SK285432B6 - Distributed bicyclic heterocycles, method of their preparation, pharmaceuticals containing them and their use - Google Patents

Abstract

Distributed bicyclic heterocycles of the general formula (I): Ra-A-Het-B-Ar-E. The invention also relates to their tautomers, their stereoisomers and their salts, which have valuable properties, as well pharmaceuticals containing them, a method of their preparation and their use.

Description

Technical field

The present invention relates to novel disubstituted heterocyclic compounds having the general formula (I):

R ^and -A-Het-B-Ar-E (I), their tautomers, stereoisomers, mixtures thereof and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids or bases having valuable properties.

Compounds having the general formula (I) in which E represents a cyano group are valuable intermediates for the preparation of said compounds having the general formula (I); the compounds having the general formula (I) in which E represents the group R ^b NH-C (= NH) -, as well as their tautomers and their stereoisomers, have valuable pharmacological properties, in particular thrombin inhibitory activity and prolong thrombin time.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides compounds of formula (I):

R ^and -A-Het-B-Ar-E (I) as well as a process for their preparation, pharmaceutical compositions containing said pharmacologically active compounds and their use.

In the above general formula

A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group,

B represents an ethylene group in which one methylene group bonded to the radical Ar may be replaced by an oxygen or sulfur atom, or a group -NR ¹ -, wherein R ¹ represents a hydrogen atom, or a C ₄ - 4 alkyl group,

E is R ^b NH-C (= NH) - in which

R ^b represents a hydrogen atom, a hydroxyl group, C ₁ . _9- alkoxycarbonyl, cylohexyloxycarbonyl, phenyl-C 1-6 -alkoxycarbonyl, benzoyl, n-C 1-6 -alkyloxycarbonyl, benzoyl, C 1-6 -alkyloxycarbonyl; _{A 3-} alkylbenzoyl or pyridinoyl group, wherein the ethoxy moiety at the 2-position of said C _1-9 -alkoxycarbonyl group may additionally be substituted by a C 1-8 -alkylsulfonyl or 2- (C _1-3 -alkoxy) -ethyl group,

Ar represents a 1,4-phenylene group, optionally substituted by a chlorine atom or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group,

Het represents 1- (C _1-3 -alkyl) -2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolyllene, 2,5-benzothiazolylene, 1- (C _1-3 -alkyl) -2,5- indolylénovú, 1 - (C]. _3-alkyl) -2, 5-imidazo [4,5-A] pyridinylénovú, 3- _(C1 .3 alkyl) -2,7-imidazo [l, 2- a] pyridinylene or 1-C 1-6 -alkyl-1-thienop-4-imidazolylene and

R ^a represents a group R ² NR ³ - in which

R ² is C _{first A 4-} alkyl group, which may be substituted by a carboxyl group, C ₁ . _6- alkyloxycarbonyl, benzyloxycarbonyl, C _1-6 alkylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl,

C ₂ . _{A 4-} alkyl group substituted with a hydroxy-, benzyloxy-, carboxy-C1-6 group; _3- alkylamino-; _{-Alkoxycarbonyl-3-Ct.j} alkylamino, N- _{(Art. 3} alkyl) carboxy-C _N -alkylamino or N (C _b3 alkyl) C |. _3- alkoxycarbonyl-C 1-6 -alkylamino. wherein said groups cannot be substituted for an α-carbon atom adjacent to a nitrogen atom,

R ³ represents C ₇ -cycloalkyl, propargyl, the unsaturated moiety cannot be bonded directly to the nitrogen atom of R ² NR ³ -, a phenyl group optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group, or is optionally a methyl group substituted pyrazolyl, pyridazinyl or pyridinyl, or

R ² and R ³ together with the intervening nitrogen atom represent a 5- to 7-membered cycloalkyleneimine group, optionally substituted with a carboxyl group or a C _1-4 -alkoxycarbonyl group on which the phenyl ring may be additionally fused, their tautomers, stereoisomers and their salts .

Preferred compounds having the above formula (I) are those in which

A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group,

B represents an ethylene group in which the methylene group attached to the Ar radical can be replaced by an oxygen or sulfur atom, or -NR ¹ -, wherein R ¹ represents a hydrogen atom or a methyl group, E represents a group R ^b NH-C (= NH )-, in which

R ^b represents a hydrogen atom, a hydroxyl group, C 1-6. ₉ -alkoxycarbonyl, cylohexyloxykarbonylovú, benzyloxycarbonyl, benzoyl, pC _{l. A 3-} alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety at the 2-position of said C 1-6 -alkoxycarbonyl group may additionally be substituted by C _1-3 -alkylsulfonyl or 2- (C ₃ -alkoxy) ethyl,

Ar represents a 1,4-phenylene group optionally substituted by a chlorine atom or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group,

Het means 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5- imidazo [4,5-b] pyridinylene, 3-methyl-2,7-imidazo [1,2-u] pyridinylene or 1-methyl-2,5-thieno [2,3-d] imidazo a lylene group; and

R ^a represents a group R ² NR ³ - in which

R ² represents a C _1-3 -alkyl group which may be substituted by a carboxyl group, C 1-6 -alkyl; _6- alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl,

C-j alkyl, substituted by hydroxy, benzyloxy, carboxy-C ^ _{-alkylamino, C?} -alkoxycarbonyl-C] .3-alkylamino, N-ľCj.j -alkyl is C i-j-carboxy-alkylamino or _N-fC-l .3 alkyl) -C ₁ _3-alkoxycarbonyl-C _{first A 3-} alkylamino group, wherein said groups cannot be substituted for an α-carbon atom adjacent to a nitrogen atom,

R ³ represents a propargyl group, the unsaturated moiety cannot be bonded directly to the nitrogen atom of the group R ² NR ³ -, a phenyl group optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group, or a pyridinyl group,

They are tautomers, stereoisomers and salts thereof.

The most preferred compounds having the aforementioned general formula (I) are those in which

A represents a carbonyl group bonded to the benzo or thieno moiety of the group Het,

B represents an ethylene group in which the methylene group bonded to the radical Ar can be replaced by -NR ¹ -, wherein

R ¹ represents a hydrogen atom or a methyl group,

E is R ^b NH-C (= NH) - in which

R ^b is hydrogen, hydroxy, C ₉ -alkoxycarbonyl, cylohexyloxykarbonylovú, benzyloxycarbonyl, benzoyl, _{pC. A 3-} alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety at the 2-position of said C 6 -alkoxycarbonyl group may additionally be substituted by methylsulfonyl or 2-ethoxyethyl,

Ar is 1,4-phenylene, optionally substituted with methoxy, or is 2,5-thienylene,

Het means 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno [2,3-d] imidazolylene and

R ^a represents a group R ² NR ³ - in which

R ² represents a C 1-6 alkyl group which may be substituted by a carboxyl group, C 1. _6- alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl,

C ₂ . _3- alkyl, substituted with hydroxy, benzyloxy, carboxy-C ₁ . _3- alkylamino-, C 1. _3- alkoxycarbonyl-C 1-6 -alkylamino-, N- (C _1-3 -alkyl) -carboxy-C 1-6 -alkyloxycarbonyl- _3- alkylamino- or N-C 1-6 -alkyl-C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino, wherein said groups cannot be substituted for the α-carbon atom adjacent to the nitrogen atom,

R ³ represents a phenyl group optionally substituted by a fluorine atom, or represents a 2-pyridinyl group, tautomeric forms of said compounds, stereoisomers and salts thereof.

Examples of the most preferred compounds of the present invention include:

(a) 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxyethyl) -amide, (b) N-phenyl-N- (2-hydroxycarbonylethyl) 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid-amide, (c) 1-methyl-N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1-Methyl-2- [N- (N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid) -2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid 4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid, (e) 1-methyl-2- [N- (4-amidino) - (2-pyridyl) -N- (hydroxycarbonylethyl) -amide -phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid 1-methyl-2- [2- (2-amidino-) - (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide; thiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid, 1-methyl-2- [N- (4-) - (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide; 1-Methyl-2- [2- (4-amidino) - (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide (amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid phenyl) ethyl] benzimidazole-5-yl-ka (i) N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1

-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid, (j) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-ylcarboxylic acid amide, (k) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] - 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid amide, (1) N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide 1 -methyl-2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid, (m) N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) - 1-methyl-2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid amide, (n) N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid, (o) N-phenyl-N - [(2-hydroxycarbonylethyl-N-methyl)] 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid -2-aminoethyl] -amide, (p) N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole) -amide 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-yl-5-yl-carboxylic acid, (q) N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide 1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazole-5-yl-carboxylic acid, (r) N-phenyl-N- (2-hydroxycarbonylethyl) -amide 1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazole (1-methyl-2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide; 5-yl-carboxylic acid, 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxylic acid, N-phenyl-N- (2-methoxycarbonylethyl) -amide, and (u) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-d] -imidazol-5-yl- N-phenyl-N- (2-hydroxycarbonylethyl) -amide- carboxylic acid, and tautomers, stereoisomers, and salts thereof.

The compounds of the invention may be prepared by methods known per se, for example by the method described below.

a) The preparation of a compound having the general formula (I) in which E represents a group R (HC) b) in which R ^b represents a hydrogen atom, a hydroxy group or a C _1-3 -alkyl group can be carried out by:

by converting the compound, optionally directly in the reaction mixture of the compound of the general formula formed

R ^and -A-Het-B-Ar-C (= NH) -Z '(II) in which

A, B, Ar, Het and R ^and are designated in front and

Z ¹ is alkoxy or aralkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy, or Z ¹ is alkylthio or aralkylthio such as methylthio, ethylthio, n-propylthio or benzylthio , with an amine having the general formula

H ₂ N - R ^b '(III) in which

R ^b represents a hydrogen atom, a hydroxyl group or a C ₁₂ -alkyl group.

Conversion of the compound of formula (II) is conveniently carried out in a solvent environment such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at temperatures between 20 and 120 ° C with the compound of formula (III) ) or a corresponding acid addition salt such as ammonium carbonate.

A compound having the general formula (II) can be obtained, for example, by converting a compound having the general formula (I) in which E represents a cyano group, with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in in the presence of an acid such as hydrochloric acid, or by converting the corresponding amides 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 at 20 ° C, or , suitably in a solvent environment such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the formed thioamide with the corresponding alkyl halide or aralkyl halide.

b) For a compound of general formula (I), wherein R ^a -A- group and E are as defined with the proviso that R ^and -Askupina contains a carboxy group and E is as defined, or a group R ^a -A- is and E is NH2-C (= NH) -, or R ^and -A- contains a carboxyl group and E is NH2-C (= NH) -, a compound of formula (IV) is converted

R ^and -A-Het-B-Ar-C-E '(IV) wherein

A, B, Ar and Het are as defined above and R ^and -A and E 'have the same meaning as for R ^and -A- except that R ^and ' -A- contain a group convertible by hydrolysis, acid treatment or and E 'is as defined above, or E' is a group convertible by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis to NH2-C (= NH) -, and R ^and -A- have a radical, thermolysis or hydrogenation to a carboxyl group; same as R ^and -A-, or R ^and -A- contains a group which is convertible into a carboxyl group by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, and E 'is an acid hydrolysis group or a base, by thermolysis or by hydrogenolysis convertible into the group NH2-C (= NH) -, by hydrolysis, treatment with an acid or base, by thermolysis or by hydrogenolysis to a compound of the general formula (I) in which: j the group R ^and -A- and E is as defined above, with the group R ^and -A- containing a carboxyl group and E being as defined at the front, or the group R ^and -A- having the same meaning as above and E being the group NH2-C (= NH) -, or the group R ^and -A- contains a carboxyl group and E represents the group NH2-C (= NH) -.

Suitable carboxyl-convertible groups include, for example, a carboxyl-protected protecting group as well as functional derivatives thereof, for example unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters, which are suitably convertible to carboxyl groups by hydrolysis an ester thereof with tertiary alcohols, for example a tert-butyl ester, which is conveniently converted to a carboxyl group by treatment with acid or thermolysis, and an ester thereof with aralkanols, for example a benzyl ester, which is conveniently converted to a carboxyl group by hydrogenolysis.

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

If the group R ^a '-A- and / or E' contains, for example, a tert-butyl or tert-butyloxycarbonyl group in the compound of formula (IV), this group can be cleaved by treatment with an acid such as trifluoroacetic acid, formic, p -toluenesulfonic, sulfuric, hydrochloric, phosphoric or polyphosphoric acid suitably in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or suitably by heat treatment in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvents used, for example between heat 40 and 120 ° C.

If the group R ^and -A- and / or E * contains, for example, a benzyloxy- or benzyloxycarbonyl group in the compound of formula (IV), it can also be cleaved by hydrolysis in the presence of hydrogenation catalysts such as palladium / carbon in a suitable a solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, for example at room temperature, and under a hydrogen pressure of from 0.1 to 0.5 bar.

c) The preparation of a compound having the general formula (I) and which already contains ester groups in the defined group R ^and -A- can be carried out by converting a compound having the general formula (V)

R ^a '- A - Het - B - Ar - E (V) in which

B, E, Ar and Het have already been determined and the group R ^a '-A- has the same meaning as the group R ^a -A- except that the group R ^a ' -A- contains a carboxyl group or contains a group which may be via alcohol to an ester group, with an alcohol of formula (VI)

HO - R ⁷ (VI) in which:

R ⁷ is R ⁷ , is C 1-6. _{A 6-} alkyl or benzyl group, or formamidacetals thereof, or a compound having the general formula (VII)

From ² - R ⁷ (VII) in which

R ⁷ has already been identified and

Z ² represents a replaceable group such as a halogen atom, for example a chlorine or bromine atom.

Conversion with an alcohol of formula (VI) is conveniently carried out in a solvent environment or in a solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, or dioxane, preferably in an alcohol environment of formula (VI) optionally in the presence of an acid such as hydrochloric acid or in the presence of a water-binding agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorous trichloride Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or Ν, Ν'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine diethyl ester, or triphenylphosphine diethyl ester N-ethyl-diisopropyl preferably amine or N, N-dimethylaminopyridine, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

Conversion with the compound of formula (VII) is conveniently carried out in a solvent environment such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium iodide or potassium iodide and preferably in a solvent. 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-ethyldiisopropylamine or N-methylmorpholine, which may simultaneously act as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, preferably at -10 and 80 ° C.

d) Preparation of a compound of formula (I) wherein R ^b is an in vivo cleavable residue is accomplished by conversion of a compound of formula (VIII)

R ^and -A-Het-B-Ar-C (= NH) -NH ₂ (VIII) in which

^And R, A, Het, B and Ar have been defined, with a compound of general formula (IX)

Z ² -R ⁸ (IX) wherein

R ⁸ is C ₁ . ₉ alkoxycarbonyl group, a cyclohexyloxy group, a phenyl-C ^ alkoxycarbonyl, benzoyl, p-C ₃ -alkylbenzoylovú group, or pyridinoyl group, wherein the ethoxy moiety in the 2 position of said C ₁ _ ₉ -alkoxykarhonylovcj group is further optionally substituted C 1-6 -alkylsulfonyl or 2- (C _1-3 -alkoxy) -ethyl, and

Z ^{2 is a} displaceable group such as a halogen atom, for example a chlorine, bromine or iodine atom.

The conversion is preferably carried out in a solvent environment such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20 ° C and the boiling point of the solvent used.

Conversion with a compound of formula (IX) wherein Z ² is a displaceable group is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate , potassium tert-butylate or N-ethyldiisopropylamine at temperatures between 0 and 60 ° C.

e) To prepare a benzimidazolyl or benzothiazolyl compound having the general formula (I) in which B is an ethylene group, a compound having the general formula (XV) is reacted.

in which

R ^a , A have already been defined and Y represents a sulfur or nitrogen atom substituted by C 1. _{A 3-} alkyl group or a cyclopropyl group, with a compound having the general formula

HO - CO - CH ₂ CH ₂ - Ar - E (XVI) in which

Ar and E have already been determined, or with a reactive derivative of said compound (XVI).

This conversion is conveniently carried out in a solvent environment or in a solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a water scavenger, e.g. in the presence of isobutyl chloroformate, tetraethyl ester carbonic acid, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentachloride, Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1-dicyclohexylcarbodiimide 3,3-tetramethyluronium tetrafluoroborate (1-hydroxybenztriazole, N, N'-carbonyldiimidazole or triphenylphosphine) -tetrachloromethane and optionally with the addition of a base such as pyridine, 4-dimethylamino pyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C. Conversion of an appropriate reactive derivative of a compound of formula (XVI), such as an ester, imidazolide or halide thereof, with an amine of formula (XV) is conveniently carried out in a solvent environment such as methylene chloride, ether or terahydrofuran and preferably in the presence of a tertiary organic base, such as triethylamine, N-ethyldiisopropylamine or N-methylmorpholine, which may also serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

f) For the preparation of a compound of formula (I) wherein R ² is C ₁ . _{The 4-} alkyl group, which is substituted by an alkylsulfonylaminocarbonyl group, is converted to a compound having the general formula (IXX) * ^{2 '} . CN - A - Het - B - Ar - E (ixx) in which

R ³ , A, B, E, Ar and Het have already been identified and

R ² represents C _{first A 4-} alkyl group which is a substituted carboxyl group, or reactive derivatives thereof, with a salt of a compound of formula (XX)

C _1-6 -alkyl-SO ₂ -NH ₂ (XX).

The conversion is preferably carried out with an appropriate reactive derivative of a compound having the general formula (XIX), such as an ester, imidazolide or halide thereof with a salt of a compound having the general formula (XX), preferably its alkali salt such as the sodium salt. a solvent environment such as methylene chloride, ether, ethanol, tetrahydrofuran or dimethylformamide at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

In the conversions described so far, optionally, reactive groups such as hydroxy, carboxy, amino, alkylamino or imino groups can be protected during the conversion with conventional protecting groups, which can be cleaved again after the conversion.

Suitable hydroxyl protecting groups are trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl.

Suitable carboxyl protecting groups are trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydro-pyranyl and acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butyl or tert-butyl are suitable for protecting amino, alkylamino or imino groups. butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl and, in addition, a phthalyl group for protecting the amino group.

Optional subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or is lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

However, cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium on carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid. by adding an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of 0.1 to 0.7 MPa, preferably at a pressure of from 0.3 to 0.5 MPa.

The cleavage of the methoxybenzyl group may also be carried out in the presence of an oxidizing agent such as cerium ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C, preferably at room temperature.

However, the cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

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

Cleavage of the phthalyl residue is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent environment such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

Cleavage of the allyloxyalkyl moiety is accomplished by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under an inert gas protective atmosphere, or by treatment with a catalytic amount of native tris- (triphenyldosphine) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazobicyclo [2.2.2] octane at temperatures between 20 and 70 ° C

The compounds of formulas (II) to (XX) used as starting materials are in part known in the literature and can be prepared in the literature by the methods described herein, the preparation of other compounds is described in the Examples below.

For example, a compound of formula (II) may be prepared by converting the corresponding nitrile, which may conveniently be prepared by methods f to h, with the appropriate thio- or alcohol in the presence of hydrogen chloride or hydrogen bromide. The compounds of formulas (IV), (V), (VIII), (X) and (XIX) used as starting materials may conveniently be obtained by the process of the invention.

The starting compound of formula (XI) in which U is a halomethyl group may conveniently be prepared by ring closure of the corresponding ester which is substituted in the ω-position with a suitable halogen atom and a methoxyacetamide group to the corresponding bicyclic 2-alkoxymethyl group, optionally followed by hydrolysis, and optionally followed by amidation of the prepared carboxylic acid with the appropriate amine, converting the obtained alkoxymethyl to the corresponding halomethyl compound, which, if desired, can then be converted to the desired compound using the corresponding compound. The ring closure is carried out with a suitable carboxylic acid derivative to give a starting compound having the general formula (XI) in which U represents a hydroxy-, mercapto- or amino- group.

The starting compound having the general formula (XIII) is prepared by ring closure of the corresponding disubstituted ester, followed by saponification of the obtained ester and then amidation of the prepared carboxylic acid with the appropriate amine.

In addition, the ring-substituted imidazopyridine obtained in the 5-position with a methyl group can be converted via the corresponding N-oxide to the corresponding hydroxymethyl compound which is converted to the desired carboxylic acid of formula (XIII) by oxidation.

The compounds of formulas (III), (VI), (VII), (IX) and (XII) used as starting materials can be prepared by conventional methods, for example by reducing the aromatic ester which is substituted in the ω position with an optionally substituted amino group and nitro, followed by ring closure of the prepared o-diamino compound with a suitable carboxylic acid.

Prepared compounds having the general formula (I) can be further subdivided into their enantiomers and / or diastereomers.

For example, the prepared compounds of formula (I), which are in the form of a racemate, can be resolved in a known manner (see Allinger NL and Eliel EL in: Topics in Stereochemistry, Vol. 6, Wiley Interscience 1971) into optical antipodes and compounds of formula (I) with at least 2 asymmetric carbons can be separated into diastereomers by known methods on the basis of their physical chemical differences, for example by chromatography and / or fractional crystallization; if obtained in racemic form, they can then be separated into the enantiomers as described above.

Separation of the enantiomers is preferably effected by column chromatography on chiral phases or by recrystallization from an optically active solvent, or by conversion with an optically active substance, in particular acids and their active derivatives or with alcohols which form salts or derivatives such as ester or amide with the racemic compound, and separating the mixtures of diastereomeric salts or derivatives thus obtained, for example, based on different solubilities; free antipodes can be liberated from the pure diasteromeric salts or derivatives by treatment with a suitable reagent. Particularly useful are optically active acids such as the D- and L-forms of tartaric or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphoric acid, glutamic acid, aspartic acid or choline acid. A suitable optically active alcohol is, for example, (+) or (-) menthol and a suitable optically active acyl residue in the amides is, for example, a (+) or (-) methyloxycarbonyl radical.

The prepared compounds having the formula (I) can be converted into salts, in particular for pharmaceutical purposes, into physiologically acceptable salts of said compounds, with inorganic or organic acids. Examples of such acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Where the novel compounds of formula (1) obtained contain a carboxyl group, they can be converted into salts with inorganic or organic bases as required, in particular for pharmaceutical purposes into physiologically acceptable salts. Suitable bases for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, diethanolamine and triethanolamine.

It has already been stated that the novel compounds of the general formula (I) and their salts have valuable properties. Compounds of formula (I) in which E represents a cyano group are valuable intermediates for the preparation of other compounds of formula (I); the compounds of the general formula (I) in which E represents the group R ^b NH-C (= NH) - as well as their tautomers, stereoisomers, their physiologically acceptable salts have valuable pharmacological properties, in particular thrombin inhibitory action, prolong thrombin time and have an inhibitory effect on related serine proteases such as trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI and factor XII, wherein some compounds, for example the compound of Example 16, simultaneously have some inhibitory effect on platelet aggregation.

For example, the effect of the following compounds A to G on thrombin time was tested as follows: A = 2- [N- (4-amidinophenyl) aminomethyl] - N-phenyl-N- (2-carboxyethyl) -amide benzothiazole-5-carboxylic acid, B = 1-methyl-2- [2- (4-amidino-phenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide,

C = 1-methyl-2 - [(4-amidinophenyl) -oxyethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylmethyl) -amide,

D = 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylethyl) -amide,

E = 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide,

F = N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl -carboxylic and

G = 1-Methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide.

Test conditions; materials:

- plasma, from human citrus

- test thrombin (bovine), 30 U / ml, Behring Werke, Marburg

- Diethyl barbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg

- Coagulometer, type Biomatic B10, Sarstedt.

Test procedure:

The determination of the thrombin time was performed using a Coagulometer, type B10 from Sarstedt.

The test substance was added to the manufacturer's prescribed test containers along with 0.1 mL of human citrate plasma and 0.1 mL of diethyl barbiturate (in another DBA buffer) buffer. The contents of the vial were incubated at 37 ° C for one minute. The precipitation reaction was initiated by the addition of 0.3 U of test thrombin in 0.1 ml DBA buffer. After the addition of thrombin, the time to precipitate the stick was measured using the apparatus. As a control -

comparative samples served batches to which 0.1 ml DBA buffer was added.

By definition, the effective concentration of the compound at which the thrombin time was doubled compared to the control was evaluated from the dose-effect curve.

