Benzimidazoles having antithrombotic activity

The present invention relates to new benzimidazoles of general formula ##STR1## wherein PA1 R.sub.a to R.sub.c, A, Ar and B are defined as in claim 1, the tautomers, the stereoisomers, the mixtures thereof the prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions, instead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties. The compounds of the above general formula I wherein R.sub.c denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I wherein R.sub.c denotes one of the amidino groups mentioned in claim 1 which have valuable pharmacological properties, particularly an antithrombotic activity.

DESCRIPTION OF THE INVENTION
 The present invention relates to benzimidazoles of general formula
 ##STR2##
 their tautomers, their stereoisomers, the mixtures thereof, their prodrugs,
 the derivatives thereof which contain a group which is negatively charged
 under physiological conditions instead of a carboxy group, and the salts
 thereof, particularly the physiologically acceptable salts thereof with
 inorganic or organic acids or bases which have valuable properties.
 The compounds of the above general formula I wherein R.sub.c denotes a
 cyano group are valuable intermediates for preparing the other compounds
 of general formula I, and the compounds of the above general formula I
 wherein R.sub.c denotes one of the following amidino groups, as well as
 their tautomers, their stereoisomers, the mixtures thereof, their
 prodrugs, the derivatives thereof which contain a group which is
 negatively charged under physiological conditions instead of a carboxy
 group, and their salts, particularly the physiologically acceptable salts
 thereof with
 The present application thus relates to the new compounds of the above
 general formula I as well as the preparation thereof, the pharmaceutical
 compositions containing the pharmacologically active compounds, the
 preparation and use thereof.
 In the above general formula
 Ar denotes a phenylene or naphthylene group optionally substituted by a
 fluorine, chlorine or bromine atom, by a trifluoromethyl, C.sub.1-3 -alkyl
 or C.sub.1-3 -alkoxy group,
 a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or
 pyridazinylene group optionally substituted in the carbon skeleton by a
 C.sub.1-3 -alkyl group,
 A denotes a C.sub.1-3 -alkylene group,
 B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or
 sulphonyl group, an imino group optionally substituted by a C.sub.1-3
 -alkyl group wherein the alkyl moiety may be mono- or disubstituted by a
 carboxy group,
 R.sub.a denotes an R.sub.1 --CO--C.sub.3-5 -cycloalkyl group wherein
 R.sub.1 denotes a C.sub.1-3 -alkoxy, amino, C.sub.1-4 -alkylamino or
 di-(C.sub.1-4 -alkyl)-amino group wherein each alkyl moiety may be
 substituted by a carboxy group,
 a 4- to 7-memberecl cycloalkyleneimino or cycloalkenyleneimino group which
 may be substituted by a hydroxy group or by one or two C.sub.1-3 -alkyl
 groups, whilst an alkyl substituent may simultaneously be substituted by a
 hydroxy, C.sub.1-3 -alkoxy, carboxy, carboxy-C.sub.1-3 -alkoxy,
 carboxy-C.sub.1-3 -alkylamino, N-(C.sub.1-3 -alkyl)-N-(carboxy-C.sub.1-3
 -allyl)-amino, carboxy-C.sub.1-3 -alkylaminocarbonyl, N-(C.sub.1-3
 -alkyl)-N-(carboxy-C.sub.1-3 -alkyl)-aminocarbonyl, carboxy-C.sub.1-3
 -alkylaminocarbonylamino, 1-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.1-3
 -alkyl)-aminocarbonylamino, 3-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.1-3
 -alkyl)-aminocarbonylamino or 1,3-di-(C.sub.1-3
 -alkyl)-3-(carboxy-C.sub.1-3 -alkyl)-aminocarbonylamino group,
 a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy
 group,
 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a
 C.sub.1-3 -alkyl group, to which a phenyl ring is fused via two adjacent
 carbon atoms,
 a morpholino, piperazino, N-(C.sub.1-3 -alkyl)-piperazino, pyrrolino,
 3,4-dehydro-piperidino or pyrrol-1-yl group,
 an R.sub.2 -CX-C.sub.3-5 -cycloalkyl group wherein
 R.sub.2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered
 heteroaryl group optionally substituted by a C.sub.1-3 -alkyl group,
 wherein the 6-membered heteroaryl group contains one, two or three
 nitrogen atoms and the 5-membered heteroaryl group contains an imino group
 optionally substituted by a C.sub.1-3 -alkyl group, an oxygen or sulphur
 atom or an imino group optionally substituted by a C.sub.1-3 -alkyl group
 and an oxygen or sulphur atom or one or two nitrogen atoms and the
 abovementioned alkyl substituent may be substituted by a carboxy,
 carboxy-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3
 -alkyl)-carboxy-C.sub.1-3 -alkylamino group, and
 X denotes an oxygen atom, a C.sub.1-3 -alkylimino, C.sub.1-3 -alkoxyimino,
 C.sub.1-3 -alkylhydrazino, di-(C.sub.1-3 -alkyl)-hydrazino, C.sub.2-4
 -alkanoyl-hydrazino, N-(C.sub.1-3 -alkyl)-C.sub.2-4 -alkanoylhydrazino or
 C.sub.1-3 -alkylidene group each of which may be substituted in the alkyl
 or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy
 group,
 a C.sub.1-3 -alkyl or C.sub.3-5 -cycloalkyl group substituted by an
 imidazole or imidazolone group wherein
 the imidazole ring may be substituted by a phenyl or carboxy group and by
 one or two C.sub.1-3 -alkyl groups or by one, two or three C.sub.1-3
 -alkyl groups, wherein the substituents may be identical or different and
 one of the abovementioned alkyl substituents may simultaneously be
 substituted by a carboxy group or may be substituted in the 2 or 3
 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3 -alkylamino,
 N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or di-(C.sub.1-3
 -alkyl)-amino group, and
 the imidazolone ring may be substituted by a C.sub.1-3 -alkyl group, whilst
 the alkyl substituent may be substituted by a carboxy group or in the 2 or
 3 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3 -alkylamino,
 N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or di-(C.sub.1-3
 -alkyl)-amino group, and
 additionally a phenyl or pyridine ring may be fused to the abovementioned
 imidazole or imidazolone rings via two adjacent carbon atoms,
 an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two
 C.sub.1-3 -alkyl groups, whilst at the same time an alkyl substituent may
 be substituted by a carboxy group,
 a C.sub.1-4 -alkyl group which is substituted
 by a C.sub.1-3 -alkyl-Y.sub.1 -C.sub.1-3 -alkyl, HOOC-C.sub.1-3
 -alkyl-Y.sub.1 -C.sub.1-3 -alkyl, tetrazolyl-C.sub.1-3- alkyl-Y.sub.2,
 R.sub.3 NR.sub.4 -- or R.sub.3 NR.sub.4 -C.sub.1-3 -alkyl group and
 by an isoxazolidinylcarbonyl group optionally substituted by a C.sub.1-3
 -alkyl group, by a pyrrolino-carbonyl, 3,4-dehydropiperidinocarbonyl,
 pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C.sub.1-3
 -alkylaminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl or 4- to
 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned
 groups the cycloalkyleneimino moiety may be substituted by one or two
 C.sub.1-3 -alkyl groups and at the same time each alkyl moiety or alkyl
 substituent in the abovementioned C.sub.1-3 -alkylaminocarbonyl,
 di-(C.sub.1-3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups
 may be substituted by a carboxy group, and the remaining hydrogen atoms of
 the C.sub.1-4 -alkyl group may be wholly or partially replaced by fluorine
 atoms wherein
 R.sub.3 denotes a hydrogen atom or a C.sub.1-3 -alkyl group optionally
 substituted by a carboxy group and
 R.sub.4 denotes a hydrogen atom, a C.sub.1-3 -alkyl-Y.sub.1 -C.sub.1-3
 -alkyl-Y.sub.2, carboxy-C.sub.1-3 -alkyl-Y.sub.1 -C.sub.1-3
 -alkyl-Y.sub.2, C.sub.1-3 -alkyl-Y.sub.2 or carboxy-C.sub.1-3
 -alkyl-Y.sub.2 group or
 R.sub.3 and R.sub.4 together with the nitrogen atom between them denote an
 4- to 7-membered cycloalkyleneimino group optionally substituted by a
 carboxy, C.sub.1-3 -alkyl or carboxy-C.sub.1-3 -alkyl group wherein
 Y.sub.1 denotes a carbon--carbon bond, an oxygen atom, a sulphenyl,
 sulphinyl, sulphonyl, --NH--, --NH--CO-- or --NH--CO--NH-- group and
 Y.sub.2 denotes a carbon--nitrogen bond or a carbonyl, sulphonyl, imino or
 --NH--CO-- group, wherein the carbonyl group of the --NH--CO-- group is
 linked to the nitrogen atom of the R.sub.3 NR.sub.4 -group, and the imino
 groups occurring in the definition of the groups Y.sub.1 and Y.sub.2 may
 each additionally be substituted by a C.sub.1-3 -alkyl or
 carboxy-C.sub.1-3 -alkyl group,
 a C.sub.1-3 -alkyl or C.sub.3-5 -cycloalkyl group substituted by a R.sub.5
 NR.sub.6 -group wherein
 R.sub.5 denotes a hydrogen atom, a C.sub.1-3 -alkyl, C.sub.5-7 -cycloalkyl,
 phenylcarbonyl, phenylsulphonyl or pyridinyl group and
 R.sub.6 denotes a C.sub.1-3 -alkyl, carboxy-C.sub.1-3 -alkyl or
 carboxy-C.sub.1-3 -alkylcarbonyl group,
 a C.sub.1-3 -alkyl group which is substituted by a C.sub.2-4 -alkanoyl or
 C.sub.5-7 -cycloalkanoyl group and by a C.sub.1-3 -alkyl group substituted
 by a chlorine, bromine or iodine atom,
 R.sub.b denotes a hydrogen atom or a C.sub.1-3 -alkyl group and
 R.sub.c denotes a cyano group or an amidino group optionally substituted by
 one or two C.sub.1-3 -alkyl groups.
