WO2000050419A1 - Substituted bicyclic heterocycles and the use thereof as thrombin inhibitors - Google Patents

Abstract

The invention relates to novel bicyclic heterocycles of general formula (I), in which Ra, X1 to X4, Y, B, Ar and E are defined as in Claim No. 1, as well as to their tautomers, stereoisomers, mixtures and salts which comprise valuable properties. The compounds of general formula (I), in which (E) represents a cyano group, depict valuable intermediate products for producing the remaining compounds of general formula (I), and the compounds of general formula (I), in which E represents an RbNH-C(=NH) group, comprise valuable pharmacological properties, especially a thrombin inhibiting effect and an effect which prolongs thrombin time.

Description

 SUBSTITUTED BICYCLIC HETEROCYCLES AND THE USE THEREOF AS THROMBININE HIBΓΓOREN

The present invention relates to new substituted bicyclic heterocycles of the general formula

their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable properties.

The compounds of the general formula I in which E represents a cyano group represent valuable intermediates for the preparation of the other compounds of the general formula I. The compounds of the general formula I in which E represents an RkNH-C (= NH) group as well as their tautomers and their

Stereoisomers have valuable pharmacological properties, in particular an action which inhibits thrombin and prolongs the thrombin time.

The present application thus relates to the new compounds of the general formula I, their preparation, medicaments containing the pharmacologically active compounds of the formula I and their use.

In the general formula above means R _{a is} a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom, in which

a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or

a methylene group in the 4-position through an oxygen or sulfur atom or through a -NR - ^ - group, where R * _] _ a

Represents hydrogen atom or a (, - _] __g-alkyl group, can be replaced and one or two further methylene groups can be replaced by carbonyl groups in a ring thus obtained containing two heteroatoms,

where the 5-, 6- or 7-membered saturated heterocyclic rings described above can also be benzo-fused via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C _] __3-alkyl or C] __ 3-alkoxy group,

or a group of the formula

in the

R _{c represents} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C- * j__3-alkyl or C _] __3-alkoxy group and

R _] _ is as defined above, or a 5-membered heteroaromatic group which is bonded via a nitrogen atom and which contains one, two or three nitrogen atoms and which can be benzocondensed via two adjacent carbon atoms,

where the 5-membered heteroaromatic group in the carbon skeleton by C -__ g-alkyl-, carboxy-, Cι_4-alkoxy-carbonyl-, carboxy- (C _] _-. 4 ₎ -alkyl-, C -__ 4-alkoxycarbonyl- ( C1- .4) alkyl, phenyl, pyridyl, furanyl or

Thienyl groups can be mono- or disubstituted independently of one another and a carboxy group contained in the radicals mentioned can also be replaced by a group which can be converted into a carboxy group in vivo,

the phenyl part of a benzo-fused 5-membered heteroaromatic group by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ^ .. 3 alkyl or

C -__ 3-alkoxy group can be substituted and

the heteroaromatic group, including an optionally fused-on phenyl part, can also be partially hydrogenated, the dihydro derivatives being preferred, and the resulting -NH groups can also be replaced by the -NR • _] _ groups defined above,

a tetrazolyl group bonded via a nitrogen atom or

a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom can be substituted by a C 1-6 alkyl group,

Y is an oxygen or sulfur atom or one optionally substituted by a C _] __g-alkyl or C3_7-cycloalkyl group

Imino group, Xi, X2 / X3 and X4 each represent a methine group or

one or two of the radicals X _] _, X ^, X3 and X4 each have a nitrogen atom and the other radicals each have a methine group,

B is an ethylene group in which a methylene group, which is either linked to the bicyclic heterocycle of the formula I or to the group Ar, by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, carbonyl or -NR 1 - Group can be replaced, where R _] _ is defined as mentioned above,

Ar is optionally substituted by 'a fluorine, chlorine or bromine atom, by a trifluoromethyl, C -__ 3 alkyl or _C] __3 alkoxy phenylene or naphthylene group,

an optionally substituted in the carbon skeleton by a C * _] __3 alkyl group, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group and

E is a cyano or R ^ NH-C (= NH) group in which

Rk represents a hydrogen atom, a hydroxyl group or a residue which can be split off in vivo.

The compounds of the general formula I above, which contain a residue which can be split off in vivo, thus represent so-called drugs and compounds of the general formula I which contain two residues which can be split off in vivo, so-called double prodrugs.

A group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C] __ g-alkanol, a phenyl-C;] __ 3-alkanol, a C3_9-cycloalkanol, wherein a C5_ ₈ cycloalkanol additionally by one or two C] __ 3 alkyl groups can be substituted

C5_8-Cycloalkanol, in which a methylene group in 3 - or

4 -position by an oxygen atom or by an optionally by a Cι-3-alkyl-, phenyl-C- _] __3 -alkyl-, phenyl-

Cι_3-alkoxycarbonyl or C2_g alkanoyl group substituted

Imino group is replaced and the cycloalkanol part can also be substituted by one or two Cχ_3 alkyl groups, a C4_7 cycloalkenol, a C3_5 ~ alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C3 -.5-alkynol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-C] __ 3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which is additionally in the bicycloalkyl part by one or two C _Q __3 alkyl groups can be substituted, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R ₂ -CO-0- (R3CR4) -OH,

by doing

R2 is a C 1-8 alkyl, C5_7 cycloalkyl, phenyl or phenyl

C _] __3 alkyl group,

R3 is a hydrogen atom, a ι_ 2 alkyl, C5_7 cycloalkyl or phenyl group and

R4 represents a hydrogen atom or a C _3 alkyl group. len,

or under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group such as a benzoyl or pyridinoyl group optionally substituted by a C 1 -C 3 -alkyl group, for example the benzoyl or p-ethyl group. benzoyl -, p-isopropyl-benzoyl- or nico- _ -

tinoyl group, or a C ^. ^ g alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C ₁ _ ₁ g alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl -, Isopropoxycarbonyl-, Butoxycarbonyl-, tert. Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, no-nyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl- C __ g-alkoxycarbonyl group such as benzyloxycarbonyl, phenyl or phenylcarbonyl, phenyl or ethylcarbonyl, phenyl or phenylcarbonyl, phenyl or phenyl- a C - ** ^* __3-alkylsulfonyl-C2 -4 -alkoxycarbonyl-, C ^ _3 -alkoxy-C2_4 -alkoxy- C ₂ _4-alkoxycarbonyl- or R ₂ CO-0- (R3CR4) -O-CO Group in which R ₂ to R4 are defined as mentioned above,

to understand.

The preferred prodrug residues for a carboxy group are a C ₁ -g alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyc- lohexyloxycarbonyl group or phenyl-C] __ 3-alkoxycarbonyl group such as the benzyloxycarbonyl group and

for an imino or amino group a C _] __g-alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-Ci - ^ - alkoxycarbonyl group such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C _] __3-alkyl group such as the benzoyl or 4-ethyl benzoyl group, a pyridinoyl group such as the nicotinoyl group, a C _] __3-alkylsulfonyl-n-C2_3-alkoxycarbonyl or ^c l-3 ~ alkoxy-C2-3 * -alkoxy-C2-4-alkoxycarbonyl group such as the 2-Methylsulfonylethoxycarbonyl- or 2- (2-ethoxy) ethoxycarbonyl group into consideration.

Furthermore, the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms and alkanoyl parts which contain more than 3 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc. on.

The following groups are mentioned as examples for the rest R _a :

Pyrrolidin-1-yl-, piperidin-1-yl-,

2,3-dioxo-3,4-dihydro-2H-quinoxalin-l-yl-, 2-methyl-benzimidazol-1-yl-,

4-ethyl-3-oxo-3, 4-dihydro-2H-quinoxalin-l-yl-, 4-0x0-3, 4-dihydro-phthalazin-l-yl-, 2-0xo-piperidin-l-yl- , Butanesultam-1-yl, l-isobutyl-lH-tetrazol-5-yl-, 3-methyl-5-phenyl-pyrazole-1-yl-,

3- (2-ethoxycarbonylethyl) -5-phenyl-pyrazol-1-yl -, 3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) -pyrazol-1-yl -, 3- (2-hydroxycarbonylethyl) - 5-phenyl-pyrazol-1-yl, 3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) -pyrazol - 1-yl, 3 -ethoxycarbonyl- 5- (thiophene-2-yl) -pyrazole -1- yl-, 3-carboxy-5- (thiophene-2-yl) -pyrazol-1-yl-, 3-methyl-5 - (2-furyl) -pyrazole-1-yl -, 3-ethoxycarbonylmethyl-5-phenyl -pyrazole -1-yl-, 3 -hydroxycarbonylmethyl- 5-phenyl-pyrazol-1 -yl -, 3-ethoxycarbonyl-5-tert. butyl-pyrazole -1-yl-, 3-carboxy-5-tert. butyl-pyrazole -1-yl-,

5 -hydroxycarbonylmethyl -4- (2-pyridyl) -isoxazol-3 -yl-, l-phenyl-4- (2-hydroxycarbonylethyl) -imidazol-2-yl-, 1-cyclopentyl -4 -hydroxycarbonylmethyl-imidazol-2 - yl-, 2 -hydroxycarbonylmethyl -5 -phenyl- imidazol-1-yl -, 3 - (3 - pyridyl) - 5 - (2-hydroxycarbonylethyl) -4H- [1, 2, 4] triazole -

4 -yl -,

3-phenyl-5-hydroxycarbonylmethyl-isoxazole -4 -yl -,

3-isobutyl-5- (2-hydroxycarbonylethyl) isoxazol-4-yl-,

3-hydroxycarbonylmethyl -5- (2-pyridyl) - isoxazol-4 -yl-,

3-phenyl-5- (3-hydroxycarbonylpropyl) isothiazol-4-yl and

3-hydroxycarbonylmethyl-5- (3-pyridyl) isothiazol-4-yl.