The results obtained are shown in the following table.

substance thrombin time (ED ₂₀ ov μΜ) A 0.04 B 0.06 C 0.15 D 0.03 E 0.09 F 0.03 G 0.03

Using compounds A, D, E and G up to a dose of 1 mg per kg i.v. for example, no acute toxic side effects could be detected in rats. The compounds are therefore well tolerated by the organism.

Because of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the prophylaxis and treatment of vascular and arterial thrombotic diseases, such as the treatment of deep vascular thrombosis of the lower extremities, suppression of reoclusion following bypass surgery or angiosplastia (PT (C) A). occlusion in peripheral arterial diseases such as pulmonary embolism, scattered intravascular clots, for the prophylaxis of coronary thrombosis, for the prophylaxis of cerebral slaughter, and for the suppression of occlusion of artificial vessels or stenosis. In addition, the compounds of the invention are useful for antithrombotic support in thrombolytic treatment, such as treatment with rt-PA or streptokinase, for suppressing long-term restenosis after PT (C) A, for preventing metastasis and growth of coagulation-dependent tumors and fibrin-dependent inflammatory processes.

Dosages for intravenous administration of 0.1 to 30 mg.kg ^-1 , preferably 0.3 to 10 mg.kg ^-1 , and for oral administration of 0.1 to 50 mg.kg ^-1 , preferably 0.3 up to 30 mg.kg ^-1 , 1 to 4 times daily. The compounds of the invention having the formula (I) prepared for this purpose can be optionally processed in combination with other active ingredients, together with one or more conventional inert carriers and / or diluents, for example corn starch, milk sugar, raw sugar , microcrystalline cellulose, magnesium stearate, polyvinypyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or stearate or cellulose fatty acids or suitable fat blends, for conventional forms of pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Introductory notes to examples

Polygram-Kieselgel plates from E. Merck, Darmstadt were used to determine Rf values unless otherwise indicated in the individual examples.

EKA mass spectra (ElektrosprayMassenspektren von Kationen) are described, for example, in Chemie unserer Zeit 6, 308-316 (1991).

Example 1

3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [4,5-b] pyridine-6-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

a) 6-Methylamino-5-nitro-nicotinic acid methyl ester

1.6 g (7.4 mmol) of 6-chloro-5-nitronicotinic acid methyl ester (see Bemie et al., J. Chem. Soc, 2950 (1951)) was stirred for 30 minutes in 20 ml of an aqueous 40% methylamine solution. at room temperature. The reaction mixture was then diluted with ice water and the precipitated yellow precipitate was filtered off and dried.

The yield was 1.2 g (80% of theory).

_Rf value: 0.66 (silica gel; ethyl acetate / ethanol / acetic ľadovákyselina = 90: 5: 5).

b) 5-Amino-6-methylamino-nicotinic acid methyl ester

To a solution of 3.1 g (15 mmol) of methyl 6-methylamino-5-nitro-nicotinate in 100 mL of ethanol in dichloromethane (3: 1) was added 1 g of palladium on carbon (10% palladium) and the resulting suspension was hydrogenated under 0.5 MPa of hydrogen for 1.5 hours. The catalyst was then filtered off and the solvent was evaporated in vacuo. The obtained oil product was directly used for further synthesis.

The yield was 2.4 g (92% of theory).

_Rf value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

c) 5- [2- (4-Cyanophenyl) ethylcarbonylamino] -6-methylamino-nicotinic acid methyl ester

A solution of 2.6 g (15 mmol) of 3- (cyanophenyl) propionic acid in 25 ml of absolute tetrahydrofuran was mixed with 2.4 g (15 mmol) of Ν, Ν'-carbonyl-diimidazole and stirred at room temperature for 20 minutes, then a solution of 2.3 g (13 mmol) of methyl 5-amino-6-methylaminotinic acid ester in 25 ml of dimethylformamide was added to the imidazolide and the mixture was heated at 100 ° C for 3 hours. After removal of the solvent in vacuo, the product obtained was triturated in ethyl acetate, the organic phase was washed with water and dried over sodium sulphate and again freed from the solvent. The obtained residue was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane / ethanol = 19: 1).

The yield was 2.1 g of a beige solid (50% of theory).

_Rf value: 0.54 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

d) 3-Methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5- d] pyridine-6-carboxylic acid methyl ester

A solution of 2.0 g (5.9 mmol) of methyl 5- (2- (4-cyanophenyl) ethylcarbonylamino) -6-methylaminonicotinic acid in 50 ml of glacial acetic acid was heated at 100 ° C for 1 hour. It was dissolved in dichloromethane, washed with sodium bicarbonate solution, dried with sodium sulfate and the solvent was distilled off again.

The yield was 1.7 g of a brown solid (89% of theory).

_{R f} value: 0.50 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

e) 3-Methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5-b] pyridine-6-carboxylic acid

A solution of 3.2 g (10 mmol) of methyl 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5-b] pyridine-6-carboxylic acid methyl ester in 150 ml of methanol was mixed with solution 1. 1.5 g of lithium hydroxide in 20 ml of water and the mixture was stirred at room temperature for 24 hours. Then the mixture was diluted with 50 ml of water, the alcohol was distilled off and the aqueous phase was washed with acetic acid ester. After acidification with dilute hydrochloric acid, the solution was extracted several times with dichloromethane / methanol (9: 1), the organic phase was dried over sodium sulfate and the solvent was distilled off.

The yield was 2.1 g of a beige solid (70% of theory).

_Rf value: 0.38 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

f) 3-Methyl-2- [2- (4-cyanophenyl) ethyl] imidazo (4,5->) pyridine-6-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A solution of 2.0 g (6.5 mmol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo (4,5-b) pyridine-6-carboxylic acid in 100 ml of dichloromethane was mixed with 20 ml of dichloromethane. ml of thionyl chloride and refluxed for 2 hours After distilling off the liquid components, the crude product was mixed twice more and evaporated with dichloromethane, and the crude acid chloride (2 g) was then suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g. (6.5 mmol) of N- (2-ethoxycarbonylethyljaniline) was then added dropwise over 5 minutes triethylamine (0.73 g, 7.2 mmol). After stirring for 1 hour, the solvent was evaporated in vacuo, the residue was stirred in acetic acid ester, the organic phase was washed with water and dried over sodium sulfate After distilling off the solvent, the title compound was isolated as a brownish oil by flash chromatography (silica gel; dichloromethane to dichloromethane / ethanol = 49: 1).

The yield was 1.9 (65% of theory).

_Rf value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

g) 3-Methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [4,5-b] pyridine-6-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.8 g (3.7 mmol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [4,5-a] pyridine, n-phenyl-N- (2-ethoxycarbonylethyl) amide The -6-carboxylic acid was stirred at 0 ° C for 16 hours in 100 ml of ethanol saturated with hydrogen chloride, and then at room temperature until the absence of starting material was detected by thin layer chromatography. After the solvent was distilled off, the oily residue was dissolved in 50 ml of absolute ethanol and 3.6 g (37 mmol) of ammonium carbonate was added. After 4 hours, the solvent was distilled off in vacuo. The crude product obtained was purified by flash chromatography (silica gel; gradient: dichloromethane / ethanol 19: 1 to 4: 1) and the purification was repeated.

The yield was 1.6 g of a beige-colored solid (80% of theory).

_Rf value: 0.30 (silica gel; ethyl acetate / ethanol / ammonia 90: 5: 5).

Example 2

3-Methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [4,5- d] pyridine-6-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

A solution of 535 mg (1.0 mmol) of 3-methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-6] pyridine- N-phenyl-N- (2-ethoxycarbonylethyl) -amide. Of 6-carboxylic acid in 10 ml of ethanol was mixed with 5 ml of NaOH solution (c _NaOH = 2 molar ³ ) and stirred at room temperature for 2 hours. It was then diluted with 10 mL of water, the alcohol was distilled off, the aqueous phase was washed with 20 mL of acetic acid ester and acidified with concentrated hydrochloric acid to give white crystals of the title compound. Yield 375 mg (74%).

_Rf value: 0.23 (silica gel; ethyl acetate / ethanol / ammonia 90: 5: 5).

C ₂₆ H ₂₆ N ₆ O ₃ (470.54) Mass Spectrum: (M + H) ⁺ = 471.

Example 3

3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-6] pyridine-6-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 1 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide 3-methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo [4,5- 6] -pyridine-6-carboxylic acid, methanolic solution of hydrogen chloride, methanol and ammonium carbonate.

The yield was 75% of the theoretical yield,

C ₂₆ H ₂₇ N ₇ O ₃ (485.55)

Rf value: 0.31 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

EKA-MS: (M + H) < ^{+ &gt}; = 486.

Example 4

3-Methyl-2- [2- (4-amidino-phenyl) -ethyl] -imidazo [4,5-a] pyridine-6-carboxylic acid N-phenyl-N-ethoxycarbonylmethyl-amide hydrochloride

The compound was prepared analogously to Example 1 from 3-methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo [4,5-a] pyridine-6-N-phenyl-N-ethoxycarbonylmethyl-amide. -carboxylic, ethanolic solution of hydrogen chloride, ethanol and ammonium carbonate.

The yield was 84% of the theoretical yield,

C ₂₆ H ₂₇ N ₇ O ₃ (484.56)

_Rf value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-MS: (M + H) < ^{+ &gt}; = 485.

Example 5

3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-a] pyridine-6-carboxylic acid N-phenyl-N-hydroxycarbonylmethyl-amide hydrochloride

The compound was prepared analogously to Example 2 from 3-methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [4,5-6] pyridine-, N-phenyl-N-ethoxycarbonylmethyl amide hydrochloride. 6-carboxylic acid and sodium hydroxide.

The yield was 85% of the theoretical yield, C ₂₅ H ₂₄ N ₆ O ₃ (456.51)

Rf value: 0.19 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

EKA-MS: (M + H) @ + = 457.

Example 6

2- [2- (4-amidinophenyl) ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydro-indol-1-ylcarbonyl) imidazo [4,5-a] pyridine hydrochloride

The compound was prepared analogously to Example 1 from 2- [2- (4-cyanophenyl) ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydroindol-1-ylcarbonyl) -imidazo [4, 5-Z] pyridine, methanolic solution of hydrogen chloride, methanol and ammonium carbonate.

The yield was 20% of the theoretical yield,

C ₂₇ H ₂₆ N ₆ O ₃ (482.54)

Rf value: 0.30 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

EKA-MS: (M + H) < ^{+ &gt}; = 483.

Example 7

2- [2- (4-amidinophenyl) ethyl] -3-methyl-6- (2-carboxy-2,3-dihydroindol-1-ylcarbonyl) imidazo [4,5-b] pyridine hydrochloride

The compound was prepared analogously to Example 2 from 2- [2- (4-amidinophenyl) ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydroindol-1-ylcarbonyl) imidazo [4] hydrochloride. 5-b] pyridine and sodium hydride.

The yield was 90% of the theoretical yield, C ₂₆ H ₂₄ N ₆ O ₃ (468.52)

_Rf value: 0.24 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-MS: (M + H) < ^{+ &gt}; = 469, (M + Na) = 491.

Example 8

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -imidazo [4,5-6] pyridin-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) 2-Amino-3-methylamino-6-methyl-pyridine

8.35 g (50 mmol) of 2-methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529 (1994)) was dissolved in 300 ml of acetic acid ester, 1.5 g of Raney nickel were added and the suspension was hydrogenated for 3.5 hours at room temperature. Then, the catalyst was filtered off and the filtrate was concentrated. The residue was then crystallized from petroleum ether to give 5.75 g (84% of theory) of olive green crystals.

C ₁₇ H _n N ₃ (137.40)

Mp 112-113 ° C.

b) 1,5-Dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridine

11.4 g (63 mmol) of 4-cyanoxyacetic acid were dissolved in 200 ml of absolute tetrahydrofuran and 10.2 g (63 mmol) of N, N'-carbonyldiimidazole were added at room temperature. After 15 minutes at 60 ° C, 5.70 g (41.5 mmol) of 2-amino-3-methylamino-6-methylpyridine was added. After 2 hours at 60 ° C, the solvent was distilled off, the crystalline residue was mixed with water, washed with water and dried. After crystallization from ethanol, 9.95 g (91% of theory) of white crystals were obtained. C ₁₆ H ₁₄ N ₄ O (278.32)

Mass Spectrum: M ⁺ = 278.

c) 1,5-Dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-a] pyridine-4-N-oxide

2.62 g (10 mmol) of 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] imidazo [4,5-a] pyridine were suspended in 125 ml of dichloromethane and 2.62 g (12, 7 mmol) of m-chloroperoxybenzoic acid, giving a clear solution. After two hours at room temperature, the solvent was distilled off and the residue was stirred in sodium bicarbonate solution. After 30 minutes, the resulting white crystalline product was filtered off with suction, washed with water and dried at 40 ° C.

Yield: 2.45 g (83%) of C ₁₆ H ₁₄ N ₄ O ₂ (294.30)

Mass Spectrum: M ⁺ = 294.

d) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -5-hydroxymethylimidazo [4,5-b] pyridine

2.40 g (8.2 mmol) of 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] imidazo [4,5-a] pyridine-4-N-oxide was suspended in 75 ml of dichloromethane and added with 2.4 mL of trifluoroacetic anhydride (16.9 mmol) to give a clear solution. After 16 hours at room temperature, the solvent was distilled off, the viscous residue obtained was dissolved in 50 ml of dichloromethane, and the solution was then overlaid with sodium bicarbonate solution. After 3 hours of vigorous stirring, the resulting precipitate was filtered off with suction, washed with water and dried at 40 ° C.

The yield was 1.85 of white powder (78% of theory),

C ₁₆ H ₄ N ₄ O ₂ (294.30) The melting point of the product was 172 ° C.

e) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridine-5-carbaldehyde

3.65 g (12.5 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-hydroxymethyl-imidazo [4,5-b] pyridine was dissolved in 500 ml of dichloromethane and 15.0 was added. g of manganese dioxide. After 96 hours at room temperature, the mixture was filtered through diatomaceous earth and the solvent was distilled off. The filtrate was concentrated, the crystalline precipitate was triturated in ether, filtered off with suction and dried. The yield of white powder product was 3.05 g (84% of theory),

C ₁₆ H ₁₂ N ₄ O ₂ (292.30) Melting point: 231-234 ° C.

f) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -5-carboxyimidazo [4,5-a] pyridine

1.25 g (4.3 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5- d] pyridine-5-carbaldehyde was dissolved in 10 ml of formic acid at 0 ° C was added 1 mL of hydrogen peroxide (33%). The mixture was kept at 4 ° C for 12 hours, during which time a precipitate formed, which was filtered off with suction, washed with water and dried at 40 ° C. Yield: 0.81 g (61%), C ₁₆ H ₁₂ N ₄ O ₃ (308.7).

g) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5- d] pyridin-5-yl- N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide; carboxylic acid

308 mg (1.0 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-carboxyimidazo [4,5- d] pyridine was suspended in 5 ml of dimethylformamide and 303 mg (3.0 ml) was added. N-methylmorpholine and 321 mg (1.0 mol) of O- (benztriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2 mmol) of N- (2-pyridyl) -3-aminopropionic acid methyl ester in 2 mL of dimethylformamide was added to give a clear solution. After 12 hours at room temperature, the reaction mixture was stirred into ice water. After extraction three times with acetic acid ester, the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue obtained was chromatographed on silica gel using dichloromethane / ethanol (90: 1 to 25: 1).

The yield of the product as a white powder was 165 mg (35%).

C ₂₅ H ₁₂ N ₆ O ₄ (407.50) Mp 139-140 ° C.

h) 1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -imidazo [4,5-a] pyridin-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared by converting 140 mg (0.3 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] imidazo [4, N- (2-methoxycarbonylethyl) amide N- (2-methoxycarbonylethyl) amide. 5-Ŕ] pyridin-5-yl-carboxylic acid with ethanol, saturated hydrogen chloride and ammonium carbonate / ethanol analogously to Example 1g. The product obtained was purified by chromatography on a silica gel using dichloromethane / ethanol (19: 1 to 4: 1) as eluent.

The yield of the product as a white powder was 48 mg (36% of theory),

C ₂₆ H ₂₇ N ₇ O ₄ (501.57) Mass Spectrum: (M + H) ₊ = 502.

Example 9

2- [N - [(4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 4-Fluoro-3-methoxyacetamido-benzoic acid ethyl ester A solution of 2.8 g (15.3 mmol) of 3-amino-4-fluoro-benzoic acid ethyl ester (see LS Fosdick, AF Dodds, J. Amer. Chem. Soc.) 65, 2305 (1943)) and 1.56 ml (1.85 g = 17.0 mmol) of methoxyacetyl chloride in 50 ml of chlorobenzene were stirred at 50 ° C for 1 hour and then at reflux for 15 minutes. condenser. The solvent was then distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; dichloromethane / ethanol = 100: 1). The desired compound was initially obtained as an oily substance which solidified for several days.

Yield: 3.8 g (98% of theory) _Rf value: 0.38 (silica gel; dichloromethane / methanol -19: 1).

b) 2-Methoxymethyl-benzothiazole-5-carboxylic acid ethyl ester

A mixture of 0.3 g (11.7 mmol) of 4-fluoro-3-methoxyacetamidobenzoic acid and 2.1 g (5.2 mmol) of Lawesson's reagent in 90 ml of toluene was refluxed for 6 hours, added again. Lawesson's reagent (1 g) and the reaction mixture was then heated at 120 ° C for 6 hours. After the solvent was replaced with xylene, the mixture was heated at 180 ° C for an additional 8 hours. Then the solvent was distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; acetic acid ester / petroleum ether = 5:95) and concentrated again.

Yield of product as yellow crystals was 2.1 g (72% of theory),

Rf value: 0.55 (silica gel; acetic acid ester / petroleum ether = 3: 7).

c) 2-Methoxymethyl-benzothiazole-5-carboxylic acid

A mixture of 2.1 g (8.36 mmol) of 2-methoxymethyl- benzothiazole-5-karboxylovcj and 16 ml of sodium hydroxide solution (c = 2 _{to 0} mol.dm H ^'3), together with 60 ml of ethanol was stirred for 1 hour at room temperature. Then the alcohol was distilled off. The crude product was stirred with water (20 mL), washed with 50 mL of diethyl ether, and the aqueous phase was acidified with concentrated hydrochloric acid using ice cooling. The title compound precipitated as a beige-pink material, which was filtered off with suction, washed with water and dried. Yield: 1.6 g (86% of theory) _Rf value: 0.12 (silica gel; dichloromethane / ethanol = 29: 1).

d) 2-methoxymethylbenzthiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A suspension of 1.6 g (7.2 mmol) of 2-methoxymethylbenzothiazole-5-carboxylic acid in 60 ml of dichloromethane was mixed with 1.6 ml (22 mmol) of thionyl chloride and the reaction mixture was heated under reflux for 1 hour. The solid dissolved within 20 minutes. After distilling off the liquid components, the residue was stirred twice more in dichloromethane and the solvent was always distilled off. The crude acid chloride thus obtained was mixed with 50 ml of tetrahydrofuran. This mixture was added dropwise to a mixture of 1.4 g (21 mmol) of triethylamine in 50 ml of tetrahydrofuran; after the addition, the reaction mixture was stirred overnight at room temperature. Then the solvent was distilled off in vacuo, the residue was stirred in 30 ml of dichloromethane, this solution was washed with water and dried using sodium sulfate. After distilling off the solvent, the title compound was isolated as a brown oil by flash chromatography (silica gel; dichloromethane / ethanol gradient 98.5: 1.5 to 80: 20).

Yield: 2.05 g (72% of theory) _Rf value: 0.40 (silica gel; ethyl acetate / petroleum ether = 1: 1).

e) 2- [N- (4-Cyanophenyl) aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A mixture of 2.05 g (5.14 mmol) of 2-methoxymethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide and 5.7 ml (5.7 mmol) of boron tribromide solution (c _BBr3 = 1 mol.dm ³ ) in dichloromethane was dissolved in another portion of dichloromethane (60 ml) and stirred at room temperature for 16 hours. The reaction mixture was then washed with 40 ml of saturated sodium bicarbonate solution, the organic phase was dried over sodium sulfate and the solvent was evaporated. The crude 2-bromomethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide (2.4 g) thus obtained was stirred with 5.0 ml of Ν, Ν-diisopropylethylamine and mixed with O, 64 g (5.4 mmol) of 4-aminobenzonitrile. After heating at 130 ° C for 1 hour, the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; gradient: acetic acid ester / petroleum ether = 1: 3 to 1: 1) to give the eluate after concentration. orange colored rigid foam.

Yield: 1.1 g (44% of theory) _Rf value: 0.35 (GCL silica, ethyl acetate / petroleum ether = 7: 3).

f) 2- [N - [(4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.1 g (2.27 mmol) of 2- [N - [(4-cyanophenyl) aminomethyl] benzothiazole-5-N-phenyl-N- (2-ethoxycarbonylethyl) amide was dissolved in 100 ml of hydrogen-saturated ethanol. The mixture was stirred at 0 ° C for 5 hours and then at room temperature until thin layer chromatography showed no starting material. The solvent was then distilled off at a bath temperature of not more than 30 ° C, the oily residue was dissolved in 100 ml of absolute ethanol and mixed with

1.6 g (22 mmol) of ammonium carbonate. After stirring at room temperature for 18 hours, the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water / methanol = 19: 1 to 4: 1). Concentration of the eluate afforded the title compound as a white foam.

Yield: 0.77 g (63% of theory) _Rf value: 0.19 (silica gel; dichloromethane / ethanol = 3: 7)

C ₂₇ H ₂₇ N ₅ O ₃ S (501.60)

Mass Spectrum: (M + H) ⁺ = 502.

Example 10

2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxy-ethyl) -amide

0.45 g (0.84 mmol) of 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5- N -phenyl-N- (2-ethoxycarbonylethyl) -amide was dissolved in 15 ml of ethanol. carboxylic acid and the solution was mixed with 2 m NaOH solution (c _NaOH = 2 mol.dm &^lt; ³ >); the reaction mixture was stirred at room temperature for 4 hours. It was then acidified with 3 ml of hydrochloric acid (c _H c = = 2 mol.dm ³ ) and the solvent was distilled off. The crude product obtained was dissolved in 5 ml of dichloromethane / ethanol (2: 1) and the undissolved sodium chloride was filtered off. After distilling off the solvent, the title compound was obtained as a yellow foam.

Yield: 0.26 g (67% of theory) _Rf value: 0.47 (silica gel; methanol / 5% aqueous saline solution = 6: 4).

C ₂₅ H ₂₃ N ₅ O ₃ S (476.55) Mass Spectrum: (M + H) ⁺ = 474.

Example 11

2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide dihydrochloride

The compound was prepared in a manner analogous to Example 9, from 2- [N - [(4-cyanophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide. , a methanolic solution of hydrochloric acid, methanol and ammonium carbonate.

Yield: 68%. C ₂₅ H ₂₄ N ₆ O ₃ S (488.57)

_Rf value: 0.13 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) ⁺ = 489th

Example 12

2- [2- (4-amidinophenyl) ethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylmethyl) amide

The compound was prepared in a manner analogous to Example 9 from 2- [2- (4-cyanophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate.

Yield: 95% of theory. C ₂₆ H ₂₅ N ₅ O ₃ S (487.58)

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid), EKA mass spectrum: (M + H) ⁺ = 488.

Example 13

2- [N- (4-amidino-phenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 9 from 2- [N- (4-cyanophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate.

Yield: 68%. C ₂₅ H ₂₄ N ₆ O ₃ S (488.57)

_Rf value: 0.14 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) ⁺ = 489th

Example 14

2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) amide dihydrochloride

The compound was prepared in a manner analogous to Example 10 from 2- [N- (4-amidinophenyl) aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide and sodium hydroxide dihydrochloride.

Yield: 90% of theory. C ₂₃ H ₂₀ N ₆ O ₃ S (460.52)

R _f value: not given,

EKA-MS: (M + H) < ^{+ &gt}; = 461, (M + Na) < ^{+ &gt}; = 483, (M + 2Na) ⁺ = 253.

Example 15

2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 2- [N- (4-Cyanophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 9e from 4-cyano-N-methyl-aniline and 2-methoxymethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide.