 The carboxy groups mentioned in the definitions of the abovementioned
 groups may also be replaced by a group which can be converted in vivo into
 a carboxy group or by a group which is negatively charged under
 physiological conditions, or
 the amino and imino groups mentioned in the definitions of the
 abovementioned groups may also be substituted by a group which can be
 cleaved in vivo. Groups of this kind are described, for example, in WO
 98/46576 and by N. M. Nielson et al. in International Journal of
 Pharmaceutics 39, 75-85 (1987).
 A group which can be converted in vivo into a carboxy group may be, for
 example, a hydroxymethyl group, a carboxy group esterified with an
 alcohol, wherein the alcoholic moiety is preferably a C.sub.1-6 -alkanol,
 a phenyl-C.sub.1-3 -alkanol, a C.sub.3-9 -cycloalkanol, whilst a C.sub.5-8
 -cycloalkanol may additionally be substituted by one or two C.sub.1-3
 -alkyl groups, a C.sub.5-8 -cycloalkanol wherein a methylene group in the
 3- or 4-position is replaced by an oxygen atom or by an imino group
 optionally substituted by a C.sub.1-3 -alkyl, phenyl-C.sub.1-3 -alkyl,
 phenyl-C.sub.1-3 -alkoxycarbonyl or C.sub.2-6 -alkanoyl group and the
 cycloalkanol moiety may additionally be substituted by one or two
 C.sub.1-3 -alkyl groups, a C.sub.4-7 -cycloalkenol, a C.sub.3-5 -alkenol,
 a phenyl-C.sub.3-5 -alkenol, a C.sub.3-5 -alkynol or phenyl-C.sub.3-5
 -alkynol, with the proviso that no bond to the oxygen atom starts from a
 carbon atom which carries a double or triple bond, a C.sub.3-8
 -cycloalkyl-C.sub.1-3 -alkanol, a bicycloalkanol with a total of 8 to 10
 carbon atoms, which may additionally be substituted in the bicycloalkyl
 moiety by one or two C.sub.1-3 -alkyl groups, a
 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
EQU R.sub.d --CO--O--(R.sub.e CR.sub.f)--OH,
 wherein
 R.sub.d denotes a C.sub.1-8 -alkyl, C.sub.5-7 -cycloalkyl, phenyl or
 phenyl-C.sub.1-3 -alkyl group,
 R.sub.e denotes a hydrogen atom, a C.sub.1-3 -alkyl, C.sub.5-7 -cycloalkyl
 or phenyl group and
 R.sub.f denotes a hydrogen atom or a C.sub.1-3 -alkyl group,
 a group which is negatively charged under physiological conditions may be a
 tetrazol-5-yl, phenylcarbonylamino-carbonyl,
 trifluormethylcarbonylaminocarbonyl, C.sub.1-6 -alkylsulphonylamino,
 phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino,
 C.sub.1-6 -alkylsulphonylaminocarbonyl, phenylsulphonylamino-carbonyl,
 benzylsulphonylaminocarbonyl or perfluoro-C.sub.1-6
 -alkylsulphonylaminocarbonyl group
 and a group which can be cleaved in vivo from an imino or amino group may
 be, for example, a hydroxy group, an acyl group such as a benzoyl group
 optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine
 atoms, by C.sub.1-3 -alkyl or C.sub.1-3,-alkoxy groups, wherein the
 substituents may be identical or different, a pyridinoyl group or a
 C.sub.1-16 -alkanoyl group such as the formyl, acetyl, propionyl,
 butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or
 allyloxycarbonyl group, a C.sub.1-16 -alkoxycarbonyl or C.sub.1-16
 -alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially
 replaced by fluorine or chlorine atoms, such as the methoxycarbonyl,
 ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
 tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl,
 nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,
 dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy,
 ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy,
 isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy,
 pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy,
 decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or
 hexadecylcarbonyloxy group, a phenyl-C.sub.1-6 -alkoxycarbonyl group such
 as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl
 group, a 3-amino-propionyl group wherein the amino group may be mono- or
 disubstituted by C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl groups and the
 substituents may be identical or different, a C.sub.1-3
 -alkylsulphonyl-C.sub.2-4 -alkoxycarbonyl, C.sub.1-3 -alkoxy-C.sub.2-4
 -alkoxy-C.sub.2-4 -alkoxycarbonyl, R.sub.d --CO--O--(R.sub.d
 CR.sub.f)--O--CO--, C.sub.1-6 -alkyl-CO--NH--(R.sub.g CR.sub.h)--O--CO--
 or C.sub.1-6 -alkyl-CO--O--(R.sub.g CR.sub.h)--(R.sub.g CR.sub.h)--O--CO--
 group wherein R.sub.d to R.sub.f are as hereinbefore defined,
 R.sub.g and R.sub.h, which may be identical or different, denote hydrogen
 atoms or C.sub.1-3 -alkyl groups.
 Moreover, the saturated alkyl and alkoxy moieties which contain more than 2
 carbon atoms mentioned in the above definitions also include the branched
 isomers thereof, such as, for example, the isopropyl, tert.butyl, isobutyl
 group etc.
