T)2 ) or (c) a ring as in (a) or (b) having a fused phenyl or pyridine ring); imidazolidine-2,4-dion-5-yl (optionally substituted by 1 or 2 T, (optionally substituted by COOH)); 1-4C alkyl (substituted by T-Y1-A, HOOC-A-Y1-A, tetrazolyl-A-Y2, NR3R4, or A-NR3R4; isoxazolidinylcarbonyl (optionally substituted by T), pyrrolidino-carbonyl, 3,4-dehydropyrrolidino-carbonyl, pyrrol-1-ylcarbonyl, COOH or CONH2; CONHT, CON(T)2 or 4-7 membered cycloalkyleneiminocarbonyl (optionally substituted by 1 or 2 T (optionally substituted by COOH)); and one or more F); T or 3-5C cycloalkyl, (both substituted by NR5R6); or T (substituted by 2-4C alkanoyl or 5-7C cycloalkanoyl and by chloro-, bromo- or iodo-(1-3C) alkyl); R1 = OT, NH2, NHT or N(T)2 (T is optionally substituted by COOH); 4-7 membered cycloalkyleneimino or cycloalkenyleneimino (both optionally substituted by 1 or 2 T, (optionally substituted by OH, OT, COOH, O-A-COOH, N(T')-A-COOH, CO-N(T')-A-COOH or N(T')CON(T')-A-COOH)); 4-7 membered cycloalkyleneimino substituted by OH; 5-7C cycloalkyleneimino (optionally substituted by T), having a phenyl ring fused to two adjacent C; or morpholino, piperazino, N(T)-piperazino, pyrrolidino, 3,4-dehydropyrrolidino or pyrrol-1-yl; T' = H or T; R2 = phenyl, naphthyl, 5-membered heteroaryl (containing one N(T'), O and/or S; or 1 or 2 N) or 6-membered heteroaryl (containing 1-3 N), all optionally substituted by T (optionally substituted by COOH, -O-A-COOT' or -N(T')-A-COOH); X = O, N(T), N(OT), NNHT, NN(T)2, NNHCOT, NN(T)COT or 1-3C alkylidene (where T moieties are optionally substituted by COOH); R3 = H or T (optionally substituted by COOH); R4 = H, T-Y1-A-Y2, HOOC-A-Y1-A-Y2, T-Y2 or HOOC-A-Y2; or NR3R4 = 4-7 membered cycloalkyleneimino (optionally substituted by COOH, T or A-COOH); Y1 = direct bond, O, S, SO, SO2, N(T'), N(ACOOH), NHCO or NHCONH; Y2 = direct bond, CO, SO2, N(T'), N(ACOOH) or NHCO (where the CO of NHCO is bonded to NR3R4); R5 = H, T, 5-7C cycloalkyl, PHCO, PhSO2 or pyridinyl; R6 = T, A-COOH or CO-A-COOH; Rb = H or T; Rc = CN or amidino (optionally substituted by 1 or 2 T). An Independent claim is also included for the preparation of (I).

Description

The present invention relates to benzimidazoles of the general formula

their tautomers, their stereoisomers, their mixtures, their Prodrugs, their derivatives, in place of a carboxy group a group negatively charged under physiological conditions and their salts, especially their physiological compatible salts with inorganic or organic acids or bases which have valuable properties.

The compounds of the above general formula I, in which R _{c represents} a cyano group, are valuable intermediates for the preparation of the remaining compounds of the general formula I, and the compounds of the above general formula I, in which R _{c represents} one of the following amidino groups, as well as their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives containing in place of a carboxy group a negatively charged group under physiological conditions, and their salts, in particular their physio logically acceptable salts with inorganic or organic salts, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect.

The subject of the present application are thus the new ones Compounds of the above general formula I and their forth  position ent. the pharmacologically active compounds ent medicines, their manufacture and use.

In the above general formula
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenylene or naphthylene group,
a thienylene, thiazolylene, pyridinyl, pyrimidinyl, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C _1-3 -alkyl group,
A is a C _1-3 -alkylene group,
B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C _1-3 -alkyl group, in which the alkyl moiety may be mono- or disubstituted by a carboxy group,
R _{a is} an R ₁ -CO-C _3-5 -cycloalkyl group in which
R _{1 is} a C _1-3 -alkoxy, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino group, in each of which the alkyl moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C _1-3 alkyl groups, wherein an alkyl substituent is simultaneously represented by a 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- (carboxyC _1-3 -alkyl) -aminocarbonyl, carboxyC _1-3 -alkylaminocarbonylamino, 1- (C _{1- 3-} alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino, 3- (C _1-3 alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino or 1, May be substituted by 3-di (C _1-3 alkyl) -3- (carboxy C _1-3 alkyl) aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C _1-3 -alkyl group to which a phenyl ring has been fused via two adjacent carbon atoms,
represents a morpholino, piperazino, N- (C _1-3 alkyl) piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
an R ₂ -CX-C _3-5 cycloalkyl group in which
R _{2 is} a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group, the 6-membered heteroaryl group containing one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally substituted by a C _1-3 alkyl group-substituted imino group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl imino group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent by a Carboxy, carboxyC _1-3 -alkoxy, carboxyC _1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group, and
X is an oxygen atom, a C _1-3 -alkylimino, C _1-3 -alkoxyimino, C _1-3 -alkylhydrazino, di (C _1-3 -alkyl) -hydrazino, C _2-4 -alkanoyl hydrazino -, N- (C _1-3 alkyl) -C _2-4 -alkanoylhydrazino- or C _1-3 -Al kylidengruppe each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety by a carboxy group, represent
a substituted by an imidazole or imidazolone group 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 by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups, where the substituents may be the same or different and one of the aforementioned alkyl substituents simultaneously through a carboxy group or in the 2- or 3-position by an 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 group may be substituted, and
the imidazolone ring may be substituted by a C _1-3 -alkyl group, the alkyl substituent being substituted by a carboxy group or in the 2- or 3-position by an amino, C _2-4 -alkanoylamino, C _1-3 -alkylamino , N- (C _2-4 -alkanoyl) -C _1-3 -al kylamino- or di- (C _1-3 alkyl) amino group may be substituted, and
in addition to the abovementioned imidazole and imidazole rings it is possible for a phenyl or pyridine ring to be fused via two adjacent carbon atoms,
an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent may be substituted by a carboxy group,
a C _1-4 alkyl group, the
by a C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl-, HOOC-C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl, tetrazolyl-C _1-3 -alkyl- Y ₂ , R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by an isoxazolidinylcarbonyl group optionally substituted by a C _1-3 -alkyl group, by a pyrrolo-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-ylcarbonyl, carboxy, aminocarbonyl, C _1-3 Alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonylgruppe substituted, wherein in the above-mentioned groups, the Cycloalkyleniminoteil substituted by one or two C _1-3 alkyl groups and simultaneously an alkyl moiety or alkyl substituent of the above-mentioned C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of C _1-4 - Alkyl group may be wholly or partially replaced by fluorine atoms, in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy C _2-3 alkyl group and
R _{4 is} a hydrogen atom, a 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 a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C _1-3 -alkyl or carboxy-C _1-3 -alkyl group, in which
Y _{1 is} a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH, -NH-CO or -NH-CO-NH group and
Y _{2 represents} a carbon-nitrogen bond or a carbonyl, sulfonyl or -NH-CO group, wherein the carbonyl group of the -NH-CO group is linked to the nitrogen atom of the R ₃ NR ₄ group, and which in the Definition of the radicals Y ₁ and Y ₂ occurring imino groups may each be additionally substituted by a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a C _1-3 alkyl or C _3-5 cycloalkyl group substituted by an R ₅ NR ₆ group in which
R _{5 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and
R _{6 represents} a C _1-3 -alkyl, carboxy-C _1-3 -alkyl or carboxy-C _1-3 -alkylcarbonyl group,
a C _1-3 alkyl group which is substituted by C _2-4 alkanoyl or C _5-7 cycloalkanoyl group and by a C _1-3 alkyl group substituted by a chlorine, bromine or iodine atom,
R _{b is} a hydrogen atom or a C _1-3 alkyl group and
R _{c is} a cyano group or an optionally substituted by one or two C _1-3 alkyl groups amidino group.

The carboxy groups mentioned in the definition of the above-mentioned groups may also be replaced by a group convertible in vivo into a carboxy group or by a group negatively charged under physiological conditions, or
The amino and imino groups mentioned in the definition of the abovementioned radicals may also be substituted by an in vivo cleavable radical.

By way of example, a group which can be converted into a carboxy group in vivo is a hydroxymethyl group, an alcohol group esterified with an alcohol, in which the alcoholic part is preferably a C _1-6 -alkanol, a phenyl-C _1-3 -alkanol, a C _{3 -9-} cycloalkanol, wherein a C _5-8 -cycloalkanol may additionally be substituted by one or two C _1-3 -alkyl groups, a C _5-8 -cycloalkanol, in which a methylene group in the 3- or 4-position by an oxygen atom or is replaced by a given imino substituted by a C _1-3 alkyl, phenyl-C _1-3 alkyl, phenyl C _1-3 alkoxycarbonyl or C _2-6 alkanoyl imino group and the cycloalkanol part additionally by one or two C _1-3 alkyl groups, a C _4-7 cycloalkenol, a C _3-5 alkenol, a phenyl C _3-5 alkenol, a C _3-5 alkinol or phenyl-C _3-5 -alkinol with the proviso that no bond to the oxygen atom emanates from a carbon atom, which is a double or triple carries a C _3-8 -cycloalkyl-C _1-3 -alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms, which may be additionally substituted in the bicycloalkyl moiety by one or two C _1-3 -alkyl groups, a 1,3- Dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R _d -CO-O- (R _e CR _f ) -OH,

in that
R _{d is} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{e is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{f represents} a hydrogen atom or a C _1-3 alkyl group,
under a group negatively charged under physiological conditions, such as tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C _1-6 alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C _1-6 alkylsulfonylaminocarbonyl , Phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoroC _1-6 -alkylsulfonylaminocarbonyl group
and under a residue cleavable in vivo from an imino or amino group, for example, a hydroxy group, an acyl group such as an optionally fluorine, chlorine, bromine or iodine atoms, by C _1-3 alkyl or C _1-3 Alkoxy groups mono- or di-substituted benzoyl group wherein the substituents may be the same or different, a pyridinoyl group or a C _1-16 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. Butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecycloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenylC _1-6 -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C _1-3 alkylsulfonylC _2-4 alkoxycarbonyl, C _1-3 alkoxyC _2-4 alkoxyC _2-4 alkoxycarbonyl or R _d COO- (R _d CR _f ) -O-CO-group in which R _d to R _f are defined as mentioned above,
to understand.

Furthermore, those in the definition of the above include mentioned saturated alkyl and alkoxy moieties exceeding 2 Contain carbon atoms, including their branched isomers such as for example, the isopropyl, tert-butyl, isobutyl group etc.

Preferred compounds are those of the general formula

in the
A is a C _1-3 -alkylene group,
B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C _1-3 -alkyl group, in which the alkyl moiety may be mono- or disubstituted by a carboxy group,
R _{a is} an R ₁ -CO-C _3-5 -cycloalkyl group in which
R _{1 is} a C _1-3 -alkoxy, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino group, in each of which the alkyl moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C _1-3 alkyl groups, wherein an alkyl substituent is simultaneously represented by a 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- (carboxyC _1-3 -alkyl) -aminocarbonyl, carboxyC _1-3 -alkylaminocarbonylamino, 1- (C _{1- 3-} alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino, 3- (C _1-3 alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino or 1, May be substituted by 3-di (C _1-3 alkyl) -3- (carboxy C _1-3 alkyl) aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C _1-3 -alkyl group to which a phenyl ring has been fused via two adjacent carbon atoms,
represents a morpholino, piperazino, N- (C _1-3 alkyl) piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
an R ₂ -CX-C _3-5 cycloalkyl group in which
R _{2 is} a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group, the 6-membered heteroaryl group containing one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally substituted by a C _1-3 alkyl group-substituted imino group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl imino group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent by a Carboxy, carboxyC _1-3 -alkoxy, carboxyC _1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group, and
X is an oxygen atom, a C _1-3 -alkylimino, C _1-3 -alkoxyimino, C _1-3 -alkylhydrazino, di (C _1-3 -alkyl) -hydrazino, C _2-4 -alkanoyl hydrazino -, N- (C _1-3 alkyl) -C _2-4 -alkanoylhydrazino- or C _1-3 -Al kylidengruppe each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety by a carboxy group, represent
a substituted by an imidazole or imidazolone group 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 by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups, where the substituents may be the same or different and one of the aforementioned alkyl substituents simultaneously by a carboxy group or in the 2- or 3-position by an 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 group, and
the imidazolone ring may be substituted by a C _1-3 -alkyl group, the alkyl substituent being substituted by a carboxy group or in the 2- or 3-position by an amino, C _2-4 -alkanoylamino, C _1-3 -alkylamino , N- (C _2-4 -alkanoyl) -C _1-3 -al kylamino- or di- (C _1-3 alkyl) amino group may be substituted, and
in addition to the abovementioned imidazole and imidazole rings it is possible for a phenyl or pyridine ring to be fused via two adjacent carbon atoms,
an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 alkyl groups, wherein at the same time an alkyl substituent may be substituted by a carboxy group,
a C _1-4 alkyl group, the
by a C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl-, HOOC-C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl, tetrazolyl-C _1-3 -alkyl- Y ₂ , R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by an isoxazolidin-1-ylcarbonyl group optionally substituted by a C _1-3 alkyl group, by a pyrroli nocarbonyl, 2,3-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C Substituted _1-3 -alkylaminocarbonyl, di- (C _1-3 alkyl) -aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonylgruppe, wherein in the above-mentioned groups of the Cycloalkyleniminoteil by one or two C _1-3 alkyl groups and at the same time each an alkyl part or alkyl substituent of the above-mentioned C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or cycloalkyleniminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of C. _1-4 alkyl group may be wholly or partially replaced by fluorine atoms, in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, a 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 a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C _1-3 -alkyl or carboxy-C _1-3 -alkyl group, in which
Y _{1 is} a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH, -NH-CO or -NH-CO-NH group and
Y _{2 represents} a carbon-nitrogen bond or a carbonyl, sulfonyl or -NH-CO group, wherein the carbonyl group of the -NH-CO group is linked to the nitrogen atom of the R ₃ NR ₄ group, and which in the Definition of the radicals Y ₁ and Y ₂ occurring imino groups may each be additionally substituted by a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a C _1-3 alkyl or C _3-5 cycloalkyl group substituted by an R ₅ NR ₆ group in which
R _{5 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and
R _{6 represents} a C _1-3 -alkyl, carboxy-C _1-3 -alkyl or carboxy-C _1-3 -alkylcarbonyl group,
a C _1-3 alkyl group which is substituted by C _2-4 alkanoyl or C _5-7 cycloalkanoyl group and by a C _1-3 alkyl group substituted by a chlorine, bromine or iodine atom,
R _{b is} a hydrogen atom or a C _1-3 alkyl group and
R _{c represents} a cyano group or an amidino group which may be substituted by one hydroxy group, by one or two C _1-3 -alkyl groups, by one or two C ₁ -alkoxycarbonyl groups,
the carboxy, amino and imino groups mentioned in the definition of the abovementioned radicals may furthermore be substituted by an in vivo cleavable radical,
their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of the above general formula Ia are those in which
A is a C _1-3 -alkylene group,
B is an oxygen atom, a methylene, imino or N- (C _1-3 -alkyl) -imino group, in which the alkyl moiety may be substituted by a carboxy group,
R _{a is} a substituted in the 1-position by the R ₁ -CO-radical C _3-5 cycloalkyl group in which
R _{1 is} a C _1-3 -alkoxy, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino group, in each of which the alkyl moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C _1-3 alkyl groups, wherein an alkyl substituent is simultaneously represented by a 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- (carboxyC _1-3 -alkyl) -aminocarbonyl, carboxyC _1-3 -alkylaminocarbonylamino, 1- (C _{1- 3-} alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino, 3- (C _1-3 alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino or 1, May be substituted by 3-di (C _1-3 alkyl) -3- (carboxy C _1-3 alkyl) aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C _1-3 -alkyl group to which a phenyl ring has been fused via two adjacent carbon atoms,
represents a morpholino, piperazino, N- (C _1-3 alkyl) piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
a substituted in the 1-position by the R ₂ -CX radical C _3-5 cycloalkyl group, in which
R _{2 is} a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group, the 6-membered heteroaryl group containing one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally substituted by a C _1-3 alkyl group-substituted imino group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl imino group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent by a Carboxy, carboxyC _1-3 -alkoxy, carboxyC _1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group, and
X represents an oxygen atom, a C _1-3 -alkylimino, C _1-3 -alkoxyimino or C _1-3 -alkylidene group, each of which may be substituted by a carboxy group in the alkyl or alkoxy part,
a substituted in 1-position by an imidazole or imidazolone C _1-3 alkyl group in which
the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups, where the substituents may be the same or different and one of the aforementioned alkyl substituents simultaneously by a carboxy group or in the 2- or 3-position by an 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 group, and
the imidazolone ring may be substituted by a C _1-3 -alkyl group, the alkyl substituent being substituted by a carboxy group or in the 2- or 3-position by an amino, C _2-4 -alkanoylamino, C _1-3 -alkylamino , N- (C _2-4 -alkanoyl) -C _1-3 -al kylamino- or di- (C _1-3 alkyl) amino group may be substituted, and
in addition to the abovementioned imidazole and imidazole rings it is possible for a phenyl or pyridine ring to be fused via two adjacent carbon atoms,
an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent may be substituted by a carboxy group,
a C _1-4 alkyl group, in the 1-position
by an R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl - Isoxazolidin-1-ylcarbonyl or 4- to 7-membered cycloal kyleniminocarbonylgruppe substituted, wherein substituted in the above-mentioned groups of the cycloalkylenimine by one or two C _1-3 alkyl groups and at the same time each an alkyl moiety or alkyl substituent of the aforementioned C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C _1-4 alkyl group may be wholly or partly replaced by fluorine atoms can be in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, 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 a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1-position by a carboxy, C _1-3 -alkyl or carboxy- _1-3- alkyl group, in which
Y _{2 represents} a carbon-nitrogen bond or a carbonyl or -NH-CO group, wherein the carbonyl group of the -NH-CO group is linked to the nitrogen atom of the R ₃ NR ₄ group, and in the definition of the radical Y _2- occurring imino group may additionally be substituted by a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a substituted in the 1-position by an R ₅ NR ₆ group C _1-3 alkyl or C _3-5 cycloalkyl group, in which
R _{5 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and
R _{6 represents} a C _1-3 -alkyl, carboxy-C _1-3 -alkyl or carboxy-C _1-3 -alkylcarbonyl group,
a C _1-3 alkyl group which is substituted by C _2-4 alkanoyl or C _5-7 cycloalkanoyl group and by a C _1-3 alkyl group substituted by a chlorine, bromine or iodine atom,
R _{b is} a C _1-3 alkyl group and
R _{c is} an amidino group which is optionally substituted by a C _1-8 -alkoxycarbonyl group,
their C-alkanol esters, their N-benzyloxycarbonyl-amidines and their benzoyl optionally in the benzoyl moiety by fluorine, chlorine, bromine or iodine atoms, by C _1-3 alkyl or C _1-3 alkoxy mono- or disubstituted benzoyl group, wherein the substituents may be the same or different, substituted N-benzoyl-amidines,
their tautomers, their stereoisomers and their salts.

