DE19907813A1 - Substituted bicyclic heterocycles, their preparation and their use as pharmaceuticals - 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

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

their tautomers, their stereoisomers, their mixtures and their Salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, which are worth have full properties.

The compounds of the general formula I in which E represents a cyano group are valuable intermediates for the preparation of the remaining compounds of the general formula I. The compounds of the general formula I in which E is an R _b NH-C (= NH) group and their tautomers and their stereoisomers have valuable pharmacological properties, in particular a thrombin-inhibiting and thrombin-prolonging effect.

The subject of the present application are thus the new Ver compounds of the general formula I, their preparation, Arznei agent containing the pharmacologically active compounds of the formula I and their use.

In the above general formula
Ra is _a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom in which
a methylene group in the 2-position may be replaced by a carbonyl or sulfonyl group or
a methylene group in the 4-position by an oxygen or sulfur atom or by an -NR ₁ group, wherein R _{1 represents} a hydrogen atom or a C _1-6 alkyl group, he can be set and in a thus obtained, two hetero atoms containing Ring one or two more methylene groups may be replaced by carbonyl groups,
wherein the above-described 5-, 6- or 7-membered saturated heterocyclic rings may also be benzo-fused via two adjacent carbon atoms and the phenyl moiety may be optionally substituted by a C _1-3 -alkyl or C _1-3 -alkoxy group,
or a group of the formula

in the
R _c denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C _1-3 -alkyl or C _1-3 -alkoxy group and
R ₁ is defined as mentioned above,
or a 5-membered heteroaromatic group bonded via a nitrogen atom which contains one, two or three nitrogen atoms and which may be benzoically condensed via two adjacent carbon atoms,
wherein the 5-membered heteroaromatic group in the carbon skeleton by C _1-6 alkyl, carboxy, C _1-4 alkoxy carbonyl, carboxy (C _1-4 ) alkyl, C _1-4 alkoxycarbonyl - (C _1-4 ) alkyl, phenyl, pyridyl, furanyl or thienyl groups may be mono- or disubstituted independently and a carboxy group contained in said radicals contained carboxy group also by an in vivo group into a carboxy group Group can be replaced,
the phenyl part of a benzo-fused 5-membered heteroaromatic group may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 -alkyl or C _1-3 -alkoxy group, and
the heteroaromatic group may also be partially hydrogenated, with the inclusion of a possibly fused-on phenyl moiety, the dihydroderivatives being preferred, and resulting -NH groups also being able to be replaced by -NR ₁ groups as defined above,
a tetrazolyl group bonded via a nitrogen atom or
a tetrazolyl group bonded via the carbon atom in which a nitrogen atom may be substituted by a C _1-6 alkyl group,
Y is an oxygen or sulfur atom or an imino group optionally substituted by a C _1-6 -alkyl or C _3-7 -cycloalkyl group,
X ₁ , X ₂ , X ₃ and X _{4 are} each a methine group or one or two of the radicals X ₁ , X ₂ , X ₃ and X _{4 are} each a nitrogen atom and the remaining radicals are each a methine group,
B is an ethylene group in which a methylene group linked to either the bicyclic heterocycle of formula I or to the group Ar is substituted by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, carbonyl or -NR ₁ group may be replaced, wherein R ₁ is defined as mentioned above,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenylene or naphthylene group,
an optionally substituted in the carbon skeleton by a C _1-3 alkyl group substituted thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or Pyridazinylengruppe and
E is a cyano or R _b NH-C (= NH) group in which
R _{b represents} a hydrogen atom, a hydroxy group or an in vivo cleavable residue.

The compounds of the above general formula I, which have a vivo cleavable remainder, thus represent so-called Pro drugs and compounds of general formula I, the two in vivo cleavable residues contain, so-called double prodrugs represents.

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

R _{2 is} -CO-O- (R ₃ CR ₄ ) -OH,

in that
R _{2 is} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{3 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{4 represents} a hydrogen atom or a C _1-3 -alkyl group,
or under one of an imino or amino group in vivo from cleavable radical, for example, a hydroxy group, an acyl group such as an optionally substituted by a C _1-3 alkyl group benzoyl or pyridinoyl group, for. Benzoyl, p-ethylbenzoyl, p-isopropylbenzoyl or nicotinic group, or a C _1-16 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecycloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenylC _1-6 alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C _1-3 alkyl-sulfonyl-C _2-4 -alkoxycarbonyl, C _1-3 -alkoxy-C _2-4 -alkoxy-C _2-4 -alkoxycarbonyl or R ₂ CO-O- (R ₃ CR ₄ ) - O-CO group in which R ₂ to R ₄ are defined as mentioned above,
to understand.

As preferred prodrug residues for a carboxy group is a C _1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl, n-butyloxy carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or Cyc lohexyloxycarbonyl group or phenyl-C _1-3 alkoxycarbonyl group such as the benzyloxycarbonyl group and
for an imino or amino group, a C _1-9 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxy carbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n -Hep tyloxycarbonyl, n-octyloxycarbonyl or n-Nonyloxycarbonyl group, a phenyl-C _1-3 alkoxycarbonyl such as the benzyl oxycarbonyl, an optionally substituted by a C _1-3 alkyl group phenylcarbonyl group such as the benzoyl or 4-ethyl benzoyl group, a pyridinoyl group such as the nicotinic oylgruppe, a C _1-3 alkylsulfonyl-nC _2-3 alkoxycarbonyl or C _1-3 alkoxy-C _2-3 alkoxy-C _2-4 alkoxycarbonyl such as the 2- Methylsulfonylethoxycarbonyl or 2- (2-ethoxy) -ethoxycarbo nylgruppe into consideration.

Furthermore, those in the definition of the above include mentioned saturated alkyl and alkoxy moieties exceeding 2 Contain carbon atoms, as well as alkanoyl moieties that more than Contain 3 carbon atoms, including their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.

The following groups may be mentioned by way of example for the radical R _a :
Pyrrolidin-1-yl,
Piperidin-1-yl,
2,3-dioxo-3,4-dihydro-2H-quinoxaline-1-yl,
2-methyl-benzimidazol-1-yl,
4-ethyl-3-oxo-3,4-dihydro-2H-quinoxaline-1-yl,
4-oxo-3,4-dihydro-phthalazin-1-yl,
2-oxo-piperidin-1-yl,
Butansultam-1-yl,
1-isobutyl-1H-tetrazol-5-yl,
3-methyl-5-phenyl-pyrazol-1-yl,
3- (2-ethoxycarbonylethyl) -5-phenyl-pyrazol-1-yl,
3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) pyrazole-1-yl,
3- (2-hydroxycarbonylethyl) -5-phenyl-pyrazol-1-yl,
3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) pyrazole-1-yl,
3-ethoxycarbonyl-5- (thiophen-2-yl) -pyrazol-1-yl,
3-carboxy-5- (thiophen-2-yl) -pyrazol-1-yl,
3-methyl-5- (2-furyl) pyrazole-1-yl,
3-ethoxycarbonylmethyl-5-phenyl-pyrazol-1-yl,
3-hydroxycarbonylmethyl-5-phenyl-pyrazol-1-yl,
3-ethoxycarbonyl-5-tert.butyl-pyrazol-1-yl,
3-carboxy-5-tert-butyl-pyrazol-1-yl,
5-hydroxycarbonylmethyl-4- (2-pyridyl) isoxazole-3-yl,
1-phenyl-4- (2-hydroxycarbonylethyl) -imidazol-2-yl,
1-cyclopentyl-4-hydroxycarbonylmethylh-imidazol-2-yl,
2-hydroxycarbonylmethyl-5-phenyl-imidazol-1-yl,
3- (3-pyridyl) -5- (2-hydroxycarbonylethyl) -4H- [1,2,4] triazol-4-yl,
3-phenyl-5-hydroxycarbonylmethyl-isoxazol-4-yl,
3-isobutyl-5- (2-hydroxycarbonylethyl) -isoxazole-4-yl,
3-hydroxycarbonylmethyl-5- (2-pyridyl) isoxazol-4-yl,
3-phenyl-5- (3-hydroxycarbonylpropyl) -isothiazol-4-yl and
3-hydroxycarbonylmethyl-5- (3-pyridyl) -isothiazole-4-yl.

Preferred compounds of the above general formula I are those in which
Ra is _a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom in which
a methylene group in the 2-position may be replaced by a carbonyl or sulfonyl group or
a methylene group in the 4-position may be replaced by an oxygen atom or an -NR ₁ group, wherein R _{1 represents} a hydrogen atom or a C _1-3 alkyl group, and in one thus obtained ring containing two heteroatoms one or two further methylene groups may be replaced by carbonyl groups,
wherein the above-described 5- or 6-membered saturated heterocyclic rings may also be benzo-fused via two adjacent carbon atoms and the phenyl moiety may be optionally 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 C _1-3 alkyl group and
R ₁ is defined as mentioned above,
or a 5-membered heteroaromatic group bonded via a nitrogen atom which contains one or two nitrogen atoms and which may be benzo-fused via two adjacent carbon atoms,
wherein the 5-membered heteroaromatic group in the carbon skeleton by C _1-4 alkyl, carboxy, C _1-4 alkoxy carbonyl, carboxy (C _1-4 ) alkyl, C _1-4 alkoxycarbonyl - (C _1-4 ) alkyl, phenyl, pyridyl, furanyl or thienyl groups may be mono- or disubstituted independently and a carboxy group contained in said radicals contained carboxy group also by an in vivo group into a carboxy group Group can be replaced,
the phenyl part of a benzo-fused 5-membered heteroaromatic group may be substituted by a C _1-3 -alkyl or C _1-3 -alkoxy group, and
the heteroaromatic group may also be dihydrogenated with the inclusion of a possibly fused-on phenyl moiety and resulting -NH groups may also be replaced by -NR ₁ groups as defined above,
or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom may be substituted by a C _1-4 alkyl group,
Y is an oxygen atom or an imino group which is optionally substituted by a C _1-4 -alkyl group,
X ₁ , X ₂ , X ₃ and X _{4 are} each 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 ₁ group, where R ₁ is defined as mentioned above,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenylene or naphthylene group,
an optionally in the carbon skeleton by a C _1-3 alkyl substituted pyridinylene group and
E is a cyano or R _b NH-C (NHNH) group in which R _{b represents} a hydrogen atom or an in vivo cleavable radical,
their tautomers, their prodrugs, their Doppelpro drugs, their stereoisomers and their salts.