 Preferred compounds are those of general formula
 ##STR3##
 wherein
 A denotes a C.sub.1-3 -alkylene group,
 B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or
 sulphonyl group, an imino group optionally substituted by a C.sub.1-3
 -alkyl group wherein the alkyl moiety may be mono- or disubstituted by a
 carboxy group,
 R.sub.a denotes an R.sub.1 --CO-C.sub.3-5 -cycloalkyl group wherein
 R.sub.1 denotes a C.sub.1-3 -alkoxy, amino, C.sub.1-4 -alkylamino or
 di-(C.sub.1-4 -alkyl)-amino group wherein each alkyl moiety may be
 substituted by a carboxy group,
 a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which
 may be substituted by one or two C.sub.1-3 -alkyl groups, whilst an alkyl
 substituent may simultaneously be substituted by a hydroxy, C.sub.1-3
 -alkoxy, carboxy, carboxy-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3
 -alkylamino, N-(C.sub.1-3 -alkyl)-N-(carboxy-C.sub.1-3 -alkyl)-amino,
 carboxy-C.sub.1-3 -alkylaminocarbonyl, N-(C.sub.1-3-
 alkyl)-N-(carboxy-C.sub.1-3 -alkyl)-aminocarbonyl, carboxy-C.sub.1-3
 -alkylaminocarbonylamino, 1-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.1-3
 -alkyl)-aminocarbonylamino, 3-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.1-3
 -alkyl)-aminocarbonylamino or 1,3-di-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.3
 -alkyl)-aminocarbonylamino group,
 a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy
 group,
 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a
 C.sub.1-3 -alkyl group, to which a phenyl ring is fused via two adjacent
 carbon atoms,
 a morpholino, piperazino, N-(C.sub.1-3 -alkyl)-piperazino, pyrrolino,
 3,4-dehydro-piperidino or pyrrol-1-yl group,
 an R.sub.2 --CX-C.sub.3-5 -cycloalkyl group wherein
 R.sub.2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered
 heteroaryl group optionally substituted by a C.sub.1-3 -alkyl group,
 wherein the 6-membered heteroaryl group contains one, two or three
 nitrogen atoms and the 5-membered heteroaryl group contains an imino group
 optionally substituted by a C.sub.1-3 -alkyl group, an oxygen or sulphur
 atom or an imino group optionally substituted by a C.sub.1-3 -alkyl group
 and an oxygen or sulphur atom or one or two nitrogen atoms and the
 abovementioned alkyl substituent may be substituted by a carboxy,
 carboxy-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3
 -alkyl)-carboxy-C.sub.1-3 -alkylamino group, and
 X denotes an oxygen atom, a C.sub.1-3 -alkylimino, C.sub.1-3 -alkoxyimino,
 C.sub.1-3 -alkylhydrazino, di-(C.sub.1-3 -alkyl)-hydrazino, C.sub.2-4
 -alkanoylhydrazino, N-(C.sub.1-3 -alkyl)-C.sub.2-4 -alkanoylhydrazino or
 C.sub.1-3 -alkylidene group each of which may be substituted in the alkyl
 or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy
 group,
 a C.sub.1-3- alkyl or C.sub.3-5 -cycloalkyl group substituted by an
 imidazole or imidazolone group wherein
 the imidazole ring may be substituted by a phenyl or carboxy group and by
 one or two C.sub.1-3 -alkyl groups or by one, two or three C.sub.1-3
 -alkyl groups, wherein the substituents may be identical or different and
 one of the abovementioned alkyl substituents may simultaneously be
 substituted by a carboxy group or may be substituted in the 2 or 3
 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3 -alkylamino,
 N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or di-(C.sub.1-3
 -alkyl)-amino group, and
 the imidazolone ring may be substituted by a C.sub.1-3 -alkyl group, whilst
 the alkyl substituent may be substituted by a carboxy group or in the 2 or
 3 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3 -alkylamino,
 N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or di-(C.sub.1-3
 -alkyl)-amino group, and
 additionally a phenyl or pyridine ring may be fused to the abovementioned
 imidazole or imidazolone rings via two adjacent carbon atoms,
 an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two
 C.sub.1-3 -alkyl groups, whilst at the same time an alkyl substituent may
 be substituted by a carboxy group,
 a C.sub.1-4 -alkyl group which is substituted
 by a C.sub.1-3 -alkyl-Y.sub.1 -C.sub.1-3 -alkyl, HOOC-C.sub.1-3
 -alkyl-Y.sub.1 -C.sub.1-3 -alkyl, tetrazolyl-C.sub.1-3 -alkyl-Y.sub.2,
 R.sub.3 NR.sub.4 -- or R.sub.3 NR.sub.4 -C.sub.1-3 -alkyl group and
 by an isoxazolidinylcarbonyl group optionally substituted by a C.sub.1-3
 -alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl,
 pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C.sub.1-3
 -alkylaminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl or 4- to
 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned
 groups the cycloalkyleneimino moiety may be substituted by one or two
 C.sub.1-3 -alkyl groups and at the same time each alkyl moiety or alkyl
 substituent in the abovementioned C.sub.1-3 -alkylaminocarbonyl,
 di-(C.sub.1-3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups
 may be substituted by a carboxy group, and the remaining hydrogen atoms of
 the C.sub.1-4 -alkyl group may be wholly or partially replaced by fluorine
 atoms wherein
 R.sub.3 denotes a hydrogen atom or a C.sub.1-3 -alkyl group optionally
 substituted by a carboxy group and
 R.sub.4 denotes a hydrogen atom, a C.sub.1-3 -alkyl-Y.sub.1 -C.sub.1-3
 -alkyl-Y.sub.2, carboxy-C.sub.1-3 -alkyl-Y.sub.1 -C.sub.1-3
 -alkyl-Y.sub.2, C.sub.1-3 -alkyl-Y.sub.2 or carboxy-C.sub.1-3
 -alkyl-Y.sub.2 group or
 R.sub.3 and R.sub.4 together with the nitrogen atom between them denote an
 4- to 7-membered cycloalkyleneimino group optionally substituted by a
 carboxy, C.sub.1-3 -alkyl or carboxy-C.sub.1-3 -alkyl group wherein
 Y.sub.1 denotes a carbon--carbon bond, an oxygen atom, a sulphenyl,
 sulphinyl, sulphonyl, --NH--, --NH--CO-- or --NH--CO--NH-- group and
 Y.sub.2 denotes a carbon--nitrogen bond or a carbonyl, sulphonyl, imino or
 --NH--CO-- group, wherein the carbonyl group of the --NH--CO-- group is
 linked to the nitrogen atom of the R.sub.3 NR.sub.4 -- group, and the
 imino groups occurring in the definition of the groups Y.sub.1 and Y.sub.2
 may each additionally be substituted by a C.sub.1-3 -alkyl or
 carboxy-C.sub.1-3 -alkyl group,
 a C.sub.1-3 -alkyl or C.sub.3-5 -cycloalkyl group substituted by a R.sub.5
 NR.sub.6 -- group wherein
 R.sub.5 denotes a hydrogen atom, a C.sub.1-3 -alkyl, C.sub.5-7 -cycloalkyl,
 phenylcarbonyl, phenylsulphonyl or pyridinyl group and
 R.sub.6 denotes a C.sub.1-3 -alkyl, carboxy-C.sub.1-3 -alkyl or
 carboxy-C.sub.1-3 -alkylcarbonyl group,
 a C.sub.1-3 -alkyl group which is substituted by a C.sub.2-4 -alkanoyl or
 C.sub.5-7 -cycloalkanoyl group and by a C.sub.1-3 -alkyl group substituted
 by a chlorine, bromine or iodine atom,
 R.sub.b denotes a hydrogen atom or a C.sub.1-3 -alkyl group and
 R.sub.c denotes a cyano group or an amidino group which may be substituted
 by a hydroxy group, by one or two C.sub.1-3 -alkyl groups, or by one or
 two C.sub.1-8 -alkoxycarbonyl groups,
 wherein the carboxy, amino and imino groups mentioned in the definition of
 the abovementioned groups may also be substituted by a group which can be
 cleaved in vivo,
 the tautomers, stereoisomers and salts thereof.
 Particularly preferred compounds of the above general formula Ia are those
 wherein
 A denotes a C.sub.1-3 -alkylene group, B denotes an oxygen atom, a
 methylene, imino or N-(C.sub.1-3 -alkyl)-imino group wherein the alkyl
 moiety may be substituted by a carboxy group,
 R.sub.a denotes an C.sub.3-5 -cycloalkyl group substituted by the R.sub.1
 --CO group in the 1 position wherein
 R.sub.1 denotes a C.sub.1-3 -alkoxy, amino, C.sub.1-4 -alkylamino or
 di-(C.sub.1-4 -alkyl)-amino group wherein each alkyl moiety may be
 substituted by a carboxy group,
 a 4- to 7-membered cycloalkyleneimino group which may be substituted by a
 hydroxy group or by one or two C.sub.1-3 -alkyl groups, whilst an alkyl
 substituent may simultaneously be substituted by a hydroxy, C.sub.1-3
 -alkoxy, carboxy, carboxy-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3
 -alkylamino, N-(C.sub.1-3 -alkyl)-N-(carboxy-C.sub.1-3 -alkyl)-amino,
 carboxy-C.sub.1-3 -alkylaminocarbonyl, N-(C.sub.1-3
 -alkyl)-N-(carboxy-C.sub.1-3 -alkyl)-aminocarbonyl, carboxy-C.sub.1-3
 -alkylaminocarbonylamino, 1-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.1-3
 -alkyl)-aminocarbonylamino, 3-(C.sub.1-3 -alkyl)-3-(carboxy-C.sub.1-3
 -alkyl)-aminocarbonylamino or 1,3-di-(C.sub.1-3
 -alkyl)-3-(carboxy-C.sub.1-3 -alkyl)-aminocarbonylamino group,
 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a
 C.sub.1-3 -alkyl group, to which a phenyl ring is fused via two adjacent
 carbon atoms,
 a morpholino, piperazino, N-(C.sub.1-3 -alkyl)-piperazino, pyrrolino,
 3,4-dehydro-piperidino or pyrrol-1-yl group,
 a C.sub.3-5 -cycloalkyl group substituted in the 1 position by the R.sub.2
 --CX-- group, wherein
 R2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl
 group optionally substituted by a C.sub.1-3 -alkyl group, wherein the
 6-membered heteroaryl group contains one, two or three nitrogen atoms and
 the 5-membered heteroaryl group contains an imino group optionally
 substituted by a C.sub.1-3 -alkyl group, an oxygen or sulphur atom or an
 imino group optionally substituted by a C.sub.1-3 -alkyl group and an
 oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned
 alkyl substituent may be substituted by a carboxy, carboxy-C.sub.1-3
 -alkoxy, carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3
 -alkyl)-carboxy-C.sub.1-3 -alkylamino group, and
 X denotes an oxygen atom, a C.sub.1-3 -alkylimino, C.sub.1-3 -alkoxyimino
 or C.sub.1-3 -alkylidene group, each of which may be substituted in the
 alkyl or alkanoyl moiety by a carboxy group,
 a C.sub.1-3 -alkyl group substituted in the 1 position by an imidazole or
 imidazolone group wherein
 the imidazole ring may be substituted by a phenyl or carboxy group and by