Very particularly preferred compounds of general formula I are those in which
A is a methylene group,
B is an oxygen atom or an imino group,
R _{a is} a substituted in the 1-position by the R ₁ -CO-radical cyclopropyl group, in the
R _{1 is} an optionally substituted by a methyl or ethyl group pyrrolidino or piperidino group, in which in each case the methyl or ethyl part by a carboxy, carboxy-C _1-3 alkoxy, carboxy-C _1-3 alkylamino or N - (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group may be substituted,
a substituted in the 1-position by the R ₂ -CX radical cyclopropyl group, in the
R _{2 is} optionally substituted by a C _1-3 alkyl substituted phenyl, pyridyl-pyrazolyl and
X represents an oxygen atom, a C _1-3 -alkoxyimino or C _1-3 -alkylidene group which are each substituted in the alkyl or alkoxy part by a carboxy group,
a 1-imidazole substituted C _1-2 alkyl group in which the imidazole ring is replaced by a phenyl or carboxy group and by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups may be substituted, wherein the substituents may be the same or different and one of the abovementioned alkyl substituents simultaneously by a carboxy group or in the 2- or 3-position by an amino, C _2-4 alkanoylamino, C _1-3 alkyl amino, N- (C _2-4 alkanoyl) C _1-3 alkylamino or di (C _1-3 alkyl) amino group may be substituted, in addition to the above-mentioned imidazole rings via two adjacent carbon atoms Phenyl or pyridine ring may be fused,
a C _1-2 alkyl group substituted in position 1 by a benzimidazolone-1-yl group, where the imidazolone ring may be substituted by a methyl or ethyl group optionally substituted by a carboxy group,
a methyl or ethyl group in the 1-position
by an R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by a di (C _1-3 alkyl) -aminocarbonyl group, by an isoxazolidin-1-ylcarbonyl group, by a pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted by a C _1-3 alkyl group, wherein each of the above-mentioned groups has an alkyl portion or alkyl substituent may be substituted by a carboxy group in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, a 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 a 4- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy group, in which
Y _{2 represents} a carbon-nitrogen bond or a carbonyl group,
a substituted in the 1-position by an R ₅ NR ₆ group C _1-2 alkyl group in which
R _{5 is} a pyridinyl, phenylcarbonyl or phenylsulfonyl group and
R _{6 represents} a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a n-propyl group which is substituted by a chlorine atom in the 3-position and which is substituted in the 1-position by a cyclopentylcarbonyl group,
a cyclopropyl group substituted in the 1-position by a cyclopentylamino group and substituted on the nitrogen atom by a carboxy C _1-3 -alkylcarbonyl group,
R _{b is} a methyl group and
R _{c is} an amidino group which is optionally substituted by a C _1-8 -alkoxycarbonyl group,
in particular those compounds of the general formula Ia in which
A is a methylene group,
B is an imino group,
R _{a is} a substituted in the 1-position by the R ₁ -CO-radical cyclopropyl group, in the
R _{1 is} a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group, in each of which the methyl or ethyl part by a carboxy, carboxy-C _1-3 alkoxy, carboxy-C _1-3 alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group may be substituted, represents
a substituted in the 1-position by the R ₂ -CX radical cyclopropyl group, in the
R _{2 is} optionally substituted by a C _1-3 alkyl substituted phenyl, pyridyl-pyrazolyl and
X represents an oxygen atom, a C _1-3 -alkoxyimino or C _1-3 -alkylidene group which are each substituted in the alkyl or alkoxy part by a carboxy group,
an imidazole group substituted in the 1-position C _1-2 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 additionally one of the aforementioned methyl or ethyl substituents simultaneously may be substituted by a carboxy group,
a methyl or ethyl group in the 1-position
by an R ₃ NR ₄ or R ₃ NR ₄ -CH ₂ group and
by a di- (C _1-3 alkyl) -aminocarbonyl group, optionally substituted by a C _1-3 alkyl Pyrroli dinocarbonyl- or piperidinocarbonyl group, wherein in the above-mentioned groups each an alkyl part or alkyl substituent be substituted by a carboxy group can, in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 represents} a C _1-3 alkyl Y ₂ or carboxy C _1-3 alkyl Y ₂ group in which
Y _{2 represents} a carbon-nitrogen bond or a carbonyl group,
R _{b is} a methyl group and
R _{c is} an amidino group optionally substituted by a C _1-8 -alkoxycarbonyl group,
in particular those compounds of the general formula I in which the radical R _{a is} in the 5-position,
their C _1-3 -alkanol esters, their N-benzyloxycarbonyl and N-benzoyl amidines,
their tautomers, their stereoisomers and their salts.

As particularly preferred compounds, the following may be mentioned, for example:

• a) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin 1-yl-carbonyl) cyclopropyl] -benzimidazole,
• b) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyri din-2-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] - benzimidazole,
• c) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxy ethylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimi dazol,
• d) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carb oxyethyl) -pyrrolidin-1-yl-carbonyl] cyclopropyl] -benzimi dazol,
• e) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxy ethyl) -4,5-dimethyl-imidazol-1-yl-methyl] -benzimidazole
• f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxy methylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimi dazol and
• g) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methyl carboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin 1-yl-carbonyl) -ethyl] -benzimidazole

as well as their C _1-3

Alkanol esters whose N- (C _1-8

Alkoxycarbonyl) - N-benzyloxycarbonyl and N-benzoyl amidines, their tautomers, their stereoisomers and their salts.

According to the invention, the compounds of the general Formula I according to known methods, for example according to following procedures:

a) For the preparation of a compound of general formula I in which R _{c represents} a cyano group:
Cyclization of an optionally in the reaction mixture th compound of the general formula

in the
R _a , R _b , Ar, A and B are defined as mentioned above,
Z ₁ and Z ₂ , which may be the same or different, if appropriate substituted by alkyl groups having 1 to 6 carbon atoms substituted amino, hydroxy or mercapto or
Z ₁ and Z ₂ , together represent an oxygen or sulfur atom, an optionally substituted by an alkyl group having 1 to 3 carbon atoms imino group, an alkylenedioxy or Al kylendithiogruppe each having 2 or 3 carbon atoms be interpreted.

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, dimethylform amide, tetralin or in an excess of that for preparing the Compound of general formula II used acylation medium, z. B. in the corresponding nitrile, anhydride, Säureha  halide, ester or amide, for example at temperatures between 0 and 250 ° C, but preferably at the boiling point the reaction mixture, optionally in the presence of a Kon densationsmittels such as phosphorus oxychloride, thionyl chloride, Sul furyl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulf fonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, vinegar acid, acetic anhydride, N, N-dicyclohexyl-carbodiimide or optionally also in the presence of a base such as potassium ethoxide or potassium tert-butylate. The cyclization can but also without solvents and / or condensing agents be performed.

However, the reaction is particularly advantageously carried out in such a way that a compound of general formula II in the reaction mixture by reduction of a corresponding o-Ni-tro compound, optionally in the presence of a carboxylic acid of the general formula

HO-CO ^- A ^- B ^- Ar ^- CN (III),

in the
Ar, A and B are defined as mentioned above, by Acylie tion of an optionally formed in the reaction mixture ent speaking amino compound is prepared.

b) For the preparation of a compound of the general formula I in which R _{2 is} CX'-C _3-5 -cycloalkylengruppe, in which R ₂ is defined as mentioned above and X 'is one of X initially mentioned iminoreste:

Reaction of a compound of the general formula

in the
R _b , Ar, A and B are defined as mentioned above and
R _a 'represents an R ₂ -CO-C _3-5 -cycloalkylene group, wherein
R ₂ is defined as mentioned above,
with an amine of the general formula

H ₂ X '(V),

in the
X 'represents one of the initially mentioned Iminoreste X.

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

c) For the preparation of a compound of the general formula I in which R ₂ -CX "-C _3-5 -cycloalkylene group in which R ₂ is defined as mentioned above and X" is one of the above-mentioned th for X X alkylidene radicals:

Reaction of a compound of the general formula

in the
R _b , Ar, A and B are defined as mentioned above and
R _a 'represents an R ₂ -CO-C _3-5 -cycloalkylene group, wherein
R ₂ is defined as mentioned above,
with a phosphone of the general formula

Z ₃ -HX "(VI),

in the
X "is one of the abovementioned alkylidene radicals and
Z _{3 represents} a triphenylphosphono or di (C _1-3 alkoxy) phosphono group such as the triethoxyphosphono group.

The reaction is preferably carried out under protective gas in a Lö such as tetrahydrofuran, dimethylformamide, dioxane, di ethyl ether or dimethyl sulfoxide in the presence of a base such as Potassium t-butylate, sodium ethylate or sodium hydride Temperatures between -25 and 50 ° C, preferably at Tempe temperatures between -15 ° and room temperature.

d) For the preparation of a compound 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:
Reaction of a compound of the general formula which may be formed in the reaction mixture

in the
R _a , R _b , Ar, A and B are defined as mentioned above and
Z _{4 represents} an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkyl thio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine the general formula

HR ₇ NR ₈ , (VIII)

in the
R ₇ and R ₈ , which may be the same or different, each represents a hydrogen atom or a C _1-3 -alklyl group, or with its salts.

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

A compound of general formula VII is obtained in For example, by implementation of a corresponding Cyanoverbin with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of a Acid such as hydrochloric acid or by reaction of a corresponding Amides with a trialkyloxonium salt such as triethyloxonium tetra fluoroborate in a solvent such as methylene chloride, tetra hydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding Ni trils with hydrogen sulfide expediently in a Lö such as pyridine or dimethylformamide and in the presence a base such as triethylamine and subsequent alkylation of the formed thioamide with a corresponding alkyl or Aralkyl.

e) For the preparation of a compound of the general formula I in which R _{a is} an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent a carboxy or C _1-3 alkoxycarbonyl group may be substituted:
Cyclization of an optionally in the reaction mixture th compound of the general formula

in the
R _b , Ar, A and B are defined as mentioned above and
R _a "represents an aminocarbonyamino group which is substituted in the 3-position by a C _1-3 alkoxycarbonyl-C _1-3 -alkyl group.

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

f) For the preparation of a compound of general formula I in which R _{c represents} a hydroxyamidino group:
Reaction of a nitrile of the general formula

in the
R _a , R _b , Ar, A and B are defined as mentioned above, with hydroxylamine or its salts.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, Tetrahydrofuran, tetrahydrofuran / water, dioxane or dioxane / Water at temperatures between 0 and 150 ° C, preferably at Temperatures between 0 and 80 ° C, performed.

g) For the preparation of a compound of the general formula I, in which R _a contains a carboxy group and R _{c is} as defined at the outset or R _a is defined as mentioned above and R _{c is} optionally substituted by a hydroxy group or by one or two C _{1 3-} alkyl substituted amidino group represents:
Transfer of a compound of the general formula

in the
R _b , Ar, A and B are defined as mentioned above and
R _a "'and R _c ' have the meanings mentioned above for R _a and R _c , with the proviso that R _a contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, and R _c as defined at the outset, or R _{c is} a group which can be converted by hydrolysis, treatment with acid or base, thermolysis or hydrolysis into an amidino group which is optionally substituted by a hydroxy group or by one or two C _1-3 -alkyl groups, and R _{a is} as At the beginning he thinks he is defined
is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a compound of general formula I in which R _a contains a carboxy group and R _{c is} as defined above or R _a as defined above is defined and R _c represents an optionally substituted by a hydroxy group or by one or two C _1-3 alkyl substituted amidino group.

As a group which can be converted into a carboxy group, for example, a carboxyl group protected by a protective group, such as its functional derivatives, eg. B. their unsubsti tuierte or substituted amides, esters, thioesters, trimethyl silyl esters, orthoesters or imino esters, which are conveniently converted by means of hydrolysis in a carboxyl group,
their esters with tertiary alcohols, eg. B. the tert-butyl ester, which are conveniently converted by treatment with an acid or thermolysis in a carboxyl group, and
their esters with aralkanols, eg. As the benzyl ester, which are conveniently converted by means of hydrogenolysis in a carboxyl group, into consideration.

The hydrolysis is conveniently carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, Es acetic acid, trichloroacetic acid, trifluoroacetic acid or their Mixtures or in the presence of a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable Lö such as water, water / methanol, water / ethanol, what ser / isopropanol, Me 99999 00070 552 001000280000000200012000285919988800040 0002019912690 00004 99880 ethanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, z. B. at temperatures between room temperature and the boiling point temperature of the reaction mixture, carried out.

For example, if a compound of Formula XI contains the tert-butyl or tert-butyloxycarbonyly group, these may also by treatment with an acid such as trifluoroacetic acid, Formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, Phosphoric acid or polyphosphoric acid optionally in one inert solvents such as methylene chloride, chloroform, benzene, Toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, z. At temperatures between 0 and 60 ° C, or thermally optionally in an inert solvent such as methylene chloride, chloroform, Benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-To sulfonic acid, sulfuric acid, phosphoric acid or polyphos phosphoric acid, preferably at the boiling point of the used Solvent, e.g. At temperatures between 40 and 120 ° C, be split off.  

For example, if a compound of Formula XI contains the Benzyloxy or benzyloxycarbonyl group, so they can hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as Me ethanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate ester, dioxane or dimethylformamide, preferably at tempera between 0 and 50 ° C, z. At room temperature, and a Hydrogen pressure of 1 to 5 bar are split off.

h) For the preparation of a compound of the general formula I in which R _{c is} an amidino group which is substituted by one or two C _1-8 -alkoxycarbonyl groups or by an in vivo cleavable radical:
Reaction of a compound of general formula I.

in the
R _a , R _b , Ar, A and B are defined as mentioned above and
R _c "represents an amidino group, with a compound of the general formula

Z ₅ -R ₉ (XIII),

in the
R _{9 is} a C _1-8 alkoxycarbonyl group or the acyl radical of one of the aforementioned in vivo cleavable radicals and
Z _{5 is} a nucleophilic leaving group such as a halogen atom, e.g. As a chlorine, bromine or iodine atom, or a p-nitrophenyl group.

The reaction is preferably carried out in a solvent such as Me ethanol, methylene chloride, tetrahydrofuran, toluene, di  oxane, dimethyl sulfoxide or dimethylformamide, optionally in Presence of an inorganic or a tertiary organic Base, preferably at temperatures between 20 ° C and the you Detemperatur of the solvent used, carried out.

With a compound of the general formula XIII in which Z _{5 represents} a nucleofuge leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethylsulphoxide, if appropriate in the presence of a base such as sodium hydride, Potassium carbonate, potassium tert.bu tylat or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, carried out.

If, according to the invention, a compound of the general 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 represents} a hydrogen atom, this can then be reacted with a corresponding Isocyanate or carbamoyl halide are converted into a corresponding urea compound of the general formula I and / or
a compound of the general formula I which contains an NH ₂ -C _1-3 -alkenyl group, this can then with an ent speaking acrylic acid ester in a corresponding 2- (C _1-3 alkoxycarbonyl) -ethyl compound of the general Formula I überge leads and / or
a compound of general 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, then this can then with a corresponding Dihalogenalkan in a corresponding compound of general formula I, in which R ₃ and R ₄ together with the intervening nitrogen atom, a corresponding 4- to 7-membered cycloalkyleneimino compound are converted and / or
a compound of the general formula I in which R _{c is} an amino dinogruppe, then this can be converted tion by conversion with a Halogenessigsäurederivat and subsequent hydrolysis and decarboxylation in a substituted by one or two methyl groups corresponding Amidinoverbin and / or
a compound of the general formula I in which R _{c represents} a hydroxyamido group, then it can be converted into a corresponding amidino compound by means of catalytic hydrogenation and / or
a compound of the general formula I in which R _{a contains} a carboxyl group, this can then be converted by means of esterification tion in a corresponding ester.

The subsequent production of a corresponding urea Compound of the general formula I is expediently with a corresponding isocyanate or carbamoyl preferred Example in a solvent such as dimethylformamide and given if appropriate in the presence of a tertiary organic base such as Triethylamine at temperatures between 0 and 50 ° C, preferably at room temperature.

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

The subsequent production of a corresponding 4- to 7- membered cycloalkyleneimino compound of the general formula I is conveniently treated with a corresponding dihalogen preferably in a solvent such as methanol, ethanol or isopropanol in the presence of a base such as sodium carbonate at temperatures between 50 and 100 ° C, preferably at the Boiling temperature of the reaction mixture, performed.  

The subsequent alkylation is conveniently in a Solvents 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 Na triumcarbonat or potassium carbonate or in the presence of a ter tiary organic base such as N-ethyl-diisopropylamine or N-Me thyl-morpholine, which at the same time as a solvent may serve, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C, performed.

The subsequent hydrolysis is expediently either in Presence of an acid such as hydrochloric acid, sulfuric acid, phosphorus acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or their mixtures or in the presence of a base such as lithium hy hydroxide, sodium hydroxide or potassium hydroxide in a suitable manner solvents such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane and subsequent decarboxylation in Presence of an acid as described above at Tempera between -10 and 120 ° C, eg. B. at temperatures between Room temperature and the boiling temperature of the reaction mixture, carried out.

The subsequent esterification is with a corresponding Alcohol suitably in a solvent or solution medium mixture such as methylene chloride, benzene, toluene, chloroben zol, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, before but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in Presence of a dehydrating agent, e.g. In the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodi  imide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylate if appropriate in the presence of a base such as potassium carbonate, N-ethyldiisopropylamine or N, N-dimethylaminopyridine moderately at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, or with an ent speaking halide in a solvent such as methylene chloride chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylform amide 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 nat or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent at the same time, or gege optionally in the presence of silver carbonate or silver oxide Temperatures between -30 and 100 ° C, but preferably at Temperatures between -10 and 80 ° C, performed.

In the reactions described above can be given if existing reactive groups such as hydroxy, carboxy, amino no, alkylamino or imino groups during the reaction conventional protecting groups are protected, which after Umset be split off again.

For example, the protective radical for a hydroxy group is the trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group,
as protecting groups for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyra nylgruppe and
as a protective group for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy benzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the Phthalyl group into consideration.