Particularly preferred compounds of the above general formula I are those in which
R _{a is} a 5- or 6-membered saturated heterocyclic ring bonded via a nitrogen atom, wherein
a methylene group in the 2-position may be replaced by a carbonyl or sulfonyl group or
a methylene group in the 4-position of the 6-membered saturated heterocyclic ring by a -NR ₁ group, wherein R _{1 represents} a hydrogen atom or a C _1-3 alkyl group, may be replaced and in a thus obtained containing two heteroatoms Ring one or two more methylene groups may be replaced by carbonyl groups,
wherein the above-described 6-membered saturated heterocyclic rings may also be benzo-fused via two adjacent carbon atoms and the phenyl moiety may optionally be substituted by a C _1-3 -alkyl group,
or a group of the formula

in the
R _{c represents} a hydrogen atom or a C _1-3 alkyl group and
R ₁ is defined as mentioned above,
or a pyrrole-1-yl, imidazol-1-yl or pyrazol-1-yl group optionally benzo-fused via two adjacent carbon atoms,
wherein said heteroaromatics in the carbon skeleton are represented by C _1-4 alkyl, carboxy, C _1-3 alkoxycarbonyl, carboxy (C _1-2 ) alkyl, C _1-2 alkoxycarbonyl (C _1-2 ) alkyl, phenyl, pyridyl, furanyl or thienyl groups may be mono- or disubstituted, wherein the substituents may be the same or different, with the proviso that only one of the substituents is an aromatic or heteroaro matic radical, and a may also be replaced by a carboxy group which can be converted into a carboxy group in vivo in said radicals,
or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom may be substituted by a C _1-4 alkyl group,
Y is an imino group which is optionally substituted by a C _1-3 -alkyl group,
X ₁ , X ₂ , X ₃ and X _{4 are} each 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, wherein R ₁ is defined as mentioned above,
Ar is a phenylene group optionally substituted by a C _1-3 alkyl group,
E is a cyano or R _b NH-C (= NH) group in which
R _{b represents} a hydrogen atom or an in vivo cleavable radical,
their tautomers, their prodrugs, their Doppelpro drugs, their stereoisomers and their salts.

For example, the following may be mentioned as particularly preferred compounds:

• a) 1-Methyl-2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-1H- tetrazol-5-yl) -benzimidazole,
• b) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- (3-methyl- 5-phenyl-pyrazol-1-yl) -benzimidazole,
• c) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxy carbonylethyl) -5-phenyl-pyrazol-1-yl] benzimidazole,
• d) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxy carbonylethyl) -5- (3-pyridyl) pyrazole-1-yl] benzimidazole,
• e) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxy carbonylethyl) -5-phenyl-pyrazol-1-yl] benzimidazole,
• f) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxy carbonylethyl) -5- (3-pyridyl) pyrazole-1-yl] benzimidazole,
• g) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-ethoxycar carbonyl-5- (thiophen-2-yl) -pyrazol-1-yl] benzimidazole,
• h) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- [3-carboxy- 5- (thiophen-2-yl) -pyrazol-1-yl] benzimidazole,
• i) 1-methyl-2- (4-amidinophenyloxymethyl) -5- [3-methyl- 5- (2-furyl) pyrazole-1-yl] benzimidazole,
• j) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycar bonylmethyl-5-phenyl-pyrazol-1-yl) -benzimidazole,
• k) 1-methyl-2- [2- (4-amidinophenyl) ethyl] -5- [3-methyl- 5- (2-furyl) pyrazole-1-yl] benzimidazole,  
• l) 1-Methyl-2- (4-amidinophenylaminomethyl) -5- [3-methyl- 5- (2-furyl) -pyrazol-1-yl] -benzimidazole and
• m) 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-hydroxy carbonylmethyl-5-phenyl-pyrazol-1-yl) -benzimidazole,

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

The new compounds can be fah after known Ver
produce, for example, by the following methods:
a) For the preparation of a compound of the general formula I in which E is an R _b NH-C (NHNH) group in which R _{b is} a hydrogen atom or a hydroxy group:
Reaction of a compound of the general formula which may be formed in the reaction mixture

in the
R _a , X ₁ to X ₄ , Y, B and Ar are as defined above and Z _{1 is} an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkyl thio or aralkylthio group as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of the general formula

H ₂ NR _b ', (IV)

in the
R _{b represents} a hydrogen atom or a hydroxy group.

The reaction is conveniently 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 general formula III or with a corresponding acid addition salt such as ammonium carried out carbonate.

A compound of general formula III is obtained at For example, by reacting a compound of the general Formula I, in which E represents a cyano group, with a ent speaking alcohol such as methanol, ethanol, n-propanol, iso propanol or benzyl alcohol in the presence of an acid such as salt acid or by reacting a corresponding amide with a Trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or Dioxane at temperatures between 0 and 50 ° C, preferably each but at 20 ° C, or a corresponding nitrile with sulfur hydrogen conveniently in a solvent such as pyri din or dimethylformamide and in the presence of a base such as tri ethylamine and subsequent alkylation of the thio formed amides with a corresponding alkyl or aralkyl halide.

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 above, that the R _a group contains a carboxy group and E is as defined above or the R _a group as defined above and E represents an NH ₂ -C (= NH) group or the R _a group contains a carboxy group and E represents an NH ₂ -C (= NH) group:
Transfer of a compound of the general formula

in the
X ₁ to X ₄ , Y, B and Ar are as defined above and the R _a 'group and E' have the meanings mentioned for the R _a group and E, with the proviso that the R _a 'group is a by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a carboxyl group and E as defined above or E 'one by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a NH ₂ -C (= NH) group and the R _a 'group has the meanings mentioned for the R _a group, or the R _a ' group can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis Contains group and E 'represents a group convertible by hydrolysis, Behan deln with an acid or base, thermolysis or hydrogenolysis in a NH ₂ -C (= NH) group,
by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis in a compound of the general For mel I is transferred, in which the R _a group and E are defined with the proviso as mentioned above, that the R _a group Contains carboxy group and E is as defined above or the R _a group has the meanings mentioned above and E is an NH ₂ -C (= NH) group or the R _a group contains a carboxy group and E is an NH ₂ -C ( = NH) group.

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

The hydrolysis is conveniently carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, vinegar acid, trichloroacetic acid, trifluoroacetic acid or their Gemi or in the presence of a base such as lithium hydroxide, Natri hydroxide or potassium hydroxide in a suitable solvent tel such as water, water / methanol, water / ethanol, water / Isopro panol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, z. B. at Tem temperatures between room temperature and the boiling point of the Reaction mixture, carried out.

Contains the R _a 'group and / or E' in a compound of formula V, for example, the tert. Butyl or tert.Butyloxy carbonylygruppe, so they 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 Te hydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, z. B. at temperatures between 0 and 60 ° C, or thermally optionally in an inert Lösungsmit tel such as methylene chloride, chloroform, benzene, toluene, Tetrahy drofuran or dioxane and preferably in the presence of a kata lytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid , Phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, for. B. at temperatures between 40 and 120 ° C, are split off.

Contains the R _a 'group and / or E' in a compound of formula V, for example, the benzyloxy or Benzyloxycarbo nylgruppe, they can also hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a ge suitable solvent such as methanol, ethanol, ethanol / Water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, z. B. at room temperature, and a hydrogen pressure of 1 to 5 bar are split off.

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 at the outset:
Reaction of a compound of the general formula

in the
X ₁ to X ₄ , Y, B, Ar and E are as defined above and R _a "has the meanings mentioned for the R _a with the measure that R _a " a carboxyl group or one by means of an alcohol in a corresponding ester group contains convertible group, with an alcohol of the general formula

HO-R ₅ , (VII)

in the
R _{5 represents} the alkyl part of one of the above-mentioned in vivo leaving cleavable radicals except the R ₂ -CO-O- (R ₃ CR ₄ ) group for a carboxyl group, or with their formamide acetals
or with a compound of the general formula

Z ₂ -R ₆ , (VIII)

in the
R _{6 is} the alkyl part of one of the abovementioned in vivo cleavable radicals except the R ₂ -CO-O- (R ₄ CR ₅ ) group for a carboxyl group and
Z _{2 is} a leaving group such as a halogen atom, e.g. As a chlorine or bromine, represent.

The reaction with an alcohol of the general formula VII is conveniently in a solvent or solvent such as methylene chloride, benzene, toluene, chlorobenzene, tetra hydrofuran, benzene / tetrahydrofuran or dioxane, preferably however, in an alcohol of general formula VII, given if in the presence of an acid such as hydrochloric acid or in the presence a dehydrating agent, for. In the presence of chlorine isobutyl isobutyl ester, thionyl chloride, trimethylchlorosilane, Hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfone acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexyl carbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, triphe nylphosphine / carbon tetrachloride or triphenylphosphine / azo Dicarbonsäurediethylester optionally in the presence of a Base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dime Thylamino-pyridine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, carried out.

With a compound of general formula VIII is the order expediently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl formamide or acetone, optionally in the presence of a reac tion accelerator such as sodium or potassium iodide and preferential  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 at the same time, or give if appropriate in the presence of silver carbonate or silver oxide Temperatures between -30 and 100 ° C, but preferably at Temperatures between -10 and 80 ° C, performed.

d) For the preparation of a compound of the general formula I, in which R _{b represents} a residue cleavable in vivo:
Reaction of a compound of the general formula

in the
R _a , X ₁ to X ₄ , Y, B and Ar are as defined above, with a compound of the general formula

Z ₃ -R ₇ , (X)

in the
R _{7 is} an in vivo cleavable radical and
Z _{3 is} a nucleophilic leaving group such as a halogen atom, e.g. As a chlorine, bromine or iodine atom, mean.

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

With a compound of general formula X, in which Z _{3 represents} a nucleofuge leaving group, the reaction is preferably in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or Dime thylsulfoxid optionally in the presence of a base such as sodium triumhydrid, potassium carbonate, Potassium tert-butylate or N-ethyl diisopropylamine at temperatures between 0 and 60 ° C, passed through.

e) For the preparation of a compound of 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 ₁ 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, eg. In water, water / pyridine, acetone, Methylene chloride, glacial acetic acid, glacial acetic acid / acetic anhydride, more dilute Sulfuric acid or trifluoroacetic acid, and depending on the verwen Deten oxidizing agent expediently at temperatures between between -80 and 100 ° C.