 one or two C.sub.1-3 -alkyl groups or by one, two or three C.sub.1-3
 -alkyl groups, wherein the substituents may be identical or different and
 one of the abovementioned alkyl substituents may simultaneously be
 substituted by a carboxy group or may be substituted in the 2 or 3
 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3 -alkylamino,
 N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or di-(C.sub.1-3
 -alkyl)-amino group, and
 the imidazolone ring may be substituted by a C.sub.1-3 -alkyl group, whilst
 the alkyl substituent may be substituted by a carboxy group or in the 2 or
 3 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3 -alkylamino,
 N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or di-(C.sub.1-3
 -alkyl)-amino group, and
 additionally a phenyl or pyridine ring may be fused to the abovementioned
 imidazole or imidazolone rings via two adjacent carbon atoms,
 an imidazolidine-2,4-dtion-5-yl group which may be substituted by one or
 two C.sub.1-3 -alkyl groups, whilst at the same time an alkyl substituent
 may be substituted by a carboxy group,
 a C.sub.1-4 -alkyl group which is substituted in the 1 position
 by an R.sub.3 NR.sub.4 -- or R.sub.3 NR.sub.4 -C.sub.1-3 -alkyl group and
 by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl,
 imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, C.sub.1-3
 -alkylaminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl,
 isoxazolidin-1-yl-carbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl
 group, whilst in the abovementioned groups the cycloalkyleneimino moiety
 may be substituted by one or two C.sub.1-3 -alkyl groups and at the same
 time each alkyl moiety or alkyl substituent in the abovementioned
 C.sub.1-3 -alkylaminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl or
 cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group,
 and the remaining hydrogen atoms of the C.sub.1-4 -alkyl group may be
 wholly or partially replaced by fluorine atoms, wherein
 R.sub.3 denotes a hydrogen atom or a C.sub.1-3 -alkyl group optionally
 substituted by a carboxy group and
 R.sub.4 denotes a hydrogen atom, a C.sub.1-3 -alkyl-Y.sub.2 or
 carboxy-C.sub.1-3 -alkyl-Y.sub.2 group or
 R.sub.3 and R.sub.4 together with the nitrogen atom between them denote a
 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1
 position by a carboxy, C.sub.1-3 -alkyl or carboxy-C.sub.1-3 -alkyl group,
 wherein
 Y.sub.2 denotes a carbon--nitrogen bond or a carbonyl, imino or --NH--CO--
 group, wherein the carbonyl group of the --NH--CO-- group is linked to the
 nitrogen atom of the R.sub.3 NR.sub.4 -- group, and the imino group
 occurring in the definition of the groups Y.sub.2 may additionally be
 substituted by a C.sub.1-3 -alkyl or carboxy-C.sub.1-3 -alkyl group,
 a C.sub.1-3 -alkyl or C.sub.3-5 -cycloalkyl group substituted in the 1
 position by an R.sub.5 NR.sub.6 -- group, wherein
 R.sub.5 denotes a hydrogen atom, a C.sub.1-3 -alkyl, C.sub.5-7 -cycloalkyl,
 phenylcarbonyl, phenylsulphonyl or pyridinyl group and
 R.sub.6 denotes a C.sub.1-3 -alkyl, carboxy-C.sub.1-3 -alkyl or
 carboxy-C.sub.1-3 -alkylcarbonyl group,
 a C.sub.1-3 -alkyl group which is substituted by a C.sub.2-4 -alkanoyl or
 C.sub.5-7 -cycloalkanoyl group and by a C.sub.1-3 -alkyl group substituted
 by a chlorine, bromine or iodine atom,
 R.sub.b denotes a C.sub.1-3 -alkyl group and
 R.sub.c denotes an amidino group which may optionally be substituted by a
 2,2,2-trichloroethoxycarbonyl, C.sub.1-8 -alkoxycarbonyl,
 acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the
 benzoyl moiety may be mono- or disubstituted by fluorine, chlorine,
 bromine or iodine atoms, by C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy groups
 and the substituents may be identical or different,
 the C.sub.1-3 -alkanol esters, the tautomers, stereoisomers and salts
 thereof.
 Most particularly preferred compounds of general formula I are those
 wherein
 A denotes a methylene group,
 B denotes an oxygen atom or an imino group,
 R.sub.a denotes a cyclopropyl group substituted by the R.sub.1 --CO-- group
 in the 1 position, wherein
 R.sub.1 denotes a pyrrolidino or piperidino group optionally substituted by
 a methyl or ethyl group wherein each methyl or ethyl moiety may be
 substituted by a carboxy, carboxy-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3
 -alkylamino or N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino group,
 a cyclopropyl group substituted in the 1 position by the R.sub.2 --CX--
 group, wherein
 R.sub.2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted
 by a C.sub.1-3 -alkyl group and
 X denotes an oxygen atom, a C.sub.1-3 -alkoxyimino or C.sub.1-3 -alkylidene
 group, each of which is substituted in the alkyl or alkoxy moiety by a
 carboxy group,
 a C.sub.1-2 -alkyl group substituted in the 1 position by an imidazole
 group wherein the irnidazole ring may be substituted by a phenyl or
 carboxy group and by one or two C.sub.1-3 -alkyl groups or by one, two or
 three C.sub.1-3 -alkyl groups, wherein the substituents may be identical
 or different and one of the abovementioned alkyl substituents may
 simultaneously be substituted by a carboxy group or may be substituted in
 the 2 or 3 position by an amino, C.sub.2-4 -alkanoylamino, C.sub.1-3
 -alkylamino, N-(C.sub.2-4 -alkanoyl)-C.sub.1-3 -alkylamino or
 di-(C.sub.1-3 -alkyl)-amino group, whilst additionally a phenyl or
 pyridine ring may be fused to the abovementioned imidazole rings via two
 adjacent carbon atoms,
 a C.sub.1-2 -alkyl substituted in the 1 position by a benzimidazolon-1-yl
 group, whilst the imidazolone ring may be substituted by a methyl or ethyl
 group optionally substituted by a carboxy group,
 a methyl or ethyl group which is substituted in the 1 position
 by an R.sub.3 NR.sub.4 -- or R.sub.3 NR.sub.4 -C.sub.1-3 -alkyl group and
 by a di-(C.sub.1-3 -alkyl)-aminocarbonyl group, by an
 isoxazolidin-1-yl-carbonyl group, by a pyrrolidino-carbonyl or
 piperidino-carbonyl group substituted by a C.sub.1-3 -alkyl group, whilst
 in the abovementioned groups each alkyl moiety or alkyl substituent in the
 abovementioned groups may be substituted by a carboxy group, wherein
 R.sub.3 denotes a hydrogen atom or a C.sub.1-3 -alkyl group optionally
 substituted by a carboxy group and
 R.sub.4 denotes a hydrogen atom, a C.sub.1-3 -alkyl-Y.sub.2 or
 carboxy-C.sub.1-3 -alkyl-Y.sub.2 group or
 R.sub.3 and R.sub.4 together with the nitrogen atom between them denote a
 4- to 7-membered cycloalkyleneimino group optionally substituted by a
 carboxy group, wherein
 Y.sub.2 denotes a carbon--nitrogen bond, a carbonyl group or an imino group
 optionally substituted by a C.sub.1-3 -alkyl group,
 a C.sub.1-2 -alkyl group substituted in the 1 position by an R.sub.5
 NR.sub.6 -- group, wherein
 R.sub.5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and
 R.sub.6 denotes a C.sub.1-3 -alkyl or carboxy-C.sub.1-3 -alkyl group,
 an n-propyl group substituted in the 3 position by a chlorine atom, which
 is substituted in the 1 position by a cyclopentylcarbonyl group,
 a cyclopropyl group substituted in the 1 position by a cyclopentylamino
 group, which is substituted at the nitrogen atom by a carboxy-C.sub.1-3
 -alkylcarbonyl group,
 R.sub.b denotes a methyl group and
 R.sub.c denotes an amidino group which may optionally be substituted by a
 C.sub.1-8 -alkoxycarbonyl, acetoxymethyloxycarbonyl,
 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group,
 particularly those compounds of general formula Ia wherein
 A denotes a methylene group,
 B denotes an imino group,
 R.sub.a denotes a cyclopropyl group substituted by the R.sub.1 --CO-- group
 in the 1 position, wherein
 R.sub.1 denotes a pyrrolidino or piperidino group optionally substituted by
 a methyl or ethyl group wherein each methyl or ethyl moiety may be
 substituted by a carboxy, carboxy-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3
 -alkylamino or N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino group,
 a cyclopropyl group substituted in the 1 position by the R.sub.2 --CX
 group, wherein
 R.sub.2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted
 by a C.sub.1-3 -alkyl group and
 X denotes an oxygen atom, a C.sub.1-3 -alkoxyimino or C.sub.1-3 -alkylidene
 group, each of which is substituted in the alkyl or alkoxy moiety by a
 carboxy group,
 a C.sub.1-2 -alkyl group substituted in the 1 position by an imidazole
 group wherein the imidazole ring may be substituted by one to three methyl
 groups or by two methyl groups and an ethyl group, whilst additionally one
 of the abovementioned methyl or ethyl substituents may simultaneously be
 substituted by a carboxy group,
 a methyl or ethyl group which is substituted in the 1 position
 by an R.sub.3 NR.sub.4 -- or R.sub.3 NR.sub.4 --CH.sub.2 -- group and
 by a di-(C.sub.1-3 -alkyl)-aminocarbonyl, by a pyrrolidinocarbonyl or
 piperidinocarbonyl group optionally substituted by a C.sub.1-3 -alkyl
 group, whilst in the abovementioned groups each alkyl moiety or alkyl
 substituent may be substituted by a carboxy group, wherein
 R.sub.3 denotes a hydrogen atom or a C.sub.1-3 -alkyl group optionally
 substituted by a carboxy group and
 R.sub.4 denotes a C.sub.1-3 -alkyl-Y.sub.2 or carboxy-C.sub.1-3
 -alkyl-Y.sub.2 group wherein
 Y.sub.2 denotes a carbon--nitrogen bond, a carbonyl group or an imino group
 optionally substituted by a C.sub.1-3 -alkyl group,
 R.sub.b denotes a methyl group and
 R.sub.c denotes an amidino group which may optionally be substituted by a
 C.sub.1-8 -alkoxycarbonyl, acetoxymethyloxycarbonyl,
 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst
 the abovementioned compounds in which the group R.sub.a is in the 5
 position are particularly preferred,
 the C.sub.1-3 -alkanol esters, the tautomers, stereoisomers and salts
 thereof.