The optional subsequent cleavage of a used Protective residue is, for example, hydrolytically in an aqueous trigen solvent, z. In water, isopropanol / water, Te trahydrofuran / water or dioxane / water, in the presence of a Acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, Na triumhydroxide or potassium hydroxide or by ether cleavage, z. B. in the presence of iodotrimethylsilane, at temperatures zwi 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The cleavage of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radical is hydrogenolytically, for example, z. B. with hydrogen in the presence of a catalyst such as Pal ladium / coal in a solvent such as methanol, ethanol, Ethyl acetate, dimethylformamide, dimethylformamide / Ace clay or glacial acetic acid, if appropriate with the addition of an acid such as Hydrochloric acid at temperatures between 0 and 50 ° C, preferably but at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

The cleavage of a methoxybenzyl group can also in counter an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or Ace tonitrile / water at temperatures between 0 and 50 ° C, preferably However, at room temperature, done.

However, the cleavage of a 2,4-dimethoxybenzyl radical takes place preferably in trifluoroacetic acid in the presence of anisole.

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

The cleavage of a phthalyl radical is preferably carried out in Presence of hydrazine or a primary amine such as methyl amine, ethylamine or n-butylamine in a solvent such as Methanol, ethanol, isopropanol, toluene / water or dioxane Temperatures between 20 and 50 ° C.

The cleavage of an allyloxycarbonyl radical is carried out by Be treatment with a catalytic amount of tetrakis (triphenyl phosphine) -palladium (O) preferably in a solvent such as Tetrahydrofuran and preferably in the presence of an over shot of a base such as morpholine or 1,3-dimedone Temperatures between 0 and 100 ° C, preferably at room temp under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) - chloride in a solvent such as aqueous ethanol and Gege 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 used as starting materials of the general nen formulas II to XIII, which are known from the literature are obtained by literature methods, desweite their preparation is described in the examples.

The chemistry of the compounds of general formula III becomes for example, by Jack Robinson in J. Chem. Soc. 1941, 744, that of Benzimidazole by Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, by Schaumann in Hetarene III, Methods of Organic Chemistry (Houben-Weyl), 4th edition, Verlag Thieme, Stuttgart 1993, described.

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

Further, the obtained compounds of the general For mel I separated into their enantiomers and / or diastereomers become.

Thus, for example, the compounds obtained the general formula I, which occur in racemates, according to known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of the general my formula I with at least 2 asymmetric carbonato due to their physicochemical differences known methods, for. B. by chromatography and / or fractionated crystallization, into their diastereomers which, if they occur in racemic form, on closing as mentioned above in the enantiomers separated who you can.

The enantiomer separation is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with one, with the racemic compound salts or derivatives like z. As esters or amides-forming optically active substance, ins particular acids and their activated derivatives or alcohols, and separating the diastereomers thus obtained Salt mixture or derivative, e.g. B. due to different Solubilities, taking from the pure diastereonating salts or Derivatives the free antipodes by action appropriate Funds can be released. Especially common, optically active acids are, for. B. the D and L forms of wine acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, apple acid, mandelic acid, camphorsulfonic acid, glutamic acid, Aspa ricinic acid or quinic acid. As optically active alcohol comes for example, (+) - or (-) - menthol and as optically active  Acyl radical in amides, for example, the (+) - or (-) - menthyl oxycarbonylrest into consideration.

Furthermore, the compounds of the formula I can be obtained in their salts, in particular for pharmaceutical use in their physiologically acceptable salts with inorganic or organic acids are transferred. When acids come for example, hydrochloric acid, hydrobromic acid, sw felsic acid, methanesulfonic acid, phosphoric acid, fumaric acid, Bern tartaric acid, lactic acid, citric acid, tartaric acid or malein acid into consideration.

In addition, the new compounds thus obtained can be Formula I, if they contain a carboxy group, desired then in their salts with inorganic or or ganic bases, in particular for pharmaceutical applications into their physiologically acceptable salts. The bases used here are, for example, sodium hydroxide, Ka liumhydroxid, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

As already mentioned, the novel compounds of the general formula I and their salts have valuable properties. Thus, the compounds of general formula I in which R _{c represents} a cyano group, valuable Zwischenpro products for the preparation of the other compounds of general formula I, and the compounds of general formula I, in which R _{c represents} one of the aforementioned amidino groups , As well as their tautomers, their stereoisomers and their physiologically acceptable salts have valuable pharmacological properties, in particular an antithrombo tical effect, which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on a the aPTT-prolonging effect and an inhibitory effect on related serine proteases such. Trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the compounds were
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,
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-yl-carbonyl) -ethyl] -benzimidazole hydrochloride and
G = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N -methylcarboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole dihydrochloride
examined for their effect on the aPTT time extension as follows:

material

• - plasma, from human citrated blood,
• PTT Reagent, Boehringer Mannheim (524298),
• - Calcium solution (0.025 mol / l), Behring Werke, Marburg (ORH 056/57),  
• - Diethyl barbiturate buffer, Behring Werke, Mar castle (ORWH 60/61),
• - Biomatic B10 coagulometer, Desaga, Wiesloch.

execution

The aPTT time was determined using a biomatic B10 coagulometer from Desaga.

The test substance was in the manufacturer's prescribed Test vessels containing 0.1 ml of human citrated plasma and 0.1 ml of PTT Reagent given. The batch was at 37 ° C for three minutes incubated. By adding 0.1 ml of calcium solution was the Coagulation reaction started. Device-related takes place with the Entering the calcium solution measuring the time to Gerin tion of the approach. As a control approaches were used in those 0.1 ml of DBA buffer was added.

According to the definition, the dose-response curve was effective substance concentration at which the aPTT Time was doubled over control.

The following table contains the found values

The compounds according to the invention are well ver tolerable, since at therapeutic doses no toxic side effects could be observed.  

Due to their pharmacological properties are the new compounds and their physiologically acceptable salts for the prevention and treatment of venous and arterial thrombo diseases, such as the treatment of tie fen vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT (C) A), as well as the Occlusion in peripheral arterial diseases such as lungs Embolism, the disseminated intravascular coagulation, the Prophylaxis of coronary thrombosis, prophylaxis of stroke and preventing the occlusion of shunts. Zusätz Lich, the compounds of the invention are antithromes botische assistance with a thrombolytic treatment, such as with rt-PA or streptokinase, to prevent it long-term restenosis according to PT (C) A, to prevent the Metastasis and the growth of coagulation-dependent Tumors and fibrin-dependent inflammatory processes, e.g. B. in the treatment of pulmonary fibrosis.

The necessary to achieve a corresponding effect Dosage is expediently when administered intravenously 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, and in the case of oral Administration 0.1 to 50 mg / kg, preferably 0.3 to 30 mg / kg, respectively 1 to 4 times a day. For this purpose, the invention can be forth Asked compounds of formula I, optionally in Kom Combination with other active substances, together with one or several inert customary carriers and / or dilution average, z. B. with corn starch, lactose, cane sugar, micro crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / ethanol, water / Gly cerin, water / sorbitol, water / polyethylene glycol, propylene glycol col, cetylstearyl alcohol, carboxymethylcellulose or fat containing substances such as hard fat or their suitable Ge in common galenical preparations such as tablets, Dragees, capsules, powders, suspensions or suppositories einar BEITEN.  

The following examples are intended to illustrate the invention in more detail purify:

example 1 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl- carbonyl) cyclopropyl] -benzimidazole hydrochloride a. 1- (4-chloro-3-nitro-phenyl) -1-cyclopropane carboxylic acid

50.0 g (0.21 mol) of 1- (4-chlorophenyl) -1-cyclopropancarbon acid are added at -25 ° C. to 350 ml of fuming nitric acid. The solution is stirred for 15 minutes at -25 ° C and then poured onto ice-water. The precipitated product is filtered off with suction, washed with water and dried.
Yield: 58.5 g (95% of theory),
R _f value: 0.45 (silica gel, methylene chloride / methanol = 9.5: 0.5)

b. 1- (4-methylamino-3-nitro-phenyl) -1-cyclopropane carboxylic acid

20.0 g (0.083 mol) of 1- (4-chloro-3-nitro-phenyl) -1-cyclopropane carboxylic acid and 100 ml of methylamine solution (40% in H ₂ O) are heated to 80 ° C in a pressure vessel for five hours. The contents are evaporated to dryness, dissolved in water and acidified with ice-sig. The precipitated product is filtered off with suction, washed with water and dried.
Yield: 16.9 g (93% of theory),
R _f value: 0.58 (silica gel, methylene chloride / methanol = 9: 1)

c. 4- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -2-nitro-N-me thyl-aniline

2.4 g (0.01 mol) of 1- (4-methylamino-3-nitro-phenyl) -1-cyclopro pancarbonsäure are dissolved in 50 ml of dimethylformamide and after addition of 3.2 g (0.01 mol) O- (benzotriazol-1-yl) - N, N, N ', N'-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) of pyrrolidine and 1.1 g (0.01 mol) of N-methyl-morpholine stirred for 20 hours at room temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are evaporated, triturated with ether, filtered off with suction and dried ge.
Yield: 1.8 g (61% of theory),
R _f value: 0.51 (silica gel, methylene chloride / methanol = 9: 1)

d. 4- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -2-amino-N-me thyl-aniline

1.8 g (6.2 mmol) of 4- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] - 2-nitro-N-methyl-aniline are dissolved in 40 ml of methanol and 40 ml of methylene chloride and after addition of 0.4 g of palladium Activated carbon (10%) hydrogenated for 4 hours at room temperature. At closing, the catalyst is filtered off and evaporated.
Yield: 1.6 g (100% of theory),
R _f value: 0.26 (silica gel, methylene chloride / methanol = 9: 1)

e. 4- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -2- (4-cyanophe nyl) aminomethylcarbonylamino-N-methyl-aniline

Prepared analogously to Example 1c from 4- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] -2-amino-N-methylaniline, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-cyano phenylglycine and triethylamine in dimethylformamide.
Yield: 66% of theory,
R _f value: 0.51 (silica gel, methylene chloride / methanol = 9: 1)

f. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin 1-yl-carbonyl) cyclopropyl] -benzimidazole

1.7 g (0.004 mol) of 4- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino-N-methylaniline are refluxed in 7 ml of glacial acetic acid for 2 hours. The solvent is distilled off, the residue dissolved in water and extracted with methylene chloride. The organic phase is dried ge, evaporated and then chromatographed on silica gel, eluting with methylene chloride + 2 to 3% methanol.
Yield: 1.0 g (62% of theory),
R _f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1)

G. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin 1-yl-carbonyl) cyclopropyl] -benzimidazole hydrochloride

1.0 g (2.5 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] benzimidazole who dissolved in 50 ml of saturated ethanolic hydrochloric acid and 5 hours at room temperature touched. The solvent is distilled abde, the residue dissolved in 50 ml of absolute ethanol and treated with 2.3 g (25 mmol) of ammonium carbonate. After 60 hours at room temperature, it is evaporated to dryness. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol (7: 1).
Yield: 700 mg (62% of theory),
R _f value: 0.61 (silica gel, methylene chloride / methanol 4: 1)
C ₂₄ H ₂₈ N ₆ O · HCl (416.54 / 453.0)
Mass spectrum: (M + H) ⁺ = 417

Analogously 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,
R _f value: 0.25 (silica gel, methylene chloride / methanol = 4: 1)
C ₂₆ H ₃₂ N ₆ O · 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,
R _f value: 0.23 (silica gel, methylene chloride / methanol = 4: 1)
C ₂₅ H ₃₀ N ₆ O x HCl (430.56 / 467.93)
Mass spectrum: (M + H) ⁺ = 431

(3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (4-methylpiperazin-1-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride
Yield: 32% of theory,
R _f value: 0.26 (silica gel, methylene chloride / methanol / ammonia = 2: 1: 0.25)
C ₂₅ H ₃₁ N ₇ O x HCl (445.58 / 482.04)
Mass spectrum: (M + H) ⁺ = 446

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2,3-dihydro-indolin-1-yl-carbonyl) -cyclopropyl] -benzimidazole hydrochloride
Yield: 60% of theory,
R _f value: 0.34 (silica gel, methylene chloride / methanol = 4: 1)
C ₂₈ H ₂₈ N ₆ O · HCl (464.58 / 501.04)
Mass spectrum: (M + H) ⁺ = 465

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) piperidin-1-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride
Yield: 85% of theory,
R _f value: 0.57 (silica gel, methylene chloride / methanol = 4: 1)
C ₃₀ H ₃₈ N ₆ O ₃ × HCl (530.67 / 567.13)
Mass spectrum: (M + H) ⁺ = 531

(6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) pyrrolidin-1-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride
Yield: 60% of theory,
C ₂₉ H ₃₆ N ₆ O ₃ × 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-yl-carbonyl] cyclopropyl] - benzimidazole hydrochloride
Yield: 65% of theory,
C ₃₁ H ₄₁ N ₇ O ₃ × HCl (559.72 / 596.18)
Mass Spectrum:
(M + H) ⁺ = 560
(M + 2H) ⁺⁺ = 280.6

(8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(2-ethoxycarbonylmethyloxymethyl) pyrrolidin-1-ylcarbonyl] cyclopropyl] benzimidazole hydrochloride
Yield: 61% of theory,
R _f value: 0.20 (silica gel, methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)
C ₂₉ H ₃₆ N ₆ O ₄ × HCl (532.66 / 569.11)
Mass Spectrum:
(M + H) ⁺ = 533
(M + 2H) ⁺⁺ = 267

Example 2 2- (4-amidinophenylaminomethyl) -1-methyl-5- (1-cyclopentylcar carbonyl-3-chloro-n-propyl) -benzimidazole hydrochloride a. 4- [1- (cyclopentylcarbonyl) cyclopropylil-chlorobenzene

2.4 g (0.1 mol) of magnesium turnings are suspended in 10 ml of ether. After addition of a spatula tip of iodine, 14.9 g (0.1 mol) of bromocyclopentane in 40 ml of ether are slowly added dropwise, starting at the beginning by gentle heating, the reaction is started. After completion of the addition is heated for 30 minutes under reflux. Then a solution of 14.0 g (0.08 mol) of 1- (4-chlorophenyl) -1-cyclopropanecarbonitrile in 75 ml of ether is added and heated under reflux for a further 3 hours. The reaction solution is poured onto ice-water, adjusted to pH 3 with hydrochloric acid and extracted with ether. The organic extracts are dried and evaporated. The residue is chromatographed on silica gel and eluted with petroleum ether / ethyl acetate (19: 1 and 15: 1).
Yield: 3.0 g (12% of theory),
R _f value: 0.58 (silica gel, petroleum ether / ethyl acetate = 4: 1)

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

Prepared analogously to Example 1a from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -chlorobenzene and fuming nitric acid.
Yield: 87% of theory,
R _f value: 0.60 (silica gel, petroleum ether / ethyl acetate = 9: 1)

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

Prepared analogously to Example 1b from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2-nitro-chlorobenzene and aqueous methylamine solution.
Yield: 18% of theory,
R _f value: 0.54 (silica gel, methylene chloride / ethanol = 19: 1)

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

2.3 g (7.9 mmol) of 4- [1- (cyclopentylcarbonyl) cyclopropyl] -2-nitro-N-methylaniline are dissolved in 125 ml of ethyl acetate and 25 ml of ethanol and, after addition of 1.0 g of Raney nickel, hydrogenated at room temperature for 1.5 hours , It is then filtered off from the catalyst and evaporated.
Yield: 2.0 g (98% of theory),
R _f value: 0.15 (silica gel, methylene chloride / ethanol = 19: 1)

e. 4- [1- (cyclopentylcarbonyl) cyclopropyl] -2- (4-cyanophenyl aminomethylcarbonylamino) -N-methyl-aniline

Prepared analogously to Example 1c from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2-amino-N-methylaniline, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4 -Cyano-phenyl glycine and triethylamine in dimethylformamide.
Yield: 96% of theory,
R _f value: 0.54 (silica gel, methylene chloride / ethanol = 19: 1)

f. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (cyclopentylcar carbonyl) cyclopropyl] -1 H -benzimidazole

Prepared analogously to Example 1f from 4- [1- (Cyclopentylcarbo nyl) cyclopropyl] -2- (4-cyanophenyl-aminomethylcarbonylamino) - N-methyl-aniline in glacial acetic acid.
Yield: 53% of theory,
R _f value: 0.46 (silica gel, methylene chloride / ethanol = 19: 1)

G. 2- (4-amidinophenylaminomethyl) -1-methyl-5- (1-cyclopentyl carbonyl-3-chloro-n-propyl) -benzimidazole hydrochloride

Prepared analogously to Example 1g from 2- (4-cyanophenylamino methyl) -1-methyl-5- (1-cyclopentylcarbonyl-3-chloro-n-propyl) benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 61% of theory,
C ₂₅ H ₃₀ ClN ₅ O. HCl (452.00 / 488.56)
Mass spectrum: (M + H) ⁺ = 452/4 (Cl)

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 100 ml of butyllithium (1.6 M in hexane) is added dropwise at -40 to -50 ° C, a solution of 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 added dropwise a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropanecarbonitrile in 125 ml of ether. After completion of the addition, the reaction mixture is warmed to room temperature and stirred for 5 hours. The suspension is mixed with 20% hydrochloric acid and heated to 100 ° C for 30 minutes. After cooling, it is adjusted to pH 8 with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
The residue is chromatographed on alumina, eluting with petroleum ether / ethyl acetate (9: 1).
Yield: 14.0 g (46% of theory),
R _f value: 0.27 (alumina, petroleum ether / ethyl acetate = 9: 1)

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

Prepared analogously to Example 1a from 1 - [(pyridin-3-yl) carbonyl] cyclopropylbenzene and fuming nitric acid.
Yield: 53.7% of theory,
R _f value: 0.29 (alumina, petroleum ether / ethyl acetate = 4: 1)

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

Prepared analogously to Example 2d from 4- [1- [pyridin-3-yl) -car bonyl] cyclopropyl] -nitrobenzene and Raney nickel in ethyl acetate / ethanol.
Yield: 94% of theory,
R _f value: 0.51 (silica gel, methylene chloride / ethanol = 19: 1)

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

8.0 g (33.5 mmol) of 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] - aniline are dissolved in 100 ml of chlorobenzene and stirred for 2 hours at 110 ° C after addition of 15 ml of trifluoroacetic anhydride. The solvent is distilled off, the residue triturated with ether / ether ether (9: 1), filtered off and dried.
Yield: 10.0 g (88% of theory),
R _f value: 0.54 (silica gel, methylene chloride / ethanol = 19: 1)

e. 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-tri fluoracetylanilin

13 ml conc. Sulfuric acid and 16 ml of 65% nitric acid who at -5 ° C in portions with 1.7 g (5 mmol) of 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] trifluoroacetylaniline. The mixture is then stirred for 30 minutes without cooling, poured onto ice water and extracted with ethyl acetate. The organic extracts are dried and evaporated. The residue is chromatographed on silica gel and eluted with methylene chloride / ethanol (50: 1 and 25: 1). The desired fractions are evaporated, triturated with ether / petroleum ether, filtered off with suction and dried.
Yield: 1.2 g (75% of theory),
R _f value: 0.70 (silica gel, methylene chloride / ethanol = 19: 1)

f. 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-N-tri fluoroacetyl-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 for two hours Reflux heated. The insoluble material is filtered off and the solution is concentrated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (1: 1 and 1: 4).
Yield: 0.88 g (75% of theory),
R _f value: 0.38 (silica gel, petroleum ether / ethyl acetate = 1: 1)

