BG64558B1 - Disubstituted bicyclic heterocyclic compounds, their preparation and application as medicamentous forms - Google Patents

Abstract

The compounds can be applied in medicine. They have the general formula Ra-A-Het-B-Ar-E where A, B, Ar, Het and Ra have the meanings listed in the description. When E is a cyanogroup the compounds are valuable intermediate products for making other compounds with the same general formula. In case E means RbNH-C(=NH)-group the compounds show valuable pharmaceological properties, in particular thrombin inhibition effect and thrombin time elongation effect. The invention also relates to tautomers, stereoisomers, mixtures and salts of the above compounds.

Description

Technical field

The present invention relates to novel disubstituted bicyclic heterocyclic compounds of the general formula

R _a -A-Het-B-Ar-E (I), to their tautomers, to their stereoisomers, to mixtures thereof and to their salts, especially to physiologically acceptable salts with inorganic and organic acids or bases which exhibit valuable properties.

SUMMARY OF THE INVENTION

The compounds of the above general formula (I), in which E represents a cyano group, are valuable intermediates for the preparation of the remaining compounds of the general formula (I), and the compounds of the general formula (I), in which E represents one N ^ NHC (= NH) -pyrene, as well as their tautomers and their stereoisomers, exhibit valuable pharmacological properties, in particular the effect of thrombin inhibition and the effect of prolonging thrombin time.

It is therefore an object of the present invention to provide novel compounds of general formula (I) as well as methods for their preparation, medicaments containing pharmacologically active compounds, and their administration.

The designations in general formula I have the following meanings:

A means a carbonyl or sulfonyl group attached to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the Het radical, wherein said moieties cannot contain the group Rp

B means an ethylene group in which a methylene group which is bonded either to the radical Het or Ar can be replaced by an oxygen or sulfur atom with a sulfinyl, sulfonyl, carbonyl or NR1 group, wherein

R _t represents a hydrogen atom or a C _1-6 alkyl group,

E represents a cyano- or R _b NH-C (= NH) group in which

R _b represents a hydrogen atom, a hydroxy group, a C ₁₃ -alkyl group or an in-moiety,

Ar means one optionally substituted by fluorine, chlorine or bromine, by trifluoromethyl, C _1-3 alkyl or C ₍₃ alkoxy phenylene or naphthylene group, one optionally substituted in the carbon skeleton by a C ₃ -alkyl group thienylene, thiazolylene, pyridinylene, pyridinylene, pyridinylene, pyridinylene pyrazinylene or pyridazinylene group, Het means a bicyclic heterocycle of the formula

wherein

X represents a nitrogen atom and

Y represents an oxygen or sulfur atom, or one optionally substituted with a _6- alkyl or C _3-7 -cycloalkyl group, wherein an additional one or two non-angular methine groups in the phenyl moiety of the preceding bicyclic heterocycle may be replaced by one nitrogen atom , or

X represents an optionally substituted radical methine group, wherein R 1 is as defined above, and

Y represents an optionally substituted C _1-6 alkyl group or a C _3-7 cycloalkyl group substituted nitrogen atom,

Rj is defined as above,

Z represents an oxygen or sulfur atom, one of the radicals D or C represents a nitrogen atom and the other of the radicals D or G represents a methyl group, and R _a represents a C _1-6 alkyl group, one optionally substituted by a C _1-3 alkyl group substituted by C _{3 7} a cycloalkyl group such as a C, _ ₃ alkyl group may be further substituted with a carboxyl group or a group which can be converted in vivo into a carboxyl group, or an R _{2 NR;} -rpyna in which

R ₂ represents one C! "-Alkyl group which may be substituted by one carboxyl group, C 1 ₆ alkyloxy-carbonyl, benzyloxycarbonyl, Cj ₃ -alkylsulfonyl aminocarbonyl, fenilsulfonilaminokarbonilna, tri-fluorosulfonilamino-, trifluorosulfonilaminokarbonilna or 1H-tetrazolyl group, a hydroxyl, phenyl-Cj ₃ -alkoxy, carboxy-Cj ₃ -alkylamino, Cj ₃ -alkoxycarbonyl-C ₃ -alkylamino, N- _{(C (3-alkyl)} carboxy-C! ₃ -alkylamino or N- (C _t -alkyl) - Cj ^ -alkosikarbonil-Cj ₃ -alkilaminogrupa substituted ₂ An "-alkyl group, in which the said adjacent to the nitrogen atom the α-carbon atom cannot be substituted in the said groups, or one optionally with a C ₃ -a alkyl group substituted piperidinyl group, a

R 1 represents a hydrogen atom, a C 1-6 alkyl group, optionally a C _1-3 alkyl group substituted with a C _1-7 cycloalkyl group, a C _3-6 alkenyl or C _3-6 alkynyl group, wherein the unsaturated moiety cannot be directly bonded to the nitrogen atom of RjNRjgrupata, an optionally by a fluorine, chlorine or bromine atom, a C _{t 3} alkyl or Cj ₃ -alkoxy substituted phenyl group, an optionally C ₃ alkyl substituted benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl , Pyridazinyl, pyrrolyl, thienyl or imidazolyl group, or

R ₂ and R ₃ together with the nitrogen atom between them optionally represent a carboxylic or C 1-6 -alkoxycarbonyl group substituted by a 5- to 7-membered cycloalkenylamino group to which a phenyl ring may be further condensed.

The compounds of the above general formula (I) containing one in vivo leaving group represent so-called prodrugs, and the compounds of general formula (I) containing two in vivo leaving groups represent so-called double prodrugs.

By in vivo in a carboxyl group a converting group is to be understood, for example, one hydroxymethyl group, one alcohol-esterified carboxyl group, in which the alcohol moiety is preferably C ₁₆ alkanol, phenyl-C, ₃ -alkanol, C _{3 9} -cycloalkanol, wherein the C _5-8 cycloalkanol may be further substituted by one or two C ₁₃ -alkyl groups, C _5-8 cycloalkanol in which a methylene group of the 3 or 4 position may be replaced by an oxygen atom or one optionally C _{| 3} alkyl, phenyl-Cj ₃ -alkyl, phenyl-C ₃ -alkoxycarbonyl or C _{2 6} -alkanoilna substituted imino group and cycloalkanoic moiety can be further substituted with one or two C ₃ -alkyl groups, C _"7 -tsikloalkenol, C ₃₅ -alkenol, phenyl-C _3-5 -alkenol, C _3-5 -quinol or phenyl-C _3-5 -quinol, provided that the oxygen atom is not bonded to a carbon atom which is a double or triple bond, C _{3 8} -tsikloalkilCj ₃ -alkanol, bitsikloalkanol a total of 8 to 10 carbon atoms which, in the bicycloalkyl moiety can be further substituted with one or g ve C ₃ -alkyl groups, 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula

R '-CO-O- (R ₅ CR ₄ ) -OH in which

64588

R ₄ represents a C ₁₈ alkyl, C _5-7 cycloalkyl, phenyl or phenyl-C _3- alkyl group,

R ₅ represents a hydrogen atom, a C ₁₃ -alkyl, C _5-7 cycloalkyl or phenyl group, and

R ₆ represents a hydrogen atom or a C _1-3 alkyl group, or by one of the imino or amino in vivo leaving group is to be understood, for example, one hydroxyl group, one acyl group, and one optionally C _1-3 alkyl group substituted by a benzoyl or pyridinoyl group, for example benzoyl, retilbenzoilova, p-izopropilbenzoilova or nicotinoyl group, or a C ₁₆ _ alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C ₍₁₆ -alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, detsiloksikarbonilna, undetsiloksikarbonilna, dodetsiloksikarbonilna or heksadetsiloksikarbonilna group, a _phenyl-C16 alkoxycarbonyl group such as benzyloxycarbonyl, feniletoksikarbonilna or fenilpropoksikarbonilna group, a C ₍₃ -alkylsulfonyl-C ₂ "-alkoxycarbonyl, C, ₃ alkoxy-C ₂ -alkoxy-C ₂ '-alkyloxy carbonyl or R "CO-O (R ₅ CR ₆₎ -O-CO- group wherein R" to R ₆ are as defined above.