Preferred compounds of the above general formula I are those in which

R _{a is} a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom, in which

a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or

a methylene group in the 4-position can be replaced by an oxygen atom or a -NR- * j_ group, where R ^ _ represents a hydrogen atom or a C- _j __3 -alkyl group, and one or two further methylene groups can be replaced by carbonyl groups,

where the 5- or 6-membered saturated heterocyclic rings described above can also be benzo-fused via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C ₁ _3 -alkyl or C ₁ _3-alkoxy group,

or a group of the formula

in the

R _{c represents} a hydrogen atom, a trifluoromethyl or Cι_3 alkyl group and

R _] _ is as defined above,

or a 5-membered heteroaromatic group which is bonded via a nitrogen atom and which contains one or two nitrogen atoms and which can be benzo-fused via two adjacent carbon atoms,

the 5-membered heteroaromatic group in the carbon skeleton by C- * _] __4-alkyl-, carboxy-, C _1- . ₄ -alkoxy- carbonyl-, carboxy- (C _] __4 ₎ -alkyl-, Cι_ ^ -alkoxycarbonyl- (C _] __4) -alkyl-, phenyl-, pyridyl-, furanyl- or

Thienyl groups can be mono- or disubstituted independently of one another and a carboxy group contained in the radicals mentioned can also be replaced by a group which can be converted into a carboxy group in vivo,

the phenyl part of a benzo-fused 5-membered heteroaromatic group by a C -__ 3 alkyl or

C _] __3 -alkoxy group can be substituted and

the heteroaromatic group, including an optionally fused-on phenyl part, can also be dihydrogenated and the resulting -NH groups can also be replaced by the -NR _] _ groups defined above, _ | Q

or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom can be substituted by a C- _] __4 -alkyl group,

Y is an oxygen atom or an imino group which is optionally substituted by a ^c 1-4 alkyl group,

i, X2, X3 and X4 each represent a methine group,

B is an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen atom, a carbonyl or -NR ^ group, where R ^ _ is defined as mentioned above,

Ar is a phenylene or naphthylene group which is optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, Ci. 3 alkyl or C ^ - ^ - alkoxy group,

an optionally in the carbon skeleton by a C * _j __3 alkyl substituted pyridinylene group, and

E is a cyano or R ^ NH-C (= NH) group in which

Rb represents a hydrogen atom or a residue which can be split off in vivo,

mean, their tautomers, their prodrugs, their double-drugs, their stereoisomers and their salts.

Particularly preferred compounds of the general formula I above are those in which

R _{a is} a 5- or 6-membered saturated heterocyclic ring bonded via a nitrogen atom, where a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or

a methylene group in the 4-position of the 6-membered saturated heterocyclic ring by an -NR ₁ group, wherein

R _] _ represents a hydrogen atom or a C-j__3 alkyl group, can be replaced and one or two further methylene groups can be replaced by carbonyl groups in a ring thus obtained containing two heteroatoms,

the 6-membered saturated heterocyclic rings described above can also be benzocondensed via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C _] _.3 alkyl group,

or a group of the formula

in the

R _{c represents} a hydrogen atom or a C _] __3 alkyl group and

R _] _ is as defined above,

or a pyrrol-1-yl, imidazol-1-yl or pyrazol-1-yl group which is optionally benzo-fused via two adjacent carbon atoms, where the heteroaromatics mentioned in the carbon skeleton by C- _] _-. 4 -alkyl-, carboxy-, C - ^ -. 3 -alkoxycarbonyl-,

Carboxy- (Cι_2) -alkyl-, C] _. 2 -alkoxycarbonyl- (C * j__2) -alkyl-, phenyl, pyridyl, furanyl or thienyl groups can be mono- or disubstituted, the substituents being the same or different with the proviso that only one of the substituents is an aromatic or heteroaromatic radical and a carboxy group contained in the said radicals can also be replaced by a group which can be converted into a carboxy group in vivo,

or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom can be substituted by a C _] _4 alkyl group,

Y is an imino group which is optionally substituted by a C- _] __3 -alkyl group,

Xi, X2, X3 and X4 each represent a methine group,

B is an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen atom or -NR 1 group, where R] _ is defined as mentioned above,

Ar is a phenylene group optionally substituted by a C] __ 3 alkyl group,

E is a cyano or R ^ NH-C (= NH) group in which

R _] - represents a hydrogen atom or a residue which can be split off in vivo,

mean, their tautomers, their prodrugs, their double-drugs, their stereoisomers and their salts. For example, the following are mentioned as particularly preferred compounds:

(a) l-methyl-2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-1H-tetrazol-5-yl) benzimidazole,

(b) l-methyl-2- (4-amidinophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) benzimidazole,

(c) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenylpyrazol-l-yl] benzimidazole,

(d) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole,

(e) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5-phenylpyrazol-l-yl] benzimidazole,

(f) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole,

(g) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3-ethoxycarbonyl-5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole,

(h) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3-carboxy- 5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole,

(i) l-methyl-2- (4-amidinophenyloxymethyl) -5- [3-methyl- 5- (2-furyl) pyrazol-1-yl] benzimidazole,

(j) l-methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycarbonylmethyl - 5-phenyl-pyrazole - 1 -yl) -benzimidazole,

(k) l-methyl-2- [2- (4-amidinophenyl) ethyl] -5- [3-methyl- 5- (2-furyl) pyrazol-1-yl] benzimidazole, (1) l-methyl-2- (4-amidinophenylaminomethyl) -5- [3-methyl- 5- (2-furyl) pyrazol-1-yl] benzimidazole and

(m) l-methyl-2- (4-amidinophenylaminomethyl) -5- (3-hydroxycarbonylmethyl -5 -phenyl-pyrazol-1-yl) -benzimidazole,

their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts.

The new compounds can be prepared by processes known per se, for example by the following processes:

a) For the preparation of a compound of general formula I in which E represents an R ^ NH-C (= NH) group, in which R ^ represents a hydrogen atom or a hydroxy group:

Reaction of a compound of the general formula optionally formed in the reaction mixture

in the

R _a , Xi to X4, Y, B and Ar are as defined at the beginning and

Z represents 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 the general formula

H ₂ N - R _b ', (IV)

in the

Rb 'represents a hydrogen tom or a hydroxy group. The reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C., preferably at temperatures between 20 and 120 ° C., with a compound of the general formula III or with an appropriate acid addition salt such as ammonium carbonate.

A compound of general formula III is obtained, for example, by reacting a compound of general formula I in which E represents a cyano group 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 an appropriate 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 ° C., but preferably at 20 ° C., or a corresponding nitrile with hydrogen sulfide, advantageously in a solvent such as pyri- din or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.

b) For the preparation of a compound of general formula I in which the R _a group and E are defined with the proviso that the R _a group contains a carboxy group and E is as defined above or the R _a group is defined as mentioned at the beginning and E represents an H2-C (= NH) group or the R _a group contains a carboxy group and E represents an NH -C (= NH) group:

Conversion of a compound of the general formula _ ig

in der

in the

Xi to X4, Y, B and Ar are as defined in the introduction and the R _a 'group and E ^{1 have} the meanings mentioned for the R _a group and E with the proviso that the

R _a 'group one by hydrolysis, treatment with an acid or

Contains base, thermolysis or hydrogenolysis into a group which can be converted into a carboxyl group and E is as defined in the introduction or E 'is a group which can be converted into an NH2-C (= NH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and the R _a 'group for the

R _a group has the meanings mentioned above or the

R _a 'group one by hydrolysis, treatment with an acid or

Contains base, thermolysis or hydrogenolysis into a group which can be converted into a carboxyl group and E ^{1 represents} a group which can be converted into an NH2-C (= NH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,

by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a compound of the general formula I in which the R _a group and E with the

Provided that the R _a group contains a carboxy group and E is as defined in the introduction or the R _a group has the meanings mentioned above and E represents an NH2-C (= NH) group or the R _a -Group one

Contains carboxy group and E represents an NH2-C (= NH) group.

A group which can be converted into a carboxy group is, for example, a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which expediently be converted into a carboxyl group by hydrolysis,

their esters with tertiary alcohols, e.g. the tert. Butyl esters which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and

their esters with aralkanols, e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.

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

If the R _a 'group and / or E' in a compound of the formula V contains, for example, the tert. Butyl or tert. Butyloxy- carbonylygruppe, these can also by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or poly-phosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, Toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or thermally, if appropriate, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid _ _

the boiling point of the solvent used, e.g. at temperatures between 40 and 120 ° C, split off.

Contains the R _a 'group and / or E' in a compound of

Formula V, for example, the benzyloxy or benzyloxycarbonyl group, these can also be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon 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 ° C, e.g. at room temperature and a hydrogen pressure of 1 to 5 bar.

c) For the preparation of a compound of the general formula I in which the R _a group contains one of the ester groups mentioned at the outset when defining the R _a group:

Implementation of a compound of the general formula

in der

in the

Xi to X4, Y, B, Ar and E are as defined in the beginning and

R _a "has the meanings mentioned for the R _a with the proviso that R _a " contains a carboxyl group or a group which can be converted into a corresponding ester group by means of an alcohol, with an alcohol of the general formula

HO - R ₅ , (VII)

in the

R5 represents the alkyl part of one of the residues which can be removed in vivo, with the exception of the R2-CO-O- (R3CR4) group for a carboxyl group, or with its formamide acetals or with a compound of the general formula

Z ₂ - R6, ⁽ VIII ⁾

in the

Rg is the alkyl part of one of the residues which can be removed in vivo, with the exception of the R2-CO-O- (R4CR5) group for a carboxyl group and

Z2 is a leaving group such as a halogen atom, e.g. B. represent a chlorine or bromine atom.

The reaction with an alcohol of the general formula VII is advantageously carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an alcohol of the general formula VII, if appropriate in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexyl-carbodiimodicyclide, N, N 'N / N-hydroxysuccinimide, N, N '-carbonyldiimidazole or N, N ¹ -thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl diethyl ester, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N - thylamino-pyridine expediently at temp eratures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

With a compound of general formula VIII, the reaction is advantageously carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferred as 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 can also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.

d) For the preparation of a compound of the general formula I in which Rj- represents a radical which can be split off in vivo:

Implementation of a compound of the general formula

in der

in the

R _a , Xi to X4, Y, B and Ar are as defined in the introduction, with a compound of the general formula

Z ₃ - R ₇ , (X)

in the

R7 a residue which can be split off in vivo and

Z3 is a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used. With a compound of general formula X, in which Z3 represents a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert .butylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.

e) For the preparation of a compound of the general formula I in which B represents an ethylene group in which a methylene group is replaced by a sulfinyl or sulfonyl group:

Oxidation of a compound of the general formula

in the

R _a , X ^ to X ₄ , Y, Ar and E are as defined above and

B 'represents an ethylene group in which a methylene group is replaced by a sulfenyl or sulfinyl group.

The oxidation is preferably carried out in a solvent or solvent mixture, e.g. in water, water / pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, and, depending on the oxidizing agent used, expediently carried out at temperatures between -80 and 100 ° C.

To prepare a corresponding sulfinyl compound of the general formula I, the oxidation is advantageously carried out with one equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C. or in acetone at 0 to 60 ° C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or in acetone at 0 to 20 ° C and with sulfuryl chloride in methylene chloride at -70 ° C, the thioether chlorine obtained -Complex is expediently hydrolyzed with aqueous ethanol.