Yield: 57% of theory. Rf value: 0.46 (silica gel; dichloromethane / ethanol = 19: 1).

b) 2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 9 from 2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 73% of theory. C ₂₈ H ₂₉ N ₅ O ₃ S (515.64)

_Rf value: 0.29 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid). EKA-MS: (M + H) < ^{+ &gt}; = 516.

Example 16

2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner similar to Example 10 from 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide. and sodium hydroxide.

The yield of the product was 96% of the theoretical yield, C ₂₆ H ₂₅ N ₅ O ₃ S (487.58)

Rf value: 0.48 (Merck RP-8; methanol / 5% NaCl = 6: 4),

EKA-MS: (M = H) ⁺ = 488, (M + 2Na) ⁺ = 266.5.

Example 17

2 - [(4-amidinophenyl) -thiomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner similar to Example 9 from 2 - [(4-cyanophenyl) -thiomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and carbonate solution.

The yield of the product was 61% of the theoretical yield, C ₂₇ H ₂₆ N ₄ O ₃ S ₂ (518.66)

Rf value: 0.27 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid), EKA-MS: (M + H) < ^{+ &gt}; = 519.

Example 18

2 - [(4-amidinophenyl) -thiomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a similar manner to Example 10 from 2 - [(4-amidinophenyl) -thiomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide. The product yield was 95% of the theoretical yield, C ₂₅ H ₂₂ N ₄ O ₃ S ₂ (490.61)

Rf value: 0.25 (Merck RP-8; methanol / 5% NaCl = 6: 4),

EKA-MS: (M + H) ⁺ = 491, (M + Na) ⁺ = 513.

Example 19

2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 9 from N-phenyl-N- (ethoxycarbonylethyl) -amide 2

SK 285432 Β6

- [N- (4-cyanophenyl) aminomethyl] -benzothiazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 82%. C ₂₆ H ₂₅ N ₅ O ₃ S (487.58)

_Rf value: 0.21 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) ⁺ = 488th

Example 20

2- [N- (4-amidino-phenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 10 from 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide and sodium hydroxide. The yield of the product was 75% of the theoretical yield, C ₂₄ H ₂ N ₅ O ₃ S (459.53)

_Rf value: 0.14 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) ⁺ = 460, (M + Na) ⁺ = 482nd

Example 21

2- [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner similar to Example 9 from 2- [2- (4-cyanophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid solution. , ethanol and ammonium carbonate.

The yield of the product was 80% of the theoretical yield, C ₂₈ H ₂ N ₄ O ₃ S (500.62)

_Rf value: 0.30 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) ⁺ = five hundred and first

Example 22

2- [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 10 from 2- [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide.

Yield: 77% of theory. C ₂₆ H ₂₄ N ₄ O ₃ S (472.57)

_Rf value: 0.18 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid) EKA mass spectrum: (M + H) ⁺ = 473, (M + Na) ⁺ = 495. (M + H + Na) = 259.

Example 23

2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 9, from 2- [N- (4-cyanophenyl) aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 83% of the theoretical yield, C ₂₄ H ₂₉ N ₅ O ₃ (467.59)

Rf value: 0.31 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid),

EKA-MS: (M + H) < ^{+ &gt}; = 468, (2M + H) < ^{+ &gt}; = 935.

Example 24

2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-hydroxycarbonylethyl) amide hydrochloride

The compound was prepared in a manner similar to Example 10 from 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide. and sodium hydroxide. The product yield was 75% of the theoretical yield, C ₂₂ H ₂₅ N ₅ O ₃ S (439.54)

Rf value: 0.14 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid), EKA mass spectrum: (M + H) ⁺ = 440, (M + H + Na) ⁴ ' ³ = = 231.6.

Example 25

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

(a) 4-methylamino-3-nitrobenzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitrobenzoic acid chloride and 22.3 g (0.115 mol) of N- (2-ethoxycarbonylethyl) -aniline in 300 ml of tetrahydrofuran at room temperature for 15 minutes after 13.1 g (0.13 mol) of triethylamine was added dropwise with stirring. After stirring for two hours, the solvent was distilled off under a water pump vacuum and the residue was stirred with 700 ml of water. The mixture was extracted three times with 200 ml of dichloromethane, the organic extract was washed with 200 ml of hydrochloric acid _(HC c | = 2 mol.dm ^- "), and twice with 300 ml of water. It was then dried over sodium sulfate. The solvent was distilled off and the oily product thus obtained was purified by column chromatography (1 kg of silica gel; eluent: petroleum ether / acetic acid ester = 2: 1).

Yield: 35.0 g (82% of theory) _Rf value: 0.28 (silica gel; dichloromethane / ethanol = 50: 1).

b) 3-Amino-4-methylaminobenzoic acid N-phenyl- (2-ethoxycarbonylethyl) -amide

12.1 g (0.0326 mol) of n-phenyl- were hydrogenated at room temperature and under a hydrogen pressure of 0.5 MPa in 300 ml of ethanol and 150 ml of dichloromethane and about 4 g of palladium on carbon (10% palladium) added. 4-methylamino-3-nitrobenzoic acid N- (2-ethoxycarbonylethyl) -amide. Then, the catalyst was filtered off and the filtrate was concentrated. The crude product obtained was used without further purification.

Yield: 10.6 g (95% of theory), _Rf value: 0.19 (silica gel; dichloromethane / ethanol = 50: 1).

c) 1-Methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl- (2-ethoxycarbonylethyl) -amide

6.17 g (0.035 mol) of N- (4-cyanophenyl) glycine and 5.68 g (0.035 mol) of Ν, Ν'-carbonyldiimidazole were heated under reflux in 300 ml of tetrahydrofuran for 30 minutes. Then 10.6 g (0.032 mol) of 3-amino-4-methylaminobenzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide was added and the mixture was heated under reflux for a further 5 hours. The solvent was then distilled off in vacuo. The residue was dissolved in

150 ml of glacial acetic acid and the solution was refluxed for 1 hour. The glacial acetic acid was then distilled off in vacuo, the residue was dissolved in approximately 300 ml of dichloromethane, the solution was washed twice with 150 ml of water each time, and then the solution was dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g of silica gel; eluent: dichloromethane (1 to 2% ethanol)).

Yield: 8.5 g (57% of theory) _Rf value: 0.51 (silica gel; dichloromethane / ethanol = 19: 1).

d) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.2 g (2.49 mmol) of N-phenyl- (2-ethoxycarbonyl-ethyl) -amide 1-methyl-2- [N- (4-cyanophenyl) -amide was stirred in 100 ml of ethanol saturated with hydrochloric acid at room temperature for 6 hours. aminomethyl] benzimidazol-5-yl-carboxylic acid. The reaction mixture was then concentrated to dryness in vacuo, the residue was dissolved in 100 mL of ethanol, 2.5 g (26 mmol) of ammonium carbonate was added, and the mixture was allowed to stir overnight at room temperature. After distilling off the solvent, the crude product prepared was purified by column chromatography (100 g silica gel, eluent: dichloromethane / ethanol = 4: 1). Evaporation of the eluate gave the title compound as a white amorphous solid.

Yield: 1.10 g (83% of theory) _Rf value: 0.18 (silica gel; dichloromethane / ethanol = 4: 1).

C ₂₈ H ₃₀ N ₆ O ₃ . HCl (498.6), EKA-MS: (M + H) ⁺ = 499, (M + 2H) ⁺⁺ = 250, (M + H + Na) ⁺⁺ = 261.

Example 26

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-Fcnyl-N- (2-hydroxycarbonylethyl) -amide

A mixture of 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide 300 mg (0.56 mmol), 15 ml of ethanol, 4 ml of water and 120 mg (3.0 mmol) of sodium hydroxide were stirred at room temperature for 2 hours. The reaction mixture was then diluted with 20 mL of water and made glacial with acetic acid to make it acidic. The product crystallized out, which was collected by suction filtration, washed with water and dried at 60 [deg.] C. in vacuo. The product yield was 250 mg (95% of theory),

C ₂₆ H ₂₆ N ₆ O ₃ (470.5)

EKA-Mass Spectrum: (M + H) ⁺ = 471, (M + 2Na) ⁺⁺ = = 258, (M + H + Na) ⁺⁺ = 247.

Example 27

1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

a) 4-methylamino-3-chloroacetamidobenzoic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

A solution of 1.8 g (5.9 mmol) of 3-amino-4-methylaminobenzoic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide (prepared in analogy to N-phenyl-N- ( 2-ethoxycarbonylethyl) 3-amino-4-ethylaminobenzoic acid amide), 1.1 g (6.8 mmol) of N, N'-carbonyl diimidazole and 0.65 g (6.9 mmol) of chloroacetic acid in 75 ml of tetrahydrofuran was stirred for 1 hour at room temperature. The solvent was then distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; methylene chloride / ethanol = 49: 1). Yield: 1.7 g (77% of theory) _Rf value: 0.58 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

b) 2-Chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

A solution of 4-methylamino-3-chloroacetamidobenzoic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide (1.6 g, 4.3 mmol) in 25 ml of acetic acid was heated at 100 ° C for 1 hour. After the solvent was distilled off, the crude product was stirred with 40 ml of a 9: 1 mixture of methylene chloride and ethanol and washed with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated.

The yield was 1.5 g (100% of theory) of the product as a brown oil;

_Rf value: 0.63 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

c) 1-Methyl-2 - [(4-cyanophenyl) thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide

A mixture of 2-chloromethyl-1-methyl-benziimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide (1.5 g, 4.1 mmol) and 0.65 g ( 4.8 mmol) of p-cyanothiophenol in 10 ml of dimethylformamide and 10 ml of diisopropylethylamine was heated at 100 ° C for 1 hour. The solvent was then distilled off in vacuo, the crude product was dissolved in 30 ml of acetic acid ester, washed with 30 ml of water, and concentrated by flash chromatography (silica gel; methylene chloride / ethanol = 49: 1 to 19: 1). The yield was 1.5 g (79% of theory) of the product as a brown oil,

_Rt value: 0.65 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

d) 1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

1.4 g (3.01 mmol) of 1-methyl-2 - [(4-cyanophenyl) thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide in 50 ml of hydrogen chloride-saturated ethanol was stirred for 5 hours at 0 ° C, later at room temperature, until the absence of starting material was detected by thin layer chromatography. The solvent was then distilled off at a bath temperature of not more than 30 ° C, the oily residue was slurried in 40 ml of absolute ethanol and mixed with 2.8 g of ammonium carbonate. After 18 hours, the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; methylene chloride / ethanol = 19: 1 to 4: 1).

The yield was 1.3 g (83% of theory) of the product as a light beige solid;

Rf value: 0.29 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

C ₂₅ H ₃₁ N ₆ O ₃ S (481.62) EKA-MS: (M + H) ⁺ = 482.

Example 28

1-methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-hydroxycarbonylethyl) -amide

0.52 g (1.0 mmol) of 1-methyl-2 - [(4-amidinophenyl) thiomethyl] N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride was dissolved in 15 ml of ethanol. -benzimidazol-5-yl-carboxylic acid, 5 ml of sodium hydroxide solution (c _NaOH = 2 mol.dm &^lt; ^{3 >} ) was added and the mixture was stirred at room temperature for 2 hours. Then 5 ml of water was added and the alcohol was distilled off. The mixture was acidified with concentrated hydrochloric acid. The water was then distilled off in vacuo and the crude product was slurried in 5 ml of ethanol and the solution was filtered from undissolved sodium chloride. After distilling off the solvent, the title compound was obtained as a white solid

Yield: 0.43 g (88% of theory) of the product as a light beige solid;

Rf value: 0.19 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5).

C ₂₃ H ₂₇ N ₅ O ₃ S (453.57) EKA-MS: (M + H) ⁺ = 454, (M + Na) ⁺ = 476.

Example 29

1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-methylpropyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 27 from 1-methyl-2 - [(4-cyanophenyl) thiomethyl] benzimidazol-5-yl-carboxylic acid N- (2-methylpropyl) -N- (2-ethoxycarbonylethyl) amide , ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 83% of theory, C ₂₅ H _{3 I} N ₆ O ₃ S (495.65)

_Rf value: 0.30 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-MS: (M + H) < ^{+ &gt}; = 496.

Example 30

1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner similar to Example 27 from 1-methyl-2 - [(4-cyanophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic acid hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 90% of the theoretical yield, C ₂₈ H ₂₉ N ₅ O ₃ S (515.64)

_Rf value: 0.24 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-MS: (M + H) ⁺ = 516, (M + H + Na) ⁺⁺ = 269.7.

Example 31

1-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 28 from 1-methyl-2 - [(4-cyanophenyl) -thiomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide.

Yield: 76% of theory. C ₂₅ H ₂₅ N ₅ O ₃ S (487.58)

_Rf value: 0.31 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5).

EKA-MS: (M + H) ⁺ = 488, (M + Na) ⁺ = 510.

Example 32

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N- (1-methyl-piperidin-4-yl) -N-methyl-amide hydrochloride

a) 4-Chloro-3-nitrobenzenesulfonic acid N- (1-methyl-piperidin-4-yl) -N-methyl-amide

To a solution of 2.2 mL (15 mmol) of 1-methyl-4-methylaminopiperidine in 60 mL was added portionwise 3.8 g (15 mmol) of 4-chloro-3-nitrobenzenesulfonic acid chloride while cooling with ice. The reaction mixture was then stirred with cooling for 2 hours and then evaporated to dryness. The residue was stirred in about 50 ml of water and made alkaline with ammonia with vigorous stirring. The precipitated crude product was collected by suction and purified by column chromatography (250 g silica gel; eluent: dichloromethane with 1.5% ethanol). Yield: 1.6 g (31% of theory), C ₁₃ H ₁₈ ClN ₃ O ₄ S (347.8)

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

b) 4-methylamino-3-nitrobenzenesulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide

It was stirred in 30 ml of a 40% methylamine solution

1.6 g (4.6 mmol) of 4-chloro-3-nitrobenzenesulfonic acid N-methyl-N- (1-methyl-piperidin-4-yl) -amide and in a sealed flask were stirred at room temperature for 4 hours. The mixture was then diluted with 40 ml of water, the precipitated product was filtered off with suction, washed with water and dried. Yield: 1.5 g (95% of theory), C ₁₄ H ₂₂ N ₄ O ₄ S (343.4)

_Rf value: 0.45 (silica gel; dichloromethane / ethanol = 4: 1).

c) 3-Amino-4-methylaminobenzenesulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide

1.5 g (4.4 mmol) of 4-methylamino-3-nitrobenzenesulfonic acid N-methyl-N- (1-methyl-piperidin-4-yl) -amide was dissolved in 100 ml of methanol. The solution was catalytically hydrogenated (10% palladium on carbon catalyst) at room temperature and under hydrogen pressure (0.5 MPa). The catalyst was then filtered off and the filtrate was concentrated. The oily product obtained was used in the next reaction step without purification.

Yield of product was 1.4 g (100% of theory), C ₁₄ H ₂₄ N ₄ O ₂ S (312.4)

_Rf value: 0.33 (silica gel; dichloromethane / ethanol = 4: 1).

d) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide

532 mg (3.0 mmol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mmol) of 1,1'-carbonyldiimidazole were dissolved in 40 ml of tetrahydrofuran. The solution was heated to reflux for 15 minutes. 700 mg (2.24 mmol) of 3-amino-4-methylaminobenzenesulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) amide was then added and the mixture was refluxed for an additional 8 hours. It was then evaporated and the resulting oily residue was treated with 30 ml of glacial acetic acid and refluxed for 1 hour. The glacial acetic acid was then distilled off, the residue was stirred with approximately 30 ml of water and made alkaline with concentrated ammonia. It was then extracted three times with 20 ml of dichloromethane each time. The combined organic phases were dried and concentrated. The obtained product was used in the next reaction step without purification.

The product yield was 400 mg (39% of theory),

C ₂₃ H ₂₇ N ₅ O ₃ S (453.6)

_Rf value: 0.37 (silica gel; dichloromethane / ethanol = 4: 1).

e) 1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide hydrochloride

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N- (1-methylpiperidin-4-yl) -amide, ethanolic hydrochloric acid and ammonium carbonate.

Yield: 370 mg (83% of theory);

C ₂₃ H ₃₀ N ₆ O ₃ S (470.6)

EKA mass spectrum: (M + H) ⁺ = 471, (M + 2H) ⁺⁺ = 236th

Example 33

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N-phenyl-amide hydrochloride

The compound was prepared in a similar manner to Example 32 from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N-methyl-N-phenyl-amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate .

The yield of the product was 46% of the theoretical yield, C ₂ H ₂₃ N ₅ O ₃ S (449.5)

EKA-MS: (M + H) < ^{+ &gt}; = 450, (M + 2H) < ^{+ >} = = 223, (M + H + methanol) = 482.

Example 34

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazole-5-sulfonic acid, N- (3-ethoxycarbonyl-n-propyl) -N-phenylamide hydrochloride

The compound was prepared in a manner analogous to Example 32 from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazole-5-sulfonic acid N- (3-ethoxycarbonyl-n-propyl) -N-phenyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 57% of theory, of C _{28 3 I} N ₅ O ₅ S (549.7)

EKA-MS: (M + H) < ^{+ &gt}; = 550.

Example 35

1-Methyl-2 - [(3-amidinophenyl) -oxymethyl] -benzimidazole-5-sulfonic acid pyrrolidide hydrochloride

The compound was prepared in a similar manner to Example 32 from 1-methyl-2 - [(3-cyano-phenyl) oxymethyl] -benzimidazole-5-sulfonic acid pyrrolidide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 71%. C ₂₀ H ₂₃ N ₅ O ₃ S (413.5)

EKA-MS: (M + H) < ^{+ &gt}; = 414.

Example 36

1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-methoxycarbonylpropyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N- (3- tert -butyloxycarbonylpropyl) -N-phenylamide, methanol hydrochloric acid, methanol and ammonium carbonate.

Yield: 83.5% of theory. Rf value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₉ H ₃₁ N ₅ O ₃ (497.6)

EKA-MS: (M + H) < + > = 498, (M + H + Na < + > = 260.7).

Example 37

1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2 - [(amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-methoxycarbonylpropyl) -amide and sodium hydroxide. The product yield was 92% of theory, Rf value: 0.09 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₈ H ₂₉ N ₅ O ₃ (483.6)

EKA-MS: (M + H) ⁺ = 484, (M + Na) + = 506, (M + H + Na) ⁺⁺ = 253.7.

Example 38

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-ethoxycarbonylpropyl) -amide

a) 1-Methyl-2- [N- (4-cyano-phenyl) -amino-methyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-tert-butyloxycarbonyl-propyl) -amide

The compound was prepared in a manner analogous to Example 25c from 3-amino-4-methylaminobenzoic acid N- (4-cyanophenyl) glycine and N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide.

Yield: 65%. Rf value: 0.17 (silica gel; dichloromethane / methanol = 19: 1);

b) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-ethoxycarbonyl-propyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide. , ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 68% of theory, _Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₉ H ₃₂ N ₆ O ₃ (512.6)

EKA mass spectrum: (M + H) ⁺ = 513, (M + H + Na) ⁺⁺ = 268th

Example 39

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide

The compound was prepared in a manner analogous to Example 26 from N-phenyl-N- (3-ethoxycarbonylpropyl) -amide 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazole-5- dihydrochloride. ylcarboxylic acid and sodium hydroxide.

Yield: 73.5% of theory. C ₂₇ H ₂₈ N ₆ O ₃ (484.6)

EKA-MS: (M + H) ⁺ = 485, (M + 2H) = 243, (M + H + Na) ⁺⁺ = 254.

Example 40

1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide, ethanolic acid solution. hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 73% of the theoretical yield,

Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₈ H ₂₉ N ₅ O ₃ (483.6)

EKA mass spectrum: (M + H) ⁺ = 484, (M + H + Na) ⁺⁺ = 253.7.

Example 41

1-Methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) amide hydrochloride

The compound was prepared in a similar manner to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide dihydrochloride and sodium hydroxide. Yield: 97% of theory. C ₂₆ H ₂₅ N ₅ O ₃ (455.5)

EKA-MS: (M + H) ⁺ = 456, (M + Na) ⁺ = 478, (M + 2Na) ⁺⁺ = 250.6.

Example 42

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 76% of the theoretical yield,

Rf value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₇ H ₂₇ N ₅ O ₄ (485.6)

EKA mass spectrum: (M + H) ⁺ = 486, (M + H + Na) ⁺⁺ = 254.7.

Example 43

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide hydrochloride and sodium hydroxide.

The yield of the product was 58% of the theoretical yield, C _{2 S} H ₂₃ N ₅ O ₄ (457.5)

EKA-MS: (M + H) < ^{+ &gt}; = 458, (M + Na) &lt; ^{+ &gt}; = = 480, &lt; + &gt;

Example 44

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate. Yield: 74%. Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₇ H ₂₈ N _{6 O}} (484.6)

EKA mass spectrum: (M + H) ⁺ = 485, (M + H + Na) ⁺⁺ = 254th

Example 45

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide hydrochloride and hydroxide solution.

Yield: 84%. C ₂₅ H ₂₄ N ₆ O ₃ (456.5)

EKA-MS: (M + H) &lt; ^{+ &gt}; = 457, (M + Na) &lt; ^{+ &gt}; = 479, (M + 2Na) ^&lt; ^{+ &gt}; = 251.

Example 46

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (4-pyrimidyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (4-pyrimidyl) -N- (2-ethoxycarbonylethyl) amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 14% of theory, ₂ C 6 H ₂₇ N ₇ O ₄ (501.6) EKA mass spectrum: (M + H) ⁺ = 502nd

Example 47

1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanol solution hydrochloric acid, ethanol and ammonium carbonate. Yield: 44% of theory, _Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₆ H ₂₆ N ₆ O ₃ (486.5)

EKA-MS: (M + H) &lt; ^{+ &gt}; = 487, (M + 2H) &lt; ^{+ &gt;} = = 244, (M + H + Naf = 255).

Example 48

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide and sodium hydroxide.

The yield of the product was 85% of the theoretical yield, C ₂₄ H ₂₂ N 6 _{O 4} (458.5)

EKA-MS: (M + H) &lt; ^{+ &gt}; = 459, (M + Na) &lt; ^{+ &gt}; = 481, (M + 2Na) ⁺⁺ = 252.

Example 49

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide

a) 1-Methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide

The compound was prepared analogously to Example 25c from N- (4-cyanophenyl) -glycine and N- (2-pyridyl) -N-ethoxycarbonylmethylamide 3-amino-4-methylaminobenzoic acid.

The product yield was 24% of the theoretical yield.

_Rf value: 0.56 (silica gel; dichloromethane / methanol = 4: 1);

b) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide

The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide; of a carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 70% of theory, _Rf value: 0.16 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₆ H ₂₇ N ₇ O ₃ (485.6)

EKA-MS: (M + H) ⁺ = 486, (M + 2H) ^{+ t} = 243.7, (M + H + Na) ⁺⁺ = 254.6.

Example 50

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) amide hydrochloride

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide dihydrochloride. carboxylic acid and sodium hydroxide.

The yield of the product was 91% of the theoretical yield, C ₂₄ H ₂₃ N ₇ O ₃ (457.5)

EKA-MS: (M + H) ⁺ = 458, (M + Na) ⁺ = 480, (M + 2Na) ⁺⁺ = 251.7.

Example 51

1-Methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, _Rf value: 0.17 (silica gel; dichloromethane / CTAN = 4: 1);

C ₂₇ H ₂₈ N ₆ O ₃ (484.6)

EKA mass spectrum: (M + H) ⁺ = 485, (M + 2H) ⁺⁺ = 243 (M + H + Na) ^{+ t} = 254th

Example 52

1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) amide

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazole-5- (2-pyridyl) -N- (ethoxycarbonylmethyl) amide dihydrochloride. ylcarboxylic acid and sodium hydroxide.

The yield of the product was 89% of the theoretical yield, C ₂₅ H ₂₄ N ₆ O ₃ (456.5)

EKA-MS: (M + H) ⁺ = 457, (M + Na) + = 479.

Example 53

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide, methanolic solution of hydrochloric acid, methanol and ammonium carbonate. Yield: 87% of theory, _Rf value: 0.11 (silica gel; dichloromethane / ethanol - 4: 1);

C ₂₇ H ₂₈ N ₆ O ₃ (484.6)

EKA-MS: (M + H) ⁺ = 485, (M + 2H) + = 243, (M + H + Na) ⁺⁺ = 254.