Preferred prodrug groups such as carboxyl group are a C ₍ '.-Alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, izopropiloksikarbonilnasht-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group or _phenyl-C13 alkoxycarbonyl group such as a benzyloxycarbonyl group and as the imino amino group is a C, _ ₉ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloxy carbonyl, isopropyloxycarbonyl, n-butiloksikarb CO-, n, pentyloxycarbonyl, n-heksiloksikar a carbonyl, cyclohexyloxycarbonyl, pheptiloksikarbonilna, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a _phenyl-C13 alkoxycarbonyl group such as benzyl loksikarbonilna group, an optionally C _{1 3} alkyl group substituted by a phenylcarbonyl group such as benzoyl or 4-etilbenzoilova group, a pyridinoyl group such as the nicotinoyl group, a C ₃ alkylsulfonyl-n-C _{2 3} -alkoxycarbonyl or C _{t 3} -alkoxy-C _{2 3} -alkoxy-C _{2 4} alkoxycarbonyl group such as 2-metilsulfoniletoksikarboni or 2- (2-ethoxy) ethoxycarbonyl group.

In addition, the saturated alkyl or alkoxy groups containing more than 2 carbon atoms mentioned above, as well as the alkanoyl and unsaturated alkyl groups containing more than 3 carbon atoms, include their branched isomers such as isopropyl, tert-butyl, isobutyl group and the like

Preferred compounds of the general formula (I) above are those in which A denotes one with the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the Het bonded carbonyl or sulfonyl group, as previously mentioned parts may not contain the group Rp B means an ethylene group in which a methylene group which is bound to either the radical Het or Ar can be replaced by one oxygen or sulfur atom, one sulfinyl, sulfonyl, carbonyl or -NR , -group where

R represents a hydrogen atom or a C 1-6 alkyl group,

E denotes one R _b NH-C - (= NH) -pyrene in which

R 1 represents a hydrogen atom, a hydroxyl group, one

C | _{A 3-} alkyl group or an in vivo leaving group,

Ar represents an optionally fluorine, chlorine or bromine atom or by a trifluoromethyl, C ₃ alkyl or C ₃ - alkoxy substituted phenylene group, an optionally in the carbon skeleton by a _{C] 3} alkyl substituted tienileiova, tiazolilenova, piridinilenova, a pyrimidinylene, pyrazinylene or pyridazinylene group,

Het means a bicyclic heterocycle of formula

wherein

X represents a nitrogen atom and

Y represents an oxygen or sulfur atom or one optionally substituted C _3-6 alkyl or C _3-7 cycloalkyl group by an atom, wherein one or more non-angular methine groups in the phenyl moiety of the preceding bicyclic heterocycle may be replaced by one nitrogen atom, or

X represents an optionally substituted R 1 substituted methine group, wherein R 1 is as defined above, and

Y represents one optionally having C _1-6 alkyl or

A C _3-7 cycloalkyl group substituted with a nitrogen atom, or

Het means a group of formulas

>> - N

Rj is defined as above,

Z represents an oxygen or sulfur atom, one of the radicals D or G represents a nitrogen atom and the other of the radicals D or G represents a methine group, and R _a represents C _(^ alkyl group, an optionally C ₃ alkyl group substituted by _{C3 7} a -cycloalkyl group, such as a C _1-3 alkyl group may be further substituted by a carboxyl group or by a group which may be converted in vivo to a carboxyl group, or an R ₂ NR ₃ -pyrene, in which

R ₂ represents a C _{| 4} alkyl group which may be substituted with a carboxyl, Cj ₆ -alkiloksikarbonilna, benzyloxycarbonyl, Cj ₃ -alkilsulfonil- aminocarbonyl, fenilsulfonilaminokarbonilna, tri- fluorosulfonilamino-, trifluorosulfonilaminokarbonilna or 1H-tetrazolyl group, with one hydroxyl, phenyl-C ₃ -alkoxy-, carboxy-C _1-3 -alkylamino-, C ₁₃ -alkoxycarbonyl-C ₃ -alkylamino-, N- (C ₃ -alkyl) carboxy-C ₃ -alkylamino- or N- ( C, ₃ alkyl) C, j-alkoxycarbonyl-C! _{A 3-} alkylamino group substituted with a C _2-4 alkyl group, wherein in said groups the adjacent to the nitrogen-carbon atom cannot be substituted, or one optionally substituted with a C _(3- alkyl group substituted piperidinyl group, and

R ₃ represents a hydrogen atom, a C ^ alkyl group, an optionally C ₃ alkyl group substituted by _{C3 7} a cycloalkyl group, a C _zch. Alkenyl or alkynyl, wherein the unsaturated part may not be directly linked to the the nitrogen atom of the R1NR group, optionally with a fluorine, chlorine or bromine atom, with a _C13- alkyl or _C3-3- alkoxy group substituted phenyl group, optionally with C! _{A 3-} alkyl group substituted with a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl group or piperidinyl group, or

R ₂ and R ₃ together with the nitrogen atom between them optionally represent a carboxylic or C ₁₄ -alkoxycarbonyl group substituted by a 5- to 7-membered cycloalkylenimino group to which one phenyl ring, in particular those compounds, may be further condensed in which

Het represents one of the aforementioned benzimidazolylene, benzthiazolylene, benzoxazolylene, indolylene, quina

64588 zolinylene, quinoxazolinonylene, imidazo- [4,5-b] -pyridinylene, imidazo [1,2-a] pyridinylene, thiazolo [4,5-b] -pyridinylene or thieno [2,3- <1] imidazolylene groups, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts.