G. 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-N-me thyl-aniline

7.4 g (18.8 mmol) of 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-nitro-N-trifluoroacetyl-N-methyl-aniline are dissolved in 200 ml of 20% potassium hydroxide solution for one hour at 30 ° C stirred. It is then diluted with isopropanol, the organic phase separates abge, mixed with 10.0 g of alumina and evaporated to dryness. The residue is chromatographed on alumina, eluting with petroleum ether / ethyl acetate (4: 1 and 1: 1).
Yield: 2.6 g (47% of theory),
R _f value: 0.50 (silica gel, petroleum ether / ethyl acetate = 1: 1)

H. 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2-amino-N-me thyl-aniline

Prepared analogously to Example 2d from 4- [1 - [(pyridin-3-yl) -carbonyl] cyclopropyl] -2-nitro-N-methyl-aniline and Raney nickel in ethyl acetate / ethanol.
Yield: 98% of theory,
R _f value: 0.51 (silica gel, methylene chloride / ethanol = 19: 1)

i. 4- [1 - [(pyridin-3-yl) carbonyl] cyclopropyl] -2- (4-cyano phenyl) -aminomethylcarbonylamino-N-methyl-aniline

Prepared analogously to Example 1c from 4- [1 - [(pyridin-3-yl) -carbonyl] cyclopropyl] -2-amino-N-methylaniline, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-cyano phenylglycine and triethylamine in dimethylformamide.
Yield: 97% of theory,
R _f value: 0.48 (silica gel, methylene chloride / ethanol = 19: 1)

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

Prepared analogously to Example 1f from 4- (pyridin-3-yl-carbonyl) -cyclopropyl-2- (4-cyanophenyl) -aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.
Yield: 76% of theory,
R _f value: 0.52 (silica gel, methylene chloride / ethanol = 19: 1)

l. (E / Z) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin- 3-yl- (carboxymethyloxyimino) methylenl] 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 carboxy-methoxylamine hemihydrate , 0.84 ml of triethylamine, 12 g of molecular sieve 3A and 12 g of molecular sieve 4A are refluxed in 80 ml of methanol and 40 ml of toluene for 12 hours. It is then filtered off from the molecular sieve and evaporated. The residue is stirred with water, filtered off with suction and dried. The crude product is chromatographed on silica gel eluting with methylene chloride / ethanol / glacial acetic acid (25: 1: 0 and 8: 2: 0.2).
Yield: 0.9 g (48% of theory),
R _f value: 0.34 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)

m. (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyri din-3-yl) - (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] - benzimidazole hydrochloride

Prepared analogously to Example 1g from (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] benzimidazole and salt acid / ammonium carbonate in ethanol.
Yield: 60% of theory,
R _f value: 0.28 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)
C ₂₉ H ₃₁ N ₇ O ₃ × HCl (525.62 / 562.09)
Mass spectrum: (M + H) ⁺ = 526

Analogously to Example 3, the following compounds are obtained:

(1) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] benzimidazole hydrochloride
Yield: 52% of theory,
R _f value: 0.21 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)
C ₂₉ H ₃₁ N ₇ O ₃ × HCl (525.62 / 562.09)
Mass spectrum: (M + H) ⁺ = 526

(2) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl] (ethoxycarbonylmethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride
Yield: 18% of theory,
C ₃₀ H ₃₂ N ₆ O ₃ · 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-methylpyrazol-5-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride
Yield: 10% of theory,
C ₂₄ H ₂₅ N ₇ O ₃ · HCl (427.51 / 463.97)
Mass Spectrum:
(M + H) ⁺ = 428
(M + H + HCl) ^- = 464/6 (CI)

(4) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(1-methyl-pyrazol-5-yl (ethoxycarbonylmethyloxyimino) methylene] cyc lopropyl] benzimidazole hydrochloride
Yield: 80% of theory,
R _f value: 0.20 (silica gel, methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)
C ₂₈ H ₃₂ N ₈ O ₃ · HCl (528.63 / 565.08)
Mass spectrum: (M + H) ⁺ = 529

(5) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl] (3-ethoxycarbonyl-n-propyloxyimino) methylene] cyclopropyl] benzimidazole dihydrochloride
Yield: 47% of theory,
R _f value: 0.06 (silica gel, methylene chloride / methanol = 9: 1)
C ₃₂ H ₃₆ N ₆ O ₃ × 2 HCl (552.69 / 625.60)
Mass spectrum: (M + H) ⁺ = 553

Example 4 (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin- methylene (carboxymethyloxyimino)] cyclopropyl] -benzimi - 2-yl) dazol 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 are stirred in 10 ml of ethanol for 5 hours at room temperature The alcohol is distilled off and the residue is adjusted with hydrochloric acid to pH 5. The crystalline product is filtered off with suction, washed with water and dried.
Yield: 46% of theory,
R _f value: 0.10 (silica gel, methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.1)
C ₂₇ H ₂₇ N ₇ O ₃ × HCl (497.58 / 534.05)
Mass Spectrum:
(M + H) ⁺ = 498
(M + Na) ⁺ = 520

The following compounds are obtained analogously to Example 4:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) -piperidin-1-ylcarbonyl] cyclopropyl] benzimidazole hydrochloride
Yield: 94% of theory,
R _f value: 0.57 (reversed phase RP 18, methanol / 5% sodium chloride solution = 3: 2)
C ₂₈ H ₃₄ N ₆ O ₃ · HCl (502.62 / 539.08)
Mass Spectrum:
(M + H) ⁺ = 503
(M + Na) ⁺ = 525

(2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride
Yield: 98% of theory,
R _f value: 0.73 (reversed phase RP 8, methanol / 5% sodium chloride solution = 1: 2)
C ₂₆ H ₃₃ N ₇ O ₃ × HCl (491.60 / 564.54)
Mass Spectrum:
(M + H) ⁺ = 492
(M + 2H) ⁺⁺ = 247

(3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-carboxypropionylamino) -1- (ethoxycarbonyl) ethyl] benzimidazole hydrochloride
Yield: 98% of theory,
R _f value: 0.70 (RP 8, methanol / 5% sodium chloride solution = 1: 2)
C ₂₅ H ₃₀ N ₆ O ₅ × HCl (494.55 / 531.05)
Mass Spectrum:
(M + H) ⁺ = 495
(2M + H) ⁺ = 989

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) methyl] benzimidazole hydrochloride
Yield: 87% of theory,
C ₂₄ H ₂₉ N ₇ O ₃ · HCl (463.54 / 500.04)
Mass Spectrum:
(M + H) ⁺ = 464
(M + 2H) ⁺ = 232.6

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) pyrrolidin-1-ylcarbonyl] cyclopropyl] benzimidazole hydrochloride
Yield: 94% of theory,
C ₂₇ H ₃₂ N ₆ O ₃ × HCl (488.59 / 525.05)
Mass Spectrum:
(M + H) ⁺ = 489
(M + Na) ⁺ = 511

(6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -methyl] -benzimidazole hydrochloride
Yield: 49% of theory,
C ₂₅ H ₂₉ N ₇ O ₄ × HCl (491.55 / 528.01)
Mass Spectrum:
(M + H) ⁺ = 492
(M + H + Na) ⁺⁺ = 257.7

(7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride
Yield: 92% of theory,
C ₂₆ H ₃₁ N ₇ O ₄ · HCl (505.58 / 542.04)
Mass Spectrum:
(M + H) ⁺ = 506
(M + H + Na) ⁺⁺ = 264.7

(8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-carboxymethyl-imidazoline-2,4-dione-5-yl) -benzimidazole hydrochloride
Yield: 88% of theory,
C ₂₂ H ₂₃ N ₇ O ₄ · 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 hydrochloride
Yield: 54% of theory,
C ₂₇ H ₂₇ N ₇ O ₃ × HCl (497.56 / 534.09)
Mass Spectrum:
(M + H) ⁺ = 498
(M + Na) ⁺ = 520

(10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (N- (2-carboxyethyl) -N-methyl-aminomethyl) -pyrrolidin-1-ylcarbonyl] -cyclopropyl] benzimidazole hydrochloride
Yield: 100% of theory,
C ₂₉ H ₃₇ N ₇ O ₃ × HCl (531.66 / 568.12)
Mass Spectrum:
(M + H) ⁺ = 532
(M - H) ^- = 530

(11) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (2-carboxyethyl) -N- (2-pyridyl) aminomethyl] benzimidazole hydrochloride
Yield: 91% of theory,
C ₂₅ H ₂₇ N ₇ O ₂ × HCl (457.54 / 493.96)
Mass spectrum: (M + H) ⁺ = 458

(12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (N-benzenesulfonyl-N-carboxymethyl-aminomethyl) -benzimidazole hydrochloride
Yield: 84% of theory,
C ₂₅ H ₂₆ N ₆ O ₄ S × HCl (506.59 / 543.06)
Mass spectrum: (M + M) ⁺ = 507

(13) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) benzimidazol-1-ylmethyl] benzimidazole hydrochloride
Yield: 76% of theory,
C ₂₇ H ₂₇ N ₇ O ₂ × 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-carboximidazol-1-ylmethyl) benzimidazole hydrochloride
Yield: 61% of theory,
C ₂₂ H ₂₃ N ₇ O ₂ × HCl (417.47 / 453.92)
Mass spectrum: (M + H) ⁺ = 418

(15) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [3- (3-carboxy-n-propyl) -benzimidazol-2-on-1-ylmethyl] -benzimidazole hydrochloride
Yield: 86% of theory,
C ₂₈ H ₂₉ N ₇ O ₃ × 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-carboxyethyl) -imidazo [4,5-b] pyridin-2-one-1-ylmethyl] -benzimidazole hydrochloride
Yield: 83% of theory,
C ₂₆ H ₂₆ N ₈ O ₃ × HCl (498.55 / 535)
Mass Spectrum:
(M + H) ⁺ = 499
(M + Na) ⁺ = 521
(M - H) ^- = M 497
(2M - H) ^- = 995

(17) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole hydrochloride
Yield: 68% of theory,
R _f value: 0.70 (reversed phase RP 8, methanol / 5% sodium chloride solution = 6: 4)
C ₂₅ H ₂₉ N ₇ O ₂ × HCl (459.56 / 496.01)
Mass Spectrum:
(M + H) ⁺ = 460
(M + Na) ⁺ = 482
(M + H + Na) ²⁺ = 241

(18) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl] (carboxymethyloxyimino) methylene] cyclopropyl] benzimidazole dihydrochloride
Yield: 70% of theory,
C ₂₈ H ₂₈ N ₆ O ₃ · 2HCl (496.57 / 569.5)
Mass Spectrum:
(M + H) ⁺ = 497
(M - H) ^- = 495

(19) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [(pyridin-3-yl) (carboxymethylidene) methylene] cyclopropyl] -benzimidazole hydrochloride
Yield: 37% of theory
R _f value: 0.45 (reversed phase RP 8, methanol / 5% sodium chloride solution = 6: 4)
C ₂₇ H ₂₆ N ₆ O ₂ × HCl (466.55 / 503.0)
Mass spectrum: (M + H) ⁺ = 467

(20) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(1-methyl-pyrazol-5-yl) (carboxymethyloxyimino) methylene] cyclopropyl] -benzimidazole hydrochloride
Yield: 30% of theory,
R _f value: 0.25 (Reversed Phase RP 8; 5% saline / methanol = 1: 1)
C ₂₆ H ₂₈ N ₈ O ₃ · HCl (500.58 / 537.03)
Mass Spectrum:
(M + H) ⁺ = 501
(M - H) ^- = 499
(M + Cl) ⁺ = 535/537 (CI)

(21) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl] (3-carboxy-n-propyloxyimino) methylene] cyclopropyl] benzimidazole dihydrochloride
Yield: 37% of theory,
R _f value: 0.35 (reversed phase RP 8; 5% saline / methanol = 3: 2)
C ₃₀ H ₃₂ N ₆ O ₃ x 2 HCl (524.64 / 597.55)
Mass spectrum: (M + H) ⁺ = 525

Example 5 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl- carbonyl) -aminomethyl] -benzimidazole hydrochloride a. 5- (4-chlorophenyl) 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 at 55 ° C for 18 hours. The solvent is distilled off, the residue is dissolved in water and extracted with ethyl acetate. The combined organic extracts are 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 analogously to Example 1a from 5- (4-chlorophenyl) -imidazolidin-2,4-dione and fuming nitric acid.
Yield: 52% of theory,
R _f 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) -imidazolidin-2,4-dione are semi-concentrated in 20 ml. Hydrochloric acid heated to reflux for 24 hours. The solvent is distilled off, the residue was dissolved in water, filtered from the insoluble and evaporated. The residue is dissolved three times in ethanol, evaporated to dryness, triturated with ether, filtered off with suction and dried ge.
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 dicarbonate Stirred for 18 hours at room temperature. It is then diluted with 0.5 M potassium bisulfate solution and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
Yield: 6.3 g (100% of theory),
R _f 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 analogously to Example 1c from 4-chloro-3-nitro-N-tert-butyl oxycarbonyl-phenylalanine, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl diisopropylamine in tetrahydrofuran.
Yield: 68% of theory,
Melting point: 203 ° C

f. 2- (4-Methylamino-3-nitro-phenyl) -2-t-butyloxycarbonyl amino-1- (pyrrolidin-1-yl-ethanone

Prepared analogously 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,
R _f value: 0.33 (silica gel, cyclohexane / ethyl acetate = 1: 1)

G. 2- (4-methylamino-3-amino-phenyl) -2-t-butyloxycarbonyl amino-1-pyrrolidin-1-yl-ethanone

Prepared analogously 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 nol.
Yield: 100% of theory,
R _f value: 0.12 (silica gel, cyclohexane / ethyl acetate = 1: 1)

H. 2- [4-methylamino-3- (4-cyanophenylaminomethylcarbonylamino) - phenyl] -2-tert.butyloxycarbonylamino-1- (pyrrolidin-1-yl) - ethanone

Prepared analogously to Example 1c from 2- (4-methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in tetrahydrofuran.
Yield: 100% of theory,
R _f value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)

i. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin 1-yl-carbonyl) aminomethyl] benzimidazole

Prepared analogously to Example 1f from 2- [4-methylamino-3- (4-cy anophenylaminomethylcarbonylamino) -phenyl] -2-tert-butyloxy carbonylamino-1- (pyrrolidin-1-yl) -ethanone in glacial acetic acid.
Yield: 30% of theory,
R _f value: 0.19 (silica gel, methylene chloride / methanol = 9.5: 0.5)

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

Prepared analogously to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl-carbonyl) aminomethyl] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 27% of theory,
C ₂₂ H ₂₇ N ₇ O x HCl (405.50 / 441.96)
Mass spectrum: (M + H) ⁺ = 406

The following compounds are obtained analogously to Example 5:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N-acetylaminomethyl] benzimidazole hydrochloride
Yield: 29% of theory,
C ₂₄ H ₂₉ N ₇ O ₂ × HCl (447.54 / 484.54)
Mass spectrum: (M + H) ⁺ = 448

(2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (2-ethoxycarbonylethyl) -N-methyl-aminomethyl] -benzimidazole hydrochloride
Yield: 74% of theory,
C ₂₈ H ₃₇ N ₇ O ₃ × HCl (519.65 / 556.11)
Mass spectrum: (M + H) ⁺ = 520

(3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (ethoxycarbonylmethyl) aminomethyl] benzimidazole hydrochloride
Yield: 76% of theory,
C ₂₆ H ₃₃ N ₇ O ₃ × HCl (491.59 / 528.05)
Mass Spectrum:
(M + H) ⁺ = 492
(M + 2H) ⁺⁺ = 246.7

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N, N-di (ethoxycarbonylmethyl) aminomethyl] benzimidazole hydrochloride
Yield: 51% of theory,
C ₃₀ H ₃₉ N ₇ O ₅ × HCl (577.68 / 614.14)
Mass Spectrum:
(M + H) ⁺ = 578
(M + Na) ⁺ = 600

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (ethoxycarbonylmethylcarbonyl) aminomethyl] benzimidazole hydrochloride
Yield: 29% of theory,
C ₂₇ H ₃₃ N ₇ O ₄ × HCl (519.60 / 556.06)
Mass Spectrum:
(M + H) ⁺ = 520
(M + 2H) ⁺⁺ = 260.7

(6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (2-ethoxycarbonylethyl) aminomethyl] -benzimidazole hydrochloride
Yield: 84% of theory,
C ₂₇ H ₃₅ N ₇ O ₃ × 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-ethoxy carbonylethyl) amino] -1- (pyrrolidin-1-yl-carbonyl) ethyl] - benzimidazole hydrochloride a. 5- (4-chloro-3-nitro-phenyl) -5-methyl-imidazolidine-2,4-dione

To 50 ml of fuming nitric acid are 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 at -25 to -20 ° C, the reaction mixture is poured onto ice-water. The crystalline product is filtered off with suction, washed with water and dried.
Yield: 10.5 g (100% of theory),
Melting point: 173-178 ° C
R _f 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 are refluxed in 200 ml of dioxane and 700 ml of 6N hydrochloric acid for 5 days. The solution is evaporated, the residue taken up in water and extracted with ethyl acetate. The aqueous phase is evaporated, treated with toluene and evaporated to dryness. The residue is triturated with ether, filtered off with suction and dried.
Yield: 6.8 g (63% of theory),
R _f value: 0.24 (Reversed phase RP8, 5% saline / methanol = 1: 1)

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

Prepared analogously to Example 5d from 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid, pyrocarbonic di-tert-butyl dicarbonate and triethylamine in dioxane.
Yield: 9.6 g (100% of theory),
R _f value: 0.31 (Reversed phase RP8, 5% saline / methanol = 1: 2)

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

Prepared analogously to Example 1c from 2-tert-butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate Pyrrolidine and N-methylmorpholine in dimethylformamide.
Yield: 94% d. Theory,
R _f value: 0.11 (silica gel, cyclohexane / ethyl acetate = 1: 1)

e. 2- (4-Methylamino-3-nitro-phenyl) -2-t-butyloxycarbonyl amino-1- (pyrrolidin-1-yl) -propanone

Prepared analogously to Example 1b from 2- (4-chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone and methylamine solution in dimethylformamide at 160 ° C.
R _f value: 0.79 (silica gel, ethyl acetate / ethanol = 9: 1)

f. 2- (4-methylamino-3-amino-phenyl) -2-t-butyloxycarbonyl amino-1-pyrrolidin-1-yl-propanone