 The following are mentioned as examples of particularly preferred
 compounds:
 (a)
 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)-cy
 clopropyl]-benzimidazole,
 (b)
 (E/
 Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxyme
 thyloxyimino)methylene]-cyclopropyl]-benzimidazole,
 (c)
 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxyethylamino)-1-(pyrr
 olidin-1-yl-carbonyl)-ethyl]-benzimidazole,
 (d)
 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidi
 n-1-yl-carbonyl]cyclopropyl]-benzimidazole,
 (e)
 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxyethyl)-4,5-dimethyl
 -imidazol-1-yl-methyl]-benzimidazole
 (f)
 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrro
 lidin-1-yl-carbonyl)-ethyl]-benzimidazole and
 (g)
 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methylcarboxymethylcarbony
 laminomethyl)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole
 and the C.sub.1-3 -alkanol esters, the N-(C.sub.1-8 -alkoxycarbonyl),
 N-benzyloxycarbonyl and N-benzoyl-amidines, the tautomers, stereoisomers
 and salts thereof.
 According to the invention, the compounds of general formula I are prepared
 by methods known per se, for example by the following methods:
 a) In order to prepare a compound of general formula I wherein R, denotes a
 cyano group:
 cyclising a compound of general formula
 ##STR4##
 optionally formed in the reaction mixture,
 wherein
 R.sub.a, R.sub.b, Ar, A and B are as hereinbefore defined, Z.sub.1 and
 Z.sub.2, which may be identical or different, denote amino, hydroxy or
 mercapto groups optionally substituted by alkyl groups with 1 to 6 carbon
 atoms or
 Z.sub.1 and Z.sub.2 together represent an oxygen or sulphur atom, an imino
 group optionally substituted by an alkyl group with 1 to 3 carbon atoms,
 an alkylendioxy or alkylenedithio group with 2 or 3 carbon atoms.
 The cyclisation is expediently carried out in a solvent or mixture of
 solvents such as ethanol, isopropanol, glacial acetic acid, benzene,
 chlorobenzene, toluene, xylene, glycol, glycol monomethylether,
 diethyleneglycol dimethylether, sulpholane, dimethylformamide, tetraline
 or in an excess of the acylating agent used to prepare the compound of
 general formula II, e.g. in the corresponding nitrile, anhydride, acid
 halide, ester or amide, for example at temperatures between 0 and
 250.degree. C., but preferably at the boiling temperature of the reaction
 mixture, optionally in the presence of a condensing agent such as
 phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric
 acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid,
 phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride,
 N,N-dicyclohexyl-carbodiimide or optionally in the presence of a base such
 as potassium ethoxide or potassium tert.butoxide. However, the cyclisation
 may also be carried out without a solvent and/or condensing agent.
 It is particularly advantageous to perform the reaction by preparing a
 compound of general formula II in the reaction mixture by reduction of a
 corresponding o-nitro compound optionally in the presence of a carboxylic
 acid of general formula
EQU HO--C--A--B--Ar--CN (III),
 wherein
 Ar, A and B are as hereinbefore defined, by acylation of a corresponding
 amino compound optionally formed in the reaction mixture.
 b) In order to prepare a compound of general formula I wherein R.sub.a
 denotes a R.sub.2 --CX'--C.sub.3-5 -cycloalkylene group, wherein R.sub.2
 is as hereinbefore defined and X' denotes one of the imino groups
 mentioned for X hereinbefore:
 reacting a compound of general formula
 ##STR5##
 wherein
 R.sub.b, R.sub.c, Ar, A and B are as hereinbefore defined and R.sub.a '
 denotes an R.sub.2 --CO--C.sub.3-5 -cycloalkylene group, where
 R.sub.2 is as hereinbefore defined, with an amine of general formula
EQU H.sub.2 X' (V),
 wherein
 X' denotes one of the imino groups mentioned for X hereinbefore.
 The reaction is preferably carried out in a solvent such as
 methanol/toluene, ethanol, isopropanol or xylene and expediently in the
 presence of a dehydrating agent such as molecular sieve, sodium sulphate
 or calcium chloride optionally in the presence of a base such as
 triethylamine at temperatures between 50 and 100.degree. C., preferably at
 the boiling temperature of the reaction mixture.
 c) In order to prepare a compound of general formula I wherein R.sub.a
 denotes a R.sub.2 --CX"-C.sub.3-5 -cycloalkylene group, wherein R.sub.2 is
 as hereinbefore defined and X" denotes one of the alkylidene groups
 mentioned for X hereinbefore:
 reacting a compound of general formula
 ##STR6##
 wherein
 R.sub.b, R.sub.c, Ar, A and B are as hereinbefore defined and R.sub.a '
 denotes an R.sub.2 --CO-C.sub.3-5 -cycloalkylene group, where
 R.sub.2 is as hereinbefore defined,
 with a phosphone of general formula
EQU Z.sub.3 --HX" (VI),
 wherein
 X" denotes one of the alkylidene groups mentioned for X hereinbefore and
 Z.sub.3 denotes a triphenylphosphono or di-(C.sub.1-3 -alkoxy)phosphono
 group such as the triethoxyphosphono group.
 The reaction is preferably carried out under protective gas in a solvent
 such as tetrahydrofuran, dimethylformamide, dioxane, diethylether or
 dimethyl sulphoxide in the presence of a base such as potassium
 tert.butoxide, sodium ethoxide or sodium hydride at temperatures between
 -25 and 50.degree. C., preferably at temperatures between -15.degree. and
 ambient temperature.
 d) In order to prepare a compound of general formula I wherein R.sub.c
 denotes an amiaino group which may be substituted by one or two C.sub.1-3
 -alkyl groups:
 reacting a compound of general formula
 ##STR7##
 optionally formed in the reaction mixture
 wherein
 R.sub.a, R.sub.b, Ar, A and B are as hereinbefore defined and Z.sub.4
 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy,
 n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio
 group such as the methylthio, ethylthio, n-propylthio or benzylthio group,
 with an amine of general formula
EQU H--R.sub.7 NR.sub.8, (VIII)
 wherein
 R.sub.7 and R.sub.8, which may be identical or different, each denote a
 hydrogen atom or a C.sub.1-3 -alkyl group, or with the salts thereof.
 The reaction is expediently carried out in a solvent such as methanol,
 ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0
 and 150.degree. C., preferably at temperatures between 0 and 80.degree.
 C., with an amine of general formula VIII or with a corresponding acid
 addition salt such as for example ammonium carbonate or ammonium acetate.