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

A means one with a benzo, pyrido, pyrimido, pyrazino, pyridazino or thiopart of the Het bonded carbonyl or sulfonyl group, furthermore the aforementioned moieties may not contain the group R _p

B means an ethylene group in which the methylene group bound to the radical Ar may be replaced by an oxygen or sulfur atom or by an -NR, -rpy, wherein

R 1 represents a hydrogen atom or a C ₁₄ -alkyl group,

E denotes one R _b NH-C - (= NH) -pyrene in which

Rh represents a hydrogen atom, a hydroxyl, C _t-9- alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C ₃ alkoxycarbonyl, benzoyl, p-C, _3- alkylbenzoyl or pyridinoyl group, such as the ethoxy moiety in

2-position of the previous C ₉ -alkoxycarbonyl group may additionally be substituted by a Cj ₃ -alkilsulfonilova or 2 (Cj ₃ -alkoxy) ethyl group,

Ar means one optionally chlorine atom, one methyl, ethyl or methoxy group substituted 1,4-phenylene group or one

A 2,5-thienylene group,

Het stands for 1- (C ₁₃ -alkyl) -2,5-benzimidazolylene, cyclopropyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1- (C] _3- alkyl) -2,5-indolylene, 1- ( C _(3- alkyl) -2,5-imidazo [4,5-b] -pyridinylene, 3- (C ₃ -alkyl) -2,7-imidazo [1,2a] pyridinylene, or 1 (C ₃ -alkyl) - 2,5-thieno [2.3- <1] imidazolylene group and

R _a means one R ₂ NR ₃ -rpyna in which

R ₂ represents a C _1-4 alkyl group which may be substituted by one carboxylic, C _1-6 alkyloxy carbonyl, benzyloxycarbonyl, C _1-3 alkylsulfonyl-aminocarbonyl or 1H-tetrazol-5-yl group, one by hydroxyl, benzyloxy- , carboxy

C _{t 3} alkylamino, Cj ^ -alkoxycarbonyl- ^ ₃ -alkylamino, N- (Cj ₃ -alkyl) -carboxy-C ₍₃ -alkylamino or N- _{(C (3} -alkyl) -C] ₃ -alkoxycarbonyl -Cj ₃ -alkilaminogrupa substituted C _{2 4} alkyl group, in said groups adjacent to the nitrogen atom carbon atom may not be substituted,

R ₃ represents a C _3-7 cycloalkyl group, one propargyl group, wherein the unsaturated moiety cannot be directly bonded to the nitrogen atom of the R 1 -NR 1 group, optionally a fluorine or chlorine atom, to a methyl or methoxy group substituted phenyl group, optionally a methyl group substituted with a pyrazolyl, pyridazolyl or pyridinyl group, or

R ₂ and R ₃ together with the nitrogen atom between them optionally represent a carboxylic or C _{t 4} -alkoxycarbonyl group substituted by a 5- to 7-membered cycloalkyleneimino group to which one phenyl ring, their tautomers, their stereoisomers may be further condensed and their salts.

Extremely preferred compounds of the above general formula (I) are those in which

A means one with the benzo, pyrido or thieno moiety of the radical Het bonded carbonyl or sulfonyl group, furthermore the aforementioned moieties may not contain the group R _p

B means an ethylene group in which the methylene group which is bound to the radical Ar can be replaced by an oxygen or sulfur atom or by an -NR 1 -pyrrole, wherein

Rj represents a hydrogen atom or a methyl group,

E denotes one R _b NH-C - (= NH) -pyrene in which

Rh represents a hydrogen atom, a hydroxyl, C _1-9 alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, pC _{t 3} -alkylbenzoyl or nicotinoyl group, the ethoxy moiety at the 2-position of the preceding C _1-9 alkoxycarbonyl group being additionally A C _1-3 alkylsulfonyl or 2 (C _1-3 alkoxy) ethyl group,

Ar means, optionally, a chlorine atom, a methyl, ethyl or methoxy group substituted by a 1,4-phenylene group or an e6 of a 2,5-thienylene group,

Het stands for 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo [4,5- B] -pyridinylene, 3-methyl-2,7-imidazo [1,2-a] pyridinylene or 1-methyl-2,5-thieno- [2.30] imidazolylene group and

R _a denotes one RjNR ^ rpyna in which

R ₂ represents a C _1-3 alkyl group which may be substituted by one carboxyl, C _1-6 alkyloxy carbonyl, benzyloxycarbonyl, methylsulfonylamino-carbonyl or 1H-tetrazol-5-yl group, one by hydroxyl, benzyloxy, carboxy -C, _3- alkylamino-, C, _3- alkoxycarbonyl-C, _3- alkylamino-, N- (0, _3- alkyl) -carboxy-C] _3- alkylamino- or N- (C ₃ -alkyl) - A C, _3- alkoxycarbonyl-C, _3- alkylamino group substituted with a C _2-3 -alkyl group, the α-carbon atom adjacent to the nitrogen atom being unsubstituted in said groups,

R ₃ represents a propargyl group wherein the unsaturated moiety cannot be directly bonded to the nitrogen atom of the R ₁ NR ₂ group, optionally a fluorine or chlorine atom, to a methyl or methoxy group substituted phenyl group or pyridinyl group, in particular those compounds in which

A means one with the benzo or thieno moiety of the radical

Het bonded carbonyl group,

B means an ethylene group in which the methylene group bound to the radical Ar can be replaced by an -NR, -group, wherein

R represents a hydrogen atom or a methyl group,

E denotes one R _b NH-C - (= NH) -pyrene in which

Rh represents a hydrogen atom, a hydroxyl, C, _9- alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C, _3- alkylbenzoyl or nicotinoyl group, the ethoxy moiety at the 2 position of the preceding C, _9- alkoxycarbonyl additionally substituted with one methylsulfonyl or 2- ethoxyethyl group,

Ar means one optionally substituted by a methoxy group 1,4-phenylene group or a unit of 2,5-thienylene group,

Het stands for 1-methyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno [2.3 (1] imidazolylene) and

R _a denotes an R 1 NR 6 group in which

R ₂ represents one C ₃ -alkyl group which may be substituted by one carboxyl, C ₁₆ -alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1 H-tetrazol-5-yl group, one by hydroxyl, benzyloxy-, carboxy-C, _3- alkylamino, C, _3- alkoxycarbonyl-C 1-3 -alkylamino-, N- (C ₃ -alkyl) -carboxy-C ₃ -alkylamino- or N- (C ₃ -alkyl) -C ₃ -alkoxy -carbonylC, _3- alkylamino group substituted by a C _2-3 -alkyl group, and in the said groups the α-carbon atom adjacent to the nitrogen atom cannot be substituted,

R ₃ represents a fluorine atom optionally substituted phenyl group or 2-pyridinyl group, their tautomers, their stereoisomers and their salts.

For example, the following are particularly preferred compounds:

(a) N-phenyl-N- (2-carboxyethyl) -2- [N (4-amidinophenyl) -amino-methyl] -benzthiazole-5-carboxamide, (b) N-phenyl-N- (2-hydroxycarbonylethyl) -2 - [N- (4-amidino-phenyl) -N-methyl-aminomethyl] -benzthiazol-5-ylcarboxamide, (c) N-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N - ( 4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide,

d) N-phenyl-N- (3-hydroxycarbonylpropyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, (e) N- (2-pyridyl) -1H- (hydroxycarbonylmethyl) -1-methyl-2-fN- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, (f) N- (2-pyridyl) -L] - (2-hydroxycarbonylethyl) -1-methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxamide,

N- (N-(2-pyridyl) -1H- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, (h) b! - ( 2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [2- (2-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxamide, (i) N-phenyl-N- (2- hydroxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzyl

64588 Zimidazol-5-yl-carboxamide, (j) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazole -5-yl-carboxamide, (k) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -1-methyl-2- [14- (4-amidinophenyl) aminomethyl] -benzimidazole- 5-yl-carboxamide, (1) T4- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -methylaminomethyl] -benzimidazol-5-yl-carboxamide (m) N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -methylaminomethyl] -benzimidazol-5-yl-carboxamide (n) L1-phenyl -B [- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -1H-methylamine ethyl] -benzimidazol-5-yl-carboxamide, (o) T4-phenyl-N - [(N-hydroxycarbonylethyl-T4-methyl) -2-amino-ethyl] -1-methyl-2- [bI- (4amidinophenyl) -aminomethyl] -benzimidazol-5-yl-1 carboxamide, (p) N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole- 5-yl-carboxamide, (q) N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [> 1- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl- carboxamide, (d) N-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl carboxamide (s) 14- (2-pyridyl) -N- (2-hydroxycarbonyl) ethyl) -1-methyl-2- [14- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, (N-phenyl-N- (2-methoxycarbonylethyl) 1-methyl-2 - [N- (4-amidinophenyl) -aminomethyl] indol-5-yl-carboxamide, (i) N-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) - aminomethyl] -thieno [2,3-d] imidazol-5-yl-carboxamide, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts.