To prepare a sulfonyl compound of the general formula I, the oxidation is advantageously carried out starting from a corresponding sulfinyl compound with one or more equivalents of the oxidizing agent used or starting from a corresponding sulfenyl compound expediently using two or more equivalents of the oxidizing agent used, for example using hydrogen peroxide in glacial acetic acid / acetane hydride, trifluoroacetic acid or in formic acid at 20 to 100 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid or potassium permanganate in glacial acetic acid, water / sulfuric acid or in acetone at 0 to 20 ° C. Thus, for example, in the oxidation starting from a corresponding sulfenyl compound, preferably in methylene chloride, by treatment with a corresponding amount of m-chloroperbenzoic acid at temperatures between 20 ° C. and the reflux temperature of the reaction mixture, a corresponding sulfonyl compound of the general formula I, which is still may contain a small amount of the corresponding sulfinyl compound. f) for the preparation of a compound of the general formula I in which E is a cyano group and B is an ethylene group in which a methylene group which is either linked to the bicyclic heterocycle of the formula I or to the group Ar by an oxygen or sulfur atom, is replaced by a sulfinyl, sulfonyl, carbonyl or -NR ^ group, represent:

Implementation of a compound of the general formula

with a compound of the general formula

V - Ar - CN, (XIII)

in which

R _a , Xi to X4, Y and Ar are as defined in the introduction, one of the radicals U or V represents an HO, HS, HOSO, HOS0 ₂ or HNR _] _ group and the other of the radicals represents a Z3CH2 group , where Ri is as defined at the beginning and Z3 is a nucleofuge leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine at temperatures between 20 ° C and the boiling point of the solvent used, a compound of the general formula XII or XIII, in which Z3 represents a halogen atom, can also be prepared in the reaction mixture. g) For the preparation of a compound of general formula I in which Y represents an oxygen or sulfur atom or an imino group optionally substituted by a C] __-alkyl or C3_7-cycloalkyl group, X] _ to X ₄ methine groups, E a

Cyano group and B an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen or sulfur atom or by an -NR ^ group, mean:

Implementation of a compound of the general formula

in der

in the

R _a and Y are as defined above and X ^ 'to X ₄ ' each represent a methine group, with a compound of the general formula

HO-CO - B '- Ar - CN, (XV) in the

Ar is defined as mentioned at the beginning and

B 'represents an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen or sulfur atom or by an -NR i group, or by their reactive derivatives.

The reaction is expediently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, orthoacetate, tri-orthoacetate. 2,2-dimethoxypropane, tetramethoxy silane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodiimide / 1-hydroxy (benzotriazole Benzotriazol-1-yl) - 1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate / 1-hydroxybenztriazole, N , N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, advantageously at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.

The reaction of a corresponding reactive compound of the general formula XV such as its esters, imidazolides or halides with an amine of the general formula XIV is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

h) For the preparation of a compound of general formula I in which R _{a is} the 2, 3-dioxo-3, 4-dihydro-2H-quinoxalin-l-yl radical and

E the cyano group means:

Implementation of a compound of the general formula

in der bis X4 , Y, B und Ar wie eingangs definiert sind, mit Oxalsäure oder einem reaktiven Oxalsäurederivat.

in which up to X4, Y, B and Ar are as defined at the outset, with oxalic acid or a reactive oxalic acid derivative.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, ethanol or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonic acid, trimethyl orthoacetic acid, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimidodimidodimidodimidodimidodimidodimidodimidodimidodimidodimidodimidodimidium carbodimidodimide , N'-Dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl ) -1,1,3, 3-tetramethyluronium tetrafluoroborate / l-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl morpholine or triethylamine expediently carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 100 ° C.

However, the reaction is particularly preferably with a reactive oxalic acid derivative, for example an oxalic acid ester, oxalic acid halide or oxalic acid ester halide, with a diamine of the general formula XVI in a solvent such as methylene chloride, ether, ethanol or tetrahydrofuran and optionally in the presence of an organic base such as pyridine, triethylamine, N. -Ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between o and 50 ° C.

i) For the preparation of a compound of the general formula I in which R _{a is} optionally in the 2-position by a C 1-6. kyl-, Cη__ ₄ -alkoxycarbonyl- (C ₁ _ ₄ ) -alkyl-, phenyl-, pyridyl-,

Furanyl or thienyl group substituted benzimidazole -1-yl and E means the cyano group:

Implementation of a compound of the general formula

in der

in the

Xi to X ₄ , Y, B and Ar as defined in the beginning, with a

Carboxylic acid of the general formula

HO-CO - R ₈ , (XVII) in the

R8 represents a hydrogen atom, a C] __ g-alkyl, C- _] _-. 4 -alkoxycarbonyl (Ci-.4) alkyl, phenyl, pyridyl, furanyl or thienyl group, or with their reactive derivatives.

The reaction is expediently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, orthoacetate, tri-orthoacetate. 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylid -benztriazol, 2- (1H-benzotriazol-1-yl) - 1,1,3, 3 -tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3, 3 -tetramethyluronium tetrafluoroborate / l-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / Te- 2o

trachlorocarbon, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.

The reaction of a corresponding reactive compound of the general formula XVII such as its esters, imidazolides or halides with an amine of the general formula XVI is carried out, for example, in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C. The reaction can also be carried out with a mixture of the carboxylic acid of the general formula XVIII and its anhydride.

k) to prepare a compound of the general formula I wherein R _a in a position 4 optionally substituted by a

C 3 alkyl group substituted 3-oxo-3, 4-dihydro-2H-quinoxaline-1-yl group and E is the cyano group:

Implementation of a compound of the general formula

in der

in the

Xi to X4, Y, B and Ar as defined in the beginning, with a

Compound of the general formula HO-CO - CH ₂ - Z ₂ , (XVIII)

in the

Z2 is a leaving group such as a halogen atom, e.g. B. represents a chlorine or bromine atom, or with their reactive derivatives, and optionally subsequent alkylation of the nitrogen atom in the 4 position of the compound thus obtained.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonic acid, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide-dicyclide-nododicyclide / nododicyclide-nododicyclide / nododicyclide, , N, N '-dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl ) -1, 1, 3, 3 -tetramethyluronium tetrafluoroborate / 1-hydroxybenztriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl morpholine or triethylamine expediently carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 100 ° C.

The reaction of a corresponding reactive compound of the general formula XVIII, such as its esters, imidazolides or halides, with an amine of the general formula XVI is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N- Ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 50 ° C, performed.

The subsequent subsequent alkylation of the nitrogen atom is carried out using a conventional alkylating agent, for example an alkyl halide, a sulfonic acid ester, e.g. a methanesulfonic acid or p-toluenesulfonic acid ester, advantageously in a solvent or solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, potassium ter. butylate, or in the presence of an organic base such as N-ethyl-diisopropylamine, N-methyl-morpholine, triethylamine or pyridine, which can also be used as a solvent at the same time, or by alcoholysis in the presence of a strong base, for ethylation, for example by ethanolysis in the presence of sodium ethylate, preferably at temperatures between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.

In the reactions described above, any reactive groups present, such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.

For example, the trimethylsilyl, acetyl, benzoyl, tert comes as a protective residue for a hydroxyl group. Butyl, trityl, benzyl or tetrahydropyranyl group,

as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert. Butyl, benzyl or tetrahydropyranyl group and

as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl -, Benzyloxycarbonyl-, Benzyl -, Methoxy-benzyl- or 2, 4-Dimethoxybenzylgruppe and for the amino group additionally the phthalyl group into consideration.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, by hydrolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon 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 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar.

A methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.

However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

The splitting off of a tert. Butyl or tert. Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl radical 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 dioxane at temperatures between 20 and 50 ° C.

An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment 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 ° C.

The compounds of general formulas III to XVIII used as starting materials, some of which are known from the literature, are obtained by processes known from the literature, and their preparation is also described in the examples.

For example, a compound of general formula III is obtained by reacting a corresponding nitrile, which in turn is advantageously obtained in accordance with processes f to k, with a corresponding thio or alcohol in the presence of hydrogen chloride or hydrogen bromide.

A compound of the general formulas V, VI, IX and XI used as starting material is advantageously obtained in accordance with a process of the present invention. A starting compound of the general formula XII, in which U represents a halomethyl group, is expediently obtained by ring closure of a corresponding ester, which is substituted in the o-position by a suitable halogen atom and a methoxyacetamido group, to give a corresponding bicyclic 2-alkoxymethyl compound, optionally subsequent Hydrolysis and, if appropriate, subsequent amidation of a carboxylic acid thus obtained with a corresponding amine, conversion of the alkoxymethyl compound thus obtained into the corresponding halomethyl compound which, if necessary, can subsequently be converted into the desired compound by means of a corresponding compound. Carrying out the ring closure with a suitable carbonic acid derivative gives a starting compound of the general formula XII in which U represents a hydroxyl, mercapto or amino group.

The compounds of the general formulas IV, VII, VIII, X and XIII used as starting materials are obtained by trivial methods, for example by reduction of an aromatic ester which is substituted in the o-position by an optionally substituted amino group and a nitro group, and optionally subsequent ring closure the o-diamino compound thus obtained with a corresponding carboxylic acid.

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

For example, the compounds of general formula I obtained which occur in race aten can be incorporated into their optical antipodes by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971) and compounds of the general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences separate methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of suitable optically active alcohol are (+) - or (-) menthol, and the optically active acyl radical in amides is, for example, the (+) - or (-) - menthyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

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

As already mentioned at the beginning, the new compounds of the general formula I and their salts have valuable properties. Thus, the compounds of general formula I in which E represents a cyano group are valuable intermediates for the preparation of the other compounds of general formula I and the compounds of general formula I in which E represents R ^ NH-C (= NH) - Group, as well as their tautomers, their stereoisomers, their physiologically tolerable salts have valuable pharmacological properties, in particular a thrombin-inhibiting effect, an action which prolongs the thrombin time and an inhibitory action on related serine proteases such as, for. B. trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI and factor XII, with some compounds such as the compound of Example 16 also having a low platelet aggregation-inhibiting effect.

For example, the connections

A = 1-methyl-2- (4-aminophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride,

B = 1-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenylpyrazol-1-yl] benzimidazole hydrochloride,

C = 1-methyl-2- (-aminophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole,

D = 1 -methyl- 2- (4-aminophenylaminomethyl) -5- [3 -carboxy- 5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole and E = 1-methyl -2- (4-aminophenylaminomethyl) -5- (3-ethoxycarbonyl-methyl-5-phenyl-pyrazole -1-yl) -benzimidazole -hydrochloride

examined for their effect on thrombin time as follows:

Material: plasma, from human citrate blood.

Test thrombin (cattle), 30 U / ml, Behring Werke,

Marburg

Diethyl barbiturate acetate buffer, ORWH 60/61, Behring

Works, Marburg

Biomatic BIO coagulometer, Sarstedt

Execution :

The thrombin time was determined using a Biomatic BIO coagulometer from Sarstedt.

The test substance was placed in the test vessels prescribed by the manufacturer with 0.1 ml human citrate plasma and 0.1 ml diethyl barbiturate buffer (DBA buffer). The mixture was incubated at 37 ° C for one minute. The coagulation reaction was started by adding 0.3 U test thrombin in 0.1 ml of DBA buffer. Depending on the device, the time taken for the clot to clot is measured by entering thrombin. Batches in which 0.1 ml of DBA buffer were added served as a control.

According to the definition, the effective substance concentration at which the thrombin time was doubled compared to the control was determined via a dose-response curve.