For the preparation of a corresponding sulfinyl compound of general formula I, the oxidation is expediently with one equivalent of the oxidizing agent used leads, z. With hydrogen peroxide in glacial acetic acid, trifluoroacetic acid 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 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 hypo chlorite 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 resulting thioether-chlorine complex is suitably hydrolyzed with aqueous ethanol.

For the preparation of a sulfonyl compound of the general formula I is the oxidation starting from a corresponding Sulfinyl compound expediently with one or more equi valent of the oxidizing agent used or starting from a corresponding sulfenyl compound expediently with two or more equivalents of the oxidizing agent used carried out, for. B. with 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 Performic acid or m-chloroperbenzoic acid in glacial acetic acid, tri fluoroacetic acid, methylene chloride or chloroform at tempera 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. So get For example, in the oxidation starting from an ent speaking sulfenyl compound, preferably in methylene chloride by treatment with an appropriate amount of m-chloroper benzoic acid at temperatures between 20 ° C and the Rückflußtem temperature of the reaction mixture, a corresponding Sulfonylver Binding of the general formula I, which still a small Men may contain ge to the corresponding sulfinyl compound.  

f) for preparing 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 linked either to the bicyclic heterocycle of the formula I or to the group Ar is replaced by an oxygen or sulfur atom, is replaced by a sulfinyl, sulfonyl, carbonyl or -NR ₁ group, represent:
Reaction of a compound of the general formula

with a compound of the general formula

V-Ar-CN, (XIII)

in which
R _a , X ₁ to X ₄ , Y and Ar are as defined above, one of the radicals U or V is an HO, HS, HOSO, HOSO ₂ or HNR ₁ group and the other of the radicals is a Z ₃ CH Represent ₂ group, wherein R _{1 is} as defined above and Z ₃ a nuk leofuge leaving group such as a halogen atom, for. As a chlorine, bromine or iodine atom, mean.

The reaction is preferably in a solvent such as Me ethanol, ethanol, methylene chloride, tetrahydrofuran, toluene, di oxane, dimethyl sulfoxide or dimethylformamide optionally in the presence of an inorganic or a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or dimethyl aminopyridine, preferably at temperatures between 20 ° C and the boiling point of the solvent used, Runaway leads, wherein a compound of general formula XII or XIII, in which Z _{3 represents} a halogen atom, can also be prepared in Reaktionsge mixture.

g) For the preparation of a compound of general formula I in which Y is an oxygen or sulfur atom or an imino group optionally substituted by a C _1-6 -alkyl or C _3-7 -cycloalkyl group, X ₁ to X ₄ methine groups, E a cyano group and B is an ethylene group in which the methylene group linked with the group Ar can be replaced by an oxygen or sulfur atom or by a -NR ₁ group, be interpreted as:
Reaction of a compound of the general formula

in the
R _a and Y are as defined above and X ₁ 'to X ₄ ' each represent a methine group, with a compound of general formula mine

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

in the
Ar is defined as mentioned above and B 'represents an ethylene group in which the methyl group linked to the group Ar may be replaced by an oxygen or sulfur atom or by an -NR ₁ group, or with their reactive derivatives.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylform amide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / Te trahydrofuran or dioxane optionally in the presence of a dehydrating agent, for. In the presence of chloroam isobutyl ester of synthetic acid, tetraethyl orthocarbonate, Ortho trimethyl acetate, 2,2-dimethoxypropane, tetramethoxy  silane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclo hexylcarbodiimide / N-hydroxysuccinimide, N, N'-dicyclohexylcar bodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazole) 1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / Te trachlorkohlenstoff, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or Triethylamine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, carried out.

The implementation of a corresponding reactive compound of the general formula XV such as their esters, imidazolides or Halides with an amine of the general formula XIV is present preferably in a solvent such as methylene chloride, ether or tetrahydrofuran, and preferably in the presence of a ter Tienic organic base such as triethylamine, N-ethyl-diisopropyl amine or N-methylmorpholine, which at the same time as Lö can serve at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C, carried out.

h) For the preparation of a compound of the general formula I in which R _{a is} the 2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl radical and E is the cyano group:
Reaction of a compound of the general formula

in the
X ₁ to X ₄ , Y, B and Ar are as defined above, 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, dimethylform amide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / Te trahydrofuran, ethanol or dioxane optionally in the presence a dehydrating agent, for. In the presence of chlorine isobutyl isobutyl ester, tetraethyl orthocarbonate, Orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetra methoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-di cyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1H-benzo triazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium fluoroborate / 1-hydroxybenzotriazole, 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 at Temperatures between 0 and 150 ° C, preferably at tempera between 0 and 100 ° C.

However, the reaction is particularly preferred with a reak fungible oxalic acid derivative, for example an oxalic acid ester, Oxalsäurehalogenid or Oxalsäureesterhalogenid, with a diamine of 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 serve as a solvent at the same time Temperatures between 0 and 150 ° C, preferably at Tempe temperatures between 0 and 50 ° C.

i) For the preparation of a compound of the general formula I in which R _{a is} in the 2-position optionally substituted by a C _1-6 alkyl, C _1-4 alkoxycarbonyl (C _1-4 ) alkyl, phenyl -, pyridyl, furanyl or thienyl substituted benzimidazol-1-yl radical and E is the cyano group means:
Reaction of a compound of the general formula

in the
X ₁ to X ₄ , Y, B and Ar are as defined above, with a carboxylic acid of the general formula

HO-CO-R ₈ , (XVII)

in the
R _{8 represents} a hydrogen atom, a C _1-6 alkyl, C _1-4 alkoxycarbonyl (C _1-4 ) alkyl, phenyl, pyridyl, furanyl or thienyl group, or with their reactive derivatives ,

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylform amide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / Te trahydrofuran or dioxane optionally in the presence of a dehydrating agent, for. In the presence of chloroam isobutyl ester of synthetic acid, tetraethyl orthocarbonate, Ortho trimethyl acetate, 2,2-dimethoxypropane, tetramethoxy silane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclo hexylcarbodiimide / N-hydroxysuccinimide, N, N'-dicyclohexylcar bodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazole) 1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / Te  trachlorkohlenstoff, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or Triethylamine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, carried out.

The implementation of a corresponding reactive compound the general formula XVII such as their esters, imidazolides or Halides with an amine of the general formula XVI is at For example, in a solvent such as methylene chloride, ether or tetrahydrofuran, and preferably in the presence of a ter Tienic organic base such as triethylamine, N-ethyl-diisopropyl amine or N-methylmorpholine, which at the same time as Lö can serve at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C, carried out. The reaction can also be carried out with a mixture of Carboxylic acid of the general formula XVIII and its anhydride be performed.

k) For the preparation of a compound of the general formula I in which R _{a is} a 4-position optionally substituted by a C _1-6 alkyl group substituted 3-oxo-3, 4-dihydro-2H-quinoxaline-1-yl group and E represents the cyano group:
Reaction of a compound of the general formula

in the
X ₁ to X ₄ , Y, B and Ar are as defined above, with a compound of the general formula

HO-CO-CH ₂ -Z ₂ , (XVIII)

in the
Z _{2 is} a leaving group such as a halogen atom, e.g. As a chlorine or bromine atom, or with their reactive Deri 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, dimethylform amide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / Te trahydrofuran or dioxane optionally in the presence of a dehydrating agent, for. In the presence of chloroam isobutyl ester of synthetic acid, tetraethyl orthocarbonate, Ortho trimethyl acetate, 2,2-dimethoxypropane, tetramethoxy silane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclo hexylcarbodiimide / N-hydroxysuccinimide, N, N'-dicyclohexylcar bodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazole) 1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / Te trachlorkohlenstoff, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or Triethylamine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, carried out.

The implementation of a corresponding reactive compound the general formula XVIII, such as their esters, imidazolides or Halides, with an amine of general formula XVI is present preferably in a solvent such as methylene chloride, ether or tetrahydrofuran, and preferably in the presence of a ter Tienic organic base such as triethylamine, N-ethyl-diisopropyl amine or N-methylmorpholine, which at the same time as Lö can serve at temperatures between 0 and  150 ° C, preferably at temperatures between 0 and 50 ° C, carried out.

The optionally subsequent alkylation of the stick stoffatoms is with a conventional alkylating agent, at For example, an alkyl halide, a sulfonic acid ester, z. B. a Methansulfonsäure- or p-toluenesulfonic acid ester, purpose moderately in a solvent or solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, Dimethylsulfoxide, dimethylformamide or benzene optionally in the presence of an acid-binding agent, such as sodium carbo sodium, potassium hydroxide, sodium hydroxide, sodium hydride, potash um-tert-butylate, or in the presence of an organic base such as N-ethyl-diisopropylamine, N-methyl-morpholine, triethylamine or Pyridine, which also used as a solvent can be, or by alcoholysis in the presence of a star ken base for ethylation, for example, by ethanolysis in Presence of sodium ethylate, preferably at temperatures between 0 and 100 ° C, z. B. at temperatures between Raumtem temperature and 50 ° C, carried out.

In the reactions described above can be given if existing reactive groups such as hydroxy, carboxy, Amino, alkylamino or imino groups during the reaction be protected by conventional protecting groups, which according to the Implementation be split off again.

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

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

The cleavage of a benzyl, methoxybenzyl or benzyl However, oxycarbonylrestes takes place, for example, hydroge nolytically, z. B. with hydrogen in the presence of a catalysis sators such as palladium / carbon in a solvent such as Me ethanol, ethanol, ethyl acetate, dimethylformamide, Dimethylformamide / acetone or glacial acetic acid optionally under 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 from 3 to 5 bar.

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

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

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

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

The elimination of a Allyloxycarbonylrestes done by Treatment with a catalytic amount of tetrakis (triphe nylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an over shot of a base such as morpholine or 1,3-dimedone Temperatures between 0 and 100 ° C, preferably at room temp under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) - chloride in a solvent such as aqueous ethanol and Gege if appropriate in the presence of a base such as 1,4-diazabicyclo- [2.2.2] octane at temperatures between 20 and 70 ° C.