Example 54

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic acid solution. hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 79.5% of the theoretical yield, C ₂₈ H ₂₉ N ₅ O ₄ (499.6),

_Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ⁺ = 500, (M + H + Na) ⁺⁺ = 261.7.

Example 55

1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a similar manner to Example 26 from 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide. The yield of the product was 82% of the theoretical yield, C ₂₆ H ₂₅ N ₅ O ₄ (471.5)

EKA-MS: (MHI) ⁺ = 472, (M + Na) ⁺ = 494, (M + H + Na) ⁺ = 247.1, (M + 2Na) ⁺⁺ = 258.6.

Example 56

1-Methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) 1-Methyl-2- [2- (2-cyanothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25c from 3- (2-cyanothiophen-5-yl) -propionic acid and 3-amino-4-methylaminobenzoic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide.

The product yield was 18% of the theoretical yield. _Rf value: 0.66 (silica gel; dichloromethane / methanol = 9: 1);

b) 1-Methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (2-cyanothiophen-5-yl) ethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 53%. C ₂₆ H ₂₈ N ₆ O ₃ S (504.6);

_Rf value: 0.22 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-MS: (M + H) ^{@ +} = 505, (M-H @ + Na) @ ⁺ = 264.

Example 57

1-Methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to EXAMPLE 26 from 1-methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] - N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Yield: 98% of theory, C ₂₄ H ₂₄ N ₆ O ₃ S (476.6);

EKA-MS: (M + H) ^{@ +} = 477, (M + Na) ^{@ +} = 499, (M + 2H) @ ⁺ = 239.

Example 58

1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

a) 1-Methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25c from N- (4-cyanophenyl) glycine and N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 3-amino-4-methylaminobenzoic acid.

The yield of the product was 61% of the theoretical yield.

_Rf value: 0.62 (silica gel; dichloromethane / methanol = 19: 1);

b) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5- (N- (2-ethoxycarbonylethyl) -amide) - (2-ethoxycarbonylethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 71%. C ₂₇ H ₂₉ N ₇ O ₃ (499.6);

Rf value: 0.28 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-MS: (M + H) ⁺ = 500, (M + H + Na) ⁺⁺ = = 261.8, (M + 2H) ⁺⁺ = 250.8.

Example 59

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Yield: 91% of theory. C ₂₅ H ₂₅ N ₇ O ₃ (471.5);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 472, (M + H &lt; + &gt; Na) &lt; ^{+ &gt}; = 247.6, (M + 2H) &lt; ⁺ &^gt; .

Example 60

1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) 1-Methyl-2- [2- (4-cyanophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 149a from 3- (4-cyano-phenyl) -propionic acid and 3-amino-4-methylaminobenzoic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide.

The product yield was 22% of the theoretical yield.

_Rf value: 0.68 (silica gel; dichloromethane / methanol = 19: 1);

b) 1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-N- (2-ethoxycarbonylethyl) -amide. -carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 85% of the theoretical yield, C ₂₈ H ₃₀ N ₆ O ₃ (498.6);

_Rf value: 0.30 (silica gel; dichloromethane / ethanol = 5: 1);

EKA mass spectrum: (M + H) ⁺ = 499, (M + H + Na) ⁺⁺ = 261st

Example 61 1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazole-5, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Yield: 97% of theory. C ₂₆ H ₂₆ N ₆ O ₃ (470.5);

EKA-MS: (M + H) ⁺ = 471, (M + H + Na) = 247, (M + Na) ⁺ = 493.

Example 62

1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

SK 28S432 B6

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanol solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 86% of theory, C ₂₉ H ₃₁ N ₅ O ₃ (497.6);

_Rf value: 0.11 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ^{@ +} = 498, (M + H @ + Na) ^{@ +} = 249.8.

Example 63

1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner similar to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide. and sodium hydroxide. Yield: 71%. C ₂₇ H ₂₇ N ₅ O ₃ (469.6);

EKA-MS: (M + H) ⁺ = 470, (M + H + Na) ⁺ = 246.6, (M + Na) ⁺ = 492, (M + 2H) ⁺⁺ = 235.6.

Example 64

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (methoxycarbonylmethyl) amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (methoxycarbonylmethyl) amide , a methanolic solution of hydrochloric acid, methanol and ammonium carbonate.

Yield: 73%. C ₂₃ H ₂₅ N ₇ O ₃ (471.5);

Rf value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ^{@ +} = 472, (M + H @ + Na) @ ⁺ = 247.8.

Example 65

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5- (N- (2-methoxycarbonylethyl) -amide) - (2-methoxycarbonylethyl) -amide. of carboxylic acid, methanolic solution of hydrochloric acid, methanol and ammonium carbonate.

Yield: 78% of theory. C ₂₆ H ₂₇ N ₇ O ₃ (485.6);

_Rf value: 0.31 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 486, (M + H-Naf = = 254.8).

Example 66

1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide

a) 1-Methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-yl N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide carboxylate

The compound was prepared analogously to Example 25c from 3-amino-4- (3- (4-cyanophenyl) propionic acid and N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide. methylaminobenzoic.

The product yield was 67% of the theoretical yield.

IR spectral analysis (KBr): characteristic bands at 3 439.5 cm ^-1 (NH) 2 235.5 cm ^"1 (ON), 1631.6 cm" (C = O);

b) 1-Methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl- N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] amide hydrochloride carboxylic acid

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] amide -benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 92% of theory, C ₂₇ H ₂₇ N ₉ O (493.6);

EKA-MS: (M + H) ⁺ = 494, (M + Na) ⁺ = 516, (M + 2H) ⁺⁺ = 258.7.

Example 67

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N-phenyl-N- [2- (1H-tetrazo-5-yl) -ethyl] -amide hydrochloride carboxylate

The compound was prepared in a manner analogous to Example 25d from N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide 1-methyl-2- [N- (4-cyanophenyl) - aminomethyl] -benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 29% of theory, C ₂₆ H ₂₆ N ₁₀ O (494.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 495.

Example 68

1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-n-hexyloxycarbonylethyl) -amide

To about 30 ml of hydrogen chloride-saturated n-hexanol was added 0.60 g (1.1 mmol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (2-ethoxycarbonylethyl) amide hydrochloride. 4-Aminophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid was added and the mixture was stirred at room temperature for 19 hours. The hexane was then distilled off in vacuo. The residue was stirred with 5 ml of ammonia solution (c _{NH 3} = 1 mol.dm ³ ) and evaporated again. The crude product thus obtained was purified by column chromatography (silica gel; dichloromethane / methanol = 5: 1).

The product yield was 53% of theory, C ₃₁ H ₃₇ N ₇ O ₃ (555.7);

Rf value: 0.36 (silica gel; dichloromethane / ethanol = 5: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 556.

Example 69

1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) 1-Methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in analogy to Example 25c from 3-amino-4-methylaminobenzoic acid N- (4-cyanophenyl) -N-methylglycine and N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide.

The yield of the product was 71% of the theoretical yield.

_Rf value: 0.66 (silica gel; dichloromethane / methanol = 19: 1).

b) 1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 77% of theory. C ₂₈ H ₃₁ N ₇ O ₃ (513.6);

EKA mass spectrum: (M + H) ⁺ = 514, (M + H + Na) ⁺⁺ = 268.7.

Example 70

1-Methyl-2- [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -N- (2-ethoxycarbonylethyl) -amide hydrochloride. benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Yield: 66%. C ₂₆ H ₂₇ N ₇ O ₃ (485.6);

EKA-MS: (M + H) ⁺ = 486, (M + Na) ⁺ = 508, (M + 2Na) ⁺⁺ = 265.6.

Example 71

1-Methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 65%. C ₂₈ H ₃₃ N ₅ O ₃ (489.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 490.

Example 72

1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide. Yield: 89% of theory, _C26 H ₃₁ N ₃ O ₅ (461.6);

EKA-MS: (M + H) ⁺ = 462, (M + Na) ⁺ = 484, (M + H + Na) + = 242.6, (M + 2H) = 231.6.

Example 73

1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 60% of the theoretical yield,

C2 ₇ H ₃₄ N ₆ O ₃ (490.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 491.

Example 74

1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazo-5-yl-carboxylic acid N-cyclopentyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to EXAMPLE 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide.

Yield: 45% of theory, C ₂₅ H ₃₀ N ₃ O ₄ (462.6);

EKA-MS: (M + H) ⁺ = 463, (M + Na) ⁺ = 485, (M + H + Na) ⁺⁺ = 243, (M + 2Na) ⁺⁺ = 254.

Example 75

1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -benzimidazole-5- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 54% of theory, ₂ C 7 H 5 _2, N ₇ O ₃ (499.6)

EKA mass spectrum: (M + H) ⁺ = 500, (M + 2H) ⁺⁺ = 250.7.

Example 76 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide

The compound was prepared in a manner analogous to Example 26 from N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] benzimidazole-5- ylcarboxylic acid and sodium hydroxide.

Yield: 68%. C ₂₅ H ₂₅ N ₇ O ₃ (471.5);

EKA-MS: (M + H) ⁺ = 472, (M + Na) ⁺ = 494, (M + 2Na) ⁺⁺ = 258.6.

Example 77

1-Methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) amide -carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 91% of theory. C ₂₈ H ₃₀ N ₆ O ₃ (498.6);

_Rf value: 0.19 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 499.

Example 78

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] - N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide.

6-benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory. C ₂₇ H ₂₉ N ₇ O ₃ (499.6);

_Rf value: 0.09 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 500.

Example 79

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-N- (2-ethoxycarbonylethyl) -amide- dihydrochloride. -yl-carboxylic acid and sodium hydroxide.

The product yield was 85% of theory, C ₂₃ H ₂₅ N ₇ O ₃ (471.5);

EKA-MS: (M + H) ⁺ = 472, (M + 2H) ⁺⁺ = = 236.6, (M + 2Na) ⁺⁺ = 258.6.

Example 80

1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -benzimidazole N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide; Of 5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 64%. C ₂₈ H ₃₁ N ₇ O ₃ (513.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 514.

Example 81

1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride -benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Yield: 70%. C ₂₆ H ₂₇ N ₇ O ₃ (485.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 486, (M + Na) &lt; ^{+ &gt}; = = 508, (M + Na) &lt; ^{+ &gt}; = 265.6.

Example 82

1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 1-Methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25c from 3-amino-4-methylaminobenzoic acid N- (4-cyanophenyl) -N-methylglycine and N-phenyl-N- (2-ethoxycarbonylethyl) amide.

The yield of the product was 71% of the theoretical yield.

_Rf value: 0.38 (silica gel; dichloromethane / methanol = 19: 1).

b) 1-Methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazole-5- N-phenyl-N- (2-ethoxycarbonylethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% of theory, C ₂₉ H ₃₂ N ₃ O _NO (512.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 513, (M + H + Na) &lt; + ^&gt; = = 268, (M + 2H) &lt; ^{+ &gt;} = 257.

Example 83

1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5, N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Yield: 80% of theory, C ₂₇ H ₂₈ N ₆ O ₃ (484.6);

EKA-MS: (M + H) ⁺ = 485, (M-H + Na +) = 254, (M + Na) ⁺ = 507, (M-2Na) ⁺ = 265.

Example 84

1-Ethyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -N- (2-ethoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) amide - benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 85% of the theoretical yield, C ₂₈ H ₃₁ N ₇ O ₃ (513.6);

_Rf value: 0.21 (silica gel; dichloromethane / methanol = 5: 1).

EKA-MS: (M + H) &lt; ^{+ &gt}; = 514, (M + H + Na) &^lt; + &gt;

Example 85

1-Ethyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 starting from 1-ethyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. benzimidazol-5-yl-carboxylic acid, and sodium hydroxide-be (c _Na0H - 1 mol.dm ^'3).

Yield: 49%. C ₂₆ H ₂₇ N ₇ O ₃ (485.6);

EKA-MS: (M + H) ⁺ = 486, (M + H + Na) ⁺⁺ = = 254.6, (M + 2H) ⁺ = 243.6, (M + 2Na) ⁺⁺ = 265, 7th

Example 86 1-Methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazole N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 88% of theory, C ₂₈ H ₂₉ FN ₆ O ₃ (516.6);

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

EKA-MS: (M + H) &lt; ^{+ &gt}; = 517, (M + H + Na) &lt; + &^gt; = 270, (M + 2H) &lt; ^{+ &gt;} = 259.

Example 87

1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

The product yield was 45% of theory, C ₂₆ H ₂₅ FN ₆ O ₃ (488.5);

_Rf value: 0.05 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ⁺ = 489, (M + H + Na) ⁺⁺ = 267, (M + 2H) ⁺ = 256.

Example 88

1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -N- (2-ethoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) amide - benzimidazol-5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

Yield: 79% of theory, C ₂₉ H ₃₂ N ₆ O ₃ (512.6);

_Rf value: 0.10 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 513, (M + H + Na) &lt; + ^&gt; = = 268, (M + 2H) &lt; ^{+ &gt;} = 259.

Example 89 1-Methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-methyl-phenyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-N- (2-ethoxycarbonylethyl) -amide hydrochloride. -yl-carboxylic acid and sodium hydroxide.

Yield: 62%. C ₂₇ H ₂₈ N ₆ O ₃ (484.6);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 485, (M + H &lt; + &gt; Na) &lt; ⁴ &gt; = 254, (M + Na) ⁺ = 507, (M + 2Na) ⁺⁺ = 265.

Example 90

1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide

1.1 g (2.06 mmol) of 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water. benzimidazol-5-yl-carboxylic acid, 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of n-hexyl chloroformate were added, and the reaction mixture was stirred at room temperature for 2 hours. The residue was taken up in approximately 50 ml of saturated sodium chloride solution and the resulting solution was extracted three times with 20 ml of dichloromethane each, the extracts were dried over sodium sulphate and concentrated. 5% ethanol).

The product yield was 78% of the theoretical yield; C ₃₃ H ₄₂ N ₆ O ₃ (626.8);

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

EKA-MS: (M + H) &lt; ^{+ &gt}; = 627, (M + H + Na) &lt; + ^&gt; = 325, (M + 2H) &lt; ^{+ &gt}; = 314.

Example 91

1-Methyl-2- [N- [4- (N-methoxycarbonyl-amidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and methyl chloroformate.

The product yield was 41% of the theoretical yield; C ₃₀ H ₃₂ N ₆ O ₃ (556.6);

Rf value: 0.85 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ⁺ = 557, (M + H + Na +) = 290, (M + Na) ⁺ = 579.

Example 92

1-Methyl-2- [N- [4- (N-ethoxycarbonyl-amidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazole-5- hydrochloride. yl carboxylic acid and ethyl chloroformate.

The yield of the product was 62% of the theoretical yield; C ₃₀ H ₃₂ N ₆ O ₃ (556.6);

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

EKA-MS: (M + H) &lt; ^{+ &gt}; = 557, (M + H + Na) &lt; + ^&gt; = 290, (M + 2H) &lt; ^{+ &gt}; = 279.

Example 93

1-Methyl-2- [N- [4- (N-cyclohexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) amino-methyl] benzimidazol-5-yl hydrochloride carboxylic acid and cyclohexyl chloroformate.

The product yield was 25% of the theoretical yield; C ₃₄ H ₃₈ N ₆ O ₅ (610.7);

Rf value: 0.44 (silica gel; dichloromethane / ethanol = 19: 1);

EKA - MS (M + H) ⁺ = 611, (M-2H) ⁴⁺ = 306th

Example 94

1-methyl-2- [N- [4- [N- [2- (methylsulfonyl) -ethyloxycarbonyl] -amino] phenyl] -aminomethyl] -benzimidazole N- (phenyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and 2- (methylsulfonyl) ethyl chloroformate.

The yield of the product was 66% of the theoretical yield; C ₃₂ H ₃₆ N ₆ O ₇ S (648.8);

Rf value: 0.44 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-Mass Spectrum: (M + H + = 649, (Η + 2Η) + - = 325, M @ 11 U Na) @ + = 336.

Example 95

1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid hydrochloride and n-octyl chloroformate.

The product yield was 41% of the theoretical yield; C ₃₆ H 44 N ₆ O ₅ (640.8);

Rf value: 0.43 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-MS: (M + H) ⁺ = 641, (M + Na) ⁺ = 663.

Example 96

1-Methyl-2- [N- [4- (N-hydroxyl-amidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-ethoxycarbonylethyl) -amide

1.44 g (3.0 mmol) of 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] N- (phenyl) -N- (2-ethoxycarbonylethyl) amide was dissolved in 80 ml of ethanol. 1-benzimidazol-5-yl-carboxylic acid, 0.625 g (9.0 mmol) of hydroxylamine hydrochloride and 0.425 g (4.0 mmol) of sodium carbonate, and the mixture was heated at reflux for Ί hour. An additional portion of hydroxylamine hydrochloride (210 mg) and sodium carbonate (170 mg) was then added and the mixture was refluxed for an additional 5 hours. The mixture was then concentrated in vacuo. The residue was dissolved in about 30 mL of dichloromethane, the resulting solution was washed with 20 mL of water, the organic phase was dried and concentrated. The crude product obtained was purified by column chromatography (200 g silica gel; dichloromethane + 4% ethanol). The product yield was 39% of the theoretical yield; C ₂₈ H ₃₀ N ₆ O ₄ (514.6);

_Rf value: 0.15 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-MS: (M + H) ⁺ = 515, (M + Na) ⁺ = 537, (2M + H) ⁺ = 1,029, (2M + Na) ⁺ = 1,051.

Example 97

1-Methyl-2- [N- [4- (N-n-heptyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and n-heptyl chloroformate.

The product yield was 43% of the theoretical yield; C ₃ H ₄₂ N ₆ O ₅ (626.8);

_{R f} value: 0.40 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-MS: (M + H) ^{@ +} = 627, (M + H @ + Na) @ ⁺ = 325, (M + Na) ^{@ +} = 649.

Example 98

1-Methyl-2- [N- [4- (N-benzoylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (Fcnyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and benzoyl chloride. The yield of the product was 88% of the theoretical yield; C ₃₄ H ₃₂ N ₆ O ₄ (588.7);

_Rf value: 0.37 (silica gel; dichloromethane / ethanol = 19: 1);

1 H NMR Spectrum (D ₆ -DMSO): 2.61 (t, 2H), 3.54 (s, 3H), 3.76 (s, 3H), 4.10 (t, 2H), 4.61 (d, 2H), 6.83 (d, 2H), 7.05-7.55 (m, 12H), 8.03 (d, 2H), 8.25 (dd, 2H), 8.98 ( s, 1H), 10.48 (s, 1H).

Example 99

1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (phenyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- carboxylic acid and n-hexyl chloroformate.

The yield of the product was 54% of the theoretical yield; C ₃₄ H ₄₀ N _{6 O,} (612.7);

_Rf value: 0.45 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 613.

Example 100

1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (phenyl) -N- (2-n-propyloxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (2-n-propyloxycarbonylethyl) -amide hydrochloride and n-hexyl chloroformate.

The product yield was 31% of the theoretical yield; ₃ C 6 H ₄₄ N ₆ O ₅ (640.8);

_Rf value: 0.42 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-MS: (M + H) ⁺ = 641, (M + Na) ⁺ = 663, (M + H + Na) ⁺⁺ = 332.

Example 101 1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide carboxylate

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5- (N- (2-methoxycarbonylethyl) -amide) hydrochloride. yl carboxylic acid and ethyl chloroformate.

The yield of the product was 72% of the theoretical yield; C ₂₉ H ₃₁ N ₇ O ₅ (557.6);

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

EKA-MS: (M + H) ⁺ = 558, (M + N'a) - = 580, (M + H + Na) ⁺⁺ = 290.8.

Example 102 1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-octyl chloroformate.

The yield of the product was 57% of the theoretical yield; C ₃₅ H ₄₃ N ₇ O ₃ (641.8);

_Rf value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 642, (M + Na) ⁺ = 664, (M + H + Na) ⁺⁺ = 332.8.

Example 103 1-Methyl-2- [N- [4- (N-methoxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride carboxylic acid and ethyl chloroformate.

The yield of the product was 48% of the theoretical yield; _{3 I} C 29 N ₇ O ₅ (557.6);

Rf value: 0.62 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 558, (M + Na) &lt; ^{+ &gt}; = 580, (M + H + Na) &lt; + &gt; = 290.7.

Example 104

1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

A mixture of 0.12 g (3.0 mmol) of sodium hydroxide, 5 ml of water and 10 ml of methanol with 0.7 g (1.1 mmol) of N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide The 1-methyl-2- [N- [4- (Nn-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid was stirred at room temperature for 1 hour. Then the mixture was diluted with 20 ml of water and the pH of the mixture was adjusted to 6 with glacial acetic acid. Approximately 5 ml of diethyl ether was added and the mixture was stirred vigorously for one hour. Upon stirring, the product precipitated, which was collected by suction filtration, washed with a small amount of water, then with diethyl ether and dried.

The yield of the product was 80% of the theoretical yield; C ₃₄ H ₄₁ N ₇ O ₅ (627.8);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 628, (M-H = N &apos; a) ^&gt; = = 325.7, (M + Na) &lt; ^{+ &gt}; = 650, (M + 2Na) ⁺⁺ = 337.7 .

Example 105 1-Methyl-2- [N- [4- [N- (2-methylsulfonylethyloxycarbonyl) amidino] phenyl] aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide 5-yl-carboxylic acid The compound was prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-ethoxycarbonyl-ethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] hydrochloride benzimidazol-5-yl-carboxylic acid; and 2- (methylsulfonyl) ethyl chloroformate.

The product yield was 65% of the theoretical yield; C ₃ H ₃₅ N ₇ O ₇ S (649.7);

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

EKA-MS: (M + H) ⁺ = 650, (M + Na) ⁺ = 672, (M + H + Na) ⁺⁺ = 336.6, (M + 2Na) ⁺⁺ = 347.6.

Example 106 1-Methyl-2- [N- [4- (N-n-butyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5- yl carboxylic acid and n-butyl chloroformate.

The product yield was 30% of the theoretical yield; C ₃₁ H ₃₅ N ₇ O ₅ (585.7);

_Rf value: 0.62 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 586, (M + H &lt; + &gt; Na) = 304.7, ([delta] + 2H) = 293.7.

Example 107

1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-hexyl chloroformate.

The product yield was 51% of the theoretical yield; C ₃₃ H 9 N ₃ O _{7 5} (613.7);

Rf value: 0.56 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) + = 614, (M + H + Na) + = 318.7, (M + 2H) ⁺⁺ = 307.6.

Example 108

1-Methyl-2- [N- [4- (N-n-heptyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-heptyl chloroformate.

The product yield was 21% of the theoretical yield; C ₃₄ H ₄₁ N ₇ O ₅ (627.8);

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

EKA-MS: (M + H) ⁺ = 628, (M + H + Na) ⁺⁺ = = 325.7, (M + 2H) ⁺⁺ = 314.7.

Example 109 1-Methyl-2- [N- [4- (N-n-pentyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and n-pentyl chloroformate.

The product yield was 661% of the theoretical yield; C ₃₂ H ₃₇ N ₇ O ₅ (599.7);

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

EKA-MS: (M + H) ⁺ = 600, (M + H + Na) = 311.7, (M + Na) ⁺ = 622.

Example 110 1-Methyl-2- [N- [4- (N-nonyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide- carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride -carboxylic acid and n-nonyl chloroformate.

The product yield was 60% of the theoretical yield; C ₃₆ H ₄₅ N ₇ O ₅ (655.8);

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

EKA-MS: (M + H) ^{@ +} = 656, (M + H @ + Na) ^{t @ +} = 339.8, (M + Na) ^{@ +} = 678.

Example 111 1-Methyl-2- [N- [4- (N-benzoylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) amide hydrochloride and benzoyl chloride. The yield of the product was 62% of the theoretical yield; C ₃₃ H ₃₁ N ₇ O ₄ (589.7);

_Rf value: 0.50 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 590, (M + Na) ⁺ = 612.

Example 112

1-Methyl-2- [N- [4- (N-nicotinoylamidino) phenyl] aminomethyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5- ylcarboxylic and nicotinoyl chloride.