 A compound of general formula VII is obtained for example by reacting a
 corresponding cyano compound with a corresponding alcohol such as
 methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the
 presence of an acid such as hydrochloric acid or by reacting a
 corresponding amide with a trialkyloxonium salt such as
 triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride,
 tetrahydrofuran or dioxane at temperatures between 0 and 50.degree. C.,
 but preferably at 20.degree. C., or a corresponding nitrile with hydrogen
 sulphide expediently in a solvent such as pyridine or dimethylformamide
 and in the presence of a base such as triethylamine and subsequently
 alkylating the thioamide formed with a corresponding alkyl or aralkyl
 halide.
 e) In order to prepare a compound of general formula I wherein R.sub.a
 denotes an imidazolidin-2,4-dion-5-yl group which may be substituted by
 one or two C.sub.1-3 -alkyl groups, whilst at the same time an alkyl
 substituent may be substituted by a carboxy or C.sub.1-3 -alkoxycarbonyl
 group:
 cyclising a compound of general formula
 ##STR8##
 optionally formed in the reaction mixture
 wherein
 R.sub.b, Ar, A and B are as hereinbefore defined and
 R.sub.a " denotes an aminocarbonylamino group, substituted in the 3
 position by a C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkyl group.
 The reaction is preferably carried out in a solvent such as methanol,
 ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an
 acid such as hydrochloric acid at temperatures between 0 and 50.degree.
 C., but preferably at 20.degree. C.
 f) In order to prepare a compound of general formula I wherein R.sub.c
 denotes a hydroxyamidino group:
 reacting a nitrite of general formula
 ##STR9##
 wherein
 R.sub.a, R.sub.b, Ar, A and B are as hereinbefore defined, with
 hydroxylamine or the salts thereof.
 The reaction is expediently carried out in a solvent such as methanol,
 ethanol, n-propanol, water, methanol/water, tetrahydrofuran,
 tetrahydrofuran/water, dioxane or dioxane/water at temperatures between 0
 and 150.degree. C., preferably at temperatures between 0 and 80.degree. C.
 g) In order to prepare a compound of general formula I wherein R.sub.a
 contains a carboxy group and R.sub.c is as hereinbefore defined or R.sub.a
 is as hereinbefore defined and R, denotes an amidino group optionally
 substituted by a hydroxy group or by one or two C.sub.1-3 -alkyl groups:
 converting a compound of general formula
 ##STR10##
 wherein
 R.sub.b, Ar, A and B are as hereinbefore defined and R.sub.a '" and R.sub.c
 ' have the meanings given for R.sub.a and R.sub.c with the proviso that
 R.sub.a contains a group which may be converted into a carboxy group by
 hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis
 and R.sub.c is as hereinbefore defined or R.sub.c denotes a group which
 may optionally be converted by hydrolysis, treatment with an acid or base,
 thermolysis or hydrogenolysis into an amidino group substituted by a
 hydroxy group or by one or two C.sub.1-3 -alkyl groups and R.sub.a is as
 hereinbefore defined,
 is converted by hydrolysis, treatment with an acid or base, thermolysis or
 hydrogenolysis into a compound of general formula I wherein R.sub.a
 contains a carboxy group and R.sub.c is as hereinbefore defined or R.sub.a
 is as hereinbefore defined and R.sub.c denotes an amidino group optionally
 substituted by a hydroxy group or by one or two C.sub.1-3 -alkyl groups.
 A group which may be converted into a carboxy group might be, for example,
 a carboxyl group protected by a protecting group, such as the functional
 derivatives thereof, e.g. the unsubstituted or substituted amides, esters,
 thioesters, trimethylsilylesters, orthoesters or iminoesters thereof which
 are expediently converted by hydrolysis into a carboxyl group,
 the esters thereof with tertiary alcohols, e.g. the tert.butyl ester, which
 are expediently converted into a carboxyl group by treatment with an acid
 or thermolysis, and
 the esters thereof with aralkanols, e.g. the benzylester, which are
 expediently converted into a carboxyl group by hydrogenolysis.
 The hydrolysis is expediently carried out either in the presence of an acid
 such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,
 trichloroacetic acid, trifluoroacetic acid or the mixtures thereof or in
 the presence of a base such as lithium hydroxide, sodium hydroxide or
 potassium hydroxide in a suitable solvent such as water, water/methanol,
 water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran
 or water/dioxane at temperatures between -10 and 120.degree. C., e.g. at
 temperatures between ambient temperature and the boiling temperature of
 the reaction mixture.
 If a compound of formula XI for example contains the tert.butyl or
 tert.butyloxycarbonyl group, these may also be cleaved by treatment with
 an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic
 acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric
 acid optionally in an inert solvent such as methylene chloride,
 chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane
 preferably at temperatures between -10 and 120.degree. C., e.g. at
 temperatures between 0 and 60.degree. 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-toluenesulphonic acid, sulphuric acid,
 phosphoric acid or polyphosphoric acid, preferably at the boiling
 temperature of the solvent used, e.g. at temperatures between 40 and
 120.degree. C.
 If a compound of formula XI contains, for example, a benzyloxy or
 benzyloxycarbonyl group, these may also be cleaved hydrogenolytically in
 the presence of a hydrogenation catalyst such as palladium/charcoal in a
 suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic
 acid, ethyl acetate, dioxane or dimethylformamide, preferably at
 temperatures between 0 and 50.degree. C., e.g. at ambient temperature, and
 at a hydrogen pressure of from 1 to 5 bar.
 h) In order to prepare a compound of general formula I wherein R.sub.c
 denotes an amidino group which is substituted by one or two C.sub.1-8
 -alkoxycarbonyl groups or by a group which can be cleaved in vivo:
 reacting a compound of general formula I
 ##STR11##
 wherein
 R.sub.a, R.sub.b, Ar, A and B are as hereinbefore defined and
 R.sub.c " denotes an amidino group, with a compound of general formula
EQU Z.sub.5 --R.sub.9 (XIII),
 wherein
 R.sub.9 denotes a C.sub.1-8 -alkoxycarbonyl group or the acyl group of one
 of the groups which can be cleaved in vivo mentioned hereinbefore and
 Z.sub.5 denotes a nucleofugic leaving group such as a halogenatom, e.g. a
 chlorine, bromine or iodine atom, or a p-nitrophenyl group.
 The reaction is preferably carried out in a solvent such as methanol,
 ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl
 sulphoxide or dimethylformamide optionally in the presence of an inorganic
 or a tertiary organic base, preferably at temperatures between 20.degree.
 C. and the boiling temperature of the solvent used.
 With a compound of general formula XIII wherein Z.sub.5 denotes a
 nucleofugic leaving group, the reaction is preferably carried out in a
 solvent such as methylene chloride, acetonitrile, tetrahydrofuran,
 toluene, acetone/water, dimethylformamide or dimethyl sulphoxide,
 optionally in the presence of a base such as sodium hydride, potassium
 carbonate, potassium tert.butoxide or N-ethyl-diisopropylamine at
 temperatures between 0 and 60.degree. C.
 If according to the invention a compound of general formula I is obtained
 which contains a (R.sub.3 NR.sub.4)-C.sub.1-3 -alkyl group wherein at
 least one of the groups R.sub.3 or R.sub.4 denotes a hydrogen atom, this
 may subsequently be converted with a corresponding isocyanate or carbamoyl
 halide into a corresponding urea compound of general formula I and/or
 if a compound of general formula I is obtained which contains an NH.sub.2
 -C.sub.1-3 -alkyl group, this may subsequently be converted with a
 corresponding acrylic acid ester into a corresponding 2-(C.sub.1-3
 -alkoxycarbonyl)-ethyl compound of general formula I and/or
 if a compound of general formula I is obtained which contains an (R.sub.3
 NR.sub.4)-C.sub.1-3 -alkyl group wherein R.sub.3 and R.sub.4 each denote a
 hydrogen atom, this may subsequently be converted with a corresponding
 dihaloalkane into a corresponding compound of general formula I wherein
 R.sub.3 and R.sub.4 together with the nitrogen atom between them denote a
 corresponding 4- to 7-membered cycloalkyleneimino group and/or
 if a compound of general formula I is obtained wherein R.sub.c denotes an
 amidino group, this may subsequently be converted by reaction with a
 haloacetic acid derivative and subsequent hydrolysis and decarboxylation
 into a corresponding amidino compound substituted by one or two methyl
 groups and/or
 if a compound of general formula I is obtained wherein R.sub.c denotes a
 hydroxyamidino group, this may subsequently be converted into a
 corresponding amidino compound by catalytic hydrogenation and/or
 if a compound of general formula I is obtained wherein R.sub.a contains a
 carboxy group, this may subsequently be converted into a corresponding
 ester by esterification.