Prepared analogously to Example 1d from 2- (4-methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -pro panone and palladium on activated carbon / hydrogen in methanol.
Yield: 100% d. Theory,
R _f 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 analogously to Example 1c from 2- (4-methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) propane, O- (benzotriazol-1-yl) -N, N , N ', N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and N-methylmorpholine in dimethylformamide.
Yield: 37% of theory,
R _f value: 0.47 (silica gel, ethyl acetate)

H. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyl oxycarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] benz imidazole

Prepared analogously to Example 1f from 2- [4-methylamino-3- (4-cy anophenylaminomethylcarbonylamino) -phenyl] -2-tert.butyloxycar bonylamino-1- (pyrrolidin-1-yl) -propanone and glacial acetic acid.
Yield: 60% of theory,
R _f value: 0.37 (silica gel, ethyl acetate)

i. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyr rolidin-1-yl-carbonyl) -ethyl] -benzimidazole

1.3 g (2.3 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert -butyloxycarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole are obtained in 20 Dissolved dioxane and after addition of 40 ml of semiconc. Hydrochloric acid stirred for two hours at room temperature. The solution is mixed with ice, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
Yield: 0.9 g (98% of theory),
R _f value: 0.14 (silica gel, ethyl acetate / ethanol = 9: 1)

k. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- [N- (2-ethoxy carbonylethyl) amino] -1- (pyrrolidin-1-yl-carbonyl) ethyl] - benzimidazole

0.4 g (1.04 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- (1-amino-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole are dissolved in 10 ml of ethanol and after addition of 0.3 ml (2.7 mmol) of ethyl acrylate for 24 hours at 95 ° C. The solvent is distilled off, the residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (20: 1 and 4: 1).
Yield: 0.16 g (31% of theory),
R _f value: 0.26 (silica gel, ethyl acetate / ethanol = 9: 1)

l. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N- (2-ethoxy carbonylethyl) amino] -1- (pyrrolidin-1-yl-carbonyl) ethyl] - benzimidazole hydrochloride

Prepared analogously to Example 1g from 2- (4-cyano-phenylamino-methyl) -1-methyl-5- [1- [N- (2-ethoxycarbonyl-ethyl) -amino] -1- (pyrrolidin-1-yl-carbonyl) -ethyl] - benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 96% of theory,
C ₂₈ H ₃₇ N ₇ O ₃ × HCl (519.65 / 556.11)
Mass Spectrum:
(M + H) ⁺ = 520
(M + Na) ⁺ = 542

Analogously to Example 6, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonylpropionylamino) -1-ethoxycarbonyl-ethyl] -benzimidazole hydrochloride
Yield: 69% of theory,
C ₂₇ H ₃₄ N ₆ O ₅ × HCl (522.62 / 555.08)
Mass Spectrum:
(M + H) ⁺ = 523
(M + H + Na) ⁺⁺ = 273

(2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyloxymethylcarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride
Yield: 95% of theory,
C ₂₈ H ₃₅ N ₇ O ₄ × 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-ylcarbonyl) ethyl] benzimidazole hydrochloride
Yield: 20% of theory,
C ₂₉ H ₃₇ N ₇ O ₄ × 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-5- [1-dimethylamino-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride
Yield: 91% of theory,
C ₃₀ H ₄₁ N ₇ O ₃ × HCl (547.71 / 584.17)
Mass Spectrum:
(M + H) ⁺ = 548
(M - H) ^- = 546

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -1- (dimethylaminocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 40% of theory,
R _f value: 0.60 (reversed phase RP 8; 5% saline / methanol = 1/1)
C ₂₆ H ₃₅ N ₇ O ₃ × 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 hydrochloride
Yield: 77% of theory,
R _f value: 0.40 (silica gel, methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)
C ₂₇ H ₃₅ N ₇ O ₃ × HCl (505.63 / 542.08)
Mass spectrum: (M + H) ⁺ = 506

(7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -1- (N-ethyl-N-methylaminocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 85% of theory,
R _f value: 0.44 (silica gel, methylene chloride / ethanol = 9: 1)
C ₂₇ H ₃₇ N ₇ O ₃ × HCl (507.64 / 544.14)
Mass Spectrum:
(M + H) ⁺ = 508
(M + Cl) ^- = 542/4 (Cl)

(8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 99% of theory,
R _f value: 0.21 (silica gel, methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)
C ₂₆ H ₃₃ N ₇ O ₃ × HCl (491.60 / 528.05)
Mass Spectrum:
(M + H) ⁺ = 492
(M - H + HCl) ^- = 526/8 (Cl)
(M - H + 2HCl) ^- = 562/4/8 (Cl ₂ )

(9) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N, N-bis (ethoxycarbonylmethyl) amino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole hydrochloride
Yield: 65% of theory,
R _f value: 0.35 (silica gel, methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)
C ₃₁ H ₄₁ N ₇ O ₅ × 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-yl-carbonyl) -ethyl] -benzimidazole hydrochloride
Yield: 9% of theory,
R _f value: 0.50 (reversed phase RP 8, methanol / 5% saline solution = 3: 2)
C ₂₆ H ₃₃ N ₇ O ₄ × HCl (507.60 / 544.05)
Mass spectrum: (M + H) ⁺ = 508

(11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxy carbonyl-ethylamino) -1- (isoxazolidin-1-yl-carbonyl) ethyl] - benzimidazole hydrochloride

(12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (N-methyl-N-ethylaminocarbonyl) ethyl] benzimidazole dihydrochloride
Yield: 58% of theory,
R _f value: 0.70 (reversed phase RP 8, methanol / 5% saline solution = 3: 2)
C ₂₆ H ₃₅ N ₇ O ₃ x 2 HCl (493.62 / 566.52)
Mass Spectrum:
(M + H) ⁺ = 494
(M + HCl - H) ^- = 528/30 (Cl)

(13) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - ((N, N-di (ethoxycarbonylmethyl) amino) -1- (N-methyl-N-ethylaminocarbonyl) -ethyl] benzimidazole dihydrochloride
Yield: 30% of theory,
R _f value: 0.40 (reversed phase RP 8, methanol / 5% saline solution = 3: 2)
C ₃₀ H ₄₁ N ₇ O ₅ x 2 HCl (579.71 / 652.62)
Mass Spectrum:
(M + H) ⁺ = 580
(M - H) ^- = 578

(14) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (piperidinocarbonyl) ethyl] benzimidazole dihydrochloride
Yield: 82% of theory,
R _f value: 0.60 (reversed phase RP 8, methanol / 5% saline solution = 3: 2)
C ₂₈ H ₃₇ N ₇ O ₃ × 2 HCl (519.65 / 592.75)
Mass Spectrum:
(M + H) ⁺ = 520
(M - H + HCl) ^- = 534/6 (Cl)
(M - H + 2HCl) ^- = 590/2/4 (Cl ₂ )

(15) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycar bonylmethylamino) -1- (diethylaminocarbonyl) ethyl] -benzimida zole dihydrochloride

Example 7 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N-cyclopentyl- N- (3-ethoxycarbonylpropionyl) amino] cyclopropyl] benzimidazole hydrochloride a. 4 - ((1-tert.Butyloxycarbonylamino) cyclopropyl) -2-nitro-N-me thyl-aniline

15.0 g (63.5 mmol) of 4 - ((1-carboxy) cyclopropyl) -2-nitro-N-methylaniline and 17.6 ml (127 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and stirred at 0 ° C. with 8.3 g ( 76 mmol) of ethyl chloroformate. After one hour at room temperature, 0.75 g of tetrabutylammonium bromide are added. Subsequently, a solution of 6.3 g (96 mmol) sodium triazide in 20 ml of water is added dropwise. After one hour at 0 ° C, the solution is diluted with water and extracted with ethyl acetate extra hiert. The organic extracts are dried and evaporated. The residue is dissolved in 200 ml of tert-butanol and heated to reflux for two hours. The solvent is evaporated, the residue is chromatographed on silica gel and eluted with methylene chloride.
Yield: 15.5 g (77% of theory),
R _f value: 0.83 (silica gel, methylene chloride / methanol = 9.5: 0.5)

b. 4 - ((1-amino) cyclopropyl) -2-nitro-N-methylaniline hydrochloride chloride

15.5 g (0.05 mol) 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 and stirred for 7 hours at room temperature. The solvent is distilled off, the residue is triturated with ether, filtered off with suction and dried.
Yield: 98% of theory,
R _f value: 0.44 (silica gel, methylene chloride / methanol = 9.5: 0.5)

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

12.0 g (0.05 mol) of 4 - [(1-amino) cyclopropyl] -2-nitro-N-methyl-aniline hydrochloride are dissolved in 500 ml of tetrahydrofuran and, after addition of 4.1 g (0.05 mol) of cyclopentanone and 3.2 ml of glacial acetic acid Nitrogen atmosphere in portions with 13.6 g (0.064 mol) of sodium triacetoxyborohydride. After 16 hours at room temperature, dilute with sodium bicarbonate solution and extract with ethyl acetate. The organic extracts are dried and evaporated. The residue is chromatographed on silica gel and eluted with ethyl acetate / cyclohexane (1: 1).
Yield: 10.8 g (80% of theory)
R _f 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-methylaniline are dissolved in 30 ml of tetrahydrofuran and after addition of 0.45 g (4.4 mmol) of triethylamine with 0.65 g (4.4 mmol) Succinic acid ethyl ester chloride and stirred for four hours at room temperature. 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),
R _f 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 analogously to Example 1d 4- [1- (N- (3-Ethoxycarbonylpropionyl) -N-cyclopentyl-amino) cyclopropyl] -2-nitro-N-methyl-aniline and palladium on activated carbon / hydrogen in methylene chloride / ethanol.
Yield: 100% of theory,
R _f value: 0.18 (silica gel, ethyl acetate / cyclohexane = 1: 1)

f. 4- [1- (N- (3-Ethoxycarbonylpropionyl) -N-cyclopentyl-amino) - cyclopropyl] -2- (4-cyanophenyl) -aminomethylcarbonylamino-N-me thyl-aniline

Prepared analogously to Example 1c 4- [1- (N- (3-ethoxycarbonylpropionyl) -N-cyclopentyl-amino) cyclopropyl] -2-amino-N-methylaniline, O- (benzotriazol-1-yl) -N , N, N ', N'-tetramethyluronium tetra fluoroborate, 4-cyanophenylglycine and triethylamine in dimethyl formamide.
Yield: 96% of theory,
R _f 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 analogously to Example 1f from 4- [1- (N- (3-ethoxycarbonylpropionyl) -N-cyclopentyl-amino) cyclopropyl] -2- (4-cyanophenyl) -aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.
Yield: 52% of theory,
R _f value: 0.81 (silica gel, methylene chloride / methanol = 9: 1)

H. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [N-Cyclops tyl-N- (3-ethoxycarbonylpropionyl) amino] cyclopropyl] -benz imidazole hydrochloride

Prepared analogously to Example 1g from 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- [N-cyclopentyl-N- (3-ethoxycarbonylpro pionyl) amino] cyclopropyl] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol ,
Yield: 36% of theory,
C ₃₀ H ₃₈ N ₆ O ₃ × HCl (530.68 / 567.14)
Mass spectrum: (M + H) ⁺ = 531

Example 8 2- (4-amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-ethoxy carbonylmethyl-imidazolin-2,4-dion-5-yl) benzimidazole hydrochloride chloride a. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl methylaminocarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) ethyl] - benzimidazole

1.0 g (2.5 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole are dissolved in 10 ml of dimethylformamide and after addition of 0.9 ml (7.9 mmol) of ethyl isocyanatoacetate for 45 minutes at room temperature. 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).
R _f value: 0.77 (silica gel, methylene chloride / ethanol / ammonia = 9: 1: 0.01)

b. 2- (4-amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-eth oxycarbonylmethyl-imidazolin-2,4-dion-5-yl) benzimidazole hydrochloride chloride

Prepared analogously to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylaminocarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol ,
Yield: 68% of theory,
C ₂₄ H ₂₇ N ₇ O ₄ · 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 chloride a. 4- (2-tert.Butyloxycarbonylethyl) -2- (pyridylaminomethyl) - nitrochlorobenzene

13.4 g (0.053 mol) of 4-chloro-3-nitro-benzylbromide and 11.8 g (0.053 mol) of 2-tert-butyloxycarbonylethylamino-pyridine are stirred in 80 ml of N-ethyl-diisopropylamine at 90 ° C. for 3 hours. 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),
R _f value: 0.64 (silica gel, petroleum ether / ethyl acetate = 8: 2)

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

Prepared analogously to Example 1b from 4- (2-tert-butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-chlorobenzene and methylamine solution.
Yield: 20% of theory,
R _f 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-methylaniline are dissolved in 200 ml of methanol and after addition of 2 g of Raney nickel with 1 ml Hydrazine hydrate added. The solution is stirred for 30 minutes at room temperature and evaporated. The residue is chromatographed on silica gel and eluted with methylene chloride / ethanol (95: 5).
Yield: 1.2 g (82% of theory),
R _f value: 0.33 (silica gel, methylene chloride / ethanol = 9: 1)

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

Prepared analogously to Example 1c from 4- (2-tert-butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-amino-N-methylaniline, O- (benzotriazol-1-yl) -N, N, N ', N Tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine in tetrahydrofuran and ice-vinegar.
Yield: 72% of theory,
R _f value: 0.36 (silica gel, methylene chloride / ethanol = 9: 1)

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

Prepared analogously to Example 1g from 4 - [(5- (2-tert-Butyloxycar bonylethyl) -2-pyridylaminomethyl-1-methyl-benzimidazol-2-yl) methylamino] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 59% of theory,
C ₂₇ H ₃₁ N ₇ O ₂ × HCl (485.59 / 522.1)
Mass spectrum: (M + H) ⁺ = 486

Analogously to Example 9, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (ethoxycarbonylmethyl) -benzenesulfonylaminomethyl] -benzimidazole hydrochloride
Yield: 53% of theory,
C ₂₇ H ₃₀ N ₆ O ₄ S · HCl (534.64 / 571.1)
Mass spectrum: (M + H) ⁺ = 535

(2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [N-methyl-phenylcarbonylaminomethyl)] benzimidazole hydrochloride
Yield: 42% of theory,
C ₂₅ H ₂₆ N ₆ O x HCl (426.53 / 462.96)
Mass spectrum: (M + H) ⁺ = 427

Example 10 2- (4-amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-benz imidazol-1-yl) methyl] -benzimidazole hydrochloride a. 1- (4-chloro-3-nitrobenzyl) -2-methyl-benzimidazole

Prepared analogously to Example 9a from 2-methylbenzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethyl sulfoxide.
Yield: 78% of theory,
C ₁₅ H ₁₂ ClN ₃ O ₂ (301.7)
Mass spectrum: M ⁺ = 301/303

b. 1- (4-methylamino-3-nitrobenzyl) -2-methyl-benzimidazole

Prepared analogously to Example 1b from 1- (4-chloro-3-nitrobenzyl) -2-methyl-benzimidazole and methylamine.
Yield: 96% of theory,
R _f value: 0.56 (silica gel, methylene chloride / ethanol = 19: 1)

c. 1- (4-methylamino-3-aminobenzyl) -2-methyl-benzimidazole

Prepared analogously to Example 1c from 1- (4-methylamino-3-nitrobenzyl) -2-methyl-benzimidazole and hydrogen / Raney nickel.
Yield: 100% of theory,
R _f value: 0.34 (silica gel, methylene chloride / ethanol = 19: 1)

d. 2- (4-Cyanophenylaminomethyl) -1-methyl-5 - [(2-methyl-benz imidazol-1-yl) methyl] -benzimidazole

A mixture of 1.94 g (11.0 mmol) of N- (4-cyanophenyl) -glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole is refluxed in 80 ml of absolute tetrahydrofuran for 15 minutes. After addition of 2.7 g (10.46 mmol) of 1- (4-methylamino-3-aminobenzyl) -2-methylbenzimidazole, the mixture is heated under reflux for a further 16 hours. The solution is then evaporated to dryness, the residue is mixed with 80 ml of glacial acetic acid and heated under reflux for 1 hour. Thereafter, it is again evaporated to dryness, the residue thus obtained with 50 ml of water and treated with conc. Ammonia made alkaline (about pH 10). The product crystallized out is filtered off, washed with a little water and dried.
Yield: 4.1 g (96% of theory),
R _f value: 0.30 (silica gel, methylene chloride / ethanol = 19: 1)
C ₂₅ H ₂₂ N ₆ (406.5)
Mass spectrum: M ⁺ = 406

e. 2- (4-amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-benz imidazol-1-yl) methyl] -benzimidazole hydrochloride

Prepared analogously to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5 - [(2-methyl-benzimidazol-1-yl) methyl] -benz imidazole 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

The following compounds are obtained analogously to Example 10:

(1) 2- (4-Amidinophenyloxymethyl) -1-methyl-5 - [(imidazol-1-yl) methyl] benzimidazole hydrochloride
Yield: 30% of theory,
C ₂₀ H ₂₀ N ₆ O × 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) -ethyl] -benzimidazole hydrochloride
Yield: 70% of theory,
C ₂₁ H ₂₃ N ₇ x HCl (373.46 / 410)
Mass Spectrum:
(M + H) ⁺ = 374
(M + 2H) ²⁺ = 187.6

(3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethyl-4-methyl-imidazol-1-yl) -ethyl] -benzimidazole dihydrochloride
Yield: 18% of theory,
C ₂₄ H ₂₉ N ₇ x 2HCl (415.55 / 488.46)
Mass Spectrum:
(M + H) ⁺ = 416
(M + 2H) ²⁺ = 208.7

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-ethyl-4-methylimidazol-1-yl) methyl] benzimidazole dihydrochloride
Yield: 36% of theory,
C ₂₃ H ₂₇ N ₇ × 2HCl (401.52 / 437.97)
Mass Spectrum:
(M + H) ⁺ = 402
(M + 2H) ²⁺ = 201.7

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (pyridin-2-yl) -N-methyl-aminomethyl] -benzimidazole dihydrochloride
Yield: 78% of theory,
C ₂₃ H ₂₅ N ₇ × 2HCl (399.5 / 435.95)
Mass Spectrum:
(M + H) ⁺ = 400
(M + 2H) ²⁺ = 200.6

(6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-ethoxycarbonylethyl) benzimidazol-1-yl) methyl] benzimidazole dihydrochloride
Yield: 61% of theory,
C ₂₉ H ₃₁ N ₇ O ₂ × HCl (509.62 / 546.07)
Mass Spectrum:
(M + H) ⁺ = 510
(M + 2H) ²⁺ = 255.7
(M + H + Na) ²⁺ = 266.7

(7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(imidazol-1-yl) -methyl] -benzimidazole hydrochloride
Yield: 35% of theory,
C ₂₀ H ₂₁ N ₇ × HCl (359.44 / 395.89)
Mass Spectrum:
(M + H) ⁺ = 360
(M + 2H) ²⁺ = 180.6