The product yield was 40% of the theoretical yield; C ₃₂ H ₃₀ N ₈ O ₄ (590.7);

_Rf value: 0.47 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 591, (M + H + Na) ⁺ = 307, (M + Na) ⁺ = 613.

Example 113 1-Methyl-2- [N- [4- (N-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide- carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and n-hexyl chloroformate.

The product yield was 51% of the theoretical yield; C ₃₄ H ₄ N ₇ C 5 (627.8);

_Rf value: 0.53 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 628, (M + H + Na) ⁺⁺ = = 325.7, (M + 2H) ⁺⁺ = 314.7.

Example 114

1-Methyl-2- [N- [4- (N-n-octyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. γ-carboxylic acid and n-octyl chloroformate.

The yield of the product was 57% of the theoretical yield; C ₃₆ H ₄₅ N ₇ O ₅ (655.8);

_Rf value: 0.46 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 656, (M + H + Na) ⁺⁺ = 339.7, (M + 2H) = 328.7.

Example 115

1-Methyl-2- [N- [4- [N- (2-methylsulfonyl-ethyloxycarbonyl) -amidino] -phenyl] -aminomethyl] -benzimidazol-5-yl-N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide carboxylate

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl) -amide. and 2- (methylsulfonyl) ethyl formate.

The yield of the product was 72% of the theoretical yield; C ₃₀ H ₃₃ N ₇ O ₇ S (635.7);

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

EKA mass spectrum: (M + H) ⁺ = 636, (M + H + Na) ⁺⁺ = 329.8.

Example 116 1-Methyl-2- [N- [4- (N-cyclohexyl-oxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (methoxycarbonylmethyl) -amide- carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethylamide hydrochloride and cyclohexyl ester chloroformate.

The product yield was 40% of the theoretical yield; C ₃₂ H ₃₅ N ₇ O ₅ (597.7);

_Rf value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1);

EKA-MS: (M + H) ⁺ = 598, (M + Na) ⁺ = 620.

Example 117

1-Methyl-2- [N- [4- (N-methoxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethylamide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethylamide hydrochloride and methyl ester chloroformate.

The yield of the product was 62% of the theoretical yield; C ₂₈ H ₂₉ N ₇ O ₅ (543.6);

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

EKA-MS: (M + H) ⁺ = 544, (M + H + Na) ⁺⁺ = = 283.8, (M + Na) ⁺ = 566.

Example 118

1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethylamide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethylamide hydrochloride and ethyl ester chloroformate.

The product yield was 42% of the theoretical yield; C28H29N7O5 (543.6);

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

EKA-MS: (M-H) ⁺ = 544.

Example 119

1-Methyl-2- [N- [4- (Nn-octyloxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl- N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide- carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) amino-methyl] benzimidazole-5- (N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride) yl carboxylic acid and n-octyl chloroformate.

The product yield was 35% of the theoretical yield; C ₃₆ H ₄₅ N ₇ O ₅ (655.8);

Rf value: 0.28 (silica gel; dichloromethane / ethanol = 19: 1);

EKA mass spectrum: (M + H) + = 656, (M + 2H) ^'1 = 328.7.

Example 120 1-Methyl-2- [N- [4- (N-hexyloxycarbonylamidino) -phenyl] -N-methyl-aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 5-yl-carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. 5-yl-carboxylic acid and n-hexyl chloroformate.

The yield of the product was 58% of the theoretical yield; C ₃₅ H ₄₃ N ₇ O ₅ (641.2);

_Rf value: 0.42 (silica gel; dichloromethane / ethanol = 19: 1);

EKA mass spectrum: (M + H) ⁺ = 642, (M + H + Na) ⁺⁺ = 332.7.

Example 121

1-Methyl-2- [N- [4- (Nn-octyloxycarbonylamidino) -phenyl] -N-methyl-aminomethyl] -benzimidazole-5- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide yl-carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide, 5-yl-carboxylic acid and n-octyl chloroformate.

The product yield was 36% of the theoretical yield; C ₃₇ H ₄₇ N ₇ O ₅ (669.8);

EKA-MS: (M + H) ⁺ = 670, (M + H + Na) ⁺⁺ = = 346.8, (M + 2H) + = 335.6.

Example 122

1-Methyl-2- [N- [4- (N-butyloxycarbonylamidino) -phenyl] -N-methylaminomethyl] -benzimidazole-5- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide yl-carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide, 5-yl-carboxylic acid and n-butyl chloroformate.

The product yield was 34% of the theoretical yield; C ₃₃ H ₃₉ N ₇ O ₅ (613.7);

EKA-MS: (M + H) ⁺ = 614; (M + H + Na) ⁺⁺ = = 318.7; (M + Na) ⁺ = 636.

Example 123

1-Methyl-2- [N- [4- (N-benzoylamidino) -phenyl] -N-methylaminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide- carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazole hydrochloride, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. 5-yl-carboxylic acid and benzoyl chloride.

The yield of the product was 63% of the theoretical yield; C ₃₅ H ₃₅ N ₇ O ₄ (617.7);

EKA-MS: (M + H) ⁺ = 618, (M + H + Na) ⁺⁺ = = 320.7, (M + Na) ⁺ = 640.

Example 124

-Methyl-2- [N- (4-amidinophenyl) oxymethyl] -benzimidazol-5-yl- (1-ethoxycarbonylmethyl-cyclohex-1-yl) -ketone hydrochloride

a) Chlorophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone

8.4 g (40 mmol) of 3- (4-chlorobenzoyl) propionic acid were dissolved in 300 ml of tetrahydrofuran and 5.8 g (120 mmol) of sodium hydride (50-60% suspension in sodium hydride) was added in portions to this solution. paraffin oil). The reaction mixture was then stirred and refluxed for 1.5 hours, then 1,5-diiodo-pentane (8.9 mL, 60 mmol) was added dropwise and the mixture was further boiled for 3 hours. After cooling, the solution was stirred into 200 ml of ice water; tetrahydrofuran was distilled off in vacuo, the aqueous solution was acidified with hydrochloric acid (c = ci _H 2 mol.drrí ³⁾ and extracted three times with 150 ml of dichloromethane. The organic phase was dried and concentrated. The crude product obtained was purified by column chromatography (500 g silica gel; eluent dichloromethane with 1-2% ethanol)

The yield was 6.2 g (55% of theory) of the oily product;

C ₁₅ H | ₇ C1O ₃ (280.8);

Rf value: 0.56 (silica gel; dichloromethane / ethanol = 19: 1);

b) 4-Chloro-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone

7.0 g (25 mmol) of chlorophenyl- (1-hydroxycarbonylmethylcyclohex-1-yl) ketone were introduced portionwise with stirring at -5 to -10 ° C into 80 ml of fuming nitric acid. The mixture was then stirred for a further 10 minutes. The reaction mixture was then stirred in 200 ml of ice water, the precipitated product was washed with water and dried.

Yield: 7.8 g (96% of theory); C | ₅ H ₁₆ ClNO ₅ (325.8);

_Rf value: 0.41 (silica gel; petroleum ether / ethyl acetate = 4: 6);

c) 4-Methylamino-3-nitrophenyl- (1-hydroxycarbonylmethylcyclohex-1-yl) ketone

7.8 g (23.9 nmoles) of 4-chloro-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone was stirred at room temperature for 14 hours in 100 ml of a 40% aqueous methylamine solution, then diluted. 150 ml of water and acidified to a slightly acidic reaction with glacial acetic acid. The precipitated product was collected by suction filtration, washed with water and dried.

Yield: 7.1 g (93% of theory); C ₆ H ₂₀ N ₂ O ₅ (320.4);

_Rf value: 0.34 (silica gel; dichloromethane / ethanol = 19: 1)

d) 4-Methylamino-3-nitrophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone

4.9 g (15 mmol) of 4-methylamino-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone were dissolved in 100 ml of tetrahydrofuran, 2.4 g (15 mmol) of Ι, Γ-carbonyldiimidazole were added and the mixture was refluxed for 15 minutes. Then the solvent was evaporated, 30 ml of methanol were added and the mixture was again refluxed for 3 hours. After distilling off the methanol, the crude product obtained was purified by column chromatography (250 g of silica gel; eluent: dichloromethane with 1-5% ethanol).

Yield: 2.4 g (48% of theory); C ₁₇ H ₂₂ N ₂ O ₅ (334.4);

Rf value: 0.76 (silica gel; dichloromethane / ethanol = 19: 1).

e) 3-Amino-4-methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone

2.4 g (7.2 mmol) of 4-methylamino-3-nitrophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone in 100 ml of methanol at room temperature and 0.5 MPa of hydrogen were catalytically hydrogenated using 10% - palladium on coal. The crude product obtained was used in the next reaction step without purification.

Yield: 2.1 g (96% of theory); _Rf value: 0.34 (silica gel; dichloromethane / ethanol = 19: 1).

f) 3- (4-Cyanophenyloxyacetylamino) -4-methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) octone

620 mg (3.2 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of 1,1'-carbonyl-diimidazole in 50 ml of tetrahydrofuran were heated under reflux for 15 min. 0 g (3.28 mmol) of 3-amino-4-methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone and the reaction mixture was boiled for an additional 4 hours, then the solvent was evaporated and the crude product obtained was purified by column chromatography ( 150 g of silica gel, eluent: dichloromethane with 0-2% ethanol).

Yield: 1.4 g (93% of theory); C ₂₆ H ₂₉ N ₃ O ₅ (463.5);

Rf value: 0.44 (silica gel, dichloromethane / ethanol = 19: 1).

g) 1-Methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone

1.4 g (3.02 mmol) of 3- (4-cyanophenyloxyacetylamino) -4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone in 50 ml of glacial acetic acid was heated at reflux for 1 hour. The acetic acid was then distilled off, the residue was stirred with 20 ml of water, and the concentrated ammonia solution was made basic. The solution was extracted three times, each time with 20 ml of dichloromethane. The organic extracts were dried and concentrated. The crude product obtained was purified by column chromatography (100 g silica gel; eluent: dichloromethane with 0-2% ethanol).

The yield was 700 mg of product (52% of theory); C ₂₆ H ₂₇ N ₃ O ₄ (445.5).

h) 1-Methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-yl- (1-ethoxycarbonylmethyl-cyclohex-1-yl) -ketone hydrochloride

The compound was prepared analogously to Example 25d from 700 mg (1.57 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) - ketone, ethanolic hydrochloric acid and ammonium carbonate.

Yield: 390 mg (50% of theory);

C ₂₇ H ₃₂ N ₄ O ₄ (476.6);

EKA mass spectrum: (M + H) ⁺ = 477;

1 H NMR Spectrum (d ₆ -DMSO): 1.10 (t, 3H), 1.0-2.15 (m, 10H), 3.36 (s, 3H), 3.90 (s, 2H) 3.94 (q, 2H), 5.60 (s, 2H), 7.25 to 7.40 (m, 3H), 7.56 to 7.75 (m, 2H), 7.90 (d , 2H), 9.20 (br s, 4H) ppm.

Example 125 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- tert -butyl ketone hydrochloride

The compound was prepared analogously to Example 25d of 1-methyl-2 - [(4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-to-c-butyl ketone, ethanolic hydrochloric acid solution, ethanol and ammonium carbonate.

The yield of the product was 59% of the theoretical yield; C ₂₁ H ₂₅ N ₅ O (363.5);

EKA mass spectrum: (M + H) ⁺ = 364.

Example 126 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- (1-methyl-cyclopent-1-yl) -ketone hydrochloride

The compound was prepared analogously to Example 25d of 1-methyl-2 - [(4-cyanophenyl) aminomethyl] -benzimidazol-5-yl (1-methylcyclopent-1-yl) ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate . The yield of the product was 63.5% of the theoretical yield; C ₂₃ H ₂₇ N ₃ O (389.5);

EKA mass spectrum: (M + H) ⁺ = 390.

Example 127

2 - [(4-amidinophenyl) -sulfinylmethyl] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

To a solution of 0.15 g (0.27 mmol) of 2 - [(4-amidinophenyl) thiomethyl] benzothiazol-5-ylcarboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl iamide) in 10 ml of acetic acid was added 0.09 ml (approximately 0.81 mmol) of a 30% hydrogen peroxide solution and the reaction mixture was stirred at room temperature After 4 days, an additional portion of hydrogen peroxide solution (0.18 ml) was added and the mixture stirred for a further two days. solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; eluent methylene chloride / ethanol = 10: 1 to 4: 1) to yield 58% of the theoretical yield; C ₂₇ H ₂₆ N ₄ O ₄ S ₂ (534 , 66).

Rf value: 0.24 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid); EKA mass spectrum: (M + H) ⁺ = 535.

Example 128

1-Methyl-2 - [(4-amidinophenyl) sulfonylmethyl] -benzimidazol-5-yl-carboxylic acid N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide

To a solution of 0.40 g (0.70 mmol) of N- (n-propyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2 - [(4-amidophenyl) thiomethyl] -benzimidazole hydrochloride 5-yl-carboxylic acid in 10 ml formic acid was added 2 ml of 30% hydrogen peroxide solution and the mixture was stirred at room temperature for 16 hours. The solvent was then distilled off under vacuum to give the title compound as a beige-colored solid (with a small proportion of 1-methyl-2 - [(N- (n-propyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride). 4-amidinophenyl) sulfinylmetyl] benzimidazol-5-yl-carboxylic acid.

The product yield was 95% of the theoretical yield; C 25 H ₃₁ N ₆ O ₅ S (513.62);

Rf value: 0.50 (silica gel; acetic acid / ethanol / hydrochloric acid ester ( _cHa = 1 mol.dm &^lt; ^{3 &gt;} ) = 50: 45: 5);

EKA mass spectrum: (M + H) ⁺ = 514.

Example 129

2- [N- (4-amidinophenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 5-Amino-6-chloro-nicotinic acid methyl ester

To a solution of 1.08 g (5.00 mmol) of 6-chloro-5-nitro-nicotinic acid methyl ester (see: AH Berrie, GT Newbold, FS Spring: J. Chem. Soc. 2 590 (1951)) in 25 mL of absolute ethanol was gradually added 0.53 mL (29 mmol) of water, 3.2 g (57 mmol) of iron powder and 0.030 mL of concentrated hydrochloric acid, and the reaction mixture was heated to boiling. Then, an equal amount of water, iron powder and hydrochloric acid was added once more, and the mixture was heated at reflux for 30 minutes. The precipitate formed was filtered off, washed with ethanol and the solvent was distilled off in vacuo. The yield of a yellow-green solid was 0.75 g (81% of theory);

C ₇ H ₇ C1N ₂ O ₂ (186.60);

Rf value: 0.31 (silica gel; acetic acid ester / petroleum ether = 1: 4);

YEF mass spectrum: M ⁺ = 186 and 188 (chlorine isotope).

b) 6-Chloro-5-methoxyacetamidonicotinic acid methyl ester

A solution of 0.75 g (4.02 mmol) of 5-amino-6-chloro-nicotinic acid methyl ester and 0.43 g = 0.35 ml (4.5 mmol) of methoxyacetyl chloride in 20 ml of chlorobenzene was stirred at 110 ° C for 1 hour. C. After removal of the solvent in vacuo, the product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 100: 1); the eluate was concentrated again in vacuo and subsequently digested with petroleum ether.

The yield of pale yellow amorphous solid product was 0.55 g (53% of theory);

Rf value: 0.33 (silica gel; acetic acid ester / petroleum ether = 1: 4).

c) 2-Methoxymethyl-thiazolo [5,4- d] pyridin-6-yl-carboxylic acid methyl ester

A mixture of 0.53 g (2.05 mmol) of 6-chloro-5-methoxyacetamidonicotinic acid methyl ester and 0.42 g (1.0 mmol) of Lawesson's reagent in 25 ml of xylene was heated at reflux for 16 h. After removal of the solvent in vacuo, the product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 100: 1); the eluate was concentrated again in vacuo.

The yield of a yellow-colored amorphous solid was 0.33 g (67% of theory);

_Rf value: 0.52 (silica gel; ethyl acetate / petroleum ether = 1: 4).

d) 2-Methoxymethyl-thiazolo [5,4-a] pyridin-6-yl-carboxylic acid

A mixture of 1.1 g (4.62 mmol) of 2-methoxymethylthiazolo [5,4-b] pyridine-6-carboxylic acid methyl ester and 9.2 ml of sodium hydroxide solution (c _NaOH = 2 mol.dm ^-3 ) with 50 ml of ethanol was stirred at room temperature for 1 hour. Thereafter, 9.2 hydrochloric acid (c ⁼ ci _H 2 mol.dm ^-3), the alcohol was distilled off, and the mixture was diluted with 20 ml of water. The aqueous phase was ice-cooled and acidified with concentrated hydrochloric acid, whereupon a beige colored precipitate formed; the precipitate was filtered off, washed with water and dried.

Yield of the product was 1.03 g (100% of theory);

Rf value: 0.10 (silica gel; acetic acid ester / petroleum ether = 3: 7).

e) 2-Methoxymethyl-thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide

A suspension of 1.03 g (4.62 mmol) of 2-methoxymethylthiazolo [5,4-b] pyridin-6-yl-carboxylic acid in 40 ml of methylene chloride was mixed with 1.6 g = 1.0 ml (13.5 mmol) of thionyl chloride and the reaction mixture was heated to reflux. The solid dissolved slowly. After distilling off the liquid components, the crude product was mixed with methylene chloride two more times and concentrated again. The obtained acid chloride (1.2 g) was slurried in 40 ml of tetrahydrofuran and added dropwise to a mixture of 0.94 g (4.86 mmol) of N- (2-ethoxycarbonylmethyl) aniline and 2.1 ml (13.8 mmol). triethylamine in 30 ml of tetrahydrofuran; the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 200 mL of acetic acid ester, washed with 100 mL of 14% brine, and the organic phase was dried over sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol 100: 1).

Yield of the product as a yellow oil was 1.57 g (87% of theory);

Rf value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1).

f) 2- [N- (4-Cyanophenyl) -aminomethyl] -thiazolo [5,4-a] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A mixture of 2-methoxymethyl-thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide (1.54 g, 3.85 mmol) and 4.3 ml (4 Solution of boron tribromide (c _{BBr 3} = 1 mol.dm ^-3 ) in methylene chloride was dissolved in an additional 30 ml of methylene chloride and stirred at room temperature for 5 hours. The reaction mixture was then washed with 40 ml of saturated sodium bicarbonate solution, the organic phase was dried over sodium sulfate and the solvent was distilled off. The crude product (1.9 g) was stirred in 15.0 ml of Ν, opropyl-diisopropylethylamine, 0.50 g (4.2 mmol) of 4-aminobenzonitrile was added and the mixture was heated at reflux for 1 hour. After distilling off the solvent in vacuo, the crude product was stirred in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried over sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; acetic acid ester / petroleum ether = 35: 65 to: 1) and the eluate was again evaporated in vacuo.

The yield of yellow amorphous solid was 0.45 g (24% of th.);

_Rf value: 0.34 (silica gel; ethyl acetate / petroleum ether = 1: 1).

g) 2- [N- (4-amidino-phenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

0.39 g (0.803 mmol) of 2- [N- (4-cyanophenyl) aminomethyl] thiazolo [5,4-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide The reaction mixture was stirred in 40 ml of hydrogen chloride-saturated ethanol for 5 hours at 0 ° C and then at room temperature until thin layer chromatography showed that the mixture no longer contained the starting material. Thereafter, the solvent was distilled off at a bath temperature of not more than 30 ° C, the oily residue was stirred in 40 ml of absolute ethanol and 0.5 g of ammonium carbonate was added. After 18 hours, the solvent was removed in vacuo and the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 9: 1 to 4: 1).

Yield of the product as a yellow foam was 78% of the theoretical yield;

C ₂₆ H ₂₆ N ₆ O ₃ S (502.60);

Rf value: 0.19 (silica gel; methylene chloride / ethanol = 4: 1);

EKA mass spectrum: (M + H) ⁺ = 503.

Example 130

1-Methyl-2 - [(4-amidinophenyl) methylthiobenzimidazol-5-ylcarboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

a) 1-Methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A solution of 6.5 g (19 mmol) of 3-amino-4-methylaminobenzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide and

4.5 g (22.8 mmol) of N, N‘-thiocarbonyldiimidazole were dissolved in 100 ml of tetrahydrofuran under a nitrogen atmosphere, heated at 90 ° C for 4 hours and then allowed to stand at room temperature for 16 hours. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; petroleum ether / acetic acid ester = 100: 0 to 65: 35).

The yield was 6.8 g (93% of theory) of a beige-colored crystalline solid;

Rf value: 0.55 (silica gel; acetic acid ester).

b) 1-Methyl-2 [(4-cyanophenyl) methylthio] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide

A solution of 1.30 g (3.4 mmol) of 1-methyl-2-mercapto-benzimidazole-5 N-phenyl-N- (2-ethoxycarbonylethyl) -amide.

-ylcarboxylic acid, 0.52 g (3.74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) of 4-bromomethylbenzonitrile in 40 ml of absolute ethanol were stirred for 4 hours at 60 ° C and 16 hours at room temperature. . The solvent was then distilled off in vacuo, the crude product was stirred in 30 ml of methylene chloride, washed with 40 ml of water and dried over sodium sulfate. Filtration and distillation of the solvent gave the title compound as a white-beige solid.

Yield: 1.8 g (100%); _Rf value: 0.64 (silica gel; ethyl acetate).

c) 1-Methyl-2 - [(4-amidinophenyl) methylthiobenzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

1.5 g (3.0 mmol) of 1-methyl-2 [(4-cyanophenyl) methylthio] -benzimidazol-5-ylcarboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide in 80 ml of hydrogen chloride-saturated ethanol The mixture was stirred at 0 ° C for 6 hours and then at room temperature until thin layer chromatography showed the mixture to be free of starting material. Then the solvent was distilled off at a bath temperature of not more than 30 ° C, the oily residue was stirred in 80 ml of absolute ethanol, and 1.0 g (10.5 mmol) of ammonium carbonate was added. After 18 hours, the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 19: 1 to 10: 1).

The yield was 78% of the theoretical yield of a pale beige solid;

C ₂₈ H ₂₉ N ₅ O ₃ S (515.3);

_Rf value: 0.19 (silica gel; methylene chloride / ethanol = 4: 1);

EKA mass spectrum: (M + H) ⁺ = 516, (M + H + Na) ⁺⁺ = = 269.7, (M + 2H ^{+ +} = 258.7).

Example 131

1-Methyl-2 - [(4-amidinophenyl) methylthio] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) amide hydrochloride

The compound was prepared analogously to Example 10 from 1-methyl-2 - [(4-amidinophenyl) methylthio] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide and sodium hydroxide.

The yield of the product was 57% of the theoretical yield; C ₂₆ H ₂₅ N ₃ O ₃ S (487.58);

Rf value: 0.23 (reversed phase RP-8 silica gel; ethanol / 5% saline = 6: 4);

EKA mass spectrum: (M + H) ⁺ = 488, (M + Na) ⁺ = 510, (M + H + Na) ⁺⁺ = 255.6.

Example 132

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-propargyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) amino-methyl] -benzimidazol-5-yl-carboxylic acid N-propargyl-N- (2-ethoxycarbonylethyl) -amide. , ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The yield of product was 81% of the theoretical yield; C ₂₅ H ₂₈ N ₆ O ₃ (460.6);

Rf value: 0.094 (silica gel; dichloromethane / ethanol) = 4: 1);

EKA mass spectrum: (M + H) ⁺ = 461, (M + H + Na) ⁺ = = 242, (M + 2H) ⁺ = 231.

Example 133 1-Methyl-2- [2- [4- (N-hexyloxycarbonylamidino) phenyl] ethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and n-hexyl chloroformate.

The yield of the product was 72% of the theoretical yield; C35H42NA (626.8);

_Rf value: 0.54 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) ⁺ = 627, (M + Na) ⁺ = 649.

Example 134 1-Methyl-2- [2- [4- (N-benzoyl-amidino) -phenyl] -ethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and benzoyl chloride.

The product yield was 79% of the theoretical yield; C ₃₅ H ₃₄ N ₆ O ₄ (602.7);

Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) ⁺ = 603, (M + Na) ⁺ = 625.

Example 135 1-Methyl-2- [2- [4- (N-nicotinoyl-amidino) -phenyl] -ethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and nicotinic acid chloride.