 The subsequent preparation of a corresponding urea compound of general
 formula I is expediently carried out with a corresponding isocyanate or
 carbamoyl chloride, preferably in a solvent such as dimethylformamide and
 optionally in the presence of a tertiary organic base such as
 triethylamine at temperatures between 0 and 50.degree. C., preferably at
 ambient temperature,
 The subsequent preparation of a corresponding 2-(C.sub.1-3
 -alkoxy-carbonyl)-ethyl-compound is carried out with a corresponding
 acrylic acid ester, preferably in a solvent such as methanol, ethanol or
 isopropanol at temperatures between 50 and 100.degree. C., preferably at
 the boiling temperature of the reaction mixture.
 The subsequent preparation of a corresponding 4- to 7-membered
 cycloalkyleneimino compound of general formula I is expediently carried
 out with a corresponding dihaloalkane, preferably in a solvent such as
 methanol, ethanol or isopropanol in the presence of a base such as sodium
 carbonate at temperatures between 50 and 100.degree. C., preferably at the
 boiling temperature of the reaction mixture.
 The subsequent alkyLation is expediently carried out in a solvent such as
 methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide,
 dimethylformamide or acetone optionally in the presence of a reaction
 accelerator such as sodium or potassium iodide and preferably in the
 presence of a base such as sodium carbonate or potassium carbonate or in
 the presence of a tertiary organic base such as N-ethyl-diisopropylamine
 or N-methyl-morpholine, which may simultaneously act as solvent, or
 optionally in the presence of silver carbonate or silver oxide at
 temperatures between -30 and 100.degree. C., but preferably at
 temperatures between -10 and 80.degree. C.
 The subsequent hydrolysis is expediently carried out either in the presence
 of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid,
 acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures
 thereof or in the presence of a base such as lithium hydroxide, sodium
 hydroxide or potassium hydroxide in a suitable solvent such as water,
 water/methanol, water/ethanol, water/isopropanol, methanol, ethanol,
 water/tetrahydrofuran or water/dioxane and subsequent decarboxylation in
 the presence of an acid as hereinbefore described at temperatures between
 -10 and 120.degree. C., e.g. at temperatures between ambient temperature
 and the boiling temperature of the reaction mixture.
 The subsequent esterification is carried out with a corresponding alcohol,
 conveniently in a solvent or mixture of solvents such as methylene
 chloride, benzene, toluene, chlorobenzene, tetrahydrofuran,
 benzene/tetrahydrofuran or dioxan, but preferably in an excess of the
 alcohol used, optionally in the presence of an acid such as hydrochloric
 acid or in the presence of a dehydrating agent, e.g. in the presence of
 isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulphuric
 acid, hydrochloric acid, sulphuric acid, methanesulphonic acid,
 p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide,
 N,N'-dicyclohexylcarbodiimide,
 N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
 N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole,
 triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl
 azodicarboxylate, optionally in the presence of a base such as potassium
 carbonate, N-ethyldiisopropylamine or N,N-dimethylamino-pyridine
 expediently at temperatures between 0 and 150.degree. C., preferably at
 temperatures between 0 and 80.degree. C., or with a corresponding halide
 in a solvent such as methylene chloride, tetrahydrofuran, dioxane,
 dimethylsulphoxide, dimethylformamide or acetone, optionally in the
 presence of a reaction accelerator such as sodium or potassium iodide and
 preferably in the presence of a base such as sodium carbonate or potassium
 carbonate or in the presence of a tertiary organic base such as
 N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously
 act as solvent, or optionally in the presence of silver carbonate or
 silver oxide at temperatures between -30 and 100.degree. C., but
 preferably at temperatures between -10 and 80.degree. C.
 In the reactions described hereinbefore, any reactive groups present such
 as hydroxy, carboxy, amino, alkylamino or imino groups may be protected
 during the reaction by conventional protecting groups which are cleaved
 again after the reaction.
 For example, a protecting group for a hydroxy group may be a
 trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or
 tetrahydropyranyl group,
 protecting groups for a carboxy group may be a trimethylsilyl, methyl,
 ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protecting groups
 for an amino, alkylamino or imino group may be an acetyl, trifluoroacetyl,
 benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl,
 methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino
 group, a phthalyl group.
 Any protecting group used is optionally subsequently cleaved for example by
 hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,
 tetrahydrofuran/water or dioxan/water, in the presence of an acid such as
 trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the
 presence of an alkali metal base such as lithium hydroxide, sodium
 hydroxide or potassium hydroxide or by ether splitting, e.g. in the
 presence of iodotrimethylsilane, at temperatures between 0 and 100.degree.
 C., preferably at temperatures between 10 and 50.degree. C.
 However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for
 example, hydrogenolytically, e.g. with hydrogen in the presence of a
 catalyst such as palladium/charcoal in a solvent such as methanol,
 ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or
 glacial acetic acid, optionally with the addition of an acid such as
 hydrochloric acid at temperatures between 0 and 50.degree. C., but
 preferably at ambient temperature, and at a hydrogen pressure of 1 to 7
 bar, but preferably 3 to 5 bar.
 A methoxybenzyl group may also be cleaved in the presence of an oxidant
 such as cerium(IV)ammonium nitrate in a solvent such as methylene
 chloride, acetonitrile or acetonitrile/water at temperatures between 0 and
 50.degree. C., but preferably at ambient temperature.
 A 2,4-dimethoxybenzyl group, however, is preferably cleaved in
 trifluoroacetic acid in the presence of anisol.
 A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by
 treating with an acid such as trifluoroacetic acid or hydrochloric acid,
 optionally using a solvent such as methylene chloride, dioxan or ether.
 A phthalyl group is preferably cleaved in the presence of hydrazine or a
 primary amine such as methylamine, ethylamine or n-butylamine in a solvent
 such as methanol, ethanol, isopropanol, toluene/water or dioxan at
 temperatures between 20 and 50.degree. C.
 An allyloxycarbonyl group is cleaved by treating with a catalytic amount of
 tetrakis-(triphenylphosphine)-palladium(O), preferably in a solvent such
 as tetrahydrofuran and preferably in the presence of an excess of a base
 such as morpholine or 1,3-dimedone at temperatures between 0 and
 100.degree. C., preferably at ambient temperature and under an inert gas,
 or by treating with a catalytic amount of
 tris-(triphenylphosphine)-rhodium(I)chloride in a solvent such as aqueous
 ethanol and optionally in the presence of a base such as
 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70.degree. C.
 The compounds of general formulae II to XIII used as starting materials,
 some of which are known from the literature, may be obtained by methods
 known from the literature and in addition their preparation is described
 in the Examples.
 The chemistry of the compounds of general formula III is described, for
 example, by Jack Robinson in J. Chem. Soc. 1941, 744, that of the
 benzimidazoles is described by Katritzky and Rees in Comprehensive
 Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, and by Schaumann in
 Hetarene III, Methoden der organischen Chemie (Houben-Weyl), 4.sup.th
 edition, Verlag Thieme, Stuttgart 1993.
 Thus, for example, a compound of general formula II is obtained by
 acylating a corresponding o-diamino compound with a corresponding reactive
 derivative of a compound of general formula III,
 a compound of general formulae IV, VII, IX, X, XI and XII is obtained by
 cyclisation of a corresponding substituted compound according to process
 a) and if necessary subsequent reduction of any nitro group present in the
 phenyl moiety, followed by acylation, amidation and/or halogenation.
 Moreover, the compounds of general formula I obtained may be resolved into
 their enantiomers and/or diastereomers, as mentioned hereinbefore.
 Thus, for example, the compounds of general formula I obtained which occur
 as racernates may be separated by methods known per se (cf. Allinger N. L.
 and Eliel E. L. in "Topics in Stereo-chemistry", Vol. 6, Wiley
 Interscience, 1971) into their optical antipodes and compounds of general
 formula I with at least 2 asymmetric carbon atoms may be resolved into
 their diastereomers on the basis of their physical-chemical differences
 using methods known per se, e.g. by chromatography and/or fractional
 crystallisation, and, if these compounds are obtained in racemic form,
 they may subsequently be resolved into the enantiomers as mentioned above.
 The enantiomers are preferably separated by column separation on chiral
 phases or by recrystallisation from an optically active solvent or by
 reacting with an optically active substance which forms salts or
 derivatives such as e.g. esters or amides with the racemic compound,
 particularly acids and the activated derivatives or alcohols thereof, and
 separating the diastereomeric mixture of salts or derivatives thus
 obtained, e.g. on the basis of their differences in solubility, whilst the
 free antipodes may be released from the pure diastereomeric salts or
 derivatives by the action of suitable agents. optically active acids in
 common use are e.g. the D- and L-forms of tartaric acid or
 dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic
 acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid.
 An optically active alcohol may be for example (+) or (-)-menthol and an
 optically active acyl group in amides, for example, may be a (+) or
 (-)-menthyloxycarbonyl.