The following table contains the values found:

For example, when compound C was administered to rats up to a dose of 10 mg / kg i.v. no acute toxic side effects are observed. These compounds are therefore well tolerated.

Due to their pharmacological properties, the new compounds and their physiologically compatible salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts or stents. In addition, the compounds according to the invention are for antithrombotic support in a thrombolytic treatment, such as, for example, with rt-PA or streptokinase, for preventing long-term restenosis according to PT (C) A, for preventing metastasis and the growth of coagulation-dependent tumors and of fibrin-dependent inflammatory processes suitable .

The dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration and 0.1 to 50 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day. For this purpose, the provided compounds of formula I, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol , Water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures, in conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

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

Preliminary remarks

Unless otherwise stated, polygram silica gel plates from E. Merck, Darmstadt, were always used to determine the Rf values.

The EKA mass spectra (electrospray mass spectra of cations) are described, for example, in Chemistry of Our Time £., 308-316 (1991).

example 1

l-methyl-2- (4-amidinophenyloxymethyl) -5- (2,3-dioxo-3,4-di-ydro-H-quinoxaline-1-yD -benzimidazole hydrochloride)

a-) 4 -methyl am no- - (4 '-cyanophenyl oxy-ace yl ami nπ) -ni troben ol

A solution of 1.95 g (11 mmol) of 4-cyanophenyloxyacetic acid and 1.85 g (11 mmol) of N, N'-carbonyldiimidazole in 50 ml of absolute ethanol was refluxed for 30 minutes. Then 1.67 g (10 mmol) of 3-amino-4-methylamino-nitrobenzene were added and the mixture was boiled for a further 4 hours. The reaction mixture was then concentrated to about 20 ml and, after cooling, the precipitated product was filtered off with suction and washed with a little dichloromethane.

Yield: 2.3 g (64% of theory), ^C 16 ^H 14 ^N 4 ° 4 ⁽ 326.3 ⁾ Rf value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1)

b) 1-methyl -?. - (4 -cyanophenyloxy ethy] - -n tro-benzimidazole 2.3 g (7.07 mmol) of 4-methylamino-3 - (4 '-cyanophenyloxyacetylamino) -nitrobenzene were heated to reflux in 60 ml of glacial acetic acid for 45 minutes the precipitated product was filtered off with suction, washed with ethanol and diethyl ether and dried. Yield: 2.1 g (96% of theory), ^C 16 ^H 12 ^N 4 ° 5 ⁽ 308.3 ⁾

Rf value: 0.29 (silica gel; dichloromethane / ethanol = 19: 1)

cj 1 -methyl -2- (4 -cyanophenyloxymethyl) -5-am no-ben i mida ol

2.0 g (6.5 mmol) of 1-methyl -2- (4-cyanophenyloxymethyl) -5-nitrobenzimidazole were added in 70 ml of dimethylformamide after the addition of

0.5 g Pd / coal (10%) "at room temperature and 5 bar H ₂ pressure hydrogenated.

Yield: 1.55 g (86% of theory),

^C 16 ^H 14 ^N 4 ° ⁽ 278.32 ⁾

Rf value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1)

d) l-methyl-2- (4 -cyanophenyloxymethyl) -5- (2-nitro-phenylamino) -bp.ττz-i mi dazol

1.5 g (5.39 mmol) of l-methyl-2- (4 -cyanophenyloxymethyl) -5-aminobenzimidazole, 2.82 g (20 mmol) of 2-fluoro-nitrobenzene and 1 ml of N-ethyl-diisopropylamine were combined at 150 for 2 hours ° C stirred. After cooling, the product was isolated from the mixture by column chromatography on silica gel. Yield: 1.85 g (86% of theory);

C22H17N5O3 (399.42)

Rf value: 0.49 (silica gel; dichloromethane / ethanol = 19/1)

e) l-Methyl-2- (4 -cyanophenyloxymethyl) -5- (2-amino-phenyl-amine) -benzid

1.7 g (4.26 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -

5- (2-nitro-phenylamino) -benzimidazole were added after

0.5 g Pd / coal (10%) hydrogenated at room temperature and 5 bar H ₂ pressure.

Yield: 1.35 g (86% of theory),

C22H1 N5O (369.43)

Rf value: 0.36 (silica gel; dichloromethane / ethanol = 19/1) f) 1-Methyl-2- (4 -cyanophenyloxymethyl) -5- (2,3-dioxo-3,4,4-di-hydro-2H-ci noxal iη-1 -yl) -benz azole

369 mg (1.0 mmol) l-methyl-2- (4 -cyanophenyloxymethyl) -

5- (2-aminophenylamino) benzimidazole was dissolved in 25 ml of tetrahydrofuran and 1 ml of pyridine, then 0.45 ml of ethyl oxalate chloride was added at 10 ° C. and the mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness and the residue was refluxed in 50 ml of dioxane for 2 hours. Then the dioxane was distilled off, the residue was mixed with about 50 ml of water and stirred with conc. Ammonia adjusted to pH 8. The precipitated product was filtered off and purified by column chromatography on silica gel.

Yield: 105 mg (25% of theory), ^C 24 ^H 17 ^N 5 ° 3 ⁽ 423.44 ⁾ Rf value: 0.11 (silica gel; dichloromethane / ethanol = 19/1)

g) l-methyl-2- (4-amidinophenyloxymethyl) -5- (2,3-dioxo-3,4,4-di- ^ - ^ y ^■ l o-3H-c ^■ hi nox l n-1 -yl) -benzimi.d zol hydrochloride

A solution of 423 mg (1.0 mmol) of 1-methyl- 2- (4 -cyanophenyloxymethyl) -5- (2,3-dioxo-3,4, -dihydro-2H-quinoxalin-l-yl) -benzimidazole in 40 ml fresh prepared saturated ethanolic hydrochloric acid was stirred at room temperature for 6 hours. The mixture was then evaporated completely, the residue was dissolved in 40 ml of ethanol, 960 mg (10 mmol) of ammonium carbonate were added and the mixture was stirred at room temperature for 48 hours. The precipitated product was filtered off, suspended in 30 ml of water, suctioned off again and dried. Yield: 340 mg (71.5% of theory),

C ₂ 4H ₂ oN 0 ₃ (440.47)

Rf value: 0.08 (silica gel; dichloromethane / ethanol = 4/1)

Mass spectrum: (M + H) ⁺ = 441

(M + 2H) ⁺⁺ = 221 At πpi el 2.

2- (3-amidinophenyloxymethyl) -5- (pyrrolidin-1-yl) -lH-benz-i idazQ] -hydrochlori

a) 1, -ni ami no- 4 - (pyrrole idin - 1 -yl) -benzene

3.5 g (16.85 mmol) of 2-amino-4- (pyrrolidin-1-yl) nitrobenzene were added after the addition of 1.5 g of Pd / carbon (10%) in a mixture of 150 ml of methanol and 150 ml of dichloromethane at room temperature and 5 bar H ₂ pressure hydrogenated. After filtering off the catalyst and distilling off the solvent, the product was immediately reacted raw. Yield: 2.98 g C ₁₀ H ₁₅ N ₃ (177.25)

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

b) 2- (3 -cyanophenyloxymethyl) -5- (pyrrolidin-1-yl) -lH-benz imi dazo

2.98 g (16.85 mmol) of 1,2-diamino-4- (pyrrolidin-1-yl) benzene and 2.66 g (15 mmol) of 3-cyanophenyloxyacetic acid were refluxed in 40 ml of phosphorus oxychloride for 3 hours. Then the phosphorus oxychloride was distilled off in vacuo and the residue was stirred with about 10 ml of ice water, the mixture with conc. Ammonia made alkaline and the precipitated crude product is suctioned off. Chromatographic purification gave 150 mg

(3% of theory) 2- (3 -cyanophenyloxymethyl) -5- (pyrrolidin-1-yl) -lH-benzimidazole. C ₁₉ H ₁₈ N ₄ 0 (318.39)

Rf value: 0.58 (silica gel; dichloromethane / ethanol = 9: 1)

c) 2- (3-amidinophenyloxymethyl) -5- (pyrrolidin-1-yl) -lH-benz-i i dazole -hydrochloride

Prepared analogously to Example 1 from 2- (3 -cyanophenyloxymethyl) - 5- (pyrrolidin-1-yl) -lH-benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 72% of theory, Rf value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1)

^C 19 ^H 21 ^N 5 ° ⁽ 335.42 ⁾

Mass spectrum: (M + H) ⁺ = 336

(M + 2H) ⁺⁺ = 168.6

(2M + H) ⁺ = 671

At πpi el 1

1-methyl -2- (4-amidinophenyloxymethyl) -5- (2-methyl-benzimid ol -1 -yl) -benzimidazole -dihydroohl ori

a) l-Methyl-2- (4 -cyanophenyloxymethyl) -5- (2 -methyl-benzimidazole -1 -yl) -benzol

500 mg (1.35 mmol) l-methyl-2- (4 -cyanophenyloxymethyl) -

5- (2-amino-phenylamino) -benzimidazole (example le) were refluxed in 30 ml of glacial acetic acid after the addition of 2 ml of acetic anhydride for 3 hours. The mixture was then completely concentrated in vacuo and the product was isolated from the residue by chromatography on silica gel. Yield: 400 mg (75% of theory), ^C 24 ^H 19 ^N 5 ° ⁽ 393.46 ⁾ Rf value: 0.35 (silica gel; dichloromethane / ethanol = 19: 1)

b) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (2-methyl-benzimizazole-1-yl) -benzimidazole -dihydroohl ori d

Prepared analogously to Example 1 from 380 mg (0.97 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-methyl-benzimidazol-1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 420 mg (90% of theory),

Rf value: 0.16 (silica gel; dichloromethane / ethanol = 4: 1)

C24H ₂ 2 0 (410.49)

Mass spectrum: M ⁺ = 410 Example -.

1-Methyl-2- (4-amidinophenyloxymethyl) -5- (4-ethyl-3-oxo-3, 4-di-hydro-2H-ohinoxalin-l-yl) -benzimidazole -hydroπhl rid

a) 1-Methyl-2- (4 -cyanophenyloxymethyl) -5- (4-ethyl-3-oxo-3, 4- i hydro-H-ohinoxal i -1 -yl) -ben i i d zol

370 mg (1.0 mmol) 1-methyl -2- (4 -cyanophenyloxymethyl) -

5- (2-aminophenylamino) benzimidazole (Example le) were described in

20 ml of tetrahydrofuran dissolved, then 1 ml of triethylamine and

150 mg of chloroacetyl chloride were added and the mixture was stirred at room temperature for 18 hours. The mixture was then evaporated completely and the residue was refluxed in a sodium ethylate solution (150 mg in 30 ml of ethanol) for one hour. It was again evaporated to dryness and the product was isolated from the residue by column chromatography on silica gel.