The new compounds can be prepared by known methods, for example by the following methods:

a. To obtain a compound of the general formula (I) wherein E is R _b NH-C (= NH) -pyrene, in which 1 represents one hydrogen atom, one hydroxyl or C | _3- alkyl group:

Interaction of a compound of the general formula optionally obtained in the reaction mixture

R _a -A-Het-B-Ar-C (= NH) -Z ₁ , (II) in which

A, B, Ar, Het and R are defined as initially, and Z ₁ represents an alkoxy or aralkoxy group such as methoxy-, ethoxy-, η-propoxy-, isopropoxy- or benzyloxy- group, or an alkylthio or aralkylthio group such as methylthio-, an ethylthio, n-propylthio or benzylthio group having one amine of the general formula

H ₂ NR _b ', (III) in which

Rg 'represents a hydrogen atom, one hydroxyl or _{C] 3} alkyl group.

The reaction is suitably carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 20 and 120 ° C, with a compound of the general formula (III ) or with the corresponding acid addition salt such as, for example, ammonium carbonate.

A compound of general formula (II) is prepared, for example, by reacting a compound of general formula (I) in which E is a cyano group, with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid acid or by reaction of a suitable amide with a trialkyloxonium salt such as triethyloxy tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, preferably at 20 ° C, or by reaction of a suitable nitrile with with hydrogen sulphide, a suitable solvent such as pyridine or dimethylformamide, and in the presence of a base such as triethylamine and subsequent alkylation of the resulting thioamide with a suitable alkyl or aralkyl halide.

B. For the preparation of a compound of the general formula (I) in which R _a -A-rpynaTa and E are defined as initially, provided that the I _a -A-group contains a carboxyl group and E is defined as at the beginning, or the R-group is defined as initially and E represents NH ₂ -C (= NH) -pyrene or R _a -A-pyrene contains a carboxyl group and E represents NH ₂ -C (= NH) -group:

Conversion of a compound of the general formula

R _a '-A-Het-B-Ar-E, (IV) in which A, B, Ar and Het are defined as in the beginning, and And _a ' -A-group and E 'are given initially for R _a -A-rpynaTa and E meanings provided that the I _a '-A-group contains a group which, by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, can be converted to a carboxyl group, and E is defined as in onset, or E 'represents a group which, by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, can be converted to NH ₂ -C (= NH) -pyrene, and the R _a ' -A-pypy has those mentioned at the beginning for and _while -A group at the head, or _a '-A- group contains a group which, by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis can be converted into a carboxyl group, and E represents a group which, by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis can be converted to CφC (= NH) -pyrene by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis in a compound of general formula (I) in which R _a- A-pypyTa and E are defined as in the beginning, provided that the I _a -A group contains a carboxyl group and E is defined as o at the beginning, or the I _a- A-group has the meanings given initially and E represents the NH 2 C (= NH) group or the I _a- A-group contains a carboxyl group and E represents the NH 1 -C 6 NH) group.

As a group which can be converted into a carboxyl group, for example, one with a protecting group is a protected carboxyl group, as well as its derivatives, for example its unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters, which by hydrolysis is suitably converted to a carboxyl group, its esters with tertiary alcohols, for example tert-butyl ester, which by treatment with acid or thermolysis are conveniently converted into a carboxyl group, and its esters with aralkanols, e.g. benzyl ester by hydrogenolysis which are converted into appropriate carboxyl group.

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

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

If the R _aa -A-group and / or E 'in a compound of formula (IV) contains, for example, a benzyloxy or benzyloxycarbonyl group, then they may also be cleaved by hydrogenolysis in the presence of a hydrogenating catalyst such as palladium / charcoal in a suitable solvent. such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at a temperature between 0 and 50 ° C, for example at room temperature, and a hydrogen pressure of 1 to 5 bar.

64588

c. To obtain a compound of the general formula (I) in which the R-A-group contains one of the ester groups mentioned initially in the definition of the R _a -A group:

Interaction of a compound of the general formula

R ”-A-Het-B-Ar-E, (V) in which B, E, Ar and Het are defined as in the beginning, and R _a ” -A-rpynaTa contains those mentioned in the beginning for R _a -A-rpynaTa meaning, provided that R _a '-A-rpynaTa contains a carboxyl group or group, which with alcohol may be converted into a corresponding ester group, with an alcohol of the general formula ho-r ₇ , (VI) in which R _? represents the alkyl moiety of one of the initially mentioned carboxyl group leaving groups, except R ₆ -CO-O- (R _s CR ₆ ) -pyrene, or with their formamidacetals, or with a compound of the general formula z ₂ -r ₇ (VII) in which

R ₇ represents the alkyl moiety of one of the initially mentioned carboxy group in vivo leaving groups, except R ₆ -CO-O- (R 1CR ₆ ) -pyrene, and

Z ₂ represents a leaving group such as a halogen atom, a chlorine atom or a bromine atom.

The reaction with an alcohol of general formula VI is conveniently carried out in a solvent or in a mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, preferably still in an alcohol of general formula (VI), optionally in the presence of acid such as hydrochloric acid or in the presence of a water-withdrawing agent, for example in the presence of isobutyl ester of hydrochloric acid, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acids a, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, Ν, ди-dicyclohexyl-carbodiimide / M-hydroxysuccinimide, Ν, Ν'-carbonyldiimidazole or Ν, Ν'-thiophyldi-thiophyldi-thiophyldi, azodicarboxylic acid ester, optionally in the presence of a base such as potassium carbonate, N-ethyl-isopropylamine or N, N-dimethylaminopyridine, preferably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

The reaction with a compound of general formula (VII) is suitably carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of accelerators such as sodium or potassium iodide, and preferably in the presence of karyate or karyate or karate in the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methyl-morpholine, which may also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide temperatures between -30 and 100 ° C, preferably at temperatures between -10 and 80 ° C.

d. To obtain a compound of the general formula (I) wherein

Rh represents a leaving group:

Interaction of a compound of the general formula

R _g -A-Het-B-Ar-C (= NH) -NH ₂ , (VIII) in which

R _a , A, Het, B and Ar are defined as initially with a compound of the general formula

Z ₂ .R, (IX) in which

R 1 represents an in vivo leaving group and

Z ₂ means a nucleofugal leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom.

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

The reaction with a compound of the general formula (IX), in which 2 N represents a nucleofugal leaving group, is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium, potassium carbonate, potassium tert-butylate or Nethyldiisopropylamine at temperatures between 0 and 60 ° C.

e. To prepare a compound of the general formula (I) in which B represents an ethylene group in which one methylene group is replaced by a sulfinyl or sulfonyl group:

Oxidation of a compound of the general formula

R.-A-Het-B'-Ar-E, (X) in which

A, E, Ar, Het and R _a are as defined initially, and B 'represents an ethylene group in which one methylene group is replaced by a sulfenyl or sulfinyl group.