 Furthermore, the compounds of formula I may be converted into the salts
 thereof, particularly for pharmaceutical use into the physiologically
 acceptable salts with inorganic or organic acids. Acids which may be used
 for this purpose include for example hydrochloric acid, hydrobromic acid,
 sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid,
 succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
 Moreover, if the new compounds of formula I contain a carboxy group, they
 may subsequently, if desired, be converted into the salts thereof with
 inorganic or organic bases, particularly for pharmaceutical use into the
 physiologically acceptable salts thereof. Suitable bases for this purpose
 include for example sodium hydroxide, potassium hydroxide, arginine,
 cyclohexylamine, ethanol-amine, diethanolamine and triethanolamine.
 As already mentioned hereinbefore, the new compounds of general formula I
 and the salts thereof have valuable properties. Thus, the compounds of
 general formula I wherein R.sub.c denotes a cyano group are valuable
 intermediate products for preparing the other compounds of general formula
 I, and the compounds of general formula I wherein R.sub.c denotes one of
 the abovementioned amidino groups, and the tautomers, stereoisomers and
 the physiologically acceptable salts thereof have valuable pharmacological
 properties, particularly an antithrombotic activity, which is preferably
 based on an activity which influences thrombin or factor Xa, for example
 on a thrombin-inhibiting or factor Xa-inhibiting activity, on an activity
 which extends the aPTT time and on an inhibiting effect on related serine
 proteases such as, for example, trypsin, urokinase factor VIIa, factor IX,
 factor XI and factor XII.
 For example, the compounds
 A=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl-carbonyl)cy
 clopropyl]-benzimidazole-hydrochloride,
 B=(E/
 Z)-2-(4-amidiLnophenylaminomethyl)-1-methyl-5-[1-[(pyridin-2-yl)-(carboxym
 ethyloxyimino)methylene]-cyclopropyl]-benzimidazole-hydrochloride,
 C=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-carboxyethylamino)-1-(pyr
 rolidin-1-yl-carbonyl)-ethyl]-benzimidazolehydrochloride,
 D=2-(4-amidinophe:
 nylaminomethyl)-1-methyl-5-[1-[2-(2-carboxyethyl)-pyrrolidin-1-yl-carbonyl
 ]cyclopropyl]-benzimidazole-hydrochloride,
 E=2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2-carboxyethyl)-4,5-dimethy
 l-imidazol-1-yl-methyl]-benzimidazole-hydrochloride,
 F=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrr
 olidin-1-yl-carbonyl)-ethyl]-benzimidazol-ehydrochloride and
 G=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methylcarboxymethylcarbon
 ylaminomethyl)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-d
 ihydrochloride
 were investigated for their effect on extending the aPTT time as follows:
 Materials:
 Plasma, from human citrated blood,
 PTT reagent, Boehringer Mannheim (524298),
 calcium solution (0.025 Mol/l), Behring Werke, Marburg (ORH 056/57),
 diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61),
 Biomatic B10 coagulometer, Desaga, Wiesloch.
 Method:
 The aPTT time was determined using a Biomatic B10-coagulometer made by
 Messrs. Desaga.
 The test substance was added to the test vessels prescribed by the
 manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of PTT
 reagent. The mixture was incubated for three minutes at 37.degree. C. The
 clotting reaction was started by the addition of 0.1 ml of calcium
 solution. Because of the design of the apparatus, the time taken for the
 mixture to clot was measured as the calcium solution was added. Mixtures
 to which 0.1 ml of DBA buffer had been added were used as controls.
 According to the definition the effective concentration of substance at
 which the aPTT time was double that of the control was determined by means
 of a dosage/activity curve.
 The following Table contains the values found:

APTT time
 substance (ED.sub.200 in .mu.M)
 A 0.12
 B 0.42
 C 0.31
 D 0.29
 E 0.29
 F 0.20
 G 0.17
 The compounds prepared according to the invention are well tolerated, since
 no toxic side effects could be detected at therapeutic doses.
 In view of their pharmacological properties the new compounds and the
 physiologically acceptable salts thereof are suitable for the prevention
 and treatment of venous and arterial thrombotic diseases, such as for
 example the treatment of deep leg vein thrombosis, for preventing
 reocclusions after bypass operations or angioplasty (PT(C)A), and
 occlusion in peripheral arterial diseases such as pulmonary embolism,
 disseminated intravascular coagulation, for preventing coronary
 thrombosis, stroke and the occlusion of shunts. In addition, the compounds
 according to the invention are suitable for antithrombotic support in
 thrombolytic treatment, such as for example with rt-PA or streptokinase,
 for preventing long-term restenosis after PT(C)A, for preventing
 metastasis and the growth of clot-dependent tumours and fibrin-dependent
 inflammatory processes, e.g. in the treatment of pulmonary fibrosis.
 The dosage required to achieve such an effect is appropriately 0.1 to 30
 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50
 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each case administered
 1 to 4 times a day. For this purpose, the compounds of formula I prepared
 according to the invention may be formulated, optionally together with
 other active substances, with one or more inert conventional carriers
 and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline
 cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
 acid, water, water/ethanol, water/glycerol, water/sorbitol,
 water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol,
 carboxymethylcellulose or fatty substances such as hard fat or suitable
 mixtures thereof, to produce conventional galenic preparations such as
 plain or coated tablets, capsules, powders, suspensions or suppositories.

Active substance 75.0 mg
 Mannitol 50.0 mg
 water for injections ad 10.0 ml
 Preparation:
 Active substance and mannitol are dissolved in water. After packaging the
 solution is freeze-dried. To produce the solution ready for use, the
 product is dissolved in water for injections.
 EXAMPLE 23
 Dry Ampoule Containing 35 mg of Active Substance Per 2 ml
 Composition:

Active substance 35.0 mg
 Mannitol 100.0 mg
 water for injections ad 2.0 ml
 Preparation:
 Active substance and mannitol are dissolved in water. After packaging, the
 solution is freeze-dried.
 To produce the solution ready for use, the product is dissolved in water
 for injections.
 EXAMPLE 24
 Tablet Containing 50 mg of Active Substance
 Composition:

(1) Active substance 50.0 mg
 (2) Lactose 98.0 mg
 (3) Maize starch 50.0 mg
 (4) Polyvinylpyrrolidone 15.0 mg
 (5) Magnesium stearate 2.0 mg
 215.0 mg
 Preparation:
 (1), (2) and (3) are mixed together and granulated with an aqueous solution
 of (4). (5) is added to the dried granulated material. From this mixture
 tablets are pressed, biplanar, faceted on both sides and with a dividing
 notch on one side. Diameter of the tablets: 9 mm.
 EXAMPLE 25
 Tablet Containing 350 mg of Active Substance
 Preparation:

(1) Active substance 350.0 mg
 (2) Lactose 136.0 mg
 (3) Maize starch 80.0 mg
 (4) Polyvinylpyrrolidone 30.0 mg
 (5) Magnesium stearate 4.0 mg
 600.0 mg
 (1), (2) and (3) are mixed together and granulated with an aqueous solution
 of (4). (5) is added to the dried granulated material. From this mixture
 tablets are pressed, biplanar, faceted on both sides and with a dividing
 notch on one side. Diameter of the tablets: 12 mm.
 EXAMPLE 26
 Capsules Containing 50 mg of Active Substance
 Composition:

(1) Active substance 50.0 mg
 (2) Dried maize starch 58.0 mg
 (3) Powdered lactose 50.0 mg
 (4) Magnesium stearate 2.0 mg
 160.0 mg
 Preparation:
 (1) is triturated with (3). This trituration is added to the mixture of (2)
 and (4) with vigorous mixing.
 This powder mixture is packed into size 3 hard gelatin capsules in a
 capsule filling machine.
 EXAMPLE 27
 Capsules Containing 350 mg of Active Substance
 Composition:

(1) Active substance 350.0 mg
 (2) Dried maize starch 46.0 mg
 (3) Powdered lactose 30.0 mg
 (4) Magnesium stearate 4.0 mg
 430.0 mg
 Preparation:
 (1) is triturated with (3). This trituration is added to the mixture of (2)
 and (4) with vigorous mixing.
 This powder mixture is packed into size 0 hard gelatin capsules in a
 capsule filling machine.
 EXAMPLE 27
 Suppositories Containing 100 mg of Active Substance

1 suppository contains:
 Active substance 100.0 mg
 Polyethyleneglycol (M.W. 1500) 600.0 mg
 Polyethyleneglycol (M.W. 6000) 460.0 mg
 Polyethylenesorbitan monostearate 840.0 mg
 2,000.0 mg
 Method:
 The polyethyleneglycol is melted together with polyethylene sorbitan
 monostearate. At 40.degree. C. the ground active substance is
 homogeneously dispersed in the melt. It is cooled to 38.degree. C. and
 poured into slightly chilled suppository moulds.