Yield: 180 mg (41% of theory), C ₂ gH23N ₅ θ2 (437.51) Rf value: 0.46 (silica gel; dichloromethane / ethanol = 19: 1)

b) l-methyl-2- (4-amidinophenyloxymethyl) -5- (4-ethyl-3-oxo

3, 4-d.hy ro-H-quinoxal in-l-yl) -benzidol -hydrochl ori d Manufactured analogously to Example 1 from l-methyl-2- (4 -cyanophenyloxymethyl) -5- (4-ethyl- 3-oxo-3, 4-dihydro-2H-quinoxalin-l-yl) - benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 89% of theory,

Rf value: 0.29 (silica gel; dichloromethane / ethanol = 4: 1)

C ₂ gH ₂₆ Ngθ2 (454.54)

Mass spectrum: (M + H) ⁺ = 455

(M + 2H) ⁺⁺ = 228 Example. 5

l-methyl-2- (4-amidinophenyloxymethyl) -5- (4-oxo-3,4-dihydro-phf al zin-1-yl -bene i i ol -hydrooh ri

π) 2 - (4-Methyl ai o- -ni ro-benzoyl) -benzoic acid 3.05 g (10 mmol) 2- (4-chloro-3-nitro-benzoyl) -benzoic acid were dissolved in 50 ml aqueous methylamine solution (40 %) stirred for one hour at room temperature. Then it was diluted with about 100 ml of water, acidified with glacial acetic acid and then the precipitate was suction filtered, washed with water and dried. Yield: 3.0 g (100% of theory), ^C 15 ^H 12 ^N 2 ° 5 ⁽ 400.3 ⁾ Rf value: 0.61 (silica gel; dichloromethane / ethanol = 9: 1)

b) l-methylamino-2-nitro-4- (4-oxo-3,4-dihydro-phthalazine-

1 -yl) -benzene

1 ml of hydrazine hydrate (80% strength) was added to a suspension of 1.0 g (3.3 mmol) of 2- (4-methylamino-3-nitro-benzoyl) benzoic acid in 20 ml of n-butanol. Then was heated to reflux for 17 hours. After cooling, the orange-red product was filtered off, washed with ethanol and diethyl ether and dried. Yield: 850 mg (87% of theory) ^C 15 ^H 12 ^N 4 ° 3 ⁽ 296.3 ⁾ mass spectrum: M ⁺ = 296

c) l-methylamino-2-amino-4- (4-oxo-3, 4-dihydro-phthalazine-

1 -yl) -benzene

2.69 g (10 mmol) of 1-methylamino-2-nitro-4- (4-oxo-3, 4-dihydrophthalazin-1-yl) -benzene were added in 150 ml of dimethylformamide

Add 0.3 g Pd / coal (10%) at room temperature and 5 bar

H ₂ pressure hydrogenated.

Yield: 2.6 g (100% of theory),

^C 15 ^H 14 ^N 4 ° ⁽ 266.3 ⁾

Rf value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) d) 1-methyl -2- (4-cyanophenyloxymethyl) -5- (4-oxo-3,4-dihydrophthalazin-1-yl) -benzimi ol

709 mg (4.0 mmol) of 4-cyanophenyloxyacetic acid and 648 mg (4.0 mmol) of N, N '-carbonyldiimidazole were dissolved in 50 ml of absolute

Tetrahydrofuran heated to reflux for 15 minutes. Then 1.0 g (3.7 mmol) of l-methylamino-2-amino-4- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzene was added and the mixture was boiled for a further 16 hours. The mixture was then evaporated to dryness and the residue was refluxed in 50 ml of glacial acetic acid for one hour, again evaporated and the product was isolated from the residue by column chromatography on silica gel. Yield: 1.0 g (66% of theory), 24 ^H 17 ^N 5 ° 2 ⁽ 407.4 ⁾ mass spectrum: (M + H) ⁺ = 408

e) l-methyl-2- (4-amidinophenyloxymethyl) -5- (4-oxo-3, 4-dihydro-hth l azin-1-yl -benzi i dazol -hydrochl ori d

Prepared analogously to Example 1 from 1.0 g (2.45 mmol) of 1-methyl- 2- (4 -cyanophenyloxymethyl) -5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) -benzimidazole, ethanolic hydrochloric acid, ethanol and Ammonium carbonate.

Yield: 150 mg (13% of theory), C ₂ 4H2 _θ N 0 ₂ (424.5) mass spectrum: (M + H) ⁺ = 425

At πpi el ζ_

1-methyl -2- (4-aminophenylaminomethyl) -5- (2-oxopiperidin-1-yl) -benzimi azole hydrochloride

a) -Ni ro-4- (5-bromopentanoyl-amino -f1 norbenzene A solution of 3.74 g (24 mmol) of 4-fluoro-3-nitro-aniline, 4.85 g (24 mmol) of 5-bromo-valeric acid chloride and 3 ml Triethylamine in 100 ml of absolute tetrahydrofuran was stirred for two hours at room temperature and then that Mixture evaporated to dryness. The product was isolated from the residue by column chromatography on silica gel. Yield: 7.0 g (92% of theory), C ₁₁ H ₁₂ BrFN ₂ 0 ₃ (319.1)

Rf value: 0.48 (silica gel; ethyl acetate / petroleum ether = 7: 3)

bJ 2-Nitro-4- (2-oxopiperidin-l-yl) fluorobenzene

A solution of 7.0 g (21.9 mmol) of 2-nitro-4- (5-bromopentanoyl-amino) -fluorobenzene was added dropwise to a stirred suspension of 1.05 g (21.9 mmol) of sodium hydride in 200 ml of tetrahydrofuran over the course of 15 minutes Minutes, the reaction mixture was poured onto about 200 ml of ice water and then the tetrahydrofuran was distilled off. The remaining aqueous solution was extracted several times with dichloromethane, the organic phase was then washed with water, dried and concentrated. The crude product thus obtained was purified by column chromatography on silica gel. Yield: 4.1 g (79% of theory), C ₁₁ H ₁₁ FN ₂ 0 ₃ (238.2)

Rf value: 0.35 (silica gel; ethyl acetate / petroleum ether = 7: 3)

cj N-methyl - -niotro-4- (2-oxopiperidine-l -yl) -ani 1 i n

4.1 g (17 mmol) of 2-nitro-4- (2-oxo-piperidin-l-yl) -fluorobenzene were stirred in 50 ml of methylamine solution (40% in water) at room temperature for one hour. The mixture was then diluted with about 100 ml of water, the product which crystallized out was filtered off with suction, washed with water and dried. Yield: 3.9 g (92% of theory), C12H15N3O3 (249.3) Rf value: 0.23 (silica gel; ethyl acetate / petroleum ether = 9: 1)

d 1 -methylmino- -amino-4- (2-oxo-pi ei di - -yl-be ol 3.9 g (15.6 mmol) N-methyl-2-nitro-4- (2-oxo-piperidine-l- yl) - aniline were hydrogenated in 250 ml of methanol at room temperature with the addition of 0.5 g of Pd / carbon (10%) at 5 bar H ₂ pressure. Yield: 3.3 g (97% of theory) C ₁₂ H ₁₇ N ₃ 0 (219.3)

Rf value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1)

e) 1-methyl -2- (4-cyanophenylaminomethyl) -5- (2-oxopiperidine-

1 -yl) -benzi i azole

A solution of 1.06 g (6.0 mmol) of 4-cyanophenylglycine and 0.945 g (6.0 mmol) of N, N'-carbonyldiimidazole in 60 ml of tetrahydrofuran was refluxed for 30 minutes. Then 1.1 g (5.0 mmol) of l-methylamino-2-amino-4- (2-oxopiperidin-1-yl) benzene were added and the mixture was stirred at 60 ° C. for 48 hours. After cooling, the crystallized product was filtered off, washed with diethyl ether and dried. Yield: 1.15 g (61% of theory),

Rf value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)

^C 21 ^H 21 ^N 5 ° ⁽ 359.4 ⁾ mass spectrum: M ⁺ = 359

f) l-methyl-2- (4-aminophenylaminomethyl) -5- (2-oxopiperidine-

1 -yl-benzimidazole hydrochloride

Manufactured analogously to Example 1 from 1.1 g (3.0 mmol) of 1-methyl

2- (4-cyanophenylaminomethyl) -5- (2-oxopiperidin-l-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 0.75 g (61% of theory),

Mass spectrum: (M + H) ⁺ = 377

Example] 2

l-methyl-2- (4-aminophenylaminomethyl) -5- (butanesultam-1-yl) - benzimidazole hydrophilic ori

Prepared (analogously to Example 1) from l-methyl-2- (4-cyanophenylaminomethyl) -5- (butanesultam-1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 56% of theory, C ₂ oH24N 0 ₂ S (412.5)

Mass spectrum: (M + H) ⁺ = 413 Example] a

l -methyl - 2 - (4-aminophenyloxymethyl) - 5 - (1 - isobutyl - 1H-tetrazole - 5 -yl -benzimi da ol -hydrochlori d

a N- T.qobntyl -4 -chl or- 3 -nitro-be oesäiireami i d

6 ml (60 mmol) of isobutylamine, dissolved in 60, were added to a solution of 13.2 g (60 mmol) of 4-chloro-3-nitro-benzoyl chloride and 6.0 g (60 mmol) of tiethylamine in 150 ml of absolute tetrahydrofuran ml of terahydrofuran, slowly added dropwise. The mixture was then stirred for an hour, then evaporated to dryness and the product was isolated from the residue by column chromatography on silica gel. Yield: 13.5 g (88% of theory), C ₁₁ H ₁₃ C1N ₂ 0 ₃ (256.7)

Rf value: 0.64 (silica gel; dichloromethane / ethanol = 50: 1)

b 2-Ni tro-4- (1-i sobutyl-1H-tetrazole -5-yl) -πhl orbenzene To a solution of 10.3 g (40 mmol) of N-isobutyl-4-chloro-3-nitro-benzoic acid amide in 200 ml of absolute dichloromethane were added 2.6 g (40 mmol) of sodium azide, then 6.7 ml (40 mmol) of trifluoromethanoic anhydride were added dropwise with stirring at 0 ° C. The mixture was then stirred at room temperature for 40 hours. About 200 ml of 5% sodium hydrogen carbonate solution were then added with vigorous stirring, the organic phase was then separated off, the aqueous phase was extracted twice more with 50 ml of dichloromethane each time, the organic phases were combined, dried and concentrated. The product was removed from the residue by column chromatography isolated over silica gel.

Yield: 3.6 g (32% of theory),

Rf value: 0.70 (silica gel; dichloromethane / ethanol 50: 1)

^C 11 ^H 12 ^C1N 5 ° 2 ⁽ 281.7 ⁾ mass spectrum: M ⁺ = 281 cj 2-nitro-4- (1-isobutyl-lH-tetrazo -5-yl) -N-methyl ni 1 in

3.5 g (12 mmol) of 2-nitro-4- (l-isobutyl-1H-tetrazol-5-yl) chlorobenzene were stirred for 48 hours at room temperature in 35 ml of 40% strength aqueous methylamine solution, then with about 70 ml Water is added, the precipitated product is suctioned off and dried.