The oxidation is preferably carried out in a solvent or in a mixture of solvents, for example in water, water / pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, and according to the solvent used, if appropriate, -80 and 100 ° C.

For the preparation of the corresponding sulfinyl compound of the general formula (I), the oxidation is suitably carried out with one equivalent of the oxidant used, for example with hydrogen peroxide, in acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C or in acetone at O to 60 ° C, with one peracid as peracetic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C, or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -1.5 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C. iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or acetone at 0 to 20 ° C and with sulfinyl chloride in methylene chloride at -70 ° C , the ether-chlorine complex thus obtained is hydrolyzed suitably with aqueous ethanol.

For the preparation of a sulfonyl compound of the general formula (I), oxidation, starting from the corresponding sulfinyl compound, is suitably carried out with one or more equivalents of the oxidant used, or if starting from the corresponding sulfenyl compound, is carried out with two or more equivalents, respectively. the oxidant used, for example with hydrogen peroxide in glacial acetic acid / acetanhydride, trifluoroacetic acid or in formic acid at 20 to 100 ° C or in acetone at 0 to 60 ° C, with one peracid as permeat acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid or potassium permanganate in glacial acetic acid , water / sulfuric acid or in acetone at 0 to 20 ° C. For example, starting from the corresponding sulfenyl compound, oxidation, preferably in methylene chloride, by treatment with the appropriate amount of chloroperbenzoic acid at temperatures between 20 ° C and the reflux temperature of the reaction mixture, yields the corresponding sulfonyl compound of the general formula (I) , which may also contain a minimal amount of the corresponding sulfinyl compound.

f. To obtain a compound of general formula (I) in which E is a cyano group and in an ethylene group, in which a methylene group which is bonded to either the Het group or the Ar group is replaced by an oxygen or sulfur atom, with sulfinyl, sulfonyl, carbonyl or -NR _] -rpyna:

Interaction of a compound of the general formula

R _a -A-Het-U, (XI) with a compound of the general formula

Y-Ar-CN, (XII) in which

R _a , A, E, Ar and Het are defined as, initially, one of the groups U or V represents one HO-, HS-, HOSO-, HOSQ- or HNR 1 -group and the other one Z, CH ₂ -rpyna, at

64588 which R1 is defined as initially, and Z represents a nucleofugal leaving group as a halogen atom, for example a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base such as triethylamine, N-ethyldiisopropylamine-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridin-2-ylmethyl-dimethyridine, and the reflux temperature of the solvent used, wherein a compound of general formula (XI) or (XII) in which Z1 is a halogen atom can also be obtained in the reaction mixture.

g.3a to obtain a compound of general formula (I) wherein E represents one cyano group and R _{a represents} one R ₂ NR ₃ group:

Interaction of a compound of the general formula

H-A-Hel-B-Ar-CH, (XIII) in which

A, B, Het; and Ar are defined, as initially, with an amine of the general formula

Η —N. (XIV) in which

R ₂ and R ₃ are as defined at the outset or with reactive derivatives thereof.

The reaction of an acid of the general formula (XIII) is optionally carried out in a solvent or in a mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane or in the corresponding amine of general formula (III), optionally presence of a water-withdrawing agent, for example in the presence of isobutyl ester of hydrochloric acid, tetraethyl ester of ortho-carbonic acid, trimethyl ester of orthoacetic acid, 2,2-dimethoxypropane, tetramethoxy-silane, thionyl chloride, trimethyl orosilane, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, Ν, дици'dicyclohexylcarbodiimide-hydroxysuccinimide, Ν, Ν'-dicyclohexylcarbodiimide /!

hydroxybenzotriazole, 2- (1H-benzo-triazol-1-yl) -1,1,3,3-tetramethyl-uronium tetrafluoroborate, 2- (1H-benzo-triazol-1-yl) -1,1,3,3-tetramethyluronium tetra-fluoroborate / 1-hydroxybenzotriazole, Ν, Ν'-carbonyldiimidazole or triphenyl-phosphine / tetrachloromethane, and optionally by adding a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, between C and C C, preferably temperatures between 0 and 100 ° C.

The reaction of the corresponding reactive compound of the general formula (XIII) as well as its esters, imidazoles or halides with an amine of the general formula (XIV) is preferably carried out in the corresponding amine as a solvent, optionally in the presence of an additional solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methyl-morpholine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

h. For the preparation of a benzimidazolyl, benzthiazolyl or benzoxazolyl compound of the general formula (I) in which B represents an ethylene group:

Interaction of a compound of the general formula

r ^{NH2 R} a— ^A ~ f ' [, (XV) ^K YH

wherein

R _a , A and Y are defined as initially with a compound of the general formula

HO-CO-CH ₂ CH ₂ -AR-E, (XVI) in which

Ar and E are as defined initially or with reactive derivatives thereof.

The reaction is suitably carried out in a solvent or in a mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a water-withdrawing agent, for example in the presence of isobutyramethyl esteric acid orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,,, Ν'-dicyclohexyl arbodimide Ν, Ν'-dicyclohexyl-carbodiimide / N hydroxysuccinimide, Ν, Ν'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium-2-tetrafluoroniurate N-benzotriazol-1-yl) -

1,1,3,3-Tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N, N-carbonyldiimidazole or triphenylphosphine- / tetrachloromethane, and optionally when adding a base such as pyridine, 4-dimethylaminopyridine, N-methylmethylmorpholine, N-methylmethylmorpholine, N temperatures between 0 and 150 ° C, preferably temperatures between 0 and 100 ° C.

The reaction of the corresponding reactive compound of general formula (XVI), as well as of its esters, imidazoles or halides with an amine of general formula (XV), is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methyl-morpholine, which can be used at the same time as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

i. For the preparation of a quinoxalin-2-one compound of the general formula (I):

Interaction of a compound with a common-

and the formula we. Ra— A- "Mr. , (XVII) ^ NRjH wherein

R _a , R j and A are defined as initially with a compound of the general formula

HO-CO-COCHj-Ar-E, (XVIII) in which

Ar and E are as defined initially or with reactive derivatives thereof.

The reaction is suitably carried out in a solvent or in a mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, ethanol or dioxane, optionally in the presence of a stripping agent, for example in the presence of an isobutyrate. acid, ortho-carbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorous pentoxide, Ν, Ν'-dicyclic Ν, Ν'-Dicyclohexylcarbodiimide / N, -hydroxysuccinimide, Ν, Ν'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2 (1H-benzotriazol-1-yl) -1,1,3,3-tetrafluoromethoxycarbodiimide 1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N, N-carbonyldiimidazole or triphenylphosphine- / tetrachloromethane, and optionally adding a base such as pyridinamide, 4-pyridinamide, 4 -methylmorpholine or triethylamine, preferably at temperatures between 0 and 150 ° C, preferably temperatures between 0 and 100 ° C.