The compounds used as starting materials of the general my formulas III to XVIII, which partially literaturbe are known, obtained by literature methods, the Further, their preparation is described in the examples.

For example, one obtains a compound of the general Formula III by reacting a corresponding nitrile, wel in turn suitably according to the methods f to k is obtained with an appropriate thio or alcohol in Presence of chlorine or hydrogen bromide.

A compound used as starting material of the general Formulas V, VI, IX and XI are conveniently obtained according to a method of the present invention.  

A starting compound of the general formula XII, in which U represents a halomethyl group, it is more convenient example, by ring closure of a corresponding ester, in o-position by a suitable halogen atom and a meth oxyacetamido group is substituted, to a corresponding bicyclic 2-alkoxymethyl compound, optionally closing hydrolysis and optionally subsequent Ami dation of a carboxylic acid thus obtained with a corre sponding amine, conversion of the alkoxymethyl thus obtained compound in the corresponding halomethyl compound, which, if necessary, subsequently by means of an ent speaking connection in the desired compound überge can be led. If you do this the ring closure with a suitable carbonic acid derivative, we obtain an off gangue compound of general formula XII, in the U a Represents hydroxy, mercapto or amino group.

The compounds used as starting materials of the general Formulas IV, VII, VIII, X and XIII are obtained according to tri vial methods, for example by reducing an aroma table ester, which in o-position by an optionally substituted amino group and a nitro group substituted is, and optionally subsequent ring closure of the so obtained o-diamino compound with a corresponding Carboxylic acid.

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

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

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

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

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

As already mentioned, the novel compounds of the general formula I and their salts have valuable properties. Thus, the compounds of the general formula I, in which E represents a cyano group, are valuable intermediates for the preparation of the other compounds of the general formula I and the compounds of the general formula I in which E is an R _b NH-C (= NH) Group, and their Tauto mers, their stereoisomers, their physiologically acceptable salts valuable pharmacological properties, in particular a thrombin-inhibiting effect, the thrombin time ver extended effect and an inhibitory effect on related Serinpro teases such. B. trypsin, urokinase factor VIIa, Factor Xa, Factor IX, Factor XI and Factor XII, although some connec tions such as the compound of Example 16 at the same time also has a low platelet aggregation inhibitory activity.

For example, the compounds were
A = 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride,
B = 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenyl-pyrazol-1-yl] benzimidazole hydrochloride,
C = 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxy-carbonyl-ethyl) -5- (3-pyridyl) -pyrazol-1-yl] -benzimidazole,
D = 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-carboxy-5- (thiophen-2-yl) -pyrazol-1-yl] -benzimidazole and
E = 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycarbonylmethyl-5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride
for their effect on thrombin time as follows:
Material:
Plasma, of human citrated blood.
Test thrombin (bovine), 30 U / ml, Behring Werke, Marburg
Diethyl barbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg
Biomatic B10 coagulometer, Sarstedt

execution

The determination of the thrombin time was carried out with a biomatic B10 coagulometer from Sarstedt.

The test substance was in the manufacturer's prescribed Test vessels with 0.1 ml of human citrate plasma and 0.1 ml of Di ethyl barbiturate buffer (DBA buffer). The approach was incubated for one minute at 37 ° C. By adding 0.3 U Test thrombin in 0.1 ml DBA buffer was the coagulationre action started. Device-related occurs with the input of Thrombin measuring the time to coagulate the batch. The controls used were 0.1 ml DBA buffer were added.

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

The following table contains the found values:

For example, in rats, the application of Ver compound C up to a dose of 10 mg / kg i. v. no acute toxic side effects are observed. These connections are therefore well tolerated.

Due to their pharmacological properties are the new compounds and their physiologically acceptable salts for the prevention and treatment of venous and arterial thrombo diseases, such as the treatment of tie fen vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT (C) A), as well as the Occlusion in peripheral arterial diseases such as lungs Embolism, the disseminated intravascular coagulation, the Prophylaxis of coronary thrombosis, prophylaxis of stroke and preventing the occlusion of shunts or Stents. In addition, the compounds of the invention are for antithrombotic support in a thrombolytic Treatment, such as with rt-PA or streptokinase, for Prevention of long-term restenosis after PT (C) A, for Verhin the metastasis and growth of coagulation dependent tumors and fibrin-dependent inflammatory processes sen suitable.

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

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

Preliminary remarks

When determining the R _f values, unless otherwise stated, Polygram silica gel plates from E. Merck, Darmstadt, were always used.

The EKA mass spectra (electrospray mass spectra of Katio NEN), for example, in chemistry of our time 6, 308-316 (1991).

example 1 1-methyl-2- (4-amidinophenyloxymethyl) -5- (2,3-dioxo-3,4-di hydro-2H-quinoxaline-1-yl) -benzimidazole hydrochloride a) 4-Methylamino-3- (4'-cyanophenyloxy-acetylamino) -nitrobenzene

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 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 O ₄ (326.3)
R _f value: 0.26 (silica gel, dichloromethane / ethanol = 19: 1)

b) 1-Methyl-2- (4-cyanophenyloxymethyl) -5-nitrobenzimidazole

2.3 g (7.07 mmol) of 4-methylamino-3- (4'-cyanophenyloxyacetylamino) -nitrobenzene were refluxed in 60 ml of glacial acetic acid for 45 minutes. After cooling, 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 O ₅ (308.3)
R _f value: 0.29 (silica gel, dichloromethane / ethanol = 19: 1)

c) 1-methyl-2- (4-cyanophenyloxymethyl) -5-amino-benzimidazole

2.0 g (6.5 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5-nitro benzimidazole were hydrogenated in 70 ml of dimethylformamide after addition of 0.5 g of Pd / carbon (10%) at room temperature and 5 bar H ₂ pressure ,
Yield: 1.55 g (86% of theory),
C ₁₆ H ₁₄ N ₄ O (278.32)
R _f value: 0.20 (silica gel, dichloromethane / ethanol = 19: 1)

d) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-nitro-phenyl amino) -benzimidazole

1.5 g (5.39 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5-aminobenzimidazole, 2.82 g (20 mmol) of 2-fluoro-nitrobenzene and 1 ml of N-ethyl-diisopropylamine were added together at 150 ° for 2 hours C stirred. From the mixture, after cooling, the product was isolated by silica gel column chromatography.
Yield: 1.85 g (86% of theory);
C ₂₂ H ₁₇ N ₅ O ₃ (399.42)
R _f value: 0.49 (silica gel, dichloromethane / ethanol = 19/1)

e) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-amino-phenyl amino) -benzimidazole

1.7 g (4.26 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-nitrophenylamino) -benzimidazole were added after addition of 0.5 g of Pd / carbon (10%) at room temperature and 5 bar of H ₂ Hydrogenated pressure.
Yield: 1.35 g (86% of theory),
C ₂₂ H ₁₉ N ₅ O (369.43)
R _f value: 0.36 (silica gel, dichloromethane / ethanol = 19/1)

f) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2,3-dioxo-3,4-di hydro-2H-chinoxcalin-1-yl) -benzimidazole

369 mg (1.0 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-amino-phenylamino) -benzimidazole were dissolved in 25 ml of tetrahydrofuran and 1 ml of pyridine, then 0.45 ml of oxalic acid ethyl ester chloride was added at 10 ° C. and stirred for 3 hours at room temperature. It was then evaporated to dryness and the residue heated in 50 ml of dioxane for 2 hours to reflux. Then the dioxane was distilled off, the residue mixed with about 50 ml of water and with stirring with conc. Ammonia adjusted to pH 8. The precipitated product was filtered off with suction and purified by column chromatography on silica gel.
Yield: 105 mg (25% of theory),
C ₂₄ H ₁₇ N ₅ O ₃ (423.44)
R _f value: 0.11 (silica gel, dichloromethane / ethanol = 19/1)

g) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (2,3-dioxo-3,4-di hydro-2H-quinoxaline-1-yl) -benzimidazole hydrochloride

A solution of 423 mg (1.0 mmol) of 1-methyl-2- (4-cyanophenyl oxymethyl) -5- (2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl) -benzimidazole in 40 ml of freshly prepared saturated ethanolic hydrochloric acid was stirred for 6 hours at room temperature. Then, the mixture was completely evaporated, the residue dissolved in 40 ml of ethanol, 960 mg (10 mmol) of ammonium carbonate added and stirred for 48 hours at room temperature. The precipitated product was filtered off with suction, suspended in 30 ml of water, filtered off with suction again and dried.
Yield: 340 mg (71.5% of theory),
C24H ₂ ON603 (440.47)
R _f value: 0.08 (silica gel, dichloromethane / ethanol = 4/1)
Mass Spectrum:
(M + H) ⁺ = 441
(M + 2H) ⁺⁺ = 221

Example 2 2- (3-amidinophenyloxymethyl) -5- (pyrrolidin-1-yl) -1H-benz imidazole hydrochloride a) 1,2-Diamino-4- (pyrrolidin-1-yl) benzene

3.5 g (16.85 mmol) of 2-amino-4- (pyrrolidin-1-yl) -nitrobenzene were after 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 hydrogenated at 5 bar H ₂ pressure. The product was reacted after filtering off the catalyst and distilling off the solution by means of immediately raw.
Yield: 2.98 g
C ₁₀ H ₁₅ N ₃ (177.25)
R _f value: 0.44 (silica gel, dichloromethane / ethanol = 9: 1)

b) 2- (3-cyanophenyloxymethyl) -5- (pyrrolidin-1-yl) -1H-benz imidazole

2.98 g (16.85 mmol) of 1,2-diamino-4- (pyrrolidin-1-yl) -benzene and 2.66 g (15 mmol) of 3-cyanophenyloxy-acetic 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 was treated with conc. Ammonia is made alkaline and the precipitated Rohpro product sucked. Chromatographic purification gave 150 mg (3% of theory) of 2- (3-cyanophenyloxymethyl) -5- (pyrrolidin-1-yl) -1H-benzimidazole.
C ₁₉ H ₁₈ N ₄ O (318.39)
R _f value: 0.58 (silica gel, dichloromethane / ethanol = 9: 1)

c) 2- (3-amidinophenyloxymethyl) -5- (pyrrolidin-1-yl) -1H-benz imidazole hydrochloride