The yield of the product was 56% of the theoretical yield; C ₃₄ H ₃₃ N ₇ O ₄ (603.7);

_Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) ⁺ = 604, (M + Na) ⁺ = 626.

Example 136

1-Cyclopropyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared analogously to Example 25d from 1-cyclopropyl-2- [N- (4-cyanophenyl) amino-methyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 31% of the theoretical yield; C ₃ H ₃₃ N ₆ O ₃ (524.6);

_Rf value: 0.40 (silica gel; dichloromethane / methanol = 5: 1);

EKA mass spectrum: (M + H) ⁺ = 525, (M + H + Na) ⁺⁺ = = 274, (M-2H) - = 263.

Example 137

1-Cyclopropyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 26 from 1-cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and hydroxide solution. The yield of the product was 64% of the theoretical yield;

(496.6);

EKA mass spectrum: (M + H) ⁺ = 497, (M + H + Na) = ⁴ ^ ⁴ = 260, (M + Na) ⁺ = 519, (M + 2Na) ⁺⁺ 271st

Example 138

1-Methyl-2- [N- (4-amidinophenyl) -N- (n-butyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -N- (n-butyl) -aminomethyl] -benzimidazole N-phenyl-N- (2-ethoxycarbonylethyl) amide. Of 5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 62% of the theoretical yield; C ₃₂ H ₃₈ N ₆ O ₃ (554.7);

EKA mass spectrum: (M + H) ⁺ = 555, (M + H + Na) ^4-4 = 289, (M + 2H) ⁺ = 278.

Example 139

1-Methyl-2- [N- (4-amidino-2-chlorophenyl) -N-aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyano-2-chloro-phenyl) -aminomethyl] -benzimidazol-5-yl-, N-phenyl-N- (2-ethoxycarbonylethyl) -amide. of a carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 82% of the theoretical yield; C ₂₈ H ₂₉ C1N ₃ O ₆ (533.1);

EKA mass spectrum: (M + H) ⁺ = 533/5, (M + H-Na) ⁺⁺ = 278/9.

Example 140

1-methyl-2- [N- [4- (n-octyloxycarbonylamidino) phenyl] aminomethyl] benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and n. -octyl chloroformate.

The product yield was 34% of the theoretical yield; C ₃₇ H ₄₆ N ₆ O _S (654.8);

_Rf value: 0.15 (silica gel; dichloromethane / ethanol = 19: 1);

EKA mass spectrum: (M + H) ⁺ = 655, (M + H + Na) ⁺⁺ = 339 (M + Na) ⁺ = 677th

Example 141

1-Methyl-2- [N- (4-amidino-2-ethyl-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyano-2-ethyl-phenyl) -ammomethyl] -benzimidazole-5- N-phenyl-N- (2-ethoxycarbonylethyl) -amide. of carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 61% of the theoretical yield; C ₃₀ H ₃₄ N ₆ O ₃ (526.6);

EKA mass spectrum: (M + H) ⁺ = 527, (M + H + Na) ⁺ = = 275, (M + 2H) ⁺⁺ = 264.

Example 142

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid benzylamide hydrochloride

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid benzylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.

The yield of the product was 63% of the theoretical yield; C ₂₄ H ₂₄ N ₆ O (412.5);

Rf value: 0.76 (silica gel; dichloromethane / ethanol = 4: 1);

EKA mass spectrum: (M + H) ⁺ = 413.

Example 143

1-Methyl-2- [N- [4- (N- (2- (2-ethoxy-ethoxy) -ethyloxy) -carbonylamidino) -phenyl] -N- (2-ethoxycarbonylethyl) -amide N- (2-pyridyl) -amide aminomethyl] benzimidazol-5-yl-carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride. carboxylic acid and chloroformic acid ester with diethylene glycol monoethyl ether. The product yield was 43% of the theoretical yield; C ₃₄ H ₄₁ N ₇ O ₇ (659.8);

Rf value: 0.56 (gcl of silica; dichloromethane / methanol = 9: 1);

EKA mass spectrum: (M + H) ⁺ = 660, (M + H + Na) ⁺⁺ = 341.7.

Example 144

1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide. of a carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 60% of the theoretical yield; C ₂₆ H ₃₀ N ₈ O ₃ (502.6);

_Rf value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1);

EKA mass spectrum: (M + H) + ¹ = 503, (M + H + Na) ⁺⁺ = 263 (M + 2H) ⁺ = * 252nd

Example 145

3-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -imidazo [4,5- b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 1 from 3-methyl-2 - [(4-cyanophenyl) thiomethyl] imidazo [4,5-6] pyridine-6 N-phenyl-N- (2-ethoxycarbonylethyl) amide. -yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 88% of the theoretical yield; C ₂₇ H ₂₈ N ₆ O ₃ S (516.63);

_Rf value: 0.23 (silica gel; ethyl acetate / CTAN / ammonia 50: 45: 5);

EKA mass spectrum: (M + H) ⁺ = 517, (M + H + Na) ⁺⁺ = 270.

Example 146

3-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -imidazo [4,5-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in analogy to Example 1 from 3-methyl-2- [N- (4-cyanophenyl) aminomethyl] imidazo [4,5-6] pyridine-, N-phenyl-N- (2-methoxycarbonylethyl) amide. 6-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 82% of the theoretical yield; C ₂₇ H ₂₉ N ₇ O ₃ (499.58);

Rf value: 0.20 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA mass spectrum; (M + H) ⁺ = 500, (M + H + Na) ⁺⁺ = 261.7.

Example 147

3-Methyl-2 - [(4-amidinophenyl) -thiomethyl] -imidazo [4,5-b] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 2 from 3-methyl-2 - [(4-amidophenyl) -thiomethyl] -imidazo [4,5-a] pyridine hydrochloride, N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride 6-yl-carboxylic acid and sodium hydroxide. The yield of the product was 88% of the theoretical yield; C ₂₅ H ₂₄ N ₆ O ₃ S (488.56);

Rf value: 0.21 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA mass spectrum: (M + H) ⁺ = 489, (M + Na) ⁺ = 511.

Example 148

3-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -imidazo [4,5-6] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 2 from 3-methyl-2 - [(4-amidinophenyl) aminomethyl] -imidazo- [4,5-b] pyridine-, N-phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride. 6-yl-carboxylic acid and sodium hydroxide. The yield of the product was 80% of the theoretical yield; C ₃₅ H ₂ 5 N ₇ O ₃ (471.52);

_Rf value: 0.19 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5);

EKA mass spectrum: (M + H) ⁺ = 472, (M + Na) ⁺ = 494, (M + 2Na) ⁺⁺ = 258.6.

Example 149

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 1-Methyl-2- [N- (4-cyano-phenyl) -amino-methyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

2.54 g (6.2 mmol) of 3-nitro-4-methylaminobenzenesulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide was hydrogenated in a mixture of 75 ml of ethanol and 75 ml of dichloromethane. Hydrogenation was carried out at room temperature under 0.5 MPa of hydrogen using palladium on carbon (10%) as a catalyst. The obtained crude 3-amino-4-methylaminobenzenesulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide was stirred without purification in 30 ml of phosphorus oxychloride and then 1.1 g (6.2 mmol) were added.

N- (4-cyanophenyl) glycine and the mixture was refluxed for 2 hours. After cooling to room temperature and cooling, the reaction mixture was poured slowly into 70 ml of water, and the excess phosphorus oxychloride was decomposed. The resulting solution was neutralized with powdered sodium carbonate and extracted three times with 30 ml of acetic acid ester each. After evaporation of the solvent, the crude product was purified by column chromatography (100 g silica gel; eluent: cyclohexane / acetic acid ester = 2: 3).

Yield: 860 mg (26.8% of theory);

Mp: 188-191 ° C;

₂₇ C H ₂₇ N ₅ O ₃ S (517.6);

_Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1);

EKA mass spectrum: (M + H) ⁺ = 518, (M + Na) ⁺ = 540.

b) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic acid solution. hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 87% of the theoretical yield; C ₂₇ H ₃₀ N ₆ O ₄ S (534.6);

_Rf value: 0.13 (silica gel; dichloromethane / ethanol = 9: 1);

EKA mass spectrum: (M + H) ⁺ = 535, (M + H + Na) ⁺⁺ = 279th

Example 150

1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-sulfonic acid N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide. -5-sulfonic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The product yield was 38% of the theoretical yield; C ₂₅ H ₃₀ N ₈ O ₄ S (538.6);

_Rf value: 0.09 (silica gel; dichloromethane / ethanol = 9: 1);

EKA mass spectrum: (M + H) ⁺ = 539.

Example 151

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -5- (2,3-dihydroindol-1-yl-sulfonyl) -benzimidazole hydrochloride

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -5- (2,3-dihydroindol-1-ylsulfonyl) -benzimidazole, ethanolic hydrochloric acid solution, ethanol and ammonium carbonate. The product yield was 15% of the theoretical yield; C ₂₄ H ₂₄ N ₆ O ₂ S (460.6);

Rf value: 0.36 (silica gel; dichloromethane / ethanol = 4: 1);

EKA mass spectrum: (M + H) ⁺ = 461.

Example 152

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-hydroxycarbonylethyl) amide

The compound was prepared analogously to Example 26 from 1-methyl-2 - [(4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide.

The product yield was 24% of the theoretical yield;

Rf value: 0.55 (reversed phase RP-18 silica gel; methanol / 5% sodium chloride solution = 3: 2); C ₂₅ H ₂₆ N ₆ O ₄ S (506.6);

EKA mass spectrum: (M + H) ⁺ = 507, (M + Na) ⁺ = 529, (M + 2Na) ⁺⁺ = 276.

Example 153

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] 5- (isoindolin-2-yl-sulfonyl) -benzimidazole hydrochloride

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -5- (isoindolin-2-yl-sulfonyl) -benzimidazole, ethanolic hydrochloric acid solution, ethanol and ammonium carbonate . The yield of the product was 33% of the theoretical yield;

Rf value: 0.32 (silica gel; dichloromethane / ethanol = 4: 1);

C ₂₄ H ₂₄ N ₆ O ₂ S (460.6);

EKA mass spectrum: (M + H + = 461).

Example 154

2- [2- (4-amidinophenyl) -ethyl] -quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

(a) 4-Methyl-3-nitro-benzoic acid ethyl ester

To a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulfuric acid, 4.9 g (0.03 mol) of ethyl p-tolylcarboxylic acid ester was added dropwise with stirring at 5 ° C, and the mixture was stirred while cooling in an ice bath. After warming to room temperature, the mixture was poured onto ice-water and then extracted with acetic acid ester. The organic extracts were washed with sodium bicarbonate solution, dried and evaporated.

Yield: 5.7 g (90% of theory); _Rf value: 0.81 (silica gel; ethyl acetate / cyclohexane = 1: 1).

b) 4- (2-Dimethylaminovinyl) -3-nitrobenzoic acid methyl ester

1.0 g (4.8 mmol) of 4-methyl-3-nitrobenzoic acid ethyl ester, 0.74 g (6.2 mmol) of dimethylformamide dimethyl acetal and 2 ml of dimethylformamide were heated to 140 ° C with stirring for 3 hours. Then, the solvent was distilled off and the crude product obtained was used without further purification. The product yield was 1.2 g (100% of theory); Rf value: 0.54 (silica gel; acetic ester / cyclohexane = 1: 1).

c) 4-Formyl-3-nitrobenzoic acid methyl ester

1.2 g (4.8 mmol) of methyl 4- (2-dimethylaminovinyl) -3-nitrobenzoate were dissolved in 120 ml of tetrahydrofuran with water (1: 1) and after addition of 3.0 g (14.3 mmol) of periodate. The mixture was stirred at room temperature for 20 hours. The suspension was then diluted with water and methylene chloride and extracted with methylene chloride. The combined organic extracts were washed with sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel using acetic acid / cyclohexane ester (1: 3) as eluent. Yield: 0.6 g (63% of theory);

_Rf value: 0.63 (silica gel; ethyl acetate / cyclohexane = 1: 1).

d) 3-Amino-4-formyl-benzoic acid methyl ester

To a solution of 25 mL of ethanol / glacial acetic acid / water (2: 2: 1) was added 0.6 g (2.9 mmol) of 4-formyl-3-nitrobenzoic acid methyl ester, 1.2 g (21.4 mmol) of powdered iron and 0.01 ml of concentrated hydrochloric acid, and the mixture was heated to reflux. Then the iron was separated, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and evaporated. Yield: 0.3 g (58% of theory); _Rf value: 0.74 (silica gel; methylene chloride / methanol = 9.5: 0.5).

e) 3- [3- (4-Cyanophenyl) -propionylamino] -4-formyl-benzoic acid methyl ester

1.0 g (5.6 mmol) of methyl 3-amino-4-formylbenzoate and 1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride were dissolved in 50 ml of methylene chloride and after the addition of 0.7 g N-ethyldiisopropylamine (6 mmol) was stirred at room temperature for 24 hours. The mixture was then extracted with sodium bicarbonate solution. The combined organic extracts were dried and evaporated, the residue was chromatographed on silica gel using acetic acid / cyclohexane ester (1: 3) as eluent. Yield: 0.6 g (32% of theory); _Rf value: 0.60 (silica gel; ethyl acetate / cyclohexane = 1: 1).

f) 2- [2- (4-Cyanophenyl) ethyl] quinazoline-7-carboxylic acid methyl ester

0.6 g (1.8 mmol) of 3- [3- (4-cyanophenyl) -propionylamino] -4-formylbenzoic acid ethyl ester and 10 ml of methanolic ammonia solution were shaken in a pressure vessel for 36 hours. After distilling off the solvent, the residue was chromatographed on a silica gel and eluted with methylene chloride containing 0 to 1% methanol. Yield: 0.35 g (62% of theory); Rf value: 0.38 (silica gel; acetic ester / cyclohexane = 1: 1).

g) 2- [2- (4-Cyanophenyl) ethyl] quinazoline-7-carboxylic acid

0.3 g (0.94 mmol) of methyl 2- [2- (4-cyanophenyl) ethyl] quinazoline-7-carboxylic acid dissolved in 4.7 ml lithium hydroxide solution (c = 1 h _lí0 mol.drri ³ ) and 4 ml of tetrahydrofuran. The solution was stirred at room temperature for 3 hours. After addition of 4.7 ml of hydrochloric acid, the mixture was stirred for 30 minutes. The precipitated product was filtered off with suction, washed with water and dried.

Yield of product was 0.30 g (100% of theory);

Rf value: 0.1 (silica gel; acetic ester / cyclohexane = 1: 1).

h) 2- [2- (4-Cyanophenyl) ethyl] -chazolin-7-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonyl-ethyl) -amide

0.4 g (1.3 mmol) of 2- [2- (4-cyanophenyl) ethyl] quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred at 50 ° C for 60 minutes. The thionyl chloride was then distilled off, the residue was dissolved in methylene chloride, treated with 0.24 g (1.3 mmol) of methyl 3- (N-phenylamino) propionate and 0.22 ml (1.3 mmol) of N-ethyl-diisopropylamine and the batch was stirred at room temperature for 18 hours. After evaporation of the solvent in vacuo, the product was chromatographed using methylene chloride (containing 1% methanol) as eluent.

Yield of product was 0.230 mg (37% of th.);

_Rf value: 0.64 (silica gel; methylene chloride / methanol = 9: 1).

i) 2- [2- (4-amidinophenyl) -ethyl] -quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

230 mg (0.5 mmol) of 2- [2- (4-cyanophenyl) -ethyl] -quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide in 30 ml of ethanol saturated with hydrogen chloride were added. was stirred at room temperature for 8 hours. Then the mixture was evaporated to dryness in vacuo. The residue was stirred in 20 ml of ethanol, 0.5 g (5.0 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified on a silica gel using methylene chloride with ethanol (4: 1) as eluent.

The product yield was 100 mg (39% of th.);

_Rf value: 0.5 (silica gel; methylene chloride / methanol = 4: 1);

C ₂₉ H ₂₉ N ₅ O ₃ (495.59);

Mass Spectrum: (M + H) ⁺ = 496.

Example 155 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-sulfonic acid N- (1-methyl-pyrazol-4-yl) -N- (2-hydroxycarbonyl-ethyl) -amide

The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] N- (1-methyl-pyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride -benzimidazole-5-sulfonic acid and sodium hydroxide. The product yield was 95% of the theoretical yield; C ₂₃ H ₂₆ N ₈ O ₄ S (510.6);

_Rf value: 0.53 (silica gel RP-8 reverse phase column; methanol + 5% saline solution);

EKA mass spectrum: (M + H) ⁺ = 511, (M + Na) ⁺ = 533, (M + 2Na) ⁺⁺ = 278.

Example 156

1-Methyl-2- [N- (3-amidinopyridin-6-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

a) 3 - [(N-tert-Butoxycarbonyl-amino) -acetylamino] -4-methylaminobenzoic acid N- (2-pyridyl) -N- (ethoxycarbonylethyl) -amide

19.2 g (0.11 mol) of N-tert-butyloxycarbonylglycine was dissolved in 175 ml of dimethylformamide, 35.2 g (0.11 mol) of (O-benzotriazol-1-yl) -N, N, N 'were added. 3-amino-4-methylamino-benzoic acid, N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, N'-tetramethyluronium tetrafluoroborate, 11.0 g triethylamine and 34.2 g (0.10 mol) and the mixture was stirred

2.5 hours at room temperature. The reaction mixture was then stirred in 5 liters of ice water and stirred for 2 hours. The gray precipitate formed was filtered off, washed with water, dried and recrystallized from ethyl acetate after addition of activated carbon.

Yield: 39.85 g (80% of theory);

C ₂₅ H ₃₃ N ₅ O ₆ (499.6);

_Rf value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1).

b) 1-Methyl-2- (N-t-butoxy-carbonyl-aminomethyl) -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

10.0 g (0.02 mol) of N- (2-pyridyl) -N- (ethoxycarbonylethyl) -amide 3 - [(N- tert -butoxycarbonyl-amino) -acetylamino] were dissolved in 50 ml of glacial acetic acid. -4-methylamino-benzoic acid and the solution was heated under reflux for 1 hour. After distilling off the solvent, the residue was stirred with ice water and the pH was adjusted to 8 by addition of ammonia solution (c _{NH 3} = 2 mol.dm ³ ). After extraction three times with acetic acid ester, the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by chromatography using methylene chloride first, then methylene chloride / ethanol (50: 1) and finally methylene chloride / ethanol (25: 1). The appropriate fractions were combined and evaporated.

Yield: 5.85 g (61% of theory); C ₂₅ H ₃₁ N ₅ O ₅ (481.6);

Rf value: 0.70 (silica gel; methylene chloride / ethanol = 9: 1).

c) 1-Methyl-2-amino-methyl-benzimidazol-5-yl-carboxylic acid trifluoroacetate N- (2-pyridyl) -N- (ethoxycarbonylethyl) amide

4-Methyl-2- (N-tert-butoxycarbonylaminomethyl) -benzimidazole-5- (2-methoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) -amide was dissolved in 25 ml of methylene chloride. 5-trifluoroacetic acid was added and the mixture was stirred at room temperature for 5 hours. Then the solvent was evaporated and the residue was stirred in ether. The crystals formed were filtered off, washed with ether and dried.

Yield: 3.15 g (68% of theory); C ₂₀ H ₂₃ N ₅ O ₃ (381.4);

_Rf value: 0.18 (silica gel; methylene chloride / ethanol = 9: 1).

d) 1-Methyl-2- [N- (3-cyano-pyridin-6-yl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

1.5 g (3.25 mmol) of N- (2-pyridyl) -N- (ethoxycarbonylethyl) -amide 1-methyl-2-aminomethylbenzimidazol-5-yl-carboxylic acid trifluoroacetate was stirred in 10 ml of N-ethyl-diisopropylamine. and the solution was heated to 100 ° C for 15 minutes. After addition of 720 mg (5.25 mmol) of 2-chloro-5-cyanopyridine, the reaction mixture was heated at 125 ° C for 2 h. After cooling to room temperature and stirring with approximately 20 ml of water, the pH was adjusted to 4 by addition of hydrochloric acid (c _HCl = 1 mol. Dri ³ ) and the mixture was extracted three times with acetic acid ester. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by chromatography using first methylene chloride, then methylene chloride / ethanol (25: 1) and finally methylene chloride / ethanol (19: 1). The appropriate fractions were combined and evaporated.

Yield of the product was 1.05 g (67% of theory); C ₂₆ H ₂₅ N ₇ O (483.6);

Mass Spectrum: (M + H) ⁺ = 484.

e) 1-Methyl-2- [N- (3-amidino-pyridin-6-yl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared analogously to Example 25d from 1-methyl-2- [N- (3-cyanopyridin-6-yl) -aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide. 5-yl-carboxylic acid, ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate. The product yield was 38% of the theoretical yield; C ₂ H ₂₈ N ₈ O ₃ (500.6);

EKA mass spectrum: (M + H) ⁺ = 501.

Example 157

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide hydroiodide

a) 4-Nitrobenzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

16.7 g (0.1 mol) of 4-nitrobenzoic acid were refluxed in 50 ml of thionyl chloride with 3 drops of dimethylformamide. After distilling off the solvent in vacuo, the crude product was dissolved in 150 ml of tetrahydrofuran and added dropwise to a solution of 18 g (0.1 mol) of N- (2-methoxycarbonylethyl) aniline in 250 ml of tetrahydrofuran and 42 ml (0.3 mol) of triethylamine. . After stirring at room temperature for 1 hour, the mixture was diluted with 250 mL of ethyl acetate and washed twice with 200 mL of 14% brine. After distilling off the solvent and chromatographic purification (silica gel; methylene chloride), a yellow oil was obtained which solidified over time.

Yield: 32.6 g (100% of theory);

Rf value: 0.37 (silica gel; methylene chloride / methanol = 50: 1).

b) 4-aminobenzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide g (67 mmol) 4-nitro-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide in 500 ml of methanol with 2 g of 10 % palladium-on-carbon was hydrogenated under 3 bar of hydrogen for 3 hours. After filtration and distillation of the solvent, the solution was washed with ether and the white crystalline product was used directly in the next work.

Yield: 18.6 g (94% of theory); Rf value: 0.70 (silica gel; methylene chloride / ethanol = 19: 1).

c) 2-Methyl-3-thiomethyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

26.8 g (91 mmol) of 4-aminobenzzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved in 500 ml of methylene chloride, the solution was cooled to -70 ° C and freshly prepared tert- butyl chloromethane (MJ Mintz et al., Organic Synthesis Coli., Vol. 5, page 184). The reaction mixture was stirred at -70 ° C for 2 hours, then methyl thioacetone (9.46 g, 91 mmol) in methylene chloride (40 mL) was added dropwise over 30 minutes, and the mixture was stirred for an additional 1.5 hours. Then, 12.7 mL (9.1 g, 91 mmol) of triethylamine in 25 mL of methylene chloride was added. The mixture was left at -78 ° C for 30 minutes and then slowly allowed to warm to room temperature overnight. After washing twice with 50 ml of water each time, the organic phase was separated and dried over sodium sulfate. Removal of the solvent in vacuo and chromatographic purification (silica gel; acetic acid ester / petroleum ether = 2: 8 to 3: 7) gave a white amorphous solid. Yield: 24.1 g (69% of theory); C _2I H ₂₂ N ₂ O ₃ S (382.49);

_Rf value: 0.58 (silica gel; ethyl acetate / petroleum ether = 1: 1) EKA mass spectrum: (M + H) ⁺ = 382nd

d) 1- tert -Butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

8.9 g (23 mmol) of 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide were dissolved in 600 ml of ethanol, the solution was mixed with approximately 150 mg Raney nickel and the mixture was stirred at room temperature for 2 hours (as described by PG Gassman et al., Organic Synthesis Coli., Vol 6, page 601). The mixture was then filtered and the solvent was removed in vacuo. The obtained crude product (8 g) was dissolved in 200 ml of absolute tetrahydrofuran, 150 mg of dimethylaminopyridine and 6.84 g (32 mmol) of pyrocarbonate di (tert-butyl) ester were added and the mixture was stirred at 50 ° for 2.5 hours. C. Then the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; acetic acid ester / petroleum ether = 1: 4)

Yield: 10.0 g (98% of theory); _Rf value: 0.40 (silica gel; ethyl acetate / petroleum ether = 3: 7).

e) 2- [N- (4-cyanophenyl) amino-methyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

3.5 g (8 mmol) of 1-tert-butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved in 80 ml of carbon tetrachloride, 1.5 g ( 8.4 mmol) of N-bromosuccinimide and 20 mg of azobisisobutyronitrile and the mixture was heated under reflux for 2.5 hours. Then the still warm solution was filtered, the obtained filtrate was washed with saturated sodium bicarbonate solution and dried with sodium sulfate. After distilling off the solvent, the crude product was dissolved in 30 ml of N-ethyl-diisopropylamine, 1.0 g (8 mmol) of 4-aminobenzonitrile was added, and the mixture was heated under reflux for 2.5 hours. The solvent was then distilled off in vacuo and the residue was purified by chromatography (silica gel; acetic acid ester / petroleum ether = 1: 4 to 1: 1).