However, the reaction is particularly preferred with the corresponding reactive compound of the general formula (XVIII) as well as its esters, imidazoles or halides with an amine of the general formula (XVII) in a solvent such as methylene chloride, ether, ethanol or tetrahydrofuran and optionally in the presence of tertiary organic a base such as triethylamine, Nethyldiisopropylamine or N-methyl-morpholine, which can be used as solvent at a temperature between 0 and 150 ° C, preferably at a temperature between 50 and 100 ° C.

j. For preparing a compound of general formula (I), in which Rj represents a Cj ₄ alkyl group which is substituted by one alkilsulfonilaminokarbonilna group:

Interaction of a compound of the general formula

R in which

R ₃ , A, B, E and Het; are defined as in the beginning, a

R 1 ₂ represents a C ₁ -alkyl group which is substituted by a carboxyl group or its reactive derivatives with a salt of a compound of the general formula

64588

With _13- alkyl-8O ₂ ^ H ₂ (XX)

The reaction is preferably carried out with the corresponding reactive compound of the general formula (IXX) as well as its esters, imidazoles or halides with a salt of a compound of the general formula (XX), preferably with its alkali salt as the sodium salt, in a solvent 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 reactions described above, the possibly present reactive groups such as hydroxy, carboxy, alkylamino or imino groups can be protected during the reaction with the usual protecting groups which cleave after the reaction.

For example, a hydroxyl group protecting group means trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, while a carboxy group protecting group means trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl and as a protecting group for the amino, alkylamino or imino group are meant acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimer a tox-benzyl group and, for the amino group, a phthalyl group.

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

The cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl group is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium / charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, addition of an acid such as hydrochloric acid, at temperatures between 0 and 50 ° C, preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.

The cleavage of a methoxybenzyl group may also take place in the presence of an oxidizing agent such as sulfur (IU) ammonium nitrate, in a solvent such as methylene chloride, acetonitrile or acetonitrile / water, at temperatures between 0 and 50 ° C, but preferably at room temperature.

However, cleavage of the 2,4-dimethoxybenzyl group takes place mainly in trifluoroacetic acid in the presence of anisole.

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

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

The cleavage of an allyloxycarbonyl group proceeds by treatment with a catalytic amount of tetrakis- (triphenylphosphine) palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morphine or 1,3-dimedone, at temperatures between 0 and 100 ^Q C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (1) chloride, in solutions such as ethanol and optionally in the presence of a base such as 1,4-diazabicyclo [2.2.2] octane at temperatures between 20 and 70 ° C.

The starting materials of the general formulas (II) to (XX), which are partly known in the literature, are prepared by methods known in the literature, and further their preparation is described in the embodiments of the invention.

For example, a compound of general formula (II) is prepared by reacting the corresponding nitrile, which in turn is suitably prepared according to methods f to h, with the corresponding thio or alcohol in the presence of chloro or bromohydrogen.

A compound of the general formulas (IV), (V), (VIII), (X) and (IXX) used as a starting material is suitably prepared by the method of the present invention.

A starting compound of the general formula (XI) in which U represents a halogenmethyl group is conveniently obtained by cyclizing a corresponding ester which is substituted at the o-position by a suitable halogen atom or a methoxyacetamido group to the corresponding bicyclic 2-alkoxymethyl compound, optionally subsequent hydrolysis and possibly subsequent amidation of the carboxylic acid thus obtained with the corresponding amine, converting the alkoxymethyl compound thus obtained into the corresponding halogenomethyl compound which, if necessary, units that can be converted by means of a suitable compound to the desired compound. If the cyclization is carried out here with a suitable carbonic acid derivative, a starting compound of the general formula (XI) is obtained in which U represents a hydroxy, mercapto or amino group.

The starting compound of the general formula (XIII) is obtained by cyclization of the corresponding o-disubstituted ester, followed by saponification of the ester thus obtained and subsequent amidation of the carboxylic acid thus obtained with the corresponding amine.

In addition, an imidazopyridine obtained by cyclization and substituted at the 5-position with one methyl group can be converted via the corresponding N-oxide into the corresponding hydroxy-methyl compound, which by oxidation is converted to the desired carboxylic acid of the general formula (XIII ).

Compounds of general formulas (III), (VI), (VII), (IX) and (XII) used as starting materials are prepared by trivial methods, for example by reduction of an aromatic ester, which is optionally substituted by one optionally a substituted amino group, and the eventual subsequent cyclization of the thus-formed amino compound with the corresponding carboxylic acid.

In addition, the compounds of general formula (I) obtained can be separated into their enantiomers and / or diastereomers.

For example, the compounds of general formula (I) which occur in racemates can then be separated, as mentioned above, by known methods per se (see Allinger NL and Eliel EL in Topics in Stereochistry ”, Vol 6, Wiley Innterscience 1971) of their optical antipodes, and compounds of general formula (I) with at least 2 asymmetric carbon atoms can be separated on the basis of their physicochemical differences of their diastereoisomers by their own known methods, for example by chromatography and / or fractional crystallization, which, if present in racemic form, they can then be separated into enantiomers as mentioned above.

Separation of enantiomers is preferably effected by column separation on chiral phases, or by recrystallization from an optically active solvent, or by reaction with an optically active substance which, with the racemic compound, forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols and the separation of the diastereoisomeric mixture of salts or derivatives thus obtained, for example on the basis of different solubility, whereby from pure diastereoisomeric salts or n oizvodni can be obtained free antipodes by treatment with appropriate agents. Particularly used optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, almond acid, camphorsulfonic acid, gltamic acid, aspartic acid or quinic acid. For example, optically active alcohol means (+) or (-) - menthol and optically acyl radical in amides, for example (+) - or (-) - mentyloxycarbonyl radical.

The compounds of formula (I) further prepared may be converted into their salts, in particular for pharmaceutical use, in their physiologically acceptable salts with inorganic or organic acids. The acids used for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new ones thus obtained

The 64588 dienes of formula (I), if they contain a carboxyl group, can optionally be converted into their salts with inorganic or organic bases, in particular for pharmaceutical use in their physiologically acceptable salts. For this purpose, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine are used.

As mentioned in the beginning, the new compounds of general formula (I) and their salts exhibit valuable properties. Thus, the compounds of general formula (I) in which E represents a cyano group are valuable intermediates for the preparation of the remaining compounds of general formula (I), and the compounds of general formula (I) in which E represents one R _b NH-C (= NH) -pyrene as well as their tautomers, their stereoisomers, their physiologically acceptable salts exhibit valuable pharmacological properties, in particular thrombin inhibition, prolongation of thrombin time, and inhibitory action on related serine proteases such as trypsin, charoquinase, urokinase, in fact Xa, factor IX, factor XI and factor XII, as well as some compounds.

For example, the compounds of Example 16 also exhibit a weak inhibitory effect of platelet aggregation.

The compounds

A = N-phenyl-N- (2-carboxyethyl) -2- [N (4-amidinophenyl) -amino-methyl] -benzthiazole-5carboxamide,

B = N-phenyl-N- (3-hydroxycarbonylpropyl) -1-methyl-2- [2- (4-amidinophenyl) -ethyl] benzimidazol-5-yl-carboxamide,

C = B1-phenyl-N- (hydroxycarbonylmethyl) -1-methyl-2 - [(4-amidino-phenyl) -oxymethyl] -benzimidazol-5-yl-carboxamide,

D = N-phenyl-L1- (2-hydroxycarbonylethyl) -1-methyl-2- [L1- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide,

E = N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -1-methyl-2- [L- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide,

F = Ν-φβΗΗπ-Ν- [2- (1H-tetrazol-5yl) ethyl] -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxamide,

G = N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide were examined as examples of their action on thrombin time as follows:

Material: Plasma from human citrate blood;

test thrombin (bovine), 30 U / ml, Behring Werke, Marburg; diethylbarbiturate acetate buffer, ORWH 60/61

Behring Werke, Marburg;

coagulometer Biomatic BIO, Sarstedt ..