Prepared analogously to Example 1 from 2- (3-cyanophenyloxymethyl) - 5- (pyrrolidin-1-yl) -1H-benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 72% of theory,
R _f value: 0.13 (silica gel, dichloromethane / ethanol = 4: 1)
C ₁₉ H ₂₁ N ₅ O (335.42)
Mass Spectrum:
(M + H) ⁺ = 336
(M + 2H) ⁺⁺ = 168.6
(2M + H) ⁺ = 671

Example 3 1-methyl-2- (4-amidinophenyloxymethyl) -5- (2-methyl-benzimi dazol-1-yl) -benzimidazole dihydrochloride a) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-methylbenzimi dazol-1-yl) -benzimidazole

500 mg (1.35 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-amino-phenylamino) benzimidazole (Example 1e) were refluxed in 30 ml of glacial acetic acid after addition of 2 ml of acetic anhydride for 3 hours , The mixture was then concentrated completely 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 O (393.46)
R _f value: 0.35 (silica gel, dichloromethane / ethanol = 19: 1)

b) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (2-methylbenzimi dazol-1-yl) benzimidazole dihydrochloride

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),
R _f value: 0.16 (silica gel, dichloromethane / ethanol = 4: 1)
C ₂₄ H ₂₂ N ₆ O (410.49)
Mass Spectrum:
M ⁺ = 410

Example 4 1-methyl-2- (4-amidinophenyloxymethyl) -5- (4-ethyl-3-oxo-3,4-di hydro-2H-quinoxaline-1-yl) -benzimidazole hydrochloride a) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (4-ethyl-3-oxo-3,4- dihydro-2H-quinoxaline-1-yl) -benzimidazole

370 mg (1.0 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) -5- (2-amino-phenylamino) benzimidazole (Example 1e) were dissolved in 20 ml of tetrahydrofuran, then 1 ml of triethylamine and 150 mg of chloroacetyl chloride were added, and the mixture stirred for 18 hours at room temperature. The mixture was then fully evaporated continuously and the residue in a Natriumethylat- solution (150 mg in 30 ml of ethanol) heated for one hour to reflux. It was again concentrated to dryness and the product was isolated from the residue by column chromatography on silica gel.
Yield: 180 mg (41% of theory),
C ₂₆ H ₂₃ N ₅ O ₂ (437.51)
R _f value: 0.46 (silica gel, dichloromethane / ethanol = 19: 1)

b) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (4-ethyl-3-oxo) 3,4-dihydro-2H-quinoxaline-1-yl) -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenyl oxymethyl) -5- (4-ethyl-3-oxo-3,4-dihydro-2H-quinoxalin-1-yl) - benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 89% of theory,
R _f value: 0.29 (silica gel, dichloromethane / ethanol = 4: 1)
C ₂₆ H ₂₆ N ₆ O ₂ (454.54)
Mass Spectrum:
(M + H) ⁺ = 455
(M + 2H) ⁺⁺ = 228

Example 5 1-methyl-2- (4-amidinophenyloxymethyl) -5- (4-oxo-3,4-dihydro phthalazin-1-yl) -benzimidazole hydrochloride a) 2- (4-Methylamino-3-nitrobenzoyl) benzoic acid

3.05 g (10 mmol) of 2- (4-chloro-3-nitrobenzoyl) benzoic acid WUR in 50 ml of aqueous methylamine solution (40%) 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 filtered off with suction, washed with water and dried.
Yield: 3.0 g (100% of theory),
C ₁₅ H ₁₂ N ₂ O ₅ (400.3)
R _f value: 0.61 (silica gel, dichloromethane / ethanol = 9: 1)

b) 1-methylamino-2-nitro-4- (4-oxo-3,4-dihydro-phthalazine 1-yl) benzene

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

c) 1-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-dihydro-phthalazin-1-yl) -benzene were dissolved in 150 ml of dimethylformamide after addition of 0.3 g of Pd / carbon (10%). ig) hydrogenated at room temperature and 5 bar H ₂ pressure.
Yield: 2.6 g (100% of theory),
C ₁₅ H ₁₄ N ₄ O (266.3)
R _f value: 0.22 (silica gel, dichloromethane / ethanol = 19: 1)

d) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (4-oxo-3,4-dihydro- phthalazin-1-yl) -benzimidazole

709 mg (4.0 mmol) of 4-cyanophenyloxyacetic acid and 648 mg (4.0 mmol) of N, N'-carbonyldiimidazole were refluxed in 50 ml of absolute tetrahydrofuran for 15 minutes. Then 1.0 g (3.7 mmol) of 1-methylamino-2-amino-4- (4-oxo-3,4-dihydro-phthalazin-1-yl) -benzene was added and boiled for a further 16 hours. It was then evaporated to dryness and the residue was heated in 50 ml of glacial acetic acid for one hour to reflux, re-evaporated and the product was isolated from the residue by column chromatography on silica gel.
Yield: 1.0 g (66% of theory),
C ₂₄ H ₁₇ N ₅ O ₂ (407.4)
Mass Spectrum:
(M + H) ⁺ = 408

e) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (4-oxo-3,4-dihydro phthalazin-1-yl) -benzimidazole hydrochloride

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 On the monium carbonate.
Yield: 150 mg (13% of theory),
C ₂₄ H ₂ ON ₆ O ₂ (424.5)
Mass Spectrum:
(M + H) ⁺ = 425

Example 6 1-methyl-2- (4-amidinophenylaminomethyl) -5- (2-oxo-piperidin- 1-yl) -benzimidazole hydrochloride a) 2-nitro-4- (5-bromopentanoyl-amino) -fluorobenzene

A solution of 3.74 g (24 mmol) of 4-fluoro-3-nitroaniline, 4.85 g (24 mmol) of 5-bromovaleric acid chloride and 3 ml of triethylamine in 100 ml of absolute tetrahydrofuran was stirred for two hours at room temperature and then the Concentrated to dryness. From the residue, the product was isolated by silica gel column chromatography.
Yield: 7.0 g (92% of theory),
C ₁₁ H ₁₂ BrFN ₂ O ₃ (319.1)
R _f value: 0.48 (silica gel, ethyl acetate / petroleum ether = 7: 3)

b) -Nitro-4- (2-oxopiperidin-1-yl) -fluorobenzene

To a stirred suspension of 1.05 g (21.9 mmol) of sodium hydride in 200 ml of tetrahydrofuran, a solution of 7.0 g (21.9 mmol) of 2-nitro-4- (5-bromopentanoyl-amino) -fluorobenzene was added dropwise within 15 minutes. After a further 30 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 silica gel column chromatography.
Yield: 4.1 g (79% of theory),
C ₁₁ H ₁₁ FN ₂ O ₃ (238.2)
R _f value: 0.35 (silica gel, ethyl acetate / petroleum ether = 7: 3)

c) N-methyl-2-nitro-4- (2-oxo-peridin-1-yl) -aniline

4.1 g (17 mmol) of 2-nitro-4- (2-oxopiperidin-1-yl) fluorobenzene were stirred for one hour at room temperature in 50 ml of methylamine solution (40% in water). Then it was diluted with about 100 ml of water, the crystallized product was filtered off, washed with water and dried.
Yield: 3.9 g (92% of theory),
C ₁₂ H ₁₅ N ₃ O ₃ (249.3)
R _f value: 0.23 (silica gel, ethyl acetate / petroleum ether = 9: 1)

d) 1-Methylamino-2-amino-4- (2-oxopiperidin-1-yl) -benzene

3.9 g (15.6 mmol) of N-methyl-2-nitro-4- (2-oxopiperidin-1-yl) -aniline were dissolved in 250 ml of methanol at room temperature with addition of 0.5 g of Pd / carbon (10% strength). hydrogenated at 5 bar H ₂ pressure.
Yield: 3.3 g (97% of theory)
C ₁₂ H ₁₇ N ₃ O (219.3)
R _f value: 0.19 (silica gel, dichloromethane / ethanol = 19: 1)

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

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 heated to reflux for 30 minutes. Then, 1.1 g (5.0 mmol) of 1-methylamino-2-amino-4- (2-oxo-piperidin-1-yl) -benzene was added and stirred at 60 ° C for 48 hours. After cooling, the crystallized Pro product was filtered off with suction, washed with diethyl ether and dried.
Yield: 1.15 g (61% of theory),
R _f value: 0.70 (silica gel, dichloromethane / ethanol = 9: 1)
C ₂₁ H ₂₁ N ₅ O (359.4)
Mass Spectrum:
M ⁺ = 359

f) 1-methyl-2- (4-amidinophenylaminomethyl) -5- (2-oxopiperidine) 1-yl) -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1.1 g (3.0 mmol) of 1-methyl-2- (4-cyanophenylaminomethyl) -5- (2-oxo-piperidin-1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.75 g (61% of theory),
C ₂₁ H ₂₄ N ₆ O (376.5)
Mass Spectrum:
(M + H) ⁺ = 377

Example 7 1-methyl-2- (4-amidinophenylaminomethyl) -5- (butansultam-1-yl) - benzimidazole hydrochloride

Prepared (analogously to Example 1) from 1-methyl-2- (4-cyanophe nylaminomethyl) -5- (butansultam-1-yl) benzimidazole, ethanolic shear hydrochloric acid, ethanol and ammonium carbonate.
Yield: 56% of theory,
C ₂₀ H ₂₄ N ₆ O ₂ S (412.5)
Mass Spectrum:
(M + H) ⁺ = 413

Example 8 1-methyl-2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-1H-tetra- zol-5-yl) -benzimidazole hydrochloride a) N-Isohutyl-4-chloro-3-nitro-benzoic acid amide