Yield of product was 1.1 g (30% of th.); _Rf value: 0.21 (silica gel; ethyl acetate / petroleum ether = 1: 1).

f) 1-Methyl-2- [N- (4-thiocarbamoyl-phenyl) aminomethyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

1.5 g (3.3 mmol) of 2- [N- (4-cyanophenyl) aminomethyl] indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved in 60 ml of xylene, added 0.45 g (3.3 mmol) of potassium carbonate and 0.5 ml (3.3 mmol) of p-toluenesulfonic acid methyl ester were added and the reaction mixture was stirred at reflux for 4 hours. An equal amount of potassium carbonate and p-toluenesulfonic acid methyl ester was then added once more and the mixture was heated at reflux overnight. Then the mixture was filtered and washed with acetone. After concentrating the filtrate, the residue obtained was purified by chromatography (silica gel; acetic acid ester / petroleum ether = 1: 4 to 2: 3). The methylated indole obtained (yield 0.64 g, 41% of theory) was dissolved in 20 ml of pyridine and 0.67 ml (1.37 mmol) of triethylamine was added. Hydrogen sulfide gas was then added to the prepared solution. After 4.5 days, nitrogen was bubbled through the reaction solution for 30 minutes, the solvent was distilled off and the residue was purified by chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 98: 2). Yield: 0.30 g (43% of theory); C28H28N4O3S (500.62);

EKA mass spectrum: (M + H) ⁺ = 501, (M + Na) + = 523.

g) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

0.30 g (0.60 mmol) of 1-methyl-2- [N- (4-thiocarbamoyl) phenylaminomethyl] indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) amide was dissolved together with 0.75 ml (12 mmol) of methyl iodide in 20 ml of acetone and the solution was stirred at room temperature for 2 hours. The solvent was evaporated and the crude product obtained was mixed with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of methylene chloride, and the solution was stirred at 40 ° C for 20 hours. The solvent was distilled off in vacuo and the residue was purified by chromatography (silica gel; methylene chloride / ethanol = 9: 1 to 4: 1).

The yield of the product was 55% of the theoretical yield; C ₂₈ H _m N ₅ O ₃ (483.58);

_Rf value: 0.20 (silica gel; methylene chloride / ethanol 4: 1 + 1 drop of acetic acid);

EKA mass spectrum: (M + H) ⁺ = 484.

Example 158

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -ticno [2,3- d] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

(a) Methoxyacetic acid iminoethyl ester hydrochloride

A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 ml (23 g, 0.50 mol) of ethanol and 30 ml of absolute ethyl ether was cooled to 0 ° C and 22.5 g (0.62 mol) was fed over an hour. HCl gas, the reaction product crystallized at the end of the gas feed. For complete precipitation, 130 ml of diethyl ether was added and the colorless needles of the product were filtered off.

Yield: 66.4 g (86% of theory); mp 117-118 ° C.

b) 4-Hydroxymethyl-2-methoxymethyl-imidazole

A mixture of 30.6 g (0.20 mol) of iminoethyl methoxyacetate hydrochloride, 18 g (0.20 mol) of 1,3-dihydroxyacetone and 200 ml of liquid ammonia was heated in an autoclave under stirring at 2.7 MPa for 3 hours. 68 ° C (similar to P. Dzurion et al., Pharm. Pharm. 307, 470 (1974)). The ammonia was then removed and the reaction mixture was mixed with 200 ml of methylene chloride. The white precipitate formed was filtered off and washed with methylene chloride. The filtrate was concentrated and the residue obtained was purified by chromatography (alumina; methylene chloride / ethanol = 90: 10 to 85: 15);

Yield: 26.7 g (94% of theory); C ₆ H ₁₀ N ₂ O ₂ (142.20);

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

Mass Spectrum: (M) + = 142.

c) 4-Hydroxymethyl-2-methoxymethyl-1-methyl-imidazole as a 1: 1 mixture with 5-hydroxymethyl-2-methoxymethyl-1-methylimidazole

A mixture of 7.1 g (50 mmol) of 4-hydroxymethyl-2-methoxymethylimidazole, 3.0 g (53 mmol) of sprayed potassium hydroxide and 3.4 ml (0.55 mmol) of methyl iodide in 100 ml of dimethylformamide was heated at room temperature for 4 hours. 50 ° C (analogous to I. Sinclair et al., J. Med. Chem. 29, 261 (1986)). The solvent was then distilled off in vacuo and the crude product was purified by chromatography (alumina; methylene chloride / ethanol = 99: 1 to 95: 5).

Yield: 6.1 g (78% of theory, 1: 1 mixture of both regioisomers);

Rf value: 0.32 (silica gel; methylene chloride / ethanol = 19: 1).

d) 5-Chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole

A mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methylimidazole and 5-hydroxymethyl-2-methoxymethyl-1-methylimidazole (1: 1) and 7.3 g (55 mmol) of N-chlorosuccinimide is added. in 48 ml of ethylene glycol monoethyl ether and 70 ml of dioxane was heated at 50 ° C for 10 hours. Thereafter, the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 90: 10) to give the isomer-pure title compound.

Yield: 3.4 g (36% of theory); _Rf value: 0.40 (silica gcl; methylene chloride / ethanol = 19: 1).

e) 5-Chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole

3.4 g (18 mmol) of 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methylimidazole were dissolved in 100 ml of methylene chloride and manganese dioxide (2 x 6.0 g, together 0.14 mol) was added at two-hour intervals. . After 4 hours, the inorganic components were filtered off, the solvent was removed and the crude product obtained was used in the next reaction step without further purification.

Yield: 3.0 g (89% of theory); _Rf value: 0.44 (silica gel; methylene chloride / ethanol = 50: 1).

f) 1-Methyl-2-methoxymethyl-thieno [2,3-d] imidazol-5-yl-carboxylic acid ethyl ester

To a freshly prepared solution (391 mg, 17 mmol of sodium) in 15 mL of ethanol was added dropwise 1.9 mL (2.1 g, 17 mmol) of thioglycolic acid ethyl ester. After stirring at room temperature for 1 hour, it was added

1.6 g (8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole in 20 ml of absolute ethanol and heated to 80 ° C (analogous to B. Iddon et al. (J. Chem. Soc. Perkin Trans., I, 1457 (1987)). After 5 hours the solvent was distilled off, the residue was taken up in 50 ml of methylene chloride and washed with 20 ml of water. The aqueous phase was washed once more with 20 ml of methylene chloride and the combined organic phases were dried over sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by column chromatography (alumina; methylene chloride).

Yield of product was 1.0 g (46% of theory); ChHmN3O3S (254.31);

_Rf value: 0.48 (silica gel; methylene chloride / ethanol = 50: 1);

EKA mass spectrum: (M + H) ⁺ = 255, (M + Na) ⁺ = 277.

(g) 1-Methyl-2-methoxymethyl-thieno [2,3-rf] imidazol-5-yl-carboxylic acid

To a solution of 0.90 g (3.54 mmol) of 1-methyl-2-methoxymethyl-thieno [2,3-d] imidazol-5-yl-carboxylic acid ethyl ester in 30 ml of ethanol was added dropwise 5 ml of sodium hydroxide solution (c). _NIJ OH = 2 mol.dm ^'3), and the mixture was stirred for 2 hours at room temperature. The solvent was then distilled off in vacuo, the residue was stirred in 5 ml of water and washed with 10 ml of diethyl ether. The aqueous phase was acidified with 6 ml of hydrochloric acid (c = ci _H 2 mol.dm ^3), cooled to 0 DEG C., and the crystals were filtered off.

Yield: 0.50 g (63% of theory); C ₉ H ₁₀ N ₂ O ₃ S (226.26);

Rf value: 0.21 (silica gel; methylene chloride / ethanol = 9: 1+ a few drops of acetic acid); EKA mass spectrum: (M + H) ⁺ = 226.

h) 1-Methyl-2-methoxymethyl-thieno [2,3-d] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxymethyl-thieno [2,3- (Z) -imidazol-5-yl-carboxylic acid in 20 mL of methylene chloride was mixed with 2.0 mL (3.2 g (27 mmol) of thionyl chloride and the mixture was refluxed for 60 minutes, whereby the solid almost dissolved. After the volatiles were distilled off, the crude product obtained was stirred twice more in methylene chloride. After the solvent was removed again, the crude acid chloride was mixed with 20 ml tetrahydrofuran and the mixture was added dropwise to a mixture of 0.42 g (2.3 mmol) of N- (2-methoxycarbonyletal) aniline and 0.92 g (6.6 mmol). triethylamine in 30 ml of tetrahydrofuran. After stirring at 50 ° C for 16 hours, the solvent was removed and the crude product obtained was purified by chromatography (silica gel; methylene chloride / ethanol = 100: 1);

Yield: 0.66 g (77% of theory); _Rf value: 0.47 (silica gel; methylene chloride / ethanol = 19: 1).

i) 1-Methyl-2- (N-4-cyanophenyl-aminomethyl) -thieno [2,3- d] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-methoxymethyl-thieno [2,3- f] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide in 30 ml of methylene chloride 2.9 ml (2.9 mmol) of a solution of boron tribromide (c _{BBr 3} = 1 mol.dm ³ ) in methylene chloride was added dropwise at 5 ° C. After stirring at room temperature for 16 hours, the mixture was washed with 20 ml of saturated bicarbonate solution. The organic phase was separated, dried over sodium sulfate and filtered, and 14 ml of N-ethyldiisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile were added to the filtrate, and the methylene chloride was then distilled off under vacuum, and the residue was heated to 50 ° C and the solvent residues were distilled off in vacuo to give a yellow, slowly solidifying oil after chromatographic work-up (silica gel; methylene chloride / ethanol = 99: 1 to 97: 3).

Yield: 0.37 g (42% of theory); Rf value: 0.29 (silica gel; methylene chloride / ethanol = 50: 1 + a few drops of ammonia).

j) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-d] imidazol-5-yl- N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride carboxylic acid

0.38 g (0.80 mmol) of 1-methyl-2- (N-4-cyanophenylaminomethyl) thieno [2,3-d] imidazol-5-yl- N-phenyl-N- (2-methoxycarbonyl-ethyl) -amide; of carboxylic acid in 40 ml of hydrogen chloride-saturated ethanol was stirred at 0 ° C for 5 hours, then at room temperature until thin layer chromatography showed the absence of starting material in the reaction mixture. Then the solvent was distilled off at a bath temperature of not more than 28 ° C, the oily residue was stirred in 40 ml of absolute ethanol and 1.1 g of ammonium carbonate was added. After 18 hours, the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride / ethanol = 9: 1 to 4: 1).

The yield of the product was 57% of the theoretical yield; C ₂₆ H ₂₈ N ₆ O ₃ S (504.62);

_Rf value: 0.21 (silica gel; methylene chloride / ethanol 4: 1 + a few drops of acetic acid); EKA mass spectrum: (M + H) ⁺ = 505, ((M + H + Na) ⁺ = 264.

Example 159

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-rf] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 2 from N-phenyl-N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] thieno [2,3-d] imidazole hydrochloride -5-yl-carboxylic acid and sodium hydroxide. The yield was 85% of the theoretical yield, C ₂₄ H ₂₄ N ₆ O ₃ (476.56)

Rf value: 0.36 (reversed phase RP-8 silica gel; methanol + 5% sodium chloride solution);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 477, (M + Na) &lt; ^{+ &gt}; = 499, (M + 2Na) ⁺⁺ = 250.

Example 160

1-Methyl-3- [N- (4-amidinophenyl) -thiomethyl] -quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 1-Methyl-3- [N- (4-cyanophenyl) -thiomethyl] quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

A solution of 2.5 g (7.6 mmol) of 3-amino-4-methylaminobenzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide and 2.4 g (9.6 mmol) of 3- (4-cyanophenyl) ethyl ester of thio-2-oxo-propionic acid in 50 ml of ethanol was heated at boiling point for 30 minutes, after removal of the solvent, the crude product obtained was purified by chromatography (silica gel; methylene chloride) to yield 1.6 g (40% of theory). R _f value: 0.63 (silica gel; acetic acid / ethanol / ammonia ester = 90:10: 1).

b) 1-Methyl-3- [N- (4-amidinophenyl) -thiomethyl] -quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 1 from 1-methyl-3- [N- (4-cyanophenyl) thiomethyl] quinoxaline-2-one-6-N-phenyl-N- (2-methoxycarbonylethyl) -amide. -yl-carboxylic acid and ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield was 23% of the theoretical yield, C ₂₈ H ₂₇ N ₅ O ₄ S (543.64)

_Rf value: 0.25 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5);

EKA-MS: (M + H) ⁺ = 544, (M + Na) ⁺ = 566.

Example 161

3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

a) 3-Methyl-2- [2- (4-cyanophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.4 g (4.6 mmol) of 3-methyl-2- [2- (4-cyanophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid (prepared from 4-bromo) 1- (4-cyanophenyl) -1-penten-3-one and 2-aminopyridine-4-carboxylic acid methyl ester analogously to Y. Katsura et al., Chem. Pharm. Bull., 40, 1424-1438 (1992) ) was suspended in 15 ml of thionyl chloride and the mixture was heated to boiling until complete dissolution. After thionyl chloride was distilled off, the acid chloride was dissolved in 15 ml of pyridine without further purification and treated at 0 ° C with 1.0 g (5.2 mmol) of N- (2-ethoxycarbonylethyl) aniline. After one hour, the solvent was distilled off, the residue was taken up in 30 mL of methylene chloride, the solution was washed with hydrochloric acid (c = 1 ci _H mol.dm ^'3) and dried over sodium sulfate. After distilling off the solvent, a brown oil was obtained after chromatography (silica gel; methyl chloride / ethanol = 0-2%).

Yield: 1.48 g (64%), _Rf value: 0.73 (silica gel; ethyl acetate / ethanol / ammonia 90: 10: 1).

b) 3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 1 from 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [1,2-a] N-phenyl-N- (2-ethoxycarbonylethyl) -amide. pyridin-7-yl-carboxylic acid and ethanolic solution of hydrochloric acid, ethanol and ammonium carbonate.

The yield was 62% of theory. C ₂₉ H ₃₁ N ₅ O ₃ (497.6)

Rf value: 0.23 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 498.

Example 162

3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 2 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] thieno [2,3-b] N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride. imidazol-5-yl-carboxylic acid and sodium hydroxide. The yield was 92% of the theoretical yield,

C ₂₇ H ₂₇ N ₅ 0j (469.55)

Rf value: 0.19 (silica gel; acetic acid / ethanol / ammonia ester = 50: 45: 5);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 470, (M + Na) &lt; ^{+ &gt}; = = 492, (M + 2H) + = 257.7, (M + 2H) ⁺⁺ = 235.7, (M +) H + Na + = 246.7.

Example 163 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- N-phenyl-N - [(N-ethoxycarbonylethyl-N-methyl) -2-aminoethyl] -amide; carboxylic acid

The compound was prepared in a manner analogous to Example 25d from N-phenyl-N - [(N-ethoxycarbonylethyl-N-methyl) -238

1-methyl-2- [N- (4-cyano-phenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid-amino-ethyl] -amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. The yield of the product was 80% of the theoretical yield, C ₃₁ H ₃₇ N ₇ O ₃ (555.7)

_Rf value: 0.24 (silica gel; dichloromethane / methanol = 4: 1);

EKA-MS: (M + H) ⁺ = 556, (M + 2H) ⁺⁺ = = 278.8, (M + H + Na) = 289.8.

Example 164

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N - [(N-hydroxycarbonylethyl-N-methyl) -2-aminoethyl] -amide

The compound was prepared analogously to Example 26 from N-phenyl-N - [(N-ethoxycarbonylethyl) -N-methyl) -2-aminoethyl] -amide 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] hydrochloride 1-benzimiazol-5-yl-carboxylic acid and sodium hydroxide.

The yield was 79% of the theoretical yield, £ -29Η ₃₃ Ν ₇ Ο ₃ (527.6)

_Rf value: 0.43 (silica gel RP-8 reverse phase column; methanol + 5% saline solution = 6: 4); EKA-MS: (M + H) ³ = 528, (M + 2H) ³³ = 264.6, (M + H + Na) ³³ = 275.6.

Example 165

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxy-n-propyl) -amide

The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-hydrochloride N-phenyl-N- (3-benzyloxy-n-propyl) -amide. -carboxylic hydrogenation using a palladium on carbon catalyst (10% palladium) under 0.5 MPa hydrogen at room temperature.

The yield was 61% of the theoretical yield, C ₆ H ₂ gN ₆ O ₂ (456.6)

_Rf value: 0.70 (silica gel RP-18 reverse phase column; methanol + 5% saline solution = 9: 1);

EKA-MS: (M + H) ⁺ = 457, (M + H + Na) ³⁺ = 240.

Example 166 1-Methyl-2- [N- [4- (N-hexyl-oxycarbonylamidino) -phenyl] -aminomethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide carboxylate

The compound was prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- [4- (N-hexyloxycarbonylamidino) phenyl] aminomethyl] - benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

The yield was 97% of the theoretical yield,

C ₃₂ H ₃₇ N ₇ O ₅ (599.7)

_Rf value: 0.22 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) ³ = 600, (M + 2H) ⁺⁺ = = 300.8, (M + H + Na) ³³ = 311.7, (M + 2Na) + = 322, 8th

Example 167

1-methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxy-n-propyl) -amide

The compound was prepared analogously to Example 165 from 1-methyl-N-phenyl-N- (3-benzyloxy-n-propyl) -amide.

-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid by catalytic debenzylation.

The yield was 26% of the theoretical yield, C ₃₃ H ₄₀ N ₆ O ₄ (584.7)

_Rf value: 0.39 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 585, (M + H + Na) ³³ = 304, (M + Na) ³ = 607.

Example 168

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide

The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl- N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide. carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 42% of theory. C ₂₈ H ₂₉ FN ₆ O ₃ (516.6)

Rf value: 0.31 (silica gel; dichloromethane / methanol = 5: 1);

EKA-MS: (M + H) ³ = 517, (M + H + Na) ³³ = 270.

Example 169

1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl- (N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide). carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. The product yield was 90% of theory, C ₂₈ H ₂₉ FN < A (516.6)

Rf value: 0.29 (silica gel; dichloromethane / methanol = 5: 1);

EKA-MS: (M + H) + = 517, (M + H + Na) ³³ = 270.

Example 170

1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl acid N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride carboxylic acid and sodium hydroxide. The yield was 97% of the theoretical yield, C ₂₆ H ₂₅ FN ₆ O ₃ (488.5)

Rf value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ³ = 489, (M + Na) ³ = = 511, (M + 2Na) ³³ = 267.

Example 171

1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride carboxylic acid and sodium hydroxide.

The yield was 89% of the theoretical yield,

C ₂₆ H ₂₅ FN ₆ O ₃ (488.5)

_Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ⁺ = 489, (M + Na) ⁺ = 511, (M + 2Na) ⁺⁺ = 267.

Example 172

1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (4-cyano-2-methoxy-phenyl) -aminomethyl] -benzimidazole-N-phenyl-N- (2-ethoxycarbonylethyl) -amide. 5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 89% of theory, C ₂₉ H ₃₂ N ₆ O ₄ (528.6)

_Rf value: 0.13 (silica gel; dichloromethane / methanol = 4: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 529, (M + H + Na) &lt; + &^gt; = 276, (M + 2H) &lt; ⁴ &gt; = 265.

Example 173

1-Methyl-2- [N- [4- (N-4-ethylbenzoyl-amidino) -phenyl] -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide carboxylic acid

The compound was prepared in a manner analogous to EXAMPLE 90 from 1-methyl-2- [N- [4- (N-4-ethylbenzoylamidino) -phenyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide. aminomethyl] -benzimidazol-5-yl-carboxylic acid and 4-ethylbenzoyl chloride.

The yield of the product was 64% of the theoretical yield, C ₃₆ H ₃₇ N ₇ O ₄ (631.7)

Rf value: 0.78 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 632, (M + H + Na) &lt; + ^&gt; = = 327.8, (M + Na) ⁺ = 654.

Example 174 1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) -phenyl] aminomethyl] -benzimidazol-5-yl N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

The compound was prepared in a manner analogous to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-, N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. yl carboxylic acid and benzyl chloroformate.

The yield of the product was 64% of the theoretical yield, C ₃₅ H ₃₅ N ₇ O ₅ (633.6)

_Rf value: 0.60 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) ⁺ = 634; (M + H + Na) ⁺⁺ = = 328.8; (M + Na) ⁺ = 656.

Example 175

1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazole-5-, N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride. ylcarboxylic acid and sodium hydroxide.

The yield was 71% of the theoretical yield,

C ₂ 7H ₂₈ N ₆ O ₄ (500.6)

Rf value: 0.15 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) ^{@ +} = 501, (M + Na) ^{@ +} = 523, (M + 2Na) @ + = 273.

Example 176

1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) amide hydrochloride

The compound was prepared in a manner analogous to EXAMPLE 25d from 1-methyl-2- [N- (4-cyano-2-methoxyphenyl) aminomethyl] - (2-ethoxycarbonylethyl) -N- (2-ethoxycarbonylethyl) amide - benzimidazol-5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 67%. C ₂₈ H ₃₁ N ₇ O ₄ (529.6)

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

EKA-MS: (M + H) &lt; ^{+ &gt}; = 530.

Example 177

1-Methyl-2- [N- (4-amidino-2-methoxy-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 26 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride -5-yl-carboxylic acid and sodium hydroxide.

The yield was 78% of the theoretical yield, C ₂₆ H ₂₇ N ₇ O ₄ (501.6)

_{R f} value: 0.12 (silica gel; dichloromethane / ethanol = 4: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 502.

Example 178

1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 104 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 1-methyl-2- [N- [4- (N-benzyloxycarbonylamidino) -phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

The yield was 62% of the theoretical yield,

C ₃₃ H ₃₁ N ₇ O ₅ (605.7)

_Rf value: 0.26 (silica gel; dichloromethane / methanol = 9: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 606, (M + N5) &lt; ^{+ &gt}; = 628, (M-H + Na) &lt; ^{4 &gt}; = 650, (M + 2H) ⁺⁺ = 303.8, ( M + H + Na ^{+ ++} = 314.8, (M + H +) + = 325.7.

Example 179

1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl) -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-benzyloxy-n-propyl) -amide

The compound was prepared in a manner analogous to Example 25 from 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazole-5- N-phenyl-N- (3-benzyloxy-n-propyl) -amide. yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

The yield of the product was 61% of the theoretical yield, C ₃₃ H ₃₄ N ₆ O ₂ (546.7)

Rf value: 0.19 (silica gel; dichloromethane / ethanol = 4: 1);

EKA mass spectrum: (M + H) ⁺ = 547, (M + H + Na) ⁺⁺ = 285th

Example 180

1-methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-benzyloxy-n-propyl) -amide

The compound was prepared in a manner analogous to Example 90 from 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5, N-phenyl-N- (3-benzyloxy-n-propyl) -amide hydrochloride. -yl-carboxylic acid and n-hexyl chloroformate.

The product yield was 73% of theory, CÄNA (674.9);

_Rf value: 0.46 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 675, (M + H + Na) &lt; + ^&gt; = = 349, (M + Na) ⁺ = 697, (M + Kf = 713).