Thrombin time was determined using a Sarmatico Biomatic B10 coagulometer.

The test substance is placed in containers prescribed by the manufacturer with 0.1 ml human citrate blood and 0.1 ml diethyl barburate buffer (DBA buffer). The starting material was incubated for one minute at 37 ° C. By adding 0.3 U test thrombin in 0.1 ml DBA buffer, the clotting process is started. The device ensures that the timing starts with the delivery of thrombin until the material has coagulated. Samples were added to control for which 0.1 ml of DBA buffer was added.

According to the definition, the effective dose concentration of the substance at which the thrombin time is doubled relative to the control is determined by the dose-rate graph.

The following table shows the values obtained:

Compound Thrombin time A (ED ₂₀₀ in μΜ} 0.04 IN 0.06 P 0.15 IN 0.03 Well 0.09 F 0.03 Mr 0.03 By way of example, when applying A, D, E and G at doses up to 1 kg / kg i.v ,. no acute current was observed on rats- juicy side dishes. Therefore these

compounds are well tolerated.

Based on their pharmacological properties, the novel compounds and their physiologically tolerated salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases such as, for example, treatment of deep vein thrombosis, prevention of bypass occlusion or angioplasty (PT) ) A) as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, for the prevention of coronary thrombosis, for the prevention of heart attack and for the prevention of occlusion of shunts or stents. In addition, the compounds of the invention are suitable for antithrombotic help in thrombolytic treatment such as, for example, rt-PA or streptokinase, to prevent prolonged PT (C) A restenosis, to prevent metastases and the growth of coagulation-dependent tumors and fibrin-dependent inflammatory processes .

The dose required to produce the corresponding effect is 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, intravenously, and 0.1 to 50 mg / kg, preferably 0.3 to 30 m / kg, respectively, for oral administration. up to times a day. For this purpose, the compounds of the formula (I) obtained according to the invention, optionally in combination with other active substances, are processed together with one or more conventional inert carriers and / or diluents, for example corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate , polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fats such as solid fat or their cm its in the usual pharmaceutical forms such as tablets, dragees, capsules, powders, suspensions or suppositories.

Examples of carrying out the invention

The following examples illustrate the invention in more detail.

Preliminary remarks

Unless otherwise indicated, Polygram silica gel plates from E. Merck, Darmstadt were always used to determine the ^ values.

ECA mass spectra (cationic electrospray mass spectra) are described, for example, in Chemie unsrrer Zeit, 6, 308-316 (1991).

Example 1.

N-phenyl-L- (2-ethoxycarbonylethyl) -3methyl-2- [2- (4-amidino-phenyl) -ethyl] -imidazo [4,5-b] pyridine-6-carboxamide,

a) 6-Methylamino-5-nitronicotinic acid methyl ester

1.6 g (7.4 mmol) of 6-chloro-5-nitronicotinic acid methyl ester (see Bernie et dl. In J.Chem.Soc., 1951, 2590) were stirred in 20 ml of an aqueous 40% solution of methylamine for 20 minutes. 30 min at room temperature. The reaction mixture was then diluted with ice water, the precipitated yellow precipitate was filtered off and dried.

Yield: 1.2 g (80% of theory),

Rj value: 0.66 (silica gel; ethyl acetate / ethanol / glacial acetic acid = 90: 5: 5)

b) 5-Amino-6-methylaminonicotinic acid methyl ester

To a solution of 3.lg (15 mmol) of 6-methylamino-5-nitronicotinic acid methyl ester in 100 ml of ethanol / dichloromethane (3: 1) was added 1 g of palladium on carbon (10%) and the resulting suspension was hydrogenated. at 5 bar hydrogen pressure for 1.5 h at room temperature. The catalyst was then filtered and the solvent distilled in vacuo. The resulting crude oil was further used directly in the reaction.

Yield: 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-methyl-aminonicotinic acid methyl ester

A solution of 2.6 g (15 mmol) of 3- (4-cyanophenyl) propionic acid 25 ml of absolute tetrahydrofuran is mixed with 2.4 g (15 mmol) of Ν'-carbonyldiimidazole and stirred at room temperature for 20 mim. Imidazole was then reacted with a solution of 2.3 g of 13 mmol) 5-amino-6-methylaminonicotinic acid methyl ester in 25 ml of dimethylformamide and heated at 100 ° C for 3 h. After removal of the solvent in vacuo, the crude material was dissolved in ethyl acetate, the organic phase was washed with water and, after drying over sodium sulfate, was again released from the solutions

64588 near. The resulting residue was purified by flash chromatography (silica gel: gradient: dichloromethane / ethanol = 19: 1)

Yield: 2.1 g beige solid (50% of theory), R _f value: 0.54 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1).

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

A solution of 2.0 g (5.9 mmol) of 5- [2- (4-cyanophenyl) ethylcarbonylamino] -6-methylaminonicotinic acid methyl ester in 50 ml of glacial acetic acid was heated at 100 ° C for 1 h. After removal of the solvent, it was dissolved in dichloromethane, washed with sodium hydrogen carbonate solution, dried with sodium sulfate, and the solvent distilled again.

Yield: 1.7 g brown solid (89% of theory),

Rf 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 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 a solution of 1.5 g of lithium hydroxide in 20 ml of water and stirred at room temperature for 24 hours. It is then diluted with 50 ml of water, the alcohol is distilled off and the aqueous phase is washed with ethyl acetate. After acidification with dilute hydrochloric acid, it is extracted repeatedly with dichloromethane / methanol (9:11), the organic phase is dried with sodium sulfate and the solvent is distilled off.

Yield: 2.1 g beige solid (70% of theory)

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

N-phenyl-L- (2-ethoxycarbonylethyl) -3methyl-2- [2- (4-cyano-phenyl) ethyl] -imidazo [4,5b] pyridine-6-carboxamide

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 thionyl chloride and boiled 2 h under reflux. After distillation of the liquid components, the crude material was dissolved twice more in dichloromethane and the solvent was distilled each time. The crude acid chloride (2 g) thus obtained was suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g (6.5 mmol) of N- (2-ethoxycarbonylethyl) aniline.

0.73 g (7.2 mmol) of triethylamine are then added dropwise over 5 min. After stirring for 1 hour, the solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, the organic phase was washed with water and dried with sodium sulfate. After distillation of the solvent and flash chromatography (silica gel; dichloromethane to dichloromethane / ethanol = 49: 1) the desired compound was isolated as a brownish oil.

Yield: 1.9 g (65% of theory),

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

g) N-phenyl-N- (2-ethoxycarbonylethyl) -

3-methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-b] pyridine-6-carboxamide 1.8 g (3.7 mt) N-phenyl-N- (2-ethoxycarbonylethyl) -3methyl- 2- [2- (4-cyanophenyl) ethyl] -imidazo [4,5-

B] Pyridine-6-carboxamide was stirred in 100 ml of hydrogen chloride-saturated ethanol for 16 h, first at 0 ° C and then at room temperature, until no more than the starting material was detected by thin layer chromatography. The solvent was then distilled off, the oily residue was dissolved in 50 ml of absolute ethanol and mixed with 3.6 g (37 mmol) of ammonium carbonate. 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 44: 1) and concentrated again.