Yield: 3.3 g (100% of theory), C ₁₂ H ₁ 6Ngθ2 (276.3) Rf value: 0.22 (silica gel; dichloromethane / ethanol = 50: 1)

d) l-methylamino-2-amino-4- (l-isobutyl-lH-tetrazol-5-yl) - benzo]

3.3 g (11.9 mmol) of 2-nitro-4- (l-isobutyl-1H-tetrazol-5-yl) - N-methylaniline were dissolved in 150 ml of methanol at room temperature and 5 bar H ₂ pressure with the addition of 0.5 g Pd / Coal (10%) hydrogenated.

Yield: 3.0 g (100% of theory) C ₁₂ H ₁₈ N ₆ (246.3)

Rf value: 0.23 (silica gel; dichloromethane / ethanol = 19: 1)

e) l-methyl-2- (4 -cyanophenyloxymethyl) -5- (1-isobutyl-1H-etrazol-5-yl) -be .midazole

797 mg (4.5 mmol) of 4-cyano-phenoxyacetic acid and 729 mg

(4.5 mmol) of N, N'-carbonyldiimidazole was refluxed in 60 ml of absolute tetrahydrofuran for 15 minutes. Then 1.0 g (4.06 mmol) of l-methylamino-2-amino-4- (1-isobutyl-1H-tetrazol-5-yl) benzene was added and the mixture was boiled for a further 15 hours. The mixture was then evaporated to dryness, the residue was dissolved in 50 ml of glacial acetic acid and heated to reflux for 1.5 hours. It was again evaporated to dryness and the product was isolated from the residue by column chromatography on silica gel.

Yield: 1.0 g (57% of theory), ^C 21 ^H 21 ^N 7 ° ⁽ 387.5 ⁾ Rf value: 0.51 (silica gel; dichloromethane / ethanol = 19: 1) f) 1-methyl -2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-lH-t ol -5-yl) -ben ii dazol -hydrochl rd

Prepared analogously to Example 1 from 1.0 g (2.58 mmol) of 1-methyl-2- (4 -cyanophenyloxymethyl) -5- (1-isobutyl-1H-tetrazol-5-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 900 mg (79% of theory), ^C 21 ^H 24 ^N 8 ° ⁽ 404.5 ⁾ mass spectrum: (M + H) ⁺ = 405

For example

l-methyl-2- (4-aminophenylaminomethyl) -5- (3-methyl-5-phenyl-yrazole -1 -yl-benzim azole -hydrochloride)

a -Nitro-4- (3-methyl -5 -phenyl -pyra ol -1 -yl) -luorobenzene 4.15 g (20 mmol) 3 -Nitro-4-fluorophenylhydrazine, 3.25 g

(20 mmol) benzoylacetone and 2.78 ml (20 mmol) triethylamine were dissolved in 150 ml methanol and stirred for three hours at room temperature. The mixture was then evaporated to dryness and the crude product thus obtained was purified by column chromatography on silica gel. Yield: 4.40 g (74% of theory), C ₁ gH ₁₂ FN ₃ 0 ₂ (297.29) Rf value: 0.57 (silica gel; dichloromethane / ethanol = 50: 1)

b) l-Methylamino-2-nitro-4- (3-methyl-5-phenyl-pyrazol-1-yl) benzene

40 ml of methylamine solution (40% in water) were added to 4.40 g (15 mmol) of 2-nitro-4- (3-methyl -5-phenyl-pyrazol-1-yl) fluorobenzene and in a Roth bomb for two hours long on

Heated to 80 ° C. After cooling, the reaction mixture was mixed with about 100 ml of water and then the product which had crystallized out was filtered off with suction and dried. Yield: 3.90 g (85.5% of theory), ^C 17 ^H 16 ^C1N 4 ° 2 ⁽ 308.34 ⁾

Rf value: 0.38 (silica gel; dichloromethane / ethanol = 19: 1)

c) l-Methylamino-2-amino-4- (3-methyl -5-phenyl-pyrazol-1-yl) benzene

3.90 g (12.65 mmol) l-methylamino-2-nitro-4- (3-methyl -5 -phenyl-pyrazol-1-yl) -benzene were dissolved in 200 ml methanol and after adding 0.5 g Pd / carbon (10 %) hydrogenated at room temperature and 5 bar H ₂ pressure.

Yield: 3.50 g (99.4% of theory), C ₁₇ H ₁₈ N ₄ (278.36)

Rf value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1)

d) l-methyl-2- (4-cyanophenylaminomethyl) -5- (3-methyl -5 -phenylpyrazole -1 -yl) -benzene i azole

2.29 g (13.0 mmol) of 4-cyanophenylglycine and 2.11 g (13.0 mmol) of N, N'-carbonyldiimidazole were dissolved in 150 ml of tetrahydrofuran

Heated under reflux for 15 minutes. Then 3.50 g (12.57 mmol) of l-methylamino-2-amino-4- (3-methyl-5-phenyl-pyrazol-1-yl) -benzene were added and the mixture was heated for a further 24 hours. Since starting material was still visible in the thin-layer chromatogram, another 13.0 mmol of 4-cyanophenylglycine imidazolide were added and the mixture was heated under reflux for a further 24 hours. The reaction mixture was then evaporated completely and the residue was refluxed in 100 ml of glacial acetic acid for one hour. Then it was evaporated again, the residue was stirred in about 100 ml of water and concentrated. Ammonia solution made alkaline. The product was obtained by extraction with ethyl acetate and subsequent column chromatography on silica gel. Yield: 3.01 g (57% of theory), C ₂ H ₂ 2N (418.5) Rf value: 0.29 (silica gel; dichloromethane / ethanol = 19: 1) e) l-methyl-2- (4-aminophenylaminomethyl) -5- (3-methyl-

5 -phenyl -pyra zo - -yl -benz i da zol -hydrochl ori d

Manufactured analogously to Example 1 from 3.0 g. (7.17 mmol) of 1-methyl

2- (4-cyanophenylaminomethyl) -5- (3-methyl -5-phenyl-pyrazole -

1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and

Ammonium carbonate.

Yield: 2.4 g (70.9% of theory),

Rf value: 0.15 (RP-8 silica gel; methanol / 5% NaCl solution

6: 4)

C ₂ gH ₂ 5N7 (435.52) mass spectrum: (M + H) ⁺ = 436

(MH) ^~ = 434 Example IQ

l-Methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl - 5-phenyl-pyrazole -1 -yl 1 -benzimi dazol -hydrochloride) Prepared analogously to Example 1 from l-methyl- 2- (4-cyanophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenylpyrazol-1-yl] benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 80.7% of theory, ^C 30 ^H 31 ^N 7 ° 2 ⁽ 521.61 ⁾ mass spectrum: (M + H) ⁺ = 522

(M + H + Na) ⁺⁺ = 272.7

(M + 2H) ⁺⁺ = 261.7

Example] 11

1-methyl -2- (4-aminophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole hydrochloric acid

Prepared analogously to Example 1 from l-methyl-2- (4-cyanophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) -pyrazol-1-yl] -benzimidazole, more ethanolic Hydrochloric acid, ethanol and ammonium carbonate. Yield: 32% of theory, Rf value: 0.7 (RP-8 silica gel; methanol / 5% NaCl solution

4: 1)

C ₂ 9H3oN ₈ 0 ₂ (522.59)

Mass spectrum: (M + H) ⁺ = 523

(M + 2H) ⁺⁺ = 262

Rice game 12

l-Methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5-phenylpyrazol-l-yll -benzidazole

2.1 g (3.76 mmol) of l-methyl-2- (4-cyanophenylaminomethyl) -5- [3 - (2-hydroxycarbonylethyl) -5-phenyl-pyrazole -1-yl] -benzimidazole hydrochloride were dissolved in 70 ml of ethanol, then a solution of 0.80 g (20.0 mmol) of sodium hydroxide in 5 ml of water was added and the mixture was stirred at room temperature for two hours. About 100 ml of water were then added, weakly acidified with glacial acetic acid and stirred for a further 10 minutes. The precipitated product was filtered off, washed with water and dried. Yield: 1.7 g (96.9% of theory), C28H27N7O2 (493.57)

Mass spectrum: (M + H) ⁺ = 494

(M + H + Na) ⁺⁺ = 258.7

(M + 2H) ⁺⁺ = 247.7

(M + 2Na) ⁺⁺ = 269.8

Example 13.

l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl -5- (3-pyridyl-pyrazole -1 -yl 1 -benzimi dazol

Prepared analogously to Example 12 from l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) - pyrazol-1-yl] -benzimidazole hydrochloride and sodium hydroxide solution. Yield: 92% of theory, ^C 27 ^H 26 ^N 8 ° 2 ⁽ 494.56 ⁾ Mass spectrum: (M + H) ⁺ = 495

(M + Na) + = 517

(M-H + 2Na) ⁺ = 539

(M + 2Na) ⁺⁺ = 270

Rip πpi el 14.

1-methyl-2- (4-aminophenylaminomethyl) -5- [3 -ethoxycarbonyl- 5- (thiophen-2-yl) -pyrazol-1-yll -benzimidazole -hydrochl ori d Prepared analogously to Example 1 from l-methyl- 2- (4-cyanophenylaminomethyl) -5- [3 -ethoxycarbonyl- 5- (thiophene-2-yl) pyrazole - 1-yl] benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 45% of theory, Rf value: 0.68 (RP-8 silica gel; methanol / 5% NaCl solution

9: 1)

^C 26 ^H 25 ^N 7 ° 2 ^{S (} 499.58 ⁾

Mass spectrum: (M + H) ⁺ = 500

At πpi el 15.

l-methyl-2- (4-aminophenylaminomethyl) -5- [3-carboxy-5- (thihen-2-yl-pyrazole -1 -yl 1 -benzimi dazol

Prepared analogously to Example 12 from 1-methyl-2- (4-aminophenylaminomethyl) -5- [3 -ethoxycarbonyl -5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole and sodium hydroxide solution. Yield: 97.4% of theory, ^C 24 ^H 21 ^N 7 ° 2 ^{S (} 471.55 ⁾ mass spectrum: (M + H) ⁺ = 472

(M + Na) ⁺ = 494

(M-H) - = 470 Be i πpi el __ £.

l-methyl-2- (4-amidinophenyloxymethyl) -5- [3-methyl-5- (2-furyl) pyrazole -1 -yl 1 -benzidazole -hydrochloride

Prepared analogously to Example 1 from l-methyl-2- (4-cyanophenyloxymethyl) -5- [3-methyl -5- (2-furyl) pyrazol-1-yl] benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 83% of theory, Rf value: 0.58 (RP-8 silica gel; methanol / 5% NaCl solution

9: 1)