Example 181

3-Methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-yl acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylate

The compound was prepared in a manner analogous to Example 1 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide 3-methyl-2- [2- (4-cyanophenyl) ethyl] imidazo [1,1-a], m.p. 2-α-pyridin-7-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 53%. C ₂₈ H ₃₀ N ₆ O ₃ (498.59)

_Rf value: 0.42 (silica gel; ethyl acetate / ethanol / ammonia 50: 45: 5);

EKA-MS: (M + H) &lt; ^{+ &gt}; = 499, (M + H + Na) &lt; ⁴ &gt; = 261, (M-2Na) = 272, (M + 2H) ⁺⁺ = 250.

Example 182

1-Methyl-2- [N- (3-amidino-pyridin-6-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide 1-methyl-2- [N- (3-cyanopyridin-6-yl) aminomethyl] -benzimidazole -5-yl-carboxylic acid and sodium hydroxide.

The yield was 40% of the theoretical yield, C ₂₄ H ₂₄ N ₈ O ₃ (472.9)

_Rf value: 0.67 (silica gel RP-8 reverse phase; methanol / 5% saline solution = 1: 1); EKA-MS: (M + H) &lt; ^{+ &gt}; = 473.

Example 183 1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] aminomethyl] -benzimidazole-5-N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) -ethyl] -amide yl-carboxylic acid

a) 1-Methyl-2- [N- [4- (cyanophenyl) amino-methyl] benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] amide

2.0 g (4.5 mmol) of N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide of 1-methyl-2- [N- (4- (4-methoxycarbonylethyl) -amide) were dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide. cyanophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid and 0.73 g (4.7 mmol) of carbonyldiimidazole. The solution was stirred at room temperature for 30 minutes and then at 90 ° C for 2 hours. At the same time, 0.55 g (5.8 mmol) of methanesulfonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred at room temperature for 2 hours. Then, the suspension was added to the tetrahydrofuran solution at room temperature. After 12 hours at room temperature, 50 mL of water was added and the pH of the mixture was adjusted to 6.8. The solution was extracted 4 times with methylene chloride, the combined organic phases were dried over sodium sulfate, dried and concentrated. The crude product was chromatographed on a silica gel (using methylene chloride / ethanol = 40: 1 as eluent). The appropriate fractions were combined and evaporated.

Yield: 1.05 g (44% of theory), C ₂₆ H ₂₅ N ₇ O ₄ S (531.6)

_Rf value: 0.72 (silica gel; dichloromethane / methanol = 9: 1).

b) 1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] aminomethyl] -benzimidazole-5- N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] -amide yl-carboxylic acid

The compound was prepared analogously to Example 96 from N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] -amide and 1-methyl-2- [N- (4-cyano-phenyl) acid]. -aminomethyl] -benzimidazol-5-yl-carboxylic acid and hydroxylamine.

The yield was 27% of the theoretical yield,

C ₂₆ H ₂₈ N _with O ₅ S (564.6)

Rf value: 0.75 (silica gel; dichloromethane / ethanol = 7: 3 + 1% glacial acetic acid);

EKA-MS: (M + H) ⁺ = 565, (M + Na) ⁺ = 587.

Example 184

1-methyl-2- [N- (5-amidino-thiazol-2-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (5-cyanothiazol-2-yl) -aminomethyl] -N- (2-ethoxycarbonylethyl) -amide - benzimidazol-5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Example 185

1-Methyl-2- [N- (5-amidino-thiazol-2-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 26 starting from 1-methyl-2- [N- (5-amidinothiazol-2-yl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. -benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

Example 186

1-Methyl-2- [N- (2-amidinopyrazin-5-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared in a manner analogous to Example 25d from 1-methyl-2- [N- (2-cyanopyrazin-5-yl) aminomethyl] benzimidazole N- (2-ethoxycarbonylethyl) amide -5-yl-carboxylic acid, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

The yield was 19% of the theoretical yield,

C ₂₅ H ₂₇ N ₉ O ₃ (501.6)

Rf value: 0.28 (silica gel; dichloromethane / ethanol = 4: 1 + 1% glacial acetic acid);

EKA-MS: (M + H) ⁺ = 502, (M + H + Na) ^r '= 262.5.

Example 187

1-Methyl-2- [N- (2-amidino-pyrazin-5-yl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

The compound was prepared in a manner analogous to EXAMPLE 26 from 1-methyl-2- [N- (2-amidinopyrazin-5-yl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride. 1-benzimidazol-5-yl-carboxylic acid and sodium hydroxide.

The yield was 11% of the theoretical yield,

C ₂₃ H ₂₃ N ₉ O ₃ (473.5)

_Rf value: 0.55 (silica gel RP-8 reverse phase column, 5% saline solution / methanol = 6: 4); EKA-MS: (M + H) ⁺ = 474, (M + Na) ⁺ = 496.6.

Example 188 1-Methyl-2- [2- [4- (N-hexyloxycarbonylamidino) phenyl] ethyl] N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide benzimidazol-5-yl-carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [2- (4-amidinophenyl) -N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl] -amide. 1-Ethyl] -benzimidazol-5-yl-carboxylic acid and n-hexyl chloroformate.

Example 189

1-methyl-2- (N- (2-methoxy-4-n-pentoxycarbonylamidino-phenyl) aminomethyl) -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminoethyl] -benzimidazole-5- N -phenyl-N- (2-ethoxycarbonylethyl) amide hydrochloride. yl carboxylic acid and n-pentyl chloroformate. The yield was 53% of the theoretical yield,

C ₃₅ H ₄₂ N ₆ O ₆ (642.7)

_Rf value: 0.54 (silica gel; dichloromethane / ethanol = 9: 1);

EKA mass spectrum: (M + H) ⁺ = 643, (M + H + Na) ⁺⁺ = 333.4.

Example 190

1-methyl-2- [N- (4-n-heptyloxycarbonyl-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminoethyl] -benzimidazole hydrochloride, N-phenyl-N- (2-ethoxycarbonylethyl) -amide. 5-yl-carboxylic acid and n-heptyl chloroformate.

The yield was 68% of the theoretical yield, C ₃₇ H ₄₆ N ₆ O ₆ (670.8)

Rf value: 0.56 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 671, (M + H + Na) = 347.4.

Example 191

1-Methyl-2- [N- (4-ethoxycarbonyl-amidino-2-methoxyphenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amido-2-methoxyphenyl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride 1-Benzimidazol-5-yl-carboxylic acid and ethyl chloroformate. The yield was 43% of the theoretical yield,

C ₃₁ H ₃₅ N ₇ O ₆ (601.7)

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

EKA mass spectrum: (M + H) ⁺ = 602, (M + H + Na) ⁺⁺ = 312.8.

Example 192 1-Methyl-2- [N- (2-methoxy-4-n-pentoxycarbonylamidinophenyl) -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride 1-benzimidazol-5-yl-carboxylic acid and n-pentyl chloroformate.

The yield was 72% of the theoretical yield, C ₃₄ H ₄₁ N ₇ O ₆ (643.7)

_Rf value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1);

EKA-MS: (M + H) ⁺ = 644, (M + H + Na) ⁺⁺ = 333.9.

Example 193 1-Methyl-2- [N- (2-methoxy-4-n-heptyloxycarbonylamidinophenyl) -aminomethyl] -benzimidazol-5-yl- N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide carboxylic acid

The compound was prepared analogously to Example 90 from 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride 1-benzimidazole-5-carboxylic acid and n-heptyl chloroformate.

The yield was 55% of the theoretical yield, C ₃₆ H ₄₅ N ₇ O ₆ (671.8)

_Rf value: 0.54 (silica gel; dichloromethane / ethanol = 9: 1);

EKA mass spectrum: (M + H) ⁺ = 672, (M + H + Na) ⁺⁺ = 347.9.

Example 194

Dry ampoule with 75 mg of active substance per 10 ml

Ingredients: active ingredient 75 mg mannitol 50 mg

Water for injections up to 10 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. The solution for use is prepared with water for injection.

Example 195

Dry ampoule with 35 mg of active substance per 2 ml

Ingredients: active substance 35 mg mannitol 100 mg water for injections up to 2.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried.

The solution for use is prepared with water for injection.

Example 196

Tablet with 50 mg of the active substance

Ingredients:

1. the active substance

2. milk sugar

3. Corn starch

4. polyvinylpyrrolidone

5. Magnesium stearate

50.0 mg

98.0 mg

50.0 mg

15.0 mg

2.0 mg

Components 1, 2 and 3 are mixed and granulated with an aqueous solution of component 4. Component 5 is admixed to the dry granulate.

The mixture is then compressed into tablets with a double faced facet and a groove on one side. Tablet diameter: 9 mm.

Example 197

Tablet with 350 mg of the active substance

Ingredients: 1. the active substance 2. milk sugar 3. Corn starch 4. polyvinylpyrrolidone 5. Magnesium stearate 350.0 mg 136.0 mg 80.0 mg 30.0 mg 4.0 mg together 600.0 mg

Components 1, 2 and 3 are mixed and granulated with an aqueous solution of component 4. Component 5 is admixed to the dry granulate.

The mixture is then compressed into tablets with a double faced facet and a groove on one side. Tablet diameter: 12 mm.

Example 198

Capsules containing 50 mg of the active substance

Ingredients:

1. active substance 50.0 mg

2. Corn starch 58,0 mg

3. Powdered milk sugar 50.0 mg

4. magnesium stearate _______ 2.0 mg total 160.0 mg

Component 1 is triturated with component 3. This mixture is added to mixtures 2 and 4 with vigorous stirring.

This powder mixture is filled into size 3 hard gelatin plug capsules at the capsule filler.

Example 199

Capsules with 350 mg of the active substance

Ingredients:

1. active substance 350.0 mg

2. Corn starch 46,0 mg

3. Powdered milk sugar 30.0 mg

4. magnesium stearate 4.0 mg total 430.0 mg

Component 1 is triturated with component 3. This mixture is added to mixtures 2 and 4 with vigorous stirring.

The powder mixture is then filled into hard gelatin push-in capsules of size 6Be 0 on the capsule filler.

Example 200

Caps with 100 mg of active substance suppository contains:

Active ingredient 100.0 mg polyethylene glycol (MW 1500) 600.0 mg polyethylene glycol (MW 6000) 460.0 mg polyethylene sorbitol monostearate 840.0 mg total 2,000 mg

Claims (13)

PATENT CLAIMS Disubstituted bicyclic heterocyclic compounds of general formula R ^and -A-Het-B-Ar-E (I) wherein A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group, B represents an ethylene group in which one methylene group attached to the Ar radical may be replaced by an oxygen or sulfur atom, or a -NR ¹ - group, wherein R ¹ represents a hydrogen atom, or a C _1-4 alkyl group, E represents a group R ^b NH-C (= NH) - in which R ^b represents a hydrogen atom, a hydroxyl group, a C _1-9 -alkoxycarbonyl group, a cyclohexyloxycarbonyl group, a phenyl-C 1-3 -alkoxycarbonyl group, a benzoyl group, a C 1-6 -alkylbenzoyl or a pyridinoyl group, the ethoxy moiety at the 2-position of said C 1-6 alkoxycarbonyl of the group may be additionally substituted with C 1. ₃ -alkylsulfonyl or 2- (C _1-3 -alkoxy) ethyl, Ar represents a 1,4-phenylene group, optionally substituted by a chlorine atom, or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group, Het denotes 1- (C _1-3 -alkyl) -2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1- (C _1-3 -alkyl) -2, 5-indolylénovú group, a l- (C _{first 3} -alkyl) -2,5-imidazo [4,5-6] pyridinylénovú, 3- (C _{first 3} -alkyl) -2,7-imidazo [ 2-a] -pyridinylene or 1- (C _1-3 -alkyl) -2,5-thieno [2,3-d] imidazolylene group; and R ^a represents a group R ² NR ³ - in which R ² represents a C _1-4 alkyl group which may be substituted with a carboxyl group, C 1-6 alkyl; _6- alkyloxycarbonyl, benzyloxycarbonyl, C _1-6 -alkylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl, C ₂ . _{A 4-} alkyl group substituted with a hydroxy-, benzyloxy-, carboxy-C 1-4 -alkylamino-, C 1-6 -alkyl group; _3- alkoxycarbonyl-C 1-6 -alkylamino-, N-C 1-6 -alkyl-carboxy-C 1-6 -alkylamino- or N-C 1-6 -alkyl-C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino, said groups cannot be substituted on α- a carbon atom adjacent to a nitrogen atom, R ³ is C ₃ _ ₇ cycloalkyl group, a propargyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the group NR ² R ³ -, phenyl, optionally substituted by fluorine, chlorine, methyl or methoxy, or is an optionally methyl a pyrazolyl, pyridazinyl or pyridinyl substituted group, or R ² and R ³ together with the intervening nitrogen atom represent a 5- to 7-membered cycloalkyleneimine group, optionally substituted with a carboxyl group or a C _1-4 -alkoxycarbonyl group on which a phenyl ring, their tautomers, stereoisomers and their salts may be additionally fused. Disubstituted bicyclic heterocyclic compounds of general formula (I) according to claim 1, in which A represents a carbonyl group or a sulfonyl group bonded to the benzo, pyrido- or shadow part of the Het group, B represents an ethylene group in which the methylene group attached to the Ar radical can be replaced by an oxygen or sulfur atom, or -NR ¹ -, wherein R ¹ represents a hydrogen atom or a methyl group, E represents a group R ^b NH-C (= NH) - in which R ^b represents a hydrogen atom, a hydroxyl group, C 1-6. _9- alkoxycarbonyl, cylohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, pC 1-3 -alkylbenzoyl or nicotinoyl, wherein the ethoxy moiety at the 2-position of said C ₁ . _{The 9-} alkoxycarbonyl group may additionally be substituted by C 1-6. ₃ alkylsulphonyl or 2- (C _{first 3} -alkoxy) ethyl, Ar represents a 1,4-phenylene group optionally substituted by a chlorine atom or a methyl group, an ethyl group or a methoxy group, or represents a 2,5-thienylene group, Het means 1-methyl-2,5-benzimidazolyl, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5- imidazo [4,5-b] pyridinylene, 3-methyl-2,7-imidazo [1,2- <2] pyridinylene or 1-methyl-2,5-thieno [2,3-d] imidazolylene and R ^a represents a group R ² NR ³ - in which R ² represents a C 1-6 alkyl group which may be substituted by a carboxyl group, C 1-6 alkyl; _6- alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl, C 1-6 -alkyl, substituted with hydroxy-, benzyloxy-, carboxy-C 1-6 -alkylamino-, C 1-6 -alkoxycarbonyl-C 1-3 -alkylamino-, N-C 1-6 -alkyl-carboxy-C 1-6 -alkylamino- or NXC 1-6 -alkyl; -alkyl-C 1-6 -alkoxycarbonyl-C 1-6 -alkylamino-, wherein said groups cannot be substituted at the α-carbon atom adjacent to the nitrogen atom, R ³ represents a propargyl group wherein the unsaturated moiety cannot be bonded directly to the nitrogen atom of the group R ² NR ³ -, a phenyl group optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group, or a pyridinyl group, their tautomers, stereoisomers and salts thereof. The disubstituted bicyclic heterocyclic compounds of formula (I) according to claim 1, wherein: A represents a carbonyl group attached to the benzo or thieno moiety of the group Het, B represents an ethylene group in which the methylene group bonded to the radical Ar can be replaced by -NR ¹ -, wherein R ¹ represents a hydrogen atom or a methyl group, E is R ^b NH-C (= NH) - in which R @ ^b represents a hydrogen atom, a hydroxyl group, a ( ₁₄₎ -alkoxycarbonyl group, a cylohexyloxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, a p-C1. _{A 3-} alkylbenzoyl or nicotinoyl group, wherein the ethoxy moiety at the 2-position of said C 1-6 alkyl; _{The 9-} alkoxycarbonyl group may additionally be substituted by a methylsulfonyl group or a 2-ethoxyethyl group, Ar is 1,4-phenylene, optionally substituted with methoxy, or is 2,5-thienylene, Het means 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno [2,3- (Z) -imidazolylene group and R "represents a group R ² NR ³ - in which R ² represents a C 1-6 -alkyl group which may be substituted by a carboxyl, C 1-6 -alkoxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl group, C ₂ . _3- alkyl, substituted with hydroxy-, benzyloxy-, carboxy-C 1-6 -alkylamino-, C 1-6 -alkoxycarbonyl-C ₁ . _3- alkylamino-, N-t-alkyl-carboxy-C 1 -alkylamino- or N-t-C 1-6 -alkyl-C 1-6 -alkoxycarbonyl-C _1-3 -alkylamino, wherein said groups cannot be substituted on the α-carbon atom adjacent to the nitrogen atom, R ³ represents a phenyl group optionally substituted by a fluorine atom, or represents a 2-pyridinyl group, tautomeric forms of said compounds, stereoisomers and salts thereof. The disubstituted bicyclic heterocyclic compounds of formula (I) according to claim 1: (a) 2- [N- (4-amidinophenyl) -aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxyethyl) -amide, (b) 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, c) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, d) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide, (e) 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide, (f) 1-methyl-2- [2- (2-amidino-thiophen-5-yl) -ethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonyl-ethyl) -amide, (g) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, (h) 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide; (i) 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, (j) 1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazole-5-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide, k) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide . (l) 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarboryl-ethyl) -amide, m) 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonyl-ethyl) -amide, (n) 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, (o) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N - [(N-hydroxycarbonylethyl-N-methyl) -2-aminoethyl] -amide, (p) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) amide, q) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) amide, (r) 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, (s) 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] -benzimidazole-5-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide, t) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -indole-5-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide; and u) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-b] imidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, and their tautomers, precursors, double precursors, stereoisomers and salts thereof. 5. A compound according to claim 1 which is 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole-5-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide and its salt. A 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazole N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide according to claim 1, wherein the compound is a bicyclic heterocyclic compound according to claim 1. 5-carboxylic acid and its salts. A 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) amide according to claim 1 which is a bicyclic heterocyclic compound according to claim 1. 1-benzimidazole-5-carboxylic acid and its salts. A 1-methyl-2- [N- [4- (N-hexyloxycarbonylamidino) phenyl] N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide, the disubstituted bicyclic heterocyclic compound of claim 1 - aminomethyl] -benzimidazole-5-carboxylic acid and its salts. Physiologically acceptable salts of disubstituted bicyclic heterocyclic compounds according to claims 1 to 8. A pharmaceutical composition comprising a compound according to at least one of claims 1 to 8 or a salt according to claim 9, optionally together with one or more inert carriers and / or diluents. Use of a disubstituted bicyclic heterocyclic compound according to at least one of claims 1 to 8, or a salt thereof according to claim 9, for the preparation of a medicament with a thrombin time-delaying effect (Thrombinzeit), a thrombin braking effect and a braking effect on related serine proteases. Process for preparing a pharmaceutical composition according to claim 10, characterized in that the compound according to at least one of claims 1 to 8, or the salt according to claim 9, is treated by a non-chemical route with one or more carriers and / or diluents. A process for the preparation of disubstituted bicyclic heterocyclic compounds according to claims 1 to 8, characterized in that: (a) the preparation of a compound having the general formula (1) in which E represents a group R ^b NH-C (= NH) - in which R ^b represents a hydrogen atom, a hydroxy group or a β ₃ -alkyl group can be carried out by converting the compound; optionally directly in the reaction mixture of the compound of the general formula formed R ^a - A-Het-B-Ar-C (= NH) Z '(II) wherein A, B, Ar, Het and R ^a are as defined in claims 1 to 8 a Z ¹ represents an alkoxy, aralkoxy, alkylthio or aralkylthio group with an amine of the general formula H ₂ NR ^b '(III) wherein R ^b represents a hydrogen atom or a hydroxyl group, or b) for the preparation of a compound having the general formula (I), wherein the group R ^and -A- and E are as defined in claims 1 to 8, provided that the R ^and -A- group contains a carboxyl group and E is as defined in the claims 1-8, or R ^and -A- is as defined in claims 1-8 and E is NH 2 -C (= NH) -, or R ^and -A- contains a carboxyl group and E is NH 2 -C ( = NH) -, a compound of formula (IV) is converted R ^and -A-Het-B-Ar-C-E '(IV) in which A, B, Ar and Het are as defined in claims 1 to 8 and the group R ^and -A and E 'have the same meaning as in claims 1 to 8 for the group R ^and -A-, with the group R ^and -A- containing a group convertible by hydrolysis, acid or base treatment, thermolysis or hydrogenation to a carboxyl group; and E is as defined in claims 1 to 10, or E 'is a group convertible by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to NH2-C (= NH). - and the group R ^and -A- has the same meaning as the group R ^and -A- in claims 1 to 8, or the group R ^and -A- comprises a group which is hydrolyzable, acid or base treatment, thermolysis or hydrogenolysis convertible to carboxyl group and E 'means a group which is hydrolyzable, acidic or base-treated, thermolysis or hydrogenolysis convertible into an NH2-C (= NH) group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis sition of general formula (I), wherein R ^a -A- group and E are defined in the claims 1 to 8 with the proviso that the R ^a -A- group contains a carboxy group and E is defined by the claims 1 to 8, or R ^and -A- have the same meaning as in claims 1 to 8 and E represents NH2-C (= NH) -, or R ^and -A- contains a carboxyl group and E represents NH2-C (= NH) - or c) the preparation of a compound having the general formula (I) and which already contains the ester groups in claims 1 to 8 defined by the group R ^and -A- can be carried out by converting a compound having the general formula (V) R ^and -A-Het-B-Ar-E (V) in which B, E, Ar and Het are as defined in claims 1 to 8 and R ^and "-A- have the same meaning as R ^and -A- as defined in claims 1 to 8, with the group R ³ " -A - contains a carboxyl group or contains a group which can be converted into an ester group by means of an alcohol, with an alcohol of the general formula (VI) HO-R ⁷ (VI), in which R ⁷ is C 1-6. _{A 6-} alkyl or benzyl group, or a formamide acetal thereof, or a compound having the general formula (VII) From ² - R ⁷ (VII) in which R ⁷ represents a C 1-6 -alkyl or a benzyl group and Z represents a removable group, or d) preparing a compound having the general formula (I) in which R ^b represents a hydrogen atom, a hydroxyl group, C 1-6. ₉ -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-CVI-alkylbenzoylovú group or a nicotinoyl group, the ethoxy moiety in the 2 position of said C _b9 alkoxycarbonyl group is further optionally substituted C _b3 alkylsulphonyl or 2- ( 'C _b1 alkoxy) ethyl, is carried out by conversion of the compound of general formula (VIII) R ^and -A-Het-B-Ar-C (= NH) -NH ₂ (VIII) in which R ^a , A, Het, B and Ar are as defined in claims 1 to 8, with a compound having the general formula (IX) Z ² -R ⁸ (IX) wherein R ⁸ is C _1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C _3-3 -alkoxycarbonyl, benzoyl, p-C 1 -alkylbenzoyl or pyridinoyl, wherein the ethoxy moiety at the 2-position of said C _1-9 -alkoxycarbonyl group may be navyl substituted C _b3 alkylsulphonyl or 2- (Ci. ₃ -alkoxy) ethyl, and A ² exchangeable nucleophilic group, or e) for the preparation of a benzimidazolyl or benzothiazolyl compound having the general formula (I) in which B is an ethylene group, a compound having the general formula (XV) is reacted by converting a compound having the general formula (IXX) ^Ez \ -A-Het-B-Ar-B In (IXX), in which R ⁵ , A, B, E, Ar and Het have already been defined in claims 1 to 8 and R ² 'represents a C 4 -C ₄ -alkylene group which is a substituted carboxyl group, or reactive derivatives thereof with a salt of a compound having the formula ( XX) C 1-6 -alkyl-SO ₂ -NH ₂ (XX) a if desired, the protecting groups used during the conversion to protect the reactive groups are cleaved and / or, if desired, the prepared compounds of formula (I) are subsequently resolved into their stereoisomers and / or the prepared compound of formula (I) is prepared. ), into its salts, in particular for pharmaceutical use, into physiologically acceptable salts with an inorganic or organic acid or base. End of document in which R 1 and A are as defined in claims 1 to 8 and Y represents a sulfur or nitrogen atom substituted by a C 1-6 -alkyl or a cyclopropyl group, with a compound having the general formula HO - CO - CH ₂ CH ₂ - Ar - E (XVI) in which Ar and E have been defined in claims 1 to 8, or with a reactive derivative thereof, or (i) for the preparation of a compound of the general formula (I) in which R ² represents a C 4 -C ₄ -alkyl group which is substituted by an alkylsulfonylaminocarbonyl group