Yield: 1.6 g beige solid (80% of theory),

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

Example 2.

Ν-φβΗΗΗ-Ν- (2-hydroxycarbonylethyl) -3-methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-f] pyridine-6-carboxamide

Solution of 535 mg (1.0 mmol) N-phenyl N- (2-ethoxycarbonyl-ethyl) -3-methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-b] pyridine-

6-carboxamide in 10 ml ethanol was mixed with 5 ml 2N sodium hydroxide and stirred at room temperature for 2 hours. It is then diluted with 10 ml of water, the alcohol is distilled off, the aqueous phase is washed with 20 ml of ethyl acetate and acidified with concentrated hydrochloric acid, whereby the desired compound is isolated as white crystals.

Yield: 375 mg (74% of theory)

R _f value: 0.23 (silica gel; ethyl acetate / ethanol / ammonia = 90: 5: 5)

C ₂₆ H ₂₆ HN ₆ O ₃ (470.54)

Mass Spectrum: (M + H) ⁺ = 471

Example 3.

B1- (2-pyridyl) -N- (2-methoxycarbonylethyl) -3-methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride

Prepared analogously to Example 1 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -3methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo [4,5b] pyridin-6-yl] carboxamide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Yield: 75% of theory, C ₂₆ H ₂₇ N ₇ O3 (485.55)

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

ESA Mass Spectrum: (M + Well = 486 Example 41.

N-phenyl-N-ethoxycarbonylmethyl-3-methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [4,5b] pyridin-6-ylcarboxamide hydrochloride

Prepared analogously to Example 1 from 1N-phenyl-N-ethoxycarbonylmethyl-3-methyl-2 [2- (4-cyanophenyl) ethyl] imidazo [4,5-b] pyridin-6-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 84% of theory,

C ₂₇ H ₂₈ N ₆ O ₃ (484.56)

R _f value: 0.44 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA Mass Spectrum: (M + Well = 485.

Example 5.

B1-phenyl-N-hydroxacarbonylmethyl-3methyl-2- [2- (4-amidino-phenyl) -ethyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride.

Prepared analogously to Example 2 of N-phenyl-N-ethoxycarbonylmethyl-3-methyl-2 [2- (4-amidinophenyl) ethyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 85% of theory, C ₂₅ H ₂₄ N ₆ O ₃ (456.51)

R _f value: 0.19 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA Mass Spectrum: (M + Well = 457.

Example 6

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

Prepared analogously to Example 1 from 2- [2- (4-cyanophenyl) -ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl) -imidazo [4,5 -B] pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate.

Yield: 20% of theory, C ₂₇ H ₂₆ N ₆ O ₃ (482.54)

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

ESA Mass Spectrum: (M + Well = 483.

Example 7.

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

Prepared analogously to Example 2 from 2- [2- (4-amidino-phenyl) -ethyl] -3-methyl-6- (2-methoxycarbonyl-2,3-dihydroindol-1-ylcarbonyl) -imidazo [4,5-b ] pyridine hydrochloride and sodium hydroxide.

Yield: 90% of theory, C ₂₆ H ₂₄ N ₆ O ₃ (468.52)

R _f value: 0.24 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA mass spectrum: (M + H = 469 (M + Na) ⁺ = 491

Example 8.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidino-phenyl) oxymethyl] -imidazo [4,5-b] pyridin-5-ylcarboxamide

a) 2-amino-3-methylamino-6-methylpyridine 8.35 g (50 mmol) of 2-methyl-5-methylamino6-nitropyridine (Heterocycles, 38 529 (1994)) was dissolved in 300 ml of ethyl acetate and hydrogenated with 1.5 g of Raney - Nickel for 3.5 h at room temperature. The catalyst was then filtered off and the filtrate concentrated. After crystallization of the resulting petroleum ether residue, 5.75 g (84% of theory) was obtained as olive-green crystals.

C ₇ H N ₃ (137.20)

Melting point: 112-113 ° C.

b) 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridine 11.4 g (63 mmol) of 4-cyanophenoxyacetic acid were dissolved in 200 ml of absolute tetrahydrofuran and at room temperature. mixed with 10.2

64588 g (63 mmol) of Ν, ′ -carbonyldiimidazole. After 15 min at 60 ° C, 5.70 g (41.5 mmol) of 2-amino-3-methylamino-6-methylpyridine were added. After 2 h at 60 ° C, the solvent was distilled off, the crystalline residue was mixed with water, washed with water and dried. Crystallization from ethanol gave 9.95 g (91% of theory) as white crystals.

C ₁₆ H _I4 N ₄ O (278.32)

Mass Spectrum: M ⁺ = 278.

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

2.62 g (10 mmol) of 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] -pyridine were suspended in 125 ml of dichloromethane and mixed with 2.62 g (12.7 mmol) m -chloroperbenzoic acid to give a clear solution. After 2 hours at room temperature, the solvent was distilled off and the resulting residue was mixed with sodium hydrogen carbonate solution. After 30 min, the resulting white crystalline product was filtered off with a suction filter, washed with water and dried at 40 ° C.

Yield: 2.45 g (83% of theory),

C ₁₆ H _{| 4} N ₄ O ₂ (294.30)

Mass Spectrum: M ⁺ = 294

d) 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-hydroxymethyl-imidazo [4,5-b] pyridine

2.40 g (8.2 mmol) of 1,5-dimethyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] -pyridin-4-oxide are suspended in 75 ml of dichloromethane and mixed with 2.4 ml of trifluoroacetic anhydride (16.9 mmol) to give a clear solution. After 16 h at room temperature, the solvent was distilled off and the resulting viscous residue was dissolved in 50 ml of dichloromethane and coated with 50 ml of 2N sodium hydrogen carbonate solution.

After vigorous stirring for 3 hours, the resulting precipitate was filtered off with a suction filter, washed with water and dried at 40 ° C.

Yield: 1.85 g of a white powder (78% of theory),

C ₁₆ H ₁₄ N ₄ O ₂ (294.30)

Melting point: 172 ° C.

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

3.65 g (12.5 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-hydroxymethyl-imidazo [4,5-b] pyridine are dissolved in 500 ml of dichloromethane and mixed with 15.0 g of manganese dioxide . After 16 h at room temperature, it was filtered through silica gel and the solvent was distilled off. The resulting filtrate was concentrated, the crystalline precipitate was triturated with ether, filtered on a suction filter and dried.

Yield: 3.05 g of a white powder (84% of theory),

C ₁₆ H, ₂ N ₄ 0 ₂ (292.30)

Melting point: 231-234 ° C.

f) 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-carboxy-imidazo [4,5-b] pyridine

1.25 g (4.3 mmol) of 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridine-5carbaladehyde were dissolved in 10 ml of formic acid and mixed at 0 ° C with 1.0 ml of hydrogen peroxide (33%). After 12 h at 4 ° C, the resulting white precipitate was filtered off with suction filter, washed with water and dried at 40 ° C.

Yield: 0.81 g (61% of theory),

C ₁₆ H ₁₂ N ₄ O ₃ (308.7)

g) N- (2-pyridyl) -L- (2