To a solution of 13.2 g (60 mmol) of 4-chloro-3-nitro-ben zoylchlorid and 6.0 g (60 mmol) of diethylamine in 150 ml abso lutem tetrahydrofuran with stirring 6 ml (60 mmol) of iso-butylamine, dissolved in 60 ml Terahydrofuran, slowly added dropwise. It was then stirred for one hour, then evaporated to dryness and isolated from the residue by column chromatography on silica gel, the product.
Yield: 13.5 g (88% of theory),
C ₁₁ H ₁₃ ClN ₂ O ₃ (256.7)
R _f value: 0.64 (silica gel, dichloromethane / ethanol = 50: 1)

b) 2-nitro-4- (1-isobutyl-1H-tetrazol-5-yl) -chlorobenzene

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 was added 2.6 g (40 mmol) of sodium azide, then with stirring at 0 ° C 6.7 ml (40 mmol ) Trifluoromethansäureanhydrid added dropwise. The mixture was then stirred at room temperature for 40 hours. 200 ml of 5% strength sodium bicarbonate solution were then added with vigorous stirring, then the organic phase was separated off, the aqueous phase was extracted twice more with 50 ml of dichloromethane, the organic phases were combined, dried and concentrated. From the residue, the product was isolated by silica gel column chromatography.
Yield: 3.6 g (32% of theory),
R _f value: 0.70 (silica gel, dichloromethane / ethanol 50: 1)
C ₁₁ H ₁₂ ClN ₅ O ₂ (281.7)
Mass Spectrum:
M ⁺ = 281

c) -Nitro-4- (1-isobutyl-1H-tetrazol-5-yl) -N-methylaniline

3.5 g (12 mmol) of 2-nitro-4- (1-isobutyl-1H-tetrazol-5-yl) -benzene were stirred for 48 hours at room temperature in 35 ml of 40% aqueous methylamine solution, then with about 70 ml Water is added, the precipitated product is filtered off with suction and dried.
Yield: 3.3 g (100% of theory),
C ₁₂ H ₁₆ N ₆ O ₂ (276.3)
R _f value: 0.22 (silica gel, dichloromethane / ethanol = 50: 1)

d) 1-Methylamino-2-amino-4- (1-isobutyl-1H-tetrazol-5-yl) - benzene

3.3 g (11.9 mmol) of 2-nitro-4- (1-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 of Pd / Coal (10%) hy driert.
Yield: 3.0 g (100% of theory)
C ₁₂ H ₁₈ N ₆ (246.3)
R _f value: 0.23 (silica gel, dichloromethane / ethanol = 19: 1)

e) 1-methyl-2- (4-cyanophenyloxymethyl) -5- (1-isobutyl-1H- tetrazol-5-yl) -benzimidazole

797 mg (4.5 mmol) of 4-cyano-phenoxyacetic acid and 729 mg (4.5 mmol) of N, N'-carbonyldiimidazole were refluxed in 60 ml of absolute tetrahydrofuran for 15 minutes. Then 1.0 g (4.06 mmol) of 1-methylamino-2-amino-4- (1-isobutyl-1H-tetrazol-5-yl) -benzene was added and boiled for a further 15 hours. It was then evaporated to dryness, the back was dissolved in 50 ml of glacial acetic acid and heated to reflux for 1.5 hours. It was re-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 O (387.5)
R _f value: 0.51 (silica gel, dichloromethane / ethanol = 19: 1)

f) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-1H- trazol-5-yl) -benzimidazole hydrochloride

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 O (404.5)
Mass Spectrum:
(M + H) ⁺ = 405

Example 9 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-methyl-5-phenyl pyrazol-1-yl) -benzimidazole hydrochloride a) 2-nitro-4- (3-methyl-5-phenyl-pyrazol-1-yl) -fluorobenzene

4.15 g (20 mmol) of 3-nitro-4-fluoro-phenylhydrazine, 3.25 g (20 mmol) of benzoylacetone and 2.78 ml (20 mmol) of triethylamine were dissolved in 150 ml of methanol and stirred for three hours at room temperature. It 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 ₁₆ H ₁₂ FN ₃ O ₂ (297.29)
R _f value: 0.57 (silica gel, dichloromethane / ethanol = 50: 1)

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

4.40 g (15 mmol) of 2-nitro-4- (3-methyl-5-phenyl-pyrazol-1-yl) fluorobenzene were admixed with 40 ml of methylamine solution (40% in water) and two in a Roth bomb Heated to 80 ° C for hours. After cooling, the reaction mixture was mixed with about 100 ml of water and then the crystallized-based product was filtered off with suction and dried.
Yield: 3.90 g (85.5% of theory),
C ₁₇ H ₁₆ ClN ₄ O ₂ (308.34)
R _f value: 0.38 (silica gel, dichloromethane / ethanol = 19: 1)

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

3.90 g (12.65 mmol) of 1-methylamino-2-nitro-4- (3-methyl-5-phenylpyrazol-1-yl) -benzene were dissolved in 200 ml of methanol and after addition of 0.5 g of Pd / carbon ( 10%) 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)
R _f value: 0.31 (silica gel, dichloromethane / ethanol = 19: 1)

d) 1-methyl-2- (4-cyanophenylaminomethyl) -5- (3-methyl-5-phenyl) pyrazol-1-yl) -benzimidazole

2.29 g (13.0 mmol) of 4-cyanophenylglycine and 2.11 g (13.0 mmol) of N, N'-carbonyldiimidazole were refluxed in 150 ml of tetrahydrofuran for 15 minutes. Then, 3.50 g (12.57 mmol) of 1-methylamino-2-amino-4- (3-methyl-5-phenyl-pyrazol-1-yl) -benzene was added and heated for a further 24 hours. Since starting material was still visible in the thin-layer chromatogram, another 13.0 mmol of 4-cyanophenyl glycine-imidazolide were added and the mixture was heated under reflux for a further 24 hours. The reaction mixture was then completely evaporated and the residue was refluxed in 100 ml of glacial acetic acid for one hour. Then it was re-evaporated, the residue stirred in about 100 ml of water and acidified with conc. 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 ₂₆ H ₂₂ N ₆ (418.5)
R _f value: 0.29 (silica gel, dichloromethane / ethanol = 19: 1)

e) 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-methyl- 5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride

Prepared analogously to Example 1 from 3.0 g (7.17 mmol) of 1-methyl-2- (4-cyanophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) -benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate ,
Yield: 2.4 g (70.9% of theory),
R _f value: 0.15 (RP-8 silica gel, methanol / 5% NaCl solution = 6: 4)
C ₂₆ H ₂₅ N ₇ (435.52)
Mass Spectrum:
(M + H) ⁺ = 436
(M - H) ^- = 434

Example 10 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycar bonylethyl) -5-phenyl-pyrazol-1-yl] -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenyl-pyrazol-1-yl] -benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 80.7% of theory,
C ₃₀ H ₃₁ N ₇ O ₂ (521.61)
Mass Spectrum:
(M + H) ⁺ = 522
(M + H + Na) ⁺⁺ = 272.7
(M + 2H) ⁺⁺ = 261.7

Example 11 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycar bonylethyl) -5- (3-pyridyl) pyrazole-1-yl] -benzimidazole hydrochloride chloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) -pyrazol-1-yl] -benzimidazole, ethanolic hydrochloric acid, Ethanol and ammonium carbonate.
Yield: 32% of theory,
R _f value: 0.7 (RP-8 silica gel, methanol / 5% NaC ₁ solution = 4: 1)
C ₂₉ H ₃₀ N ₈ O ₂ (522.59)
Mass Spectrum:
(M + H) ⁺ = 523
(M + 2H) ⁺⁺ = 262

Example 12 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxycarboxylic bonylethyl) -5-phenyl-pyrazol-1-yl) -benzimidazole

2.1 g (3.76 mmol) of 1-methyl-2- (4-cyanophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5-phenyl-pyrazol-1-yl] -benzimidazole hydrochloride were dissolved in 70 ml of ethanol, then Add a solution of 0.80 g (20.0 mmol) of sodium hydroxide in 5 ml of water and stirred for two hours at room temperature. About 100 ml of water were then added, slightly acidified with glacial acetic acid and stirred for a further 10 minutes. The precipitated product was filtered off with suction, washed with water and dried.
Yield: 1.7 g (96.9% of theory),
C ₂₈ H ₂₇ N ₇ O ₂ (493.57)
Mass Spectrum:
(M + H) ⁺ = 494
(M + H + Na) ⁺⁺ = 258. 7
(M + 2H) ⁺⁺ = 247.7
(M + 2Na) ⁺⁺ = 269.8

Example 13 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxycarboxylic bonylethyl) -5- (3-pyridyl) pyrazole-1-yl] -benzimidazole

Prepared analogously to Example 12 from 1-methyl-2- (4-amidinophe nylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole hydrochloride and sodium hydroxide.
Yield: 92% of theory,
C ₂₇ H ₂₆ N ₈ O ₂ (494.56)
Mass Spectrum:
(M + H) ⁺ = 495
(M + Na) ⁺ = 517
(M - H + 2Na) ⁺ = 539
(M + 2Na) ⁺⁺ = 270

Example 14 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-ethoxycarbonyl 5-thiophen-2-yl) -pyrazol-1-yl] -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenyl-aminomethyl) -5- [3-ethoxycarbonyl-5- (thiophen-2-yl) -pyrazol-1-yl] -benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate ,
Yield: 45% of theory,
R _f value: 0.68 (RP-8 silica gel, methanol / 5% NaCl solution = 9: 1)
C ₂₆ H ₂₅ N ₇ O ₂ S (499.58)
Mass Spectrum:
(M + H) ⁺ = 500

Example 15 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-carboxy-5- (thio phen-2-yl) -pyrazol-1-yl] -benzimidazole

Prepared analogously to Example 12 from 1-methyl-2- (4-amidinophe nylaminomethyl) -5- [3-ethoxycarbonyl-5- (thiophen-2-yl) pyrazol-1-yl] benzimidazole and sodium hydroxide.
Yield: 97.4% of theory,
C ₂₄ H ₂₁ N ₇ O ₂ S (471.55)
Mass Spectrum:
(M + H) ⁺ = 472
(M + Na) ⁺ = 494
(M - H) ^- = 470

Example 16 1-methyl-2- (4-amidinophenyloxymethyl) -5- [3-methyl-5- (2-furyl) - pyrazol-1-yl] -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenyl oxymethyl) -5- [3-methyl-5- (2-furyl) pyrazol-1-yl] benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 83% of theory,
R _f value: 0.58 (RP-8 silica gel, methanol / 5% NaCl solution = 9: 1)
C ₂₄ H ₂₂ N ₆ O ₂ (426.47)
Mass Spectrum:
(M + H) ⁺ = 427