(8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-acetylaminoethyl) -4,5-dimethylimidazol-1-yl) methyl] benzimidazole dihydrochloride
Yield: 42% of theory,
C ₂₆ H ₃₂ N ₈ O · 2HCl (472.6 / 545.51)
Mass Spectrum:
(M + H) ⁺ = 473
(M + 2H) ²⁺ = 237
(M + H + Na) ²⁺ = 248

(9) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-aminocarbonyl-ethyl) -4,5-dimethyl-imidazol-1-yl) -methyl] -benzimidazole dihydrochloride
Yield: 68% of theory,
C ₂₅ H ₃₀ N ₈ O x 2HCl (458.6 / 531.51)
Mass Spectrum:
(M + H) ⁺ = 459
(M + 2H) ²⁺ = 230

(10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-4-ethoxycarbonylimidazol-1-yl) methyl] benzimidazole hydrochloride
Yield: 34% of theory,
C ₂₄ H ₂₇ N ₇ O ₂ · HCl (445.53 / 481.98)
Mass Spectrum:
(M + H) ⁺ = 446
(M + 2H) ²⁺ = 223.5
(M + H + Na) ²⁺ = 234.5

(11) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(3- (3-ethoxycarbonyl-n-propyl) -benzimidazol-2-on-1-yl) -methyl] -benzimidazole hydrochloride
Yield: 58% of theory,
C ₃₀ H ₃₃ N ₇ O ₃ × 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) -imidazo [4,5-b] pyridin-2-one-1-yl) -methyl] - benzimidazole hydrochloride
Yield: 29% of theory,
C ₂₈ H ₃₀ N ₈ O ₃ · HCl (526.6 / 563.05)
Mass Spectrum:
(M + H) ⁺ = 527
(M + 2H) ²⁺ = 264
(M + H + Na) ²⁺ = 275

(13) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-phenyl-imidazol-1-yl) -methyl] -benzimidazole hydrochloride
Yield: 58% of theory,
C ₂₆ H ₂₅ N ₇ x HCl (435.54 / 472)
Mass Spectrum:
(M + H) ⁺ = 436
(M + Na) ⁺ = 218.6

(14) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(4,5-dimethyl-2- (2-ethoxycarbonylethyl) -imidazol-1-yl) -methyl] -benzimidazole dihydrochloride
Yield: 52% of theory,
C ₂₇ H ₃₃ N ₇ O ₂ × 2HCl (487.61 / 560.52)
Mass Spectrum:
(M + H) ⁺ = 488
(M + 2H) ²⁺ = 244.6

Example 11 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbo nyl-azetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] benz imidazole hydrochloride a. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (2-tert-butyl oxycarbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) - ethyl] benzimidazole

0.8 g (1.86 mmol) 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole and 1.65 g (5.5 mmol) 2, Tert-Butyl 4-dibromobutyrate are dissolved in 5 ml of ethanol, mixed with 0.2 g (1.86 mmol) of sodium carbonate and stirred under nitrogen at 55 ° C. for 30 hours. After cooling, the white precipitate is filtered off and washed with ethanol. The filtrate is evaporated, the residue is chromatographed on silica gel, using as eluent ethyl acetate and ethyl acetate / ethanol / ammonia Am (20: 1: 0.01). The desired fractions are combined and evaporated.
Yield: 0.44 g (44% of theory) as a mixture of diastereomers,
C ₃₁ H ₃₈ N ₆ O ₃ (542.69)
Mass spectrum: (M + H) ⁺ = 543

b. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycar carbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] benz imidazole hydrochloride (mixture of diastereomers)

Prepared analogously to Example 1g from 2- (4-cyano-phenylamino-methyl) -1-methyl-5- [1- (2-tert-butyloxycarbonyl-azetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) -ethyl ] benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 12% of theory,
C ₂₉ H ₃₇ N ₇ O ₃ × 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) -ethoxycarbonylmethyliden) methylene] cyclopropyl] -benz imidazole hydrochloride a. (E / Z) -2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin- 3-yl) -ethoxycarbonylmethyliden) methylene] cyclopropyl] -benz imidazole

897 mg (4.0 mmol) of phosphonoacetic acid triethyl ester are dissolved under argon in 30 ml of tetrahydrofuran. At -15 ° C 449 mg (4.0 mmol) of potassium tert-butylate are added. After 30 minutes, 815 mg (2.0 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyridin-3-yl-carbonyl) -cyclopropyl] -benzimidazole are added in portions and the mixture is stirred overnight at room temperature , Thereafter, the solution for 6 hours to reflux he heated and concentrated. The residue is treated with sodium chloride solution and extracted 3 × with ethyl acetate. The united th organic phases are dried over sodium sulfate and concentrated. The residue is dissolved in dichloromethane and chromatographed on silica gel, using as eluent di chloromethane 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 - [(pyri din-3-yl) -ethoxycarbonylmethyliden) methylene] cyclopropyl] - benzimidazole hydrochloride

Prepared analogously to Example 1g from (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) -ethoxycarbonylmeylidene) -methylene] cyclopropyl] benzimidazole and hydrochloric acid / Amium carbonate in ethanol.
Yield: 58% of theory,
C ₂₉ H ₃₀ N ₆ O ₂ × HCl (494.60 / 531.05)
Mass spectrum: (M + H) ⁺ = 495

Analogously 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,
C ₂₉ H ₃₀ N ₆ O ₂ × HCl (494.60 / 531.05)
Mass spectrum: (M + H) ⁺ = 495

Example 13 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxy-aze tidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) -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] - benzimidazole hydrochloride are dissolved in 30 ml of 6 N hydrochloric acid and stirred for 13 hours at room temperature. The reaction mixture is evaporated with the addition of toluene, the residue is triturated with acetone / ether, filtered off with suction, washed with ether and dried.
Yield: 200 mg (<100% of theory, contains ammonium chloride),
C ₂₇ H ₃₃ N ₇ O ₃ × HCl (503.62 / 540.07)
Mass spectrum: (M + H) ⁺ = 504

Analogously 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,
R _f value: 0.75 (reversed phase, 5% saline / methanol = 1: 1)
C ₂₄ H ₃₁ N ₇ O ₃ · HCl (465.56 / 502.01)
Mass Spectrum:
(M + H) ⁺ = 466
(M - H + 2HCl) ^- = 537/539 (Cl ₂ )

(2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole dihydrochloride
Yield: 70% of theory,
R _f value: 0.51 (reversed phase, 5% saline / methanol = 3: 2)
C ₂₅ H ₃₁ N ₇ O ₃ x 2 HCl (477.57 / 550.48)
Mass spectrum: (M + H) ⁺ = 478

(3) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) -carboxymethylidene) -methylene] -cyclopropyl] benzimidazole hydrochloride
Yield: 65% of theory,
C ₂₇ H ₂₆ N ₆ O ₂ × HCl (466.55 / 503.0)
Mass Spectrum:
(M + H) ⁺ = 467
(M + Cl) ⁺ = 501/503 (CI)

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N -methylcarboxymethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride
Yield: 99% of theory,
R _f value: 0.55 (reversed phase RP 8, methanol / 5% saline solution = 1: 1)
C ₂₈ H ₃₅ N ₇ O ₄ x 2 HCl (533.64 / 606.64)
Mass Spectrum:
(M + H) ⁺ = 534
(M - H) ^- = 532
(M - H + HCl) ^- = 568/70 (Cl)

(5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (N-ethyl-N-methylaminocarbonyl) -ethyl] -benzimidazole dihydrochloride
Yield: 75% of theory,
R _f value: 0.54 (reversed phase RP 8, methanol / 5% saline solution = 1: 1)
C ₂₅ H ₃₃ N ₇ O ₃ x 2 HCl (479.59 / 552.59)
Mass spectrum: (M + H) ⁺ = 480

Example 14 2- [4- (N-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl- 5- [1- (2-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 hydrochloride are dissolved in 14 ml of water and 55 ml of tetrahydrofuran dissolved, mixed with 2.0 g of potassium carbonate and 1.0 ml (6 mmol) of hexyl chloroformate and stirred for 4 hours at room temperature. After removal of the solvent in vacuo, the residue is treated with brine and extracted 3 × with methylene chloride. The combined organic phases are washed with a little water, dried over magnesium sulphate and evaporated. The crude product is purified on silica gel, eluting with methylene chloride plus 2 to 7.5% ethanol. The uniform fractions are united ver, evaporated, dissolved in a little ethyl acetate and treated with trol ether. The solid formed is filtered off with suction, washed with petroleum ether and dried.
Yield: 0.8 g (43% of theory),
C ₃₃ H ₄₇ N ₇ O ₅ (621.79)
R _f value: 0.50 (silica gel, methylene chloride / ethanol = 19: 1)
Mass Spectrum:
(M + H) ⁺ = 622
(M + Na) ⁺ = 644

Example 15 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbo nylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop 2-yl] -benzimidazole hydrochloride a. 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionsäuremethyl ester

35 ml of a 1.6 molar solution of n-butyllithium in hexane (61 mmol) are added dropwise at -78 ° C. to a solution of 8.1 ml of diisopropylamine (85 mmol) in 20 ml of tetrahydrofuran. At closing, a solution of 10.0 g (50 mmol) of 2- (4-chloro-phenyl) -propionate in 30 ml of tetrahydrofuran is added dropwise at -78 ° C. Gaseous formaldehyde is then introduced into the reaction mixture at -20 ° C. for 30 minutes. After addition of 5% citric acid and glacial acetic acid is extracted with ethyl acetate. The organic phases are washed with 1 N sulfuric acid, water, saturated sodium bicarbonate solution and brine and dried over magnesium sulfate. The crude product is purified on silica gel, eluting with cyclohexane / ethyl acetate (19: 1, 9: 1, 4: 1, 1: 1 and 0: 1). The uniform fractions are combined and evaporated.
Yield: 9.7 g (84% of theory) yellow oil,
R _F value: 0.25 (silica gel, petroleum ether / ethyl acetate 4: 1)

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

Prepared analogously to Example 4 from 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid methyl ester and sodium hydroxide solution in ethanol.
Yield: 83% of theory,
R _F 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 analogously to Example 1a from 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid and nitric acid.
Yield: 90% of theory,
Melting point: 129-132 ° C
C ₁₀ H ₉ ClN ₂ O ₇ (304.64)

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

Prepared analogously to Example 6 from 2- (4-chloro-3-nitro-phenyl) -3-nitrooxy-2-methyl-propionic acid and 6 N hydrochloric acid in dioxane.
Yield: 98% of theory,
C ₁₀ H ₁₀ ClNO ₅ (259.65)
Mass Spectrum:
(M - H) ^- = 258/60 (Cl)
(2M - H) ^- = 517/9 (Cl ₂ )

e. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hy droxy-propionic acid

Prepared analogously to Example 1b from 2- (4-chloro-3-nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.
Yield: 81% of theory,
C ₁₈ H ₂₀ ClN ₂ O ₅ (344.37)
Mass spectrum: M ⁺ = 344

f. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hy droxy-1-pyrrolidin-1-yl-propan-1-one

Prepared analogously to Example 1c from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -3-hydroxy-2-meth 26485 00070 552 001000280000000200012000285912637400040 0002019912690 00004 26366yl-propionic acid and N-methylbenzylamine.
Yield: 96% of theory,
C ₂₂ H ₂₇ N ₃ O ₄ (397.48)
Mass Spectrum:
M ⁺ = 398
(M + Na) ⁺ = 420

G. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-me thansulfonyloxy-1-pyrrolidin-1-yl-propan-1-one

A solution of 1.2 g (3.0 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one in 20 ml of tetrahydrofuran is added at room temperature with 1.3 ml (9.3 mmol) of triethylamine. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonyl chloride are 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 is reacted further without purification.
Yield: 1.4 g (98% of theory)

H. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-me 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-propan-1-one in 10 ml of dimethylformamide is mixed with 20 ml of a 40% aqueous methylamine solution and heated to 100 minutes for 70 minutes. After cooling, the reaction mixture is mixed with ice-water and extracted with ethyl acetate. The or ganic phases are washed with water and with brine ge, dried over magnesium sulfate and evaporated. The crude product is purified on silica gel, using ethyl acetate / ethanol (10: 1, 9: 1, 4: 1 + 1% concentrated ammonia) as eluent. The uniform fractions are combined and evaporated.
Yield: 740 mg (61% of theory),
R _F value: 0.45 (silica gel, methylene chloride / ethanol 9: 1 + 1% concentrated ammonia)

i. 2- [4- (benzyl-methylamino) -3-nitro-phenyl] -2-methyl- 3- (N-methoxycarbonylmethylcarbonyl-methylamino) -1-pyrrolidin 1-yl-propan-1-one

Prepared analogously to Example 7d from 2- [4- (N-benzylmethylamino) -3-nitro-phenyl] -2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one and malonic acid methylester chloride.
Yield: 84% of theory,
R _F value: 0.65 (silica gel, ethyl acetate / ethanol 9: 1 + ammonia)
C ₂₇ H ₃₄ N ₄ O ₆ (510.60)
Mass Spectrum:
(M - H) ^- = 509
(M + Na) ⁺ = 533

j. 2- (4-methylamino-3-amino-phenyl) -2-methyl-3- (N-methoxycar bonylmethylcarbonyl-methylamino) -1-pyrrolidin-1-yl-propan-1-one

Prepared analogously to Example 1d from 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3- (N-methoxycarbonylmethylcarbonyl-methylamino) -1-pyrrolidin-1-yl-propane -1-one and hydrogen / palladium on charcoal.
Yield: 100% of theory,
R _F value: 0.40 (silica gel, ethyl acetate / ethanol 9: 1 + 1% concentrated ammonia)
C ₂₀ H ₃₀ N ₄ O ₄ (390.49)
Mass spectrum: M ⁺ = 390

k. 4- [2- (3- (N-Methoxycarbonylmethylcarbonyl-methylamino)) - 2-methyl-1-pyrrolidin-1-yl-propan-1-on-2-yl] -2- (4-cyano phenyl-aminomethylcarbonylamino-N-methyl-aniline

Prepared analogously to Example 1e from 2- (4-methylamino-3-amino-phenyl) -2-methyl-3- (N-methoxycarbonylmethylcarbonyl-methyl-amino) -1-pyrrolidin-1-yl-propan-1-one and O- ( Benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 95% of theory,
R _F value: 0.35 (silica gel, ethyl acetate / ethanol 9: 1 + 1% concentrated ammonia)

l. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycar bonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop 2-yl] -benzimidazole

Prepared analogously to Example 1f from 4- [2- (3- (N-Methoxycarbo nylmethylcarbonyl-methylamino)) - 2-methyl-1-pyrrolidin-1-yl-propan-1-one-2-yl] -2- (4 -cyano-phenyl) -aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.
Yield: 47% of theory,
R _f value: 0.20 (silica gel, ethyl acetate / ethanol = 9: 1)
C ₂₉ H ₃₄ N ₆ O ₄ (530.63)
Mass Spectrum:
(M + H) ⁺ = 531
(M + Na) ⁺ = 553

m. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycar bonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop 2-yl] -benzimidaol hydrochloride

Prepared analogously to Example 1g from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.
Yield: 65% of theory,
R _f value: 0.30 (silica gel, methylene chloride / methanol = 4: 1 + glacial acetic acid)
C ₃₀ H ₃₉ N ₇ O ₄ × HCl (561.69 / 598.19)
Mass Spectrum:
(M + H) ⁺ = 562
(M + Cl) ^- = 596/8 (CI)

Analogously to Example 15, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methoxycarbonylmethyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride
Yield: 89% of theory,
R _f value: 0.35 (reversed phase RP 8, methanol / 5% saline solution = 3: 2)
C ₂₈ H ₃₇ N ₇ O ₃ × 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 theory,
R _f value: 0.20 (silica gel, methylene chloride / ethanol = 8: 2 + 1% ethyl acetate)
C ₂₉ H ₃₇ N ₇ O ₄ · CH ₃ COOH (547.66 / 607.71)
Mass Spectrum:
(M + H) ⁺ = 548
(M - H) ^- = 546
(M - H + CH ₃ COOH) ^- = 606

(3) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxy carbonylmethylcarbonyl-methylamino) -2- (N-methyl-ethylamino carbonyl) prop-2-yl] -benzimidazole hydrochloride

(4) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxy carbonylmethyl-methylamino) -2- (N-methyl-N-ethylaminocarbonyl) - prop-2-yl] -benzimidazole hydrochloride

(5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxy carbonylmethylcarbonyl-methylamino) -2- (piperidinocarbonyl) - prop-2-yl] -benzimidazole hydrochloride

(6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N -ethoxy carbonylmethylsulfonyl-methylamino) -2- (piperidinocarbonyl) - prop-2-yl] -benzimidazole hydrochloride

(7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole acetate
Yield: 72% of theory,
R _f value: 0.20 (silica gel, methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)
C ₂₉ H ₃₇ N ₇ O ₄ · CH ₃ COOH (547.66 / 607.71)
Mass Spectrum:
(M + H) ⁺ = 548
(M - H) ^- = 546

(8) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxy carbonyl-ethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop 2-yl] -benzimidazole hydrochloride

(9) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycar carbonylmethylsulfonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] - benzimidazole hydrochloride

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

Example 16 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyl amino) -1- (isoxazolidin-1-yl-carbonyl) -ethyl] benzimidazole hydrochloride

Prepared by hydrolysis of 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride with sodium hydroxide in ethanol ,
Yield: 90% of theory,
R _f value: 0.65 (reversed phase RP 8, methanol / 5% saline solution = 3: 2)
C ₂₄ H ₂₉ N ₇ O ₄ · HCl (479.54 / 515.99)
Mass spectrum: (M + H) ⁺ = 480

The following compounds are prepared analogously to Example 16:

(1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxy ethylamino) -1- (isoxazolidin-1-yl-carbonyl) -ethyl] -benzimida zole hydrochloride

(2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (N-methyl-N-ethylaminocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 93% of theory,
R _f value: 0.40 (reversed phase RP 8, methanol / 5% saline solution = 1: 1)
C ₂₄ H ₃₁ N ₇ O ₃ · HCl (465.57 / 502.02)
Mass Spectrum:
(M + H) ⁺ = 466
(M + Cl - H) ^- = 500/2 (Cl)

(3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride
Yield: 89% of theory,
R _f value: 0.57 (reversed phase RP 8, methanol / 5% saline solution = 4: 3)
C ₂₇ H ₃₅ N ₇ O ₃ × 2 HCl (505.63 / 578.54)
Mass Spectrum:
(M + H) ⁺ = 506
(M + 2H) ⁺⁺ = 253
(M + H + Na) ⁺⁺ = 264.5

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride
Yield: 90% of theory,
R _f value: 0.55 (reversed phase RP 8, methanol / 5% saline solution = 4: 6)
C ₂₇ H ₃₃ N ₇ O ₄ × Hl (519.61 / 556.06)
Mass Spectrum:
(M + H) ⁺ = 520
(M - H) ^- = 518