C24H22N6O2 (426.47 ⁾

Mass spectrum: (M + H) ⁺ = 427

At πpi el _ _

l-Methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycarbonyl-ethyl -5 -phenyl-pyrol-1 -yl) -benzidiol -hydrochloride prepared analogously to Example 1 from l-methyl-2 - (4 -cyanophenyl-aminomethyl) -5- (3 -ethoxycarbonylmethyl-5-phenyl-pyrazol-1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 56% of theory, Rf value: 0.64 (RP-8 silica gel; methanol / 5% NaCL solution

9: 1)

C29H29N7O2 (507.58)

Mass spectrum: (M + H) ⁺ = 508

Example 18

l-methyl-2- [2- (4-amidinophenyl) ethyl] -5- [3-methyl-5- (2-furyl) pyrazole -1 -yl 1 -benzimidazole hydrochloride

Prepared analogously to Example 1 from l-methyl-2- [2- (4-cyano-phenyl) -ethyl] -5- [3 -methyl -5- (2-furyl) -pyrazol-1-yl] -benzimidazole, more ethanolic Hydrochloric acid, ethanol and ammonium carbonate. Yield: 91% of theory, Rf value: 0. 55 (RP-8 silica gel; methanol / 5% NaCl solution

9: 1)

C25H24N6O (424.49)

Mass spectrum: (M + H) ⁺ = 425

Example. 19

l-methyl-2- (4-aminophenylaminomethyl) -5- [3-methyl-5- (2-fuyl-pyrazole -1 -yl -benzimidazole -hydrochloric acid

Prepared analogously to Example 1 from l-methyl-2- (4-cyanopheny1-aminomethyl) -5- [3-methyl-5- (2-furyl) -pyrazol-1-yl] -benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate yield : 87% of theory, R _f value: 0.62 (RP-8 silica gel; methanol / 5% NaCl solution

49: 1)

C24H23N7O (425.48)

Mass spectrum: (M + H) ⁺ = 426

Example. 20th

l-methyl-2- (4-aminophenylaminomethyl) -5- (3-hydroxycarbonyl * ethyl -5-phenyl-pyrazole -1-yl) -benzene i dazol

Prepared analogously to Example 12 from l-methyl-2- (4-aminophenylaminomethyl) -5- (3-ethoxycarbonylmethyl-5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride and sodium hydroxide solution. Yield: 93% of theory, ^C 27 ^H 25 ^N 7 ° 2 (479.55 ⁾ mass spectrum: (M + H) ⁺ = 480

(M + Na) ⁺ = 502

(M + 2Na) ⁺⁺ = 262.7 Example] 21.

1-methyl-2- (4-aminophenylaminomethyl) -5- (3-ethoxycarbonyl - -tert. -Butyl-pyrazol-1-yl) -benzimi dazol -hydrochl ori d

Prepared analogously to Example 1 from 1-methyl -2- (4-cyanophenylaminomethyl) -5- (3-ethoxycarbonyl -5-tert-butyl-pyrazol-1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 64% of theory, Rf value: 0.63 (RP-8 silica gel; methanol / 5% NaCl solution

4: 1)

^C 26 ^H 31 ^N 7 ° 2 ⁽ 473.58 ⁾

Mass spectrum: (M + H) + = 474

example

1-methyl-2- (4-aminophenylaminomethyl) -5- (3-carboxy-5-tert. ■ bntyl-pyrazol -1-yl) -benzimidazole

Prepared analogously to Example 12 from 1-methyl-2- (4-aminophenylaminomethyl) -5- (3-ethoxycarbonyl -5-tert-butyl-pyrazole - 1-yl) -benzimidazole hydrochloride and sodium hydroxide solution. Yield: 91% of theory, C ₂ 4H ₂ 7N ₇ 0 ₂ (445.52)

Mass spectrum: (M + H) ⁺ = 446

(M + Na) + = 468 (M + 2Na) ⁺⁺ = 245.8 (M - H) ^~ = 444

At πpi el ___

Dry ampoule with 75 mg of active ingredient per 10 ml

Composition:

Active ingredient 75.0 mg

Mannitol 50.0 mg Water for injections ad 10.0 ml

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.

Example 24

Dried ampoules with 35 mg of active ingredient per ml

Composition:

Active ingredient 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml

Manufacturing:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.

The ready-to-use solution is dissolved with water for injections.

Example 25

50 mg tablet

Composition:

(1) Active ingredient 50.0 mg

(2) milk sugar 98.0 mg

(3) corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215.0 mg Manufacturing:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplane with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm.

Example 26

Tablet with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) polyvinyl pyrrolidone 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). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.

At π JPl 22.

Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg (3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate. mg

160.0 mg

Manufacturing:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

Example 28

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) Corn starch dried 46.0 mg

(3) Milk sugar powdered 30.0 mg

(4) Magnesium stearate 4.0 mg

430.0 mg

Manufacturing:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled on a capsule filling machine into hard gelatin capsules Gr6Be 0.

Example 29

Suppoπi ori n m 1 0 mg Wi kstoff

1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg

2,000.0 mg

Claims

claims 1. Substituted bicyclic heterocycles of the general formula

in the R _{a is} a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom, in which a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or a methylene group in the 4-position through an oxygen or sulfur atom or through an -NR ^ group, where R * j_ is a Hydrogen atom or a C _] _-. Represents alkyl group, can be replaced and one or two further methylene groups can be replaced by carbonyl groups in a ring thus obtained containing two heteroatoms, where the 5-, 6- or 7-membered saturated heterocyclic rings described above can also be benzo-fused via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C ^ -3-alkyl or C- * j__3-alkoxy group, or a group of the formula

in the R _{c is} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C -__ 3-alkyl or Cι_3 alkoxy group and R _Q _ is as defined above, or a 5-membered heteroaromatic group which is bonded via a nitrogen atom and which contains one, two or three nitrogen atoms and which can be benzo-fused via two adjacent carbon atoms, the 5-membered heteroaromatic group in the carbon skeleton by C ₁ _g-alkyl, carboxy, C _] __4 -alkoxycarbonyl-, carboxy- (C _] __4 ₎ -alkyl-, C _] __4 -alkoxycarbonyl- (Ci. 4) alkyl, phenyl, pyridyl, furanyl or Thienyl groups can be mono- or disubstituted independently of one another and a carboxy group contained in the radicals mentioned can also be replaced by a group which can be converted into a carboxy group in vivo, the phenyl part of a benzo-fused 5-membered heteroaromatic group by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C * _] __3-alkyl or C3__3-alkoxy group can be substituted and the heteroaromatic group, including an optionally fused-on phenyl part, is also partially hy- can be third, the dihydro derivatives being preferred, and the resulting -NH groups can also be replaced by the above-defined -NR i groups, a tetrazolyl group bonded via a nitrogen atom or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom can be substituted by a C ₁ _g alkyl group, Y is an oxygen or sulfur atom or one which is optionally substituted by a C 1-6 alkyl or C3-7 cycloalkyl group Imino group, Xi, X2, X3 and X4 each represent a methine group or one or two of the radicals X] _, X2, X3 and X4 each have a nitrogen atom and the other radicals each have a methine group, B is an ethylene group in which a methylene group, which is linked either to the bicyclic heterocycle of the formula I or to the group Ar, through an oxygen or sulfur atom, through a sulfinyl, sulfonyl, carbonyl or —NR _] _ group can be replaced, where R _] _ is defined as mentioned above, Ar is a phenylene or naphthylene group which is optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C; j__3-alkyl or Cχ_3-alkoxy group, an optionally substituted in the carbon skeleton by a C- _] __ 3 alkyl group, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group and E is a cyano or R- ^ NH-C (= NH) group in which Rk represents a hydrogen atom, a hydroxyl group or a residue which can be split off in vivo, mean, where in addition the carboxy groups mentioned above when defining the radicals can be replaced by a group which can be converted into a carboxy group in vivo and the imino or amino groups mentioned above when defining the radicals can be substituted by a radical which can be split off in vivo, their tautomers, their stereoisomers, their mixtures and their salts. 2. Substituted bicyclic heterocycles of the general formula I according to claim 1, in which R _{a is} a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom, in which a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or a methylene group in the 4-position can be replaced by an oxygen atom or an -NR i group, where R] _ represents a hydrogen atom or a C - * -__ 3 alkyl group, and one or two in a ring thus obtained containing two heteroatoms further methylene groups can be replaced by carbonyl groups, the 5- or 6-membered saturated heterocyclic rings described above can also be benzo-fused via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C- * j__3-alkyl or C _] __3-alkoxy group, or a group of the formula

in the R _{c represents} a hydrogen atom, a trifluoromethyl or Cι_3 alkyl group and R _] _ is as defined above, or a 5-membered heteroaromatic group which is bonded via a nitrogen atom and which contains one or two nitrogen atoms and which can be benzo-fused via two adjacent carbon atoms, where the 5-membered heteroaromatic group in the carbon skeleton by C * j__4 alkyl, carboxy, C _] __4 alkoxycarbonyl, carboxy (C _] __4 ₎ alkyl, C _] __4 alkoxycarbonyl - i -.4 ) alkyl, phenyl, pyridyl, furanyl or Thienyl groups can be mono- or disubstituted independently of one another and a carboxy group contained in the radicals mentioned can also be replaced by a group which can be converted into a carboxy group in vivo, the phenyl part of a benzo-fused 5-membered heteroaromatic group by a C] __ 3 -alkyl- or Cι_3-alkoxy group can be substituted and the heteroaromatic group, including an optionally fused-on phenyl moiety, is also dihydrogenated and the resulting -NH groups can also be replaced by the above-defined -NR ^ _- groups, or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom can be substituted by a C1-.4-alkyl group, Y is an oxygen atom or an imino group which is optionally substituted by a C _] __4 -alkyl group, Xi, X2, X3 and X4 each represent a methine group, B is an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen atom, a carbonyl or -NR _] _ group, where R *] _ is defined as mentioned above, Ar is a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _] __3-alkyl or C * __ 3 alkoxy group, a pyridinylene group optionally substituted in the carbon skeleton by a C 1-3 alkyl group and E is a cyano or RJ- _J NH-C (= NH) group in which R _] - represents a hydrogen atom or a residue which can be split off in vivo, mean, their tautomers, their prodrugs, their double-drugs, their stereoisomers and their salts. 3. Substituted bicyclic heterocycles of the general formula I according to claim 1, in which R _{a is} a 5- or 6-membered saturated heterocyclic ring bonded via a nitrogen atom, where a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or a methylene group in the 4-position of the 6-membered saturated heterocyclic ring by an -NR i group, where R _] _ represents a hydrogen atom or a Cχ_3 alkyl group, can be replaced and one or two further methylene groups can be replaced by carbonyl groups in a ring thus obtained containing two heteroatoms, the 6-membered saturated heterocyclic rings described above can also be benzo-fused via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C _] __3 -alkyl group, or a group of the formula