Example 17 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycarbonyl methyl-5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-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,
R _f value: 0.64 (RP-8 silica gel, methanol / 5% NaCl solution = 9: 1)
C ₂₉ H ₂₉ N ₇ O ₂ (507.58)
Mass Spectrum:
(M + H) ⁺ = 508

Example 18 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -5- [3-methyl-5- (2-fu ryl) -pyrazol-1-yl] -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- [2- (4-cyano-phenyl) -ethyl] -5- [3-methyl-5- (2-furyl) -pyrazol-1-yl] benzimidazole, ethanolic Hydrochloric acid, ethanol and ammonium carbonate.
Yield: 91% of theory,
R _f value: 0.55 (RP-8 silica gel, methanol / 5% NaCl solution = 9: 1)
C ₂₅ H ₂₄ N ₆ O (424.49)
Mass Spectrum:
(M + H) ⁺ = 425

Example 19 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-methyl-5- (2-fu ryl) -pyrazol-1-yl] -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenyl 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% NaC ₁ solution = 49: 1)
C ₂₄ H ₂₃ N ₇ O (425.48)
Mass spectrum: (M + H) ⁺ = 426

Example 20 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-hydroxycarbonyl methyl-5-phenyl-pyrazol-1-yl) -benzimidazole

Prepared analogously to Example 12 from 1-methyl-2- (4-amidinophe nylaminomethyl) -5- (3-ethoxycarbonylmethyl-5-phenyl-pyrazol-1-yl) benzimidazole hydrochloride and sodium hydroxide.
Yield: 93% of theory,
C ₂₇ H ₂₅ N ₇ O ₂ (479.55)
Mass Spectrum:
(M + H) ⁺ = 480
(M + Na) ⁺ = 502
(M + 2Na) ⁺⁺ = 262. 7

Example 21 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycarbonyl 5-tert-butyl-pyrazol-1-yl) -benzimidazole hydrochloride

Prepared analogously to Example 1 from 1-methyl-2- (4-cyanophenyl aminomethyl) -5- (3-ethoxycarbonyl-5-tert-butyl-pyrazol-1-yl) - benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 64% of theory,
R _f value: 0.63 (RP-8 silica gel, methanol / 5% NaCl solution = 4: 1)
C ₂₆ H ₃₁ N ₇ O ₂ (473.58)
Mass Spectrum:
(M + H) ⁺ = 474

Example 22 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-carboxy-5-tert- butyl-pyrazol-1-yl) -benzimidazole

Prepared analogously to Example 12 from 1-methyl-2- (4-amidinophe nylaminomethyl) -5- (3-ethoxycarbonyl-5-tert-butyl-pyrazol-1-yl) benzimidazole hydrochloride and sodium hydroxide.
Yield: 91% of theory,
C ₂₄ H ₂₇ N ₇ O ₂ (445.52)
Mass Spectrum:
(M + H) ⁺ = 446
(M + Na) ⁺ = 468
(M + 2Na) ⁺⁺ = 245.8
(M -H) ^- = 444

Example 23 Dry ampoule containing 75 mg of active ingredient per 10 ml

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

production:
Active substance and mannitol are dissolved in water. After bottling is freeze-dried. The solution to the ready-to-use solution is water for injections.

Example 24 Dry ampoule containing 35 mg of active ingredient per 2 ml

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

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

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

Example 25 Tablet with 50 mg active ingredient

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

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

Example 26 Tablet with 350 mg active ingredient

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

production:
(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part score.
Diameter of the tablets: 12 mm.

Example 27 Capsules with 50 mg active ingredient

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

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

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

Example 28 Capsules with 350 mg active ingredient

Composition: (1) Active substance 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate 4.0 mg           430, 0 mg         

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

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

Example 29 Suppositories with 100 mg of active ingredient

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

Claims (10)

1. Substituted bicyclic heterocycles of the general formula
in the
Ra is _a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom in which
a methylene group in the 2-position may be replaced by a carbonyl or sulfonyl group or
a methylene group in the 4-position by an oxygen or sulfur atom or by an -NR ₁ group, wherein R _{1 represents} a hydrogen atom or a C _1-6 alkyl group, he can be set and in a thus obtained, two hetero atoms containing Ring one or two more methylene groups may be replaced by carbonyl groups,
wherein the above-described 5-, 6- or 7-membered saturated heterocyclic rings may also be benzo-fused via two adjacent carbon atoms and the phenyl moiety may be optionally substituted by a C _1-3 -alkyl or C _1-3 -alkoxy group,
or a group of the formula
in the
R _c denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C _1-3 -alkyl or C _1-3 -alkoxy group and
R ₁ is defined as mentioned above,
or a 5-membered heteroaromatic group bonded via a nitrogen atom which contains one, two or three nitrogen atoms and which may be benzoically condensed via two adjacent carbon atoms,
wherein the 5-membered heteroaromatic group in the carbon skeleton by C _1-6 alkyl, carboxy, C _1-4 alkoxy carbonyl, carboxy (C _1-4 ) alkyl, C _1-4 alkoxycarbonyl - (C _1-4 ) alkyl, phenyl, pyridyl, furanyl or thienyl groups may be mono- or disubstituted independently and a carboxy group contained in said radicals contained carboxy group also by an in vivo group into a carboxy group Group can be replaced,
the phenyl part of a benzo-fused 5-membered heteroaromatic group may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 -alkyl or C _1-3 -alkoxy group, and
the heteroaromatic group may also be partially hydrogenated, with the inclusion of a possibly fused-on phenyl moiety, the dihydroderivatives being preferred, and resulting -NH groups also being able to be replaced by -NR ₁ groups as defined above,
a tetrazolyl group bonded via a nitrogen atom or
a tetrazolyl group bonded via the carbon atom in which a nitrogen atom may be substituted by a C _1-6 alkyl group,
Y is an oxygen or sulfur atom or an imino group optionally substituted by a C _1-6 -alkyl or C _3-7 -cycloalkyl group,
X ₁ , X ₂ , X ₃ and X _{4 are} each a methine group or one or two of the radicals X ₁ , X ₂ , X ₃ and X _{4 are} each a nitrogen atom and the remaining radicals are each a methine group,
B is an ethylene group in which a methylene group linked to either the bicyclic heterocycle of formula I or to the group Ar is substituted by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, carbonyl or -NR ₁ group may be replaced, wherein R ₁ is defined as mentioned above,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenylene or naphthylene group,
an optionally substituted in the carbon skeleton by a C _1-3 alkyl group substituted thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or Pyridazinylengruppe and
E is a cyano or R _b NH-C (= NH) group in which
R _{b represents} a hydrogen atom, a hydroxy group or an in vivo cleavable radical,
in which additionally the carboxyl groups mentioned above in the definition of 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 in the definition of the radicals can be substituted by a radical cleavable in vivo,
their tautomers, their stereoisomers, their mixtures and their salts. 2. Substituted bicyclic heterocycles of the general For mel I according to claim 1, in which
Ra is _a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom in which
a methylene group in the 2-position may be replaced by a carbonyl or sulfonyl group or
a methylene group in the 4-position may be replaced by an oxygen atom or an -NR ₁ group, wherein R _{1 represents} a hydrogen atom or a C _1-3 alkyl group, and in one thus obtained ring containing two heteroatoms one or two further methylene groups may be replaced by carbonyl groups,
wherein the above-described 5- or 6-membered saturated heterocyclic rings may also be benzo-fused via two adjacent carbon atoms and the phenyl moiety may be optionally 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 C _1-3 alkyl group and
R ₁ is defined as mentioned above,
or a 5-membered heteroaromatic group bonded via a nitrogen atom which contains one or two nitrogen atoms and which may be benzo-fused via two adjacent carbon atoms,
wherein the 5-membered heteroaromatic group in the carbon skeleton by C _1-4 alkyl, carboxy, C _1-4 alkoxy carbonyl, carboxy (C _1-4 ) alkyl, C _1-4 alkoxycarbonyl - (C _1-4 ) alkyl, phenyl, pyridyl, furanyl or thienyl groups may be mono- or disubstituted independently and a carboxy group contained in said radicals contained carboxy group also by an in vivo group into a carboxy group Group can be replaced,
the phenyl part of a benzo-fused 5-membered heteroaromatic group may be substituted by a C _1-3 -alkyl or C _1-3 -alkoxy group, and
the heteroaromatic group may also be dihydrogenated with the inclusion of a possibly fused-on phenyl moiety and resulting -NH groups may also be replaced by -NR ₁ groups as defined above,
or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom may be substituted by a C _1-4 alkyl group,
Y is an oxygen atom or an imino group which is optionally substituted by a C _1-4 -alkyl group,
X ₁ , X ₂ , X ₃ and X _{4 are} each 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 ₁ group, where R ₁ is defined as mentioned above,
Ar is an optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy substituted phenylene or naphthylene group,
an optionally in the carbon skeleton by a C _1-3 alkyl
group substituted pyridinylene group and
E is a cyano or R _b NH-C (= NH) group in which
R _{b represents} a hydrogen atom or an in vivo cleavable radical,
their tautomers, their prodrugs, their Doppelpro drugs, their stereoisomers and their salts. 3. Substituted bicyclic heterocycles of the general For mel I according to claim 1, in which
R _{a is} a 5- or 6-membered saturated heterocyclic ring bonded via a nitrogen atom, wherein
a methylene group in the 2-position may be replaced by a carbonyl or sulfonyl group or
a methylene group in the 4-position of the 6-membered saturated heterocyclic ring by a -NR ₁ group, wherein R _{1 represents} a hydrogen atom or a C _1-3 alkyl group, may be replaced and in a thus obtained containing two heteroatoms Ring one or two more methylene groups may be replaced by carbonyl groups,
wherein the above-described 6-membered saturated heterocyclic rings may also be benzo-fused via two adjacent carbon atoms and the phenyl moiety may optionally be substituted by a C _1-3 -alkyl group,
or a group of the formula
in the
R _{c represents} a hydrogen atom or a C _1-3 alkyl group and
R ₁ is defined as mentioned above,
or a pyrrole-1-yl, imidazol-1-yl or pyrazol-1-yl group optionally benzo-fused via two adjacent carbon atoms,
wherein said heteroaromatics in the carbon skeleton are represented by C _1-4 alkyl, carboxy, C _1-3 alkoxycarbonyl, carboxy (C _1-2 ) alkyl, C _1-2 alkoxycarbonyl (C _1-2 ) alkyl, phenyl, pyridyl, furanyl or thienyl groups may be mono- or disubstituted, wherein the substituents may be the same or different, with the proviso that only one of the substituents is an aromatic or heteroaro matic radical, and a may also be replaced by a carboxy group which can be converted into a carboxy group in vivo in said radicals,
or a tetrazolyl group bonded via the carbon atom, in which a nitrogen atom may be substituted by a C _1-4 alkyl group,
Y is an imino group which is optionally substituted by a C _1-3 -alkyl group,
X ₁ , X ₂ , X ₃ and X _{4 are} each 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, wherein R ₁ is defined as mentioned above,
Ar is a phenylene group optionally substituted by a C _1-3 alkyl group,
E is a cyano or R _b NH-C (= NH) group in which
R _{b represents} a hydrogen atom or an in vivo cleavable radical,
their tautomers, their prodrugs, their Doppelpro drugs, their stereoisomers and their salts. 4. The following bicyclic heterocycles of the general formula I according to claim 1:

• a) 1-methyl-2- (4-amidinophenyloxymethyl) -5- (1-isobutyl-1H-tetrazol-5-yl) -benzimidazole,
• b) 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) -benzimidazole,
• c) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5-phenyl-pyrazol-1-yl] -benzimidazole,
• d) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-ethoxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole,
• e) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxy-carbonyl-ethyl) -5-phenyl-pyrazol-1-yl] -benzimidazole,
• f) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxycarbonylethyl) -5- (3-pyridyl) pyrazol-1-yl] benzimidazole,
• g) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-ethoxycarbonyl-5- (thiophen-2-yl) -pyrazol-1-yl] -benzimidazole,
• h) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-carboxy-5- (thiophen-2-yl) -pyrazol-1-yl] -benzimidazole,
• i) 1-methyl-2- (4-amidinophenyloxymethyl) -5- [3-methyl-5- (2-furyl) -pyrazol-1-yl] -benzimidazole,
• j) 1-methyl-2- (4-amidinophenylaminomethyl) -5- (3-ethoxycarbonylmethyl-5-phenyl-pyrazol-1-yl) -benzimidazole,
• k) 1-methyl-2- [2- (4-amidinophenyl) -ethyl-5- [3-methyl-5- (2-furyl) -pyrazol-1-yl] -benzimidazole,
• 1) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-methyl-5- (2-furyl) -pyrazol-1-yl] -benzimidazole and
• m) 1-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. 5. The following bicyclic heterocycles of the general formula I according to claim 1:

• a) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3- (2-hydroxy-carbonyl-ethyl) -5- (3-pyridyl) -pyrazol-1-yl] -benzimidazole,
• b) 1-methyl-2- (4-amidinophenylaminomethyl) -5- [3-carboxy-5- (thiophen-2-yl) -pyrazol-1-yl] -benzimidazole,
• c) 1-methyl-2- (4-amidinophenylaminomethyl) -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 is an R _b NH-C (= NH) group represents. 7. A pharmaceutical composition containing a compound according to at least one of claims 1 to 5, in which E is an R _b NH-C (= NH) group, or a salt according to claim 6 besides optionally one or more inert carriers and / or dilution convey. 8. Use of a compound according to at least one of claims 1 to 5, wherein E is an R _b NH-C (= NH) group, or a salt according to claim 6 for the preparation of a drug by means of a thrombin time-prolonging effect, a thrombin-inhibiting effect and an inhibitory effect on related serine proteases. 9. A process for the preparation of a medicament according to claim 7, characterized in that non-chemical way a compound according to at least one of claims 1 to 5, in which E is an R _b NH-C (= NH) group, or a salt according to Claim 6 is incorporated in one or more inert carriers and / or diluents. 10. A process for the preparation of the compounds according to the entitlements to 1 to 6, characterized in that
a) for the preparation of a compound of general formula I in which E is an R _b NH-C (= NH) group in which R _{b is} a hydrogen atom or a hydroxy group, where appropriate, a compound formed in the reaction mixture of the general mean formula
in the
R _a , X ₁ to X ₄ , Y, B and Ar are as defined in the claims 1 to 5 defi ned and
Z _{1 represents} an alkoxy, aralkoxy, alkylthio or aralkylthio group with an amine of the general formula
H ₂ NR _b '(IV)
in the
R _{b represents} a hydrogen atom or a hydroxy group to be put or
b) for the preparation of a compound of general formula I in which the R _a group and E are defined as mentioned 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 is as defined in claims 1 to 5 and E is an NH ₂ -C (= NH) group or the R _a group contains a carboxy group and E is an NH ₂ -C (= NH) - group, a compound of the general formula
in the
X ₁ to X ₄ , Y, B and Ar are as defined in claims 1 to 5 and
the R _a 'group and E' have the meanings given for the R _a group and E in claims 1 to 5, with the proviso that the R _a 'group is one obtained by hydrolysis, treatment with an acid or base, thermolysis or E is as defined in claims 1-5 or E 'is a group convertible to an NH ₂ -C (= NH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and the R _a 'group has the meanings given for the R _a group in claims 1 to 5, or the R _a ' group is a group convertible to a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E 'is a group which can be converted into an NH ₂ -C (NHNH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I, in which the R _a group and E are defined as mentioned in claims 1 to 5, that the R _a group contains a carboxy group and E is as defined in claims 1 to 5 or the R _a group has the meanings mentioned in claims 1 to 5 and E represents an NH ₂ -C (= NH) group or the R _a group contains a carboxy group and E represents an NH ₂ -C (= NH) group, leads überge leads 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
X ₁ to X ₄ , Y, B, Ar and E are as defined in claims 1 to 5 and
R _a "have the meanings mentioned for the R _a in claims 1 to 5, with the proviso that R _a " contains a carboxy group or a group convertible by means of an alcohol into a corresponding ester group, with an alcohol of the general formula
HO-R ₅ (VII)
in the
R _{5 represents} the alkyl part of one of the in vivo cleavable radicals mentioned in claims 1 to 5 with the exception of the R ₂ -CO-O- (R ₃ CR ₄ ) - group for a carboxyl group, or with their form amide acetals
or with a compound of the general formula
Z ₂ -R ₆ (VIII)
in the
R _{6 is} the alkyl part of one of the in vivo cleavable radicals mentioned in claims 1 to 5 with the exception of the R ₂ -CO-O- (R ₄ CR ₅ ) - group for a carboxyl group and
Z _{2 represents} a leaving group, is reacted or
d) for the preparation of a compound of general formula I, in which R _{b is} a cleavable residue in vivo, a compound of the general formula Ver
in the
R _a , X ₁ to X ₄ , Y, B and Ar are as defined in claims 1 to 5 de, with a compound of the general formula
Z ₃ -R ₇ (X)
in the
R _{7 is} an in vivo cleavable radical and
Z _{3 is} a nucleofuge leaving group, is reacted 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 is replaced by a sulfinyl or sulfonyl group, a compound of the general formula
in the
R _a , X ₁ to X ₄ , Y, Ar and E are as defined in claims 1 to 5 de and
B 'is 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 linked either to the bicyclic heterocycle of the formula I or to the group Ar is replaced by an oxygen or sulfur atom, is replaced by a sulfinyl, sulfonyl, carbonyl or -NR ₁ group, represent a compound of the general formula
with a compound of the general formula
V-Ar-CN (XIII)
in which
R _a , X ₁ to X ₄ , Y and Ar are defined as defined in claims 1 to 5,
one of U or V is an HO, HS, HOSO, HOSO ₂ or HNR ₁ group and the other of the radicals is a Z ₃ CH ₂ group, wherein R _{1 is} as defined in claims 1 to 5 is and
Z _{3 is} a nucleofuge leaving group, is reacted or
g) for the preparation of a compound of general formula I in which Y is an oxygen or sulfur atom or an imino group optionally substituted by a C _1-6 -alkyl or C _3-7 -cycloalkyl group, X ₁ to X ₄ methine groups, E a cyano group and B an ethylene group in which the methyl group linked to the group Ar may be replaced by an oxygen or sulfur atom or by an -NR ₁ group, be interpreted as a compound of the general formula
in the
R _a and Y are as defined in claims 1 to 5 and X ₁ 'to X ₄ ' each represent a methine group, with a compound of the general formula Ver
HO-C-B'-Ar-CN, (XV)
in the
Ar as defined in claims 1 to 5, and B 'represents an ethylene group in which the methylene group linked to the group Ar may be replaced by an oxygen or sulfur atom or by an -NR ₁ group, or by their reactive Derivatives is implemented or
h) for the preparation of a compound of the general formula I in which R _{a is} the 2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl radical and E is the cyano group, a compound of the general formula
in the
X ₁ to X ₄ , Y, B and Ar are as defined in claims 1 to 5, 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 Ra in the 2-position optionally by a C _1-6 alkyl, C _1-4 alkoxycarbonyl (C _1-4 ) alkyl, phenyl -, pyridyl, furanyl or thienyl substituted benzimidazol-1-yl radical and E is the cyano group, a compound of the general mean of my formula
in the
X ₁ to X ₄ , Y, B and Ar are as defined in claims 1 to 5, with a carboxylic acid of the general formula
HO-CO-R ₈ (XVI I)
in the
R _{8 represents} a hydrogen atom, a C _1-6 alkyl, C _1-4 alkoxycarbonyl (C _1-4 ) alkyl, phenyl, pyridyl, furanyl or thienyl group, or with their reactive derivatives is implemented or
k) for the preparation of a compound of general formula I in which Ra represents a 4-position optionally substituted by a C _1-6 alkyl group substituted 3-oxo-3,4-dihydro-2H-quinoxaline-1-yl group and E is the cyano group, a compound of the general formula
in the
X ₁ to X ₄ , Y, B and Ar are as defined in claims 1 to 5, with a compound of the general formula
HO-CO-CH ₂ -Z ₂ (XVIII)
in the
Z _{2 is} a leaving group, or reacted with their reactive derivatives, and optionally a compound thus obtained is then alkylated in the 4-Stel development of the nitrogen atom and
if necessary, a protective moiety used during the reactions for the protection of reactive groups is split off and / or
if desired, then a compound of the general formula I thus obtained is separated into its stereoisomers and / or
a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application into its physiologically tolerated salts with an inorganic or organic acid or base.