(5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxy methyl-methylamino) -2- (N-ethyl-methylaminocarbonyl) -prop 2-yl] -benzimidazole hydrochloride

(6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxy methylcarbonyl-methylamino) -2- (N-ethyl-methylaminocarbonyl) - prop-2-yl] -benzimidazole hydrochloride

(7) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxy methylcarbonyl-methylamino) -2- (piperidinocarbonyl) -prop-2-yl] - benzimidazole hydrochloride

(8) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxy methylsulfonyl-methylamino) -2- (piperidinocarbonyl) -prop-2-yl] - benzimidazole hydrochloride

(9) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (piperidinocarbonyl) ethyl] benzimidazole hydrochloride
Yield: 81% of theory,
R _f value: 0.40 (reversed phase RP 8, methanol / 5% saline solution = 1: 1)
C ₂₆ H ₃₃ N ₇ O ₃ (491.60 / 528.05)
Mass Spectrum:
(M + H) ⁺ = 492
(M - H) ^- = 490

(10) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxy ethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benz imidazole hydrochloride

(11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxy methylsulfonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benz imidazole hydrochloride

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

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

A suspension of 1.4 g (2.4 mmol) of 2- (4-amidinophenylamino methyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride in 5 ml of N-ethyl -diisopropylamine and 2 ml of dimethylformamide is treated with 1.5 g (6 mmol) of benzoic acid 4-nitrophenyl ester, which is formed under heating in a clear solution. After 2 hours at 120 ° C, the solution is evaporated in vacuo, the residue is dissolved after cooling in dichloromethane and purified on silica gel, with first with dichloromethane, later with dichloromethane / ethanol (50: 1, 25: 1, 18: 1 ) is eluted. The uniform fractions are combined, evaporated, triturated with water, filtered off with suction and dried.
Yield: 0.7 g (49% of theory),
R _f value: 0.40 (silica gel, methylene chloride / ethanol = 19: 1)
C ₃₄ H ₃₉ N ₇ O ₄ (609.73)
Mass Spectrum:
(M + H) ⁺ = 610
(M + Na) ⁺ = 632
(M - H) ^- = 608

Analogously to Examples 14 and 17, the following compounds receive:

(1) 2- [4- (Nn-Hexyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Yield: 53% of theory,
R _f value: 0.35 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₄ H ₄₇ N ₇ O ₅ (633.79)
Mass Spectrum:
(M + Na) ⁺ = 656
(M - H) ^- = 632

(2) 2- [4- (Nn-Octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Yield: 46% of theory,
R _f value: 0.43 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₆ H ₅₁ N ₇ O ₅ (661.84)
Mass Spectrum:
(M + Na) ⁺ = 684
(M - H) ^- = 660

(3) 2- [4- (N-n-hexyloxycarbonylamidino) phenylaminomethyl] - 1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocar carbonyl) -ethyl] -benzimidazole

(4) 2- [4- (Nn-Octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole
Yield: 32% of theory,
R _f value: 0.27 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₅ H ₄₉ N ₇ O ₅ (647.82)
Mass Spectrum:
(M + Na) ⁺ = 670
(M - H) ^- = 646

(5) 2- [4- (Nn-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N -ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 52% of theory,
R _f value: 0.60 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₇ H ₅₁ N ₇ O ₆ (689.85)
Mass Spectrum:
(M + H) ⁺ = 690
(M - H) ^- = 688
(M + Na) ⁺ = 712
(M + HCl - H) ^- = 724/26 (Cl)

(6) 2- [4- (N-n-octyloxycarbonyl-amidino) -phenylaminomethyl] - 1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) - 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

(7) 2- [4- (Nn-Hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 21% of theory,
R _f value: 0.55 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₆ H ₄₉ N ₇ O ₆ (675.83)
Mass Spectrum:
(M + H) ⁺ = 676
(M + Na) ⁺ = 698
(M + HCl - H) ^- = 724/26 (Cl)

(8) 2- [4- (N-n-octyloxycarbonyl-amidino) -phenylaminomethyl] - 1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) - 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

(9) 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Yield: 34% of theory,
R _f value: 0.55 (silica gel, methylene chloride / ethanol = 9: 1 + 1% ammonia)
C ₃₃ H ₃₇ N ₇ O ₄ (595.70)
Mass Spectrum:
(M - H) ^- = 594
(M + Na) ⁺ = 618

(10) 2- [4- (N-isopropyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (N -ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 66% of theory,
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₄ H ₄₅ N ₇ O ₆ (647.77)
Mass Spectrum:
(M + H) ⁺ = 648
(M - H) ^- = 646
(M + Na) ⁺ = 670

(11) 2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N -ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 23% of theory,
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₇ H ₄₃ N ₇ O ₅ (665.79)
Mass Spectrum:
(M + H) ⁺ = 666
(M - H) ^- = 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,
R _f value: 0.60 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₆ H ₄₁ N ₇ O ₅ (651.76)
Mass Spectrum:
(M + H) ⁺ = 652
(M - H) ^- = 650
(M + Na) ⁺ = 674

(13) 2- [4- (Nn-Butyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 45% of theory,
R _f value: 0.50 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₄ H ₄₅ N ₇ O ₆ (647.77)
Mass Spectrum:
(M + H) ⁺ = 648
(M - H) ^- = 646
(M + Na) ⁺ = 670
(M - H + HCl) ^- = 682/4 (Cl)

(14) 2- [4- (N-Ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N -ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 54% of theory,
R _f value: 0.40 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₃ H ₄₃ N ₇ O ₆ (633.75)
Mass Spectrum:
(M + H) ⁺ = 634
(M - H) ^- = 632 (M + Na) ⁺ = 656

(15) 2- [4- (N -ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole
Yield: 53% of theory,
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₂ H ₄₁ N ₇ O ₆ (619.72)
Mass Spectrum:
(M + H) ⁺ = 620
(M - H) ^- = 618
(M + Na) ⁺ = 642

(16) 2- [4- (N-Pyridin-3-yl-carbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N -ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2- yl] benzimidazole
Yield: 16% of theory,
R _f value: 0.45 (silica gel, methylene chloride / ethanol = 9: 1)
C ₃₆ H ₄₂ N ₈ O ₅ (666.78)
Mass Spectrum:
(M - H) ^- = 665
(M + Na) ⁺ = 689

(17) 2- [4- (N-n-butyloxycarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocar carbonyl) -ethyl] -benzimidazole

(18) 2- [4- (N -ethyloxycarbonylamidino) -phenylaminomethyl] -1-me thyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) - ethyl] benzimidazole

(19) 2- [4- (N-benzyloxycarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbo nyl) -ethyl] -benzimidazole

(20) 2- [4- (N-pyridin-3-ylcarbonylamidino) -phenylaminomethyl] - 1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbo nyl) -ethyl] -benzimidazole

Example 18 2- [4- (N-n-Octyloxycarbonylamidino) -phenylaminomethyl] -1-me thyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) -ethyl] - benzimidazole

A solution of 0.2 g (0.3 mmol) of 2- [4- (Nn-octyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole in 3 ml of tetrahydrofuran and 2.5 ml of ethanol is mixed with 1.1 ml of 1 N sodium hydroxide solution and stirred for 4 hours at room temperature. The reaction mixture is evaporated and treated with 1 ml of 1 N hydrochloric acid. After 12 hours at room temperature (pH 4), 2 drops of ammonia (33%) are added, precipitating a pale yellow precipitate. After suction of the solid formed material, the filtrate is mixed with 1 ml of 1 N hydrochloric acid and evaporated with the addition of toluene. The residue is triturated with acetone, filtered off with suction, washed with diethyl ether and dried.
Yield: 0.1 g (50% of theory),
R _f value: 0.35 (reversed phase RP 8, methanol / 5% saline solution = 2: 1)
C ₃₄ H ₄₇ N ₇ O ₅ (633.79)
Mass Spectrum:
(M + H) ⁺ = 634
(M + H + Na) ⁺⁺ = 328.5

Example 19 2- [4- (N-hydroxyamidino) -phenylaminomethyl] -1-methyl-5- [1- (eth oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] benz imidazole

A suspension of 0.6 g (1.2 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyiamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole in 50 ml of ethanol is added Added 0.47 g (7.8 mmol) of hydroxylamine hydrochloride and 0.35 g (3.5 mmol) of sodium carbonate and heated under reflux for 17 hours. After cooling, the residue is filtered off, the filtrate is evaporated and taken up in water. After double extraction with dichloromethane, the combined organic phases are dried and evaporated. The crude product is purified on silica gel, eluting with dichloromethane / ethanol (19/1 and 7/1). The uniform fractions are combined, evaporated, triturated with diisopropyl ether and dried.
Yield: 0.025 g (4% of theory),
R _f value: 0.68 (silica gel, methylene chloride / ethanol = 4: 1)
C ₂₇ H ₃₅ N ₇ O ₄ (521.62)
Mass Spectrum:
(M - H) ^- = 520
(M + Na) ⁺ = 544

Example 20 Dry ampoule containing 75 mg of active ingredient per 10 ml composition

active substance 75.0 mg mannitol 50.0 mg Water for injections ad 10.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried. The resolution for ready to use Solution is with water for injections.

Example 21 Dry ampoule containing 35 mg of active ingredient per 2 ml composition

active substance 35.0 mg mannitol 100.0 mg Water for injections ad 2.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example 22 Tablet with 50 mg active ingredient composition

(1) Active substance 50.0 mg (2) lactose 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mg           215.0 mg         

manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part score.
Diameter of the tablets: 9 mm.

Example 23 Tablet with 350 mg active ingredient composition

(1) Active substance 350.0 mg (2) lactose 136.0 mg (3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate 4.0 mg           600.0 mg         

manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed biplan with bilateral racette and unilateral partial score.
Diameter of the tablets: 12 mm.

Example 24 Capsules with 50 mg active ingredient composition

(1) Active substance 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate 2.0 mg           160.0 mg         

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 3 bottled.

Example 25 Capsules with 350 mg active ingredient composition

(1) Active substance 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate 4.0 mg           430.0 mg         

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 0 filled.

Example 26 Suppositories containing 100 mg of active ingredient

AL = L <1 suppository contains: active substance 100.0 mg Polyethylene glycol (M.G. 1500) 600.0 mg Polyethylene glycol (M. G. 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg           2000.0 mg         

manufacturing

The polyethylene glycol is used together with Polyethylensorbi tanmonostearat melted. At 40 ° C, the milled Wirk substance homogeneously dispersed in the melt. It is at 38 ° C cooled and in weakly pre-cooled suppository forms cast.

Claims (13)