in the R _{c represents} a hydrogen atom or a C- * j__3 alkyl group and R _] _ is as defined above, or a pyrrol-1-yl, imidazole -1-yl or pyrazole -1-yl group which is optionally benzo-fused via two adjacent carbon atoms, where the heteroaromatics mentioned in the carbon skeleton by C] __ 4-alkyl-, carboxy-, C ^ _3 -alkoxycarbonyl -, Carboxy- (C ^ _2) ^_ alkyl -, C] __ 2 -alkoxycarbonyl - (C] __ 2) "alkyl, phenyl, pyridyl, furanyl or thienyl groups can be mono- or disubstituted, the substituents being the same or different with the proviso that only one of the substituents is an aromatic or heteroaromatic radical and a carboxy group contained in the said radicals can also be replaced by a group which can be converted into a carboxy group in vivo, or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom can be substituted by a C _] _-. 4 -alkyl group, Y is an imino group which is optionally substituted by a C _] __3 -alkyl group, Xi, X2, X3 and X4 each represent a methine group, B is an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen atom or -NR 1 group, where R _] _ is defined as mentioned above, Ar is a phenylene group optionally substituted by a C- _] __3-alkyl group, E is a cyano or R- ^ NH-C (= NH) group in which Rj represents a hydrogen atom or a residue which can be split off in vivo, mean, their tautomers, their prodrugs, their double-drugs, their stereoisomers and their salts. 4. The following bicyclic heterocycles of the general formula I according to claim 1: (a) l-methyl-2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-1H-tetrazol-5-yl) benzimidazole, (b) l-methyl-2- (4-aminophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) -benzimidazole, (c) l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenylpyrazol-l-yl] benzimidazole, (d) l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) pyrazole -1-yl] benzimidazole, (e) l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5-phenylpyrazol-1-yl] benzimidazole, (f) l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole, (g) l-methyl-2- (4-aminophenylaminomethyl) -5- [3-ethoxycarbonyl-5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole, (h) l-methyl-2- (4-aminophenylaminomethyl) -5- [3-carboxy- 5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole, (i) 1-methyl -2- (4-amidinophenyloxymethyl) -5- [3-methyl - 5- (2-furyl) pyrazol-1-yl] benzimidazole, (j) l-methyl-2- (4-aminophenylaminomethyl) -5- (3-ethoxycarbonylmethyl -5 -phenyl-pyrazol-1-yl) -benzimidazole, (k) l-methyl-2- [2- (4-amidinophenyl) ethyl] -5- [3-methyl - 5- (2-furyl) pyrazol-1-yl] benzimidazole, (1) 1-methyl -2- (4-aminophenylaminomethyl) -5- [J -methyl - 5- (2-furyl) pyrazol-1-yl] benzimidazole and (m) l-methyl-2- (4-aminophenylaminomethyl) -5- (3-hydroxycarbonylmethyl-5-phenyl-pyrazol -1-yl) benzimidazole, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts. 5. The following bicyclic heterocycles of the general formula I according to claim 1: (c) l-methyl-2- (4-aminophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole, (d) l-methyl-2- (4-aminophenylaminomethyl) -5- [3-carboxy- 5- (thiophene-2-yl) pyrazol-1-yl] benzimidazole, (e) l-methyl-2- (4-aminophenylaminomethyl) -5- (3-ethoxycarbonylmethyl - 5 -phenyl-pyrazol - 1-yl) -benzimidazole, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts. 6. Physiologically acceptable salts of the compounds according to claims 1 to 5, in which E represents an R ^ NH-C (= NH) group. 7. Medicament containing a compound according to at least one of claims 1 to 5, in which E represents an R ^ NH-C (= NH) group, or a salt according to claim 6 in addition optionally one or more inert carriers and / or diluents. 8. Use of a compound according to at least one of claims 1 to 5, in which E represents an R] ~, NH-C (= NH) group, or a salt according to claim 6 for the manufacture of a medicament with an action which prolongs the thrombin time, a thrombin-inhibiting effect and an inhibitory effect on related serine proteases. 9. A method for producing a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 5, in which E represents an R ^ NH-C (= NH) group, or a salt according to non-chemical means Claim 6 is incorporated into one or more inert carriers and / or diluents. 10. A process for the preparation of the compounds according to claims 1 to 6, characterized in that a) for the preparation of a compound of general formula I, in which E represents an R ^ NH-C (= NH) group, in which Rj represents a hydrogen atom or a hydroxy group, a compound of the general formula optionally formed in the reaction mixture

in the R _a , Xi to X4, Y, B and Ar are as defined in claims 1 to 5 and Z represents an alkoxy, aralkoxy, alkylthio or aralkylthio group, with an amine of the general formula H ₂ N - R _b ', (IV) in the Rb 'represents a hydrogen atom or a hydroxy group, is reacted or b) for the preparation of a compound of the general formula I in which the R _a group and E are defined with the proviso as mentioned in claims 1 to 5 that the R _a group is a Contains carboxy group and E is as defined in claims 1 to 5 or the R _a group is as defined in claims 1 to 5 and E represents an NH2-C (= NH) group or the R _a group is a carboxy group contains and E represents an NH2-C (= NH) group, a compound of the general formula

in which i to X4, Y, B and Ar are as defined in claims 1 to 5 and the R _a 'group and E' are those for the R _a group and E in the Claims 1 to 5 have the meanings provided that the R _a 'group contains a group which can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E is as defined in claims 1 to 5 or E ^{1 represents} a group which can be converted into an NH2-C (= NH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and the R _a 'group is that for the R _a group in the Claims 1 to 5 meanings mentioned or R _a 'group one by hydrolysis, treatment with an acid or Contains base, thermolysis or hydrogenolysis into a group which can be converted into a carboxyl group and E ^{1 is} a group by hydrolysis, treatment represents your group which can be converted into an NH2-C (= NH) group with an acid or base, thermolysis or hydrogenolysis, by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a compound of the general formula I in which the R _a group and E with the Provided as defined in claims 1 to 5 that the R _a group contains a carboxy group and E as in the Claims 1 to 5 is defined or the R _a group in the Claims 1 to 5 has the meanings mentioned and E represents an NH2-C (= NH) group or the R _a group contains a carboxy group and E represents an NH2-C (= NH) group, is converted or c) for the preparation of a compound of the general formula I in which the R _a group contains one of the ester groups mentioned in the definition of the R _a group in claims 1 to 5, a compound of the general formula

in the Xi to X4, Y, B, Ar and E are as defined in claims 1 to 5 and R _a "has the meanings mentioned for R _a in claims 1 to 5 with the proviso that R _a " contains a carboxy group or a group which can be converted into a corresponding ester group by means of an alcohol, with an alcohol of the general formula HO - R ₅ , (VII) in the R5 is the alkyl part of one of the residues which can be split off in vivo and is mentioned in claims 1 to 5, with the exception of R2-CO-O- (R3CR4) - Group for a carboxyl group, or with their form amidacetalen or with a compound of the general formula Z ₂ - Rg, (VIII) in the Rg is the alkyl part of one of the residues which can be split off in vivo and is mentioned in claims 1 to 5, with the exception of the R2-CO-O- (R4CR5) - Group for a carboxyl group and Z2 represent a leaving group, is implemented or d) for the preparation of a compound of the general formula I in which R _j - represents a radical which can be split off in vivo, a compound of the general formula

in the R _a , Xi to X4, Y, B and Ar are as defined in claims 1 to 5, with a compound of the general formula Z ₃ - R ₇ , (X) in the R7 a residue which can be split off in vivo and Z3 is a nucleofugic leaving group, is implemented or e) for the preparation of a compound of the general formula I in which B represents an ethylene group in which a methylene group has been replaced by a sulfinyl or sulfonyl group, a compound of the general formula

in the R _a , Xi to X4, Y, Ar and E are as defined in claims 1 to 5 and B 'represents an ethylene group in which a methylene group is replaced by a sulfenyl or sulfinyl group, is oxidized or f) for the preparation of a compound of the general formula I in which E is a cyano group and B is an ethylene group in which a methylene group which is either linked to the bicyclic heterocycle of the formula I or to the group Ar by an oxygen or sulfur atom, is replaced by a sulfinyl, sulfonyl, carbonyl or -NR ^ group represent a compound of the general formula

with a compound of the general formula V - Ar - CN, (XIII) in which R _a , Xi to X4, Y and Ar are as defined in claims 1 to 5, one of the radicals U or V is a HO, HS, HOSO, HOS0 ₂ or HNR * _] _ group and the other of the radicals is a Z3CH2 group, where R-_ is as defined in claims 1 to 5 and Z3 is a nucleofugic leaving group, is implemented or g) for the preparation of a compound of formula alllgemeinen I in which Y represents an oxygen or sulfur atom or a group optionally substituted by a C ^ g-alkyl or C3_ ₇ cycloalkyl group imino group, X ^ to X4 methine groups, E is a cyano group and B is a Ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen or sulfur atom or by an —NR] _ group means a compound of the general formula

in the R _a and Y are as defined in claims 1 to 5 and Xi 'to X4' each represent a methine group, with a compound of the general formula HO-CO - B '- Ar - CN, (XV) in the Ar is as defined in claims 1 to 5 and B 'represents an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen or sulfur atom or by an -NR ^ group, or by the same reactive derivatives is implemented or h) for the preparation of a compound of general formula I, in which R _a the 2, 3-dioxo-3, 4-dihydro-2H-quinoxalin-l-yl radical and E represents the cyano group, a compound of the general formula

in the Xi to X4, Y, B and Ar as defined in claims 1 to 5 are reacted with oxalic acid or a reactive oxalic acid derivative or i) for the preparation of a compound of the general formula I in which R _{a is} optionally in the 2-position by a C 1-6 -alkyl-, C 1-4 -alkoxycarbonyl- (C] _-. 4) -alkyl- , Phenyl, pyridyl, Furanyl or thienyl group substituted benzimidazol-1-yl radical and E is the cyano group, a compound of the general formula

in the X _] _ to X4, Y, B and Ar as defined in claims 1 to 5, with a carboxylic acid of the general formula HO-CO - R ₈ , (XVII) in the R8 represents a hydrogen atom, a C ^ _g alkyl, _C] _- 4 -alkoxycarbonyl -. (. Cη _- 4) alkyl, phenyl, pyridyl, furanyl or thienyl represents group, or is reacted with their reactive derivatives or k) to prepare a compound of general formula I wherein R _a in a position 4 optionally substituted by a C **] __ g -alkyl group substituted 3-oxo-3,4,4-dihydro-2H-quinoxa- 1in-1-yl group and E is the cyano group, a compound of the general formula

in the Xi to X, Y, B and Ar are as defined in claims 1 to 5, with a compound of the general formula HO-CO C i _o ~ Zt ~ (XVIII ^' in the Z2 represents a leaving group, or with its reactive derivatives, and optionally a compound thus obtained is then alkylated at the nitrogen atom in the 4-position and if necessary, a protective residue used during the reactions to protect reactive groups is split off and / - or if desired, a compound of the general formula I thus obtained is then separated into its stereoisomers and / or a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.