1. Benzimidazoles of the general formula
in the
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenylene or naphthylene group,
a thienylene, thiazolylene, pyridinyl, pyrimidinyl, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C _1-3 -alkyl group,
A is a C _1-3 -alkylene group,
B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C _1-3 -alkyl group, in which the alkyl moiety may be mono- or disubstituted by a carboxy group,
R _{a is} an R ₁ -CO-C _3-5 -cycloalkyl group in which
R _{1 is} a C _1-3 -alkoxy, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino group, in each of which the alkyl moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C _1-3 alkyl groups, wherein an alkyl substituent is simultaneously represented by a 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- (carboxyC _1-3 -alkyl) -aminocarbonyl, carboxyC _1-3 -alkylaminocarbonylamino, 1- (C _{1- 3-} alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino, 3- (C _1-3 alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino or 1, May be substituted by 3-di (C _1-3 alkyl) -3- (carboxy C _1-3 alkyl) aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C _1-3 -alkyl group to which a phenyl ring has been fused via two adjacent carbon atoms,
represents a morpholino, piperazino, N- (C _1-3 alkyl) piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
an R ₂ -CX-C _3-5 cycloalkyl group in which
R _{2 is} a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group, the 6-membered heteroaryl group containing one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally substituted by a C _1-3 alkyl group-substituted imino group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl imino group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent by a Carboxy, carboxyC _1-3 -alkoxy, carboxyC _1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group, and
X is an oxygen atom, a C _1-3 -alkylimino, C _1-3 -alkoxyimino, C _1-3 -alkylhydrazino, di (C _1-3 -alkyl) -hydrazino, C _2-4 -alkanoyl hydrazino -, N- (C _1-3 alkyl) -C _2-4 -alkanoylhydrazino- or C _1-3 -Al kylidengruppe each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety by a carboxy group, represent
a substituted by an imidazole or imidazolone group 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 by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups, where the substituents may be the same or different and one of the aforementioned alkyl substituents simultaneously through a carboxy group or in the 2- or 3-position by an 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 group may be substituted, and
the imidazolone ring may be substituted by a C _1-3 -alkyl group, the alkyl substituent being substituted by a carboxy group or in the 2- or 3-position by an amino, C _2-4 -alkanoylamino, C _1-3 -alkylamino , N- (C _2-4 -alkanoyl) -C _1-3 -al kylamino- or di- (C _1-3 alkyl) amino group may be substituted, and
in addition to the abovementioned imidazole and imidazole rings it is possible for a phenyl or pyridine ring to be fused via two adjacent carbon atoms,
an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent may be substituted by a carboxy group,
a C _1-4 alkyl group, the
by a C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl-, HOOC-C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl, tetrazolyl-C _1-3 -alkyl- Y ₂ , R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by an isoxazolidinylcarbonyl group optionally substituted by a C _1-3 -alkyl group, by a pyrrolo-carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-ylcarbonyl, carboxy, aminocarbonyl, C _1-3 Alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonylgruppe substituted, wherein in the above-mentioned groups, the Cycloalkyleniminoteil substituted by one or two C _1-3 alkyl groups and simultaneously an alkyl moiety or alkyl substituent of the above-mentioned C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of C _1-4 - Alkyl group may be wholly or partially replaced by fluorine atoms, in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, a 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 a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C _1-3 -alkyl or carboxy-C _1-3 -alkyl group, in which
Y _{1 is} a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH, -NH-CO or NH-CO-NH group and
Y _{2 represents} a carbon-nitrogen bond or a carbonyl, sulfonyl or -NH-CO group, wherein the carbonyl group of the -NH-CO group is linked to the nitrogen atom of the R ₃ NR ₄ group, and which in the Definition of the radicals Y ₁ and Y ₂ occurring imino groups may each be additionally substituted by a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a C _1-3 alkyl or C _3-5 cycloalkyl group substituted by an R ₅ NR ₆ group in which
R _{5 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and
R _{6 represents} a C _1-3 -alkyl, carboxy-C _1-3 -alkyl or carboxy-C _1-3 -alkylcarbonyl group,
a C _1-3 alkyl group which is substituted by C _2-4 alkanoyl or C _5-7 cycloalkanoyl group and by a C _1-3 alkyl group substituted by a chlorine, bromine or iodine atom,
R _{b is} a hydrogen atom or a C _1-3 alkyl group and
R _{c represents} a cyano group or an amidino group optionally substituted by one or two C _1-3 -alkyl groups,
their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives containing in place of a carboxy group a group negatively charged under physiological conditions, and salts thereof. 2. Benzimidazoles of the general formula
in the
A is a C _1-3 -alkylene group,
B is an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C _1-3 -alkyl group, in which the alkyl moiety may be mono- or disubstituted by a carboxy group,
R _{a is} an R ₁ -CO-C _3-5 -cycloalkyl group in which
R _{1 is} a C _1-3 -alkoxy, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino group, in each of which the alkyl moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkylenemino group which may be substituted by a hydroxy group or by one or two C _1-3 alkyl groups, wherein an alkyl substituent is simultaneously represented by a 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- (carboxyC _1-3 -alkyl) -aminocarbonyl, carboxyC _1-3 -alkylaminocarbonylamino, 1- (C _{1- 3-} alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino, 3- (C _1-3 alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino or 1, May be substituted by 3-di (C _1-3 alkyl) -3- (carboxy C _1-3 alkyl) aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C _1-3 -alkyl group to which a phenyl ring has been fused via two adjacent carbon atoms,
represents a morpholino, piperazino, N- (C _1-3 alkyl) piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
an R ₂ -CX-C _3-5 cycloalkyl group in which
R _{2 is} a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group, the 6-membered heteroaryl group containing one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally substituted by a C _1-3 alkyl group-substituted imino group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl imino group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent by a Carboxy, carboxyC _1-3 -alkoxy, carboxyC _1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group, and
X is an oxygen atom, a C _1-3 -alkylimino, C _1-3 -alkoxyimino, C _1-3 -alkylhydrazino, di (C _1-3 -alkyl) -hydrazino, C _2-4 -alkanoyl hydrazino -, N- (C _1-3 alkyl) -C _2-4 -alkanoylhydrazino- or C _1-3 -Al kylidengruppe each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety by a carboxy group, represent
a substituted by an imidazole or imidazolone group 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 by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups, where the substituents may be the same or different and one of the aforementioned alkyl substituents simultaneously by a carboxy group or in the 2- or 3-position by an 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 group, and
the imidazolone ring may be substituted by a C _1-3 -alkyl group, the alkyl substituent being substituted by a carboxy group or in the 2- or 3-position by an amino, C _2-4 -alkanoylamino, C _1-3 -alkylamino , N- (C _2-4 -alkanoyl) -C _1-3 -al kylamino- or di- (C _1-3 alkyl) amino group may be substituted, and
in addition to the abovementioned imidazole and imidazole rings it is possible for a phenyl or pyridine ring to be fused via two adjacent carbon atoms,
an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent may be substituted by a carboxy group,
a C _1-4 alkyl group, the
by a C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl-, HOOC-C _1-3 -alkyl-Y ₁ -C _1-3 -alkyl, tetrazolyl-C _1-3 -alkyl- Y ₂ , R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by an isoxazolidin-1-ylcarbonyl group optionally substituted by a C _1-3 alkyl group, by a pyrroli nocarbonyl, 2,3-dehydro-piperidinocarbonyl, pyrrol-1-yl carbonyl, carboxy, aminocarbonyl, C _{1 3-} alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or 4- to 7-membered cycloalkyleniminocarbonyl group, wherein in the above-mentioned groups, the cycloalkyleneimine moiety is substituted by one or two C _1-3 alkyl groups and at the same time each an alkyl part or alkyl substituent of the above-mentioned C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or cycloalkyleniminocarbonyl groups may be substituted by a carboxy group, 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} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, a 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 a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C _1-3 -alkyl or carboxy-C _1-3 -alkyl group, in which
Y _{1 is} a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH, -NH-CO or -NH-CO-NH group and
Y _{2 represents} a carbon-nitrogen bond or a carbonyl, sulfonyl or -NH-CO group, wherein the carbonyl group of the -NH-CO group is linked to the nitrogen atom of the R ₃ NR ₄ group, and which in the Definition of the radicals Y ₁ and Y ₂ occurring imino groups may each be additionally substituted by a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a C _1-3 alkyl or C _3-5 cycloalkyl group substituted by an R ₅ NR ₆ group in which
R _{5 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and
R _{6 represents} a C _1-3 -alkyl, carboxy-C _1-3 -alkyl or carboxy-C _1-3 -alkylcarbonyl group,
a C _1-3 alkyl group which is substituted by C _2-4 alkanoyl or C _5-7 cycloalkanoyl group and by a C _1-3 alkyl group substituted by a chlorine, bromine or iodine atom,
R _{b is} a hydrogen atom or a C _1-3 alkyl group and
R _{c represents} a cyano group or an amidino group which may be substituted by one hydroxy group, by one or two C _1-3 -alkyl groups, by one or two C _1-8 -alkoxycarbonyl groups,
the carboxy, amino and imino groups mentioned in the definition of the abovementioned radicals may furthermore be substituted by an in vivo cleavable radical,
their tautomers, their stereoisomers and their salts. 3. Benzimidazoles of the general formula Ia according to claim 2, in which
A is a C _1-3 -alkylene group,
B is an oxygen atom, a methylene, imino or N- (C _1-3 -alkyl) -imino group, in which the alkyl moiety may be substituted by a carboxy group,
R _{a is} a substituted in the 1-position by the R ₁ -CO-radical C _3-5 cycloalkyl group in which
R _{1 is} a C _1-3 -alkoxy, amino, C _1-4 -alkylamino or di- (C _1-4 -alkyl) -amino group, in each of which the alkyl moiety may be substituted by a carboxy group,
a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C _1-3 alkyl groups, wherein an alkyl substituent is simultaneously represented by a 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- (carboxyC _1-3 -alkyl) -aminocarbonyl, carboxyC _1-3 -alkylaminocarbonylamino, 1- (C _{1- 3-} alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino, 3- (C _1-3 alkyl) -3- (carboxyC _1-3 alkyl) aminocarbonylamino or 1, May be substituted by 3-di (C _1-3 alkyl) -3- (carboxy C _1-3 alkyl) aminocarbonylamino group,
a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C _1-3 -alkyl group to which a phenyl ring has been fused via two adjacent carbon atoms,
represents a morpholino, piperazino, N- (C _1-3 alkyl) piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group,
a substituted in the 1-position by the R ₂ -CX radical C _3-5 cycloalkyl group, in which
R _{2 is} a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C _1-3 alkyl group, the 6-membered heteroaryl group containing one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally substituted by a C _1-3 alkyl group-substituted imino group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl imino group and an oxygen or sulfur atom or one or two nitrogen atoms and the above-mentioned alkyl substituent by a Carboxy, carboxyC _1-3 -alkoxy, carboxyC _1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group, and
X represents an oxygen atom, a C _1-3 -alkylimino, C _1-3 -alkoxyimino or C _1-3 -alkylidene group, each of which may be substituted by a carboxy group in the alkyl or alkoxy part,
a substituted in 1-position by an imidazole or imidazolone C _1-3 alkyl group in which
the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups, where the substituents may be the same or different and one of the aforementioned alkyl substituents simultaneously by a carboxy group or in the 2- or 3-position by an 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 group, and
the imidazolone ring may be substituted by a C _1-3 -alkyl group, the alkyl substituent being substituted by a carboxy group or in the 2- or 3-position by an amino, C _2-4 -alkanoylamino, C _1-3 -alkylamino , N- (C _2-4 -alkanoyl) -C _1-3 -al kylamino- or di- (C _1-3 alkyl) amino group may be substituted, and
in addition to the abovementioned imidazole and imidazole rings it is possible for a phenyl or pyridine ring to be fused via two adjacent carbon atoms,
an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent may be substituted by a carboxy group,
a C _1-4 alkyl group, in the 1-position
by an R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl Isoxazolidin-1-ylcarbonyl or 4- to 7-membered Cycloalky leniminocarbonylgruppe substituted, wherein substituted in the above-mentioned groups of the Cycloalkyleniminoteil by one or two C _1-3 alkyl groups and at the same time each an alkyl moiety or alkyl substituent of the aforementioned C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C _1-4 alkyl group may be wholly or partly replaced by fluorine atoms can be in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, 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 a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1-position by a carboxy, C _1-3 -alkyl or carboxy-C _1-3 -alkyl group, in to those
Y _{2 represents} a carbon-nitrogen bond or a carbonyl or -NH-CO group, wherein the carbonyl group of the -NH-CO group is linked to the nitrogen atom of the R ₃ NR ₄ group, and in the definition of the radical Y _2- occurring imino group may additionally be substituted by a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a substituted in the 1-position by an R ₅ NR ₆ group C _1-3 alkyl or C _3-5 cycloalkyl group, in which
R _{5 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl group and
R _{6 represents} a C _1-3 -alkyl, carboxy-C _1-3 -alkyl or carboxy-C _1-3 -alkylcarbonyl group,
a C _1-3 alkyl group which is substituted by C _2-4 alkanoyl or C _5-7 cycloalkanoyl group and by a C _1-3 alkyl group substituted by a chlorine, bromine or iodine atom,
R _{b is} a C _1-3 alkyl group and
R _{c is} an amidino group which is optionally substituted by a C _1-8 -alkoxycarbonyl group,
their C _1-3 alkanol esters, their N-benzyloxycarbonyl-amidines and their monosubstituted or disubstituted in the benzoyl moiety optionally by fluorine, chlorine, bromine or iodine atoms, by C _1-3 alkyl or C _1-3 alkoxy Benzoyl group, where the substituents may be the same or different, substituted N-benzoyl-amidines,
their tautomers, their stereoisomers and their salts. 4. Benzimidazoles of the general formula Ia according to claim 2, in which
A is a methylene group,
B is an oxygen atom or an imino group,
R _{a is} a substituted in the 1-position by the R ₁ -CO-radical cyclopropyl group, in the
R _{1 is} an optionally substituted by a methyl or ethyl group pyrrolidino or piperidino group, in which in each case the methyl or ethyl part by a carboxy, carboxy-C _1-3 alkoxy, carboxy-C _1-3 alkylamino or N - (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group may be substituted,
a substituted in the 1-position by the R ₂ -CX radical cyclopropyl group, in the
R _{2 is} optionally substituted by a C _1-3 alkyl substituted phenyl, pyridyl-pyrazolyl and
X represents an oxygen atom, a C _1-3 -alkoxyimino or C _1-3 -alkylidene group which are each substituted in the alkyl or alkoxy part by a carboxy group,
a 1-imidazole substituted C _1-2 alkyl group in which the imidazole ring is replaced by a phenyl or carboxy group and by one or two C _1-3 alkyl groups or by one, two or three C _1-3 alkyl groups may be substituted, wherein the substituents may be the same or different and one of the abovementioned alkyl substituents simultaneously by a carboxy group or in the 2- or 3-position by an amino, C _2-4 alkanoylamino, C _1-3 alkyl amino, N- (C _2-4 alkanoyl) C _1-3 alkylamino or di (C _1-3 alkyl) amino group may be substituted, in addition to the above-mentioned imidazole rings via two adjacent carbon atoms Phenyl or pyridine ring may be fused,
a C _1-2 alkyl group substituted in position 1 by a benzimidazolone-1-yl group, where the imidazolone ring may be substituted by a methyl or ethyl group optionally substituted by a carboxy group,
a methyl or ethyl group in the 1-position
by an R ₃ NR ₄ or R ₃ NR ₄ C _1-3 alkyl group and
by a di (C _1-3 alkyl) -aminocarbonyl group, by an isoxazolidin-1-ylcarbonyl group, by a pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted by a C _1-3 alkyl group, wherein each of the above-mentioned groups has an alkyl portion or alkyl substituent may be substituted by a carboxy group in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy group C _1-3 alkyl group and
R _{4 is} a hydrogen atom, a 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 a 4- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy group, in which
Y _{2 represents} a carbon-nitrogen bond or a carbonyl group,
a substituted in the 1-position by an R ₅ NR ₆ group C _1-2 alkyl group in which
R _{5 is} a pyridinyl, phenylcarbonyl or phenylsulfonyl group and
R _{6 represents} a C _1-3 -alkyl or carboxy-C _1-3 -alkyl group,
a n-propyl group which is substituted by a chlorine atom in the 3-position and which is substituted in the 1-position by a cyclopentylcarbonyl group,
a cyclopropyl group substituted in the 1-position by a cyclopentylamino group and substituted on the nitrogen atom by a carboxy C _1-3 -alkylcarbonyl group,
R _{b is} a methyl group and
R _{c is} an amidino group which is optionally substituted by a C _1-8 -alkoxycarbonyl group,
their C _1-3 -alkanol esters, their N-benzyloxycarbonyl and N-benzoyl amidines,
their tautomers, their stereoisomers and their salts. 5. Benzimidazoles of the general formula Ia according to claim 2, in which
A is a methylene group,
B is an imino group,
R _{a is} a substituted in the 1-position by the R ₁ -CO-radical cyclopropyl group, in the
R _{1 is} a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group, in each of which the methyl or ethyl part by a carboxy, carboxy-C _1-3 alkoxy, carboxy-C _1-3 alkylamino or N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkylamino group may be substituted, represents
a substituted in the 1-position by the R ₂ -CX radical cyclopropyl group, in the
R _{2 is} optionally substituted by a C _1-3 alkyl substituted phenyl, pyridyl-pyrazolyl and
X represents an oxygen atom, a C _1-3 -alkoxyimino or C _1-3 -alkylidene group which are each substituted in the alkyl or alkoxy part by a carboxy group,
an imidazole group substituted in the 1-position C _1-2 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 additionally one of the aforementioned methyl or ethyl substituents simultaneously may be substituted by a carboxy group,
a methyl or ethyl group in the 1-position
by an R ₃ NR ₄ or R ₃ NR ₄ -CH ₂ group and
by a di- (C _1-3 alkyl) -aminocarbonyl group, optionally substituted by a C _1-3 alkyl Pyrroli dinocarbonyl- or piperidinocarbonyl group, wherein in the above-mentioned groups each an alkyl part or alkyl substituent be substituted by a carboxy group can, in which
R _{3 is} a hydrogen atom or an optionally substituted by a carboxy C _1-3 alkyl group and
R _{4 represents} a C _1-3 alkyl Y ₂ or carboxy C _1-3 alkyl Y ₂ group in which
Y _{2 represents} a carbon-nitrogen bond or a carbonyl group,
R _{b is} a methyl group and
R _{c is} an amidino group optionally substituted by a C _1-8 -alkoxycarbonyl group,
their C _1-3 -alkanol esters, their N-benzyloxycarbonyl and N-benzoyl amidines,
their tautomers, their stereoisomers and their salts. 6. Benzimidazoles of the general formula I according to at least one of claims 1 to 5, in which the radical R _{a is} in the 5-position,
their C _1-3 -alkanol esters, their N-benzyloxycarbonyl and N-benzoyl amidines,
their tautomers, their stereoisomers and their salts. 7. The following compounds of general 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-carboxyethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole,
• d) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) pyrrolidin-1-ylcarbonyl] cyclopropyl] benzimidazole,
• e) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole
• f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole and
• g) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N -methylcarboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole

and their C _1-3 alkanol esters, their N- (C _1-8 alkoxycarbonyl) -, N-benzyloxycarbonyl and N-benzoyl-amidines, their tautomers, their stereoisomers and their salts. 8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole, its C _1-3 alkanol ester, its N- (C _1-8 alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl amidines, their tautomers, its stereoisomers and its salts. 9. Physiologically acceptable salts of the compounds according to claims 1 to 8, in which R _{c represents} one of the amidino groups mentioned in claims 1 to 8. 10. A pharmaceutical composition comprising a compound according to at least one of claims 1 to 8, in which R _{c is} one of the supra in the claims to 8 mentioned amidino groups, or a salt according to claim 9 next to optionally one or more inert carriers and / or diluents , 11. Use of a compound according to at least one of claims 1 to 8, in which R _{c represents} one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9 for the preparation of a medicament having a thrombin time-prolonging action, a Thrombinhemmender effect and an inhibitory effect on related serine proteases. 12. A process for the preparation of a medicament according to claim 10, characterized in that non-chemical way a compound according to at least one of claims 1 to 8, in which R _{c is} one of the mentioned in claims 1 to 8 amidino groups, or a salt according to Claim 9 is incorporated in one or more inert carriers and / or diluent medium. 13. A process for the preparation of the compounds according to the entitlements to 1 to 9, characterized in that

• a) for the preparation of a compound of the general formula I, in which R _{c represents} a cyano group, an optionally formed in the reaction mixture compound of the general formula
  in the
  R _a , R _b , Ar, A and B as defined in claims 1 to 8 are defi ned,
  Z ₁ and Z ₂ , which may be the same or different, if appropriate substituted by alkyl groups having 1 to 6 carbon atoms substituted amino, hydroxy or mercapto or
  Z ₁ and Z ₂ , together an oxygen or sulfur atom, an optionally substituted by an alkyl group having 1 to 3 carbon atoms imino group, an alkylenedioxy or Al kylendithiogruppe each having 2 or 3 carbon atoms be interpreted, is cyclized or
• b) for preparing a compound of the general formula I in which R ₂ -CX '-C _3-5 cycloalkylene group, mentioned in the R ₂ as defined in claims 1 to 8 is as defined and X' is one of X in the claims 1 to 8 iminoreste mentioned,
  a compound of the general formula
  in the
  R _b , Ar, A and B are defined as mentioned in claims 1 to 8 and
  R _a 'represents an R ₂ -CO-C _3-5 -cycloalkylene group, wherein
  R _{2 is defined} as mentioned in claims 1 to 8,
  with an amine of the general formula
  H ₂ X '(V),
  in the
  X 'is one of the imino radicals mentioned for X in claims 1 to 8, is reacted or
• c) for the preparation of a compound of general formula I in which R ₂ -CX "-C _3-5 cycloalkylene group in which R _{2 is defined} as mentioned in claims 1 to 8 and X" is one of X for X in the claims 1 to 8 mentioned alkylidene represents represents a compound of the general formula
  in the
  R _b , Ar, A and B are defined as mentioned in claims 1 to 8 and
  R _a 'represents an R ₂ -CO-C _3-5 -cycloalkylene group, wherein
  R ₂ as defined in claims 1 to 8, is defined
  with a phosphone of the general formula
  Z ₃ -HX "(VI)
  in the
  X "is one of the alkyl radicals mentioned for X in claims 1 to 8 and
  Z _{3 represents} a triphenylphosphono or di (C _1-3 alkoxy) phosphono group, is reacted or
• d) for the preparation of a compound 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, an optionally formed in the reaction mixture Re compound of the general formula
  in the
  R _a , R _b , Ar, A and B as defined in claims 1 to 8 are defined defi ned and
  Z _{4 represents} an alkoxy, aralkoxy, alkylthio or aralkylthio group with an amine of the general formula
  HR ₇ NR ₈ (VIII)
  in the
  R ₇ and R ₈ , which may be the same or different, each represents a hydrogen atom or a C _1-3 -alkenyl group, or is reacted with its salts, or
• e) for the preparation of a compound of the general formula I in which R _{a is} an imidazolidine-2,4-dione-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein at the same time an alkyl substituent a carboxy or C _1-3 alkoxycarbonyl group may be substituted, a gege optionally formed in the mixture mixture of the general formula
  in the
  R _b , Ar, A and B are defined as mentioned in claims 1 to 8 and
  R _a "is an aminocarbonylamino group which is substituted in the 3-position by a C _1-3 alkoxycarbonyl-C _1-3 -alkyl group, is cyclized or
• f) for the preparation of a compound of the general formula I in which R _{c represents} a hydroxyamidino group, a nitrile of the general formula
  in the
  R _a , R _b , Ar, A and B as defined in claims 1 to 8 are defi ned, is reacted with hydroxylamine or its salts, or
• g) for the preparation of a compound of general formula I in which R _a contains a carboxy group and R _{c is} as defined in the claims 1 to 8 mentioned above or R _a as defined in the claims to 1 to 8 is defined and R _{c is} a if appropriate represented by a hydroxy group or by one or two C _1-3 alkyl substituted amido group, a compound of the general formula
  in the
  R _b , Ar, A and B are defined as mentioned in claims 1 to 8 and
  R _a '"and R _c ' have the meanings mentioned for R _a and R _c in claims 1 to 8 with the proviso that R _{a is} a hydrolysis by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a carboxy group contains convertible group and R _{c is defined} as mentioned in claims 1 to 8 or R _{c is} a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in an optionally by a hydroxy group or by one or two C _1-3 Al kylgruppen substituted amidino group is convertible group and R _a as defined in claims 1 to 8 defi ned,
  is converted by hydrolysis, treatment with an acid or base, Ther molysis or hydrogenolysis in a compound of general formula I in which R _a contains a carboxy group and R _{c is} as defined in claims 1 to 8 mentioned or R _a as in the Claims 1 to 8 mentioned above and R _{c is} an optionally substituted by a hydroxy group or by one or two C _1-3 alkyl groups substituted amidino group, or
• h) for the preparation of a compound of general formula I in which R _{c is} an amidino group which is substituted by one or two C _1-8 alkoxycarbonyl groups or by an in vivo cleavable radical, a compound of general formula
  in the
  R _a , R _b , Ar, A and B as defined in claims 1 to 8 are defi ned and
  R _c "represents an amidino group, with a compound of the general formula
  Z ₅ -R ₉ (XIII),
  in the
  R _{9 is} a C _1-8 alkoxycarbonyl group or the acyl radical of one of the aforementioned in vivo cleavable radicals and
  Z _{5 is} a nucleophilic leaving group, is reacted and, if desired, then a compound of general formula I thus obtained, which contains a (R ₃ NR ₄ ) -C _1-3 alkyl group, in which at least one of R ₃ or R ₄ a Represents hydrogen atom is amoylhalogenid with a corresponding isocyanate or Carbo converted into a corresponding urea compound of general formula I and / or
  a compound of the general formula I thus obtained, which contains an NH ₂ -C _1-3 -alkyl group, is converted with a corresponding acrylic acid ester into a corresponding 2- (C _1-3 -alkoxycarbonyl) -ethyl compound of the general formula I, and /or
  a compound of the general 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, with a corresponding diha logenalkan in a corresponding compound of the general formula I, in which R ₃ and R ₄ together with the intervening nitrogen atom, a corresponding 4- to 7-membered cycloalkyleneimino compound is converted and / or
  a compound of the general formula I in which R _{c is} an amidino group is converted with a haloacetic acid derivative and subsequent hydrolysis and decarboxylation into a corresponding amidino compound substituted by one or two methyl groups and / or
  a compound of general formula I thus obtained, in which R _{c represents} a hydroxyamidino group, is converted by means of catalytic hydrogenation into a corresponding amidino compound and / or
  a compound of the general formula I in which R _a contains a carboxy group is converted by means of esterification into a corresponding ester and / or
  a protective moiety used during the reactions for the protection of reactive groups is split off and / or
  a compound of general formula I thus obtained is separated into its stereoisomers and / or
  a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application into its physiologically tolerated salts with an inorganic or organic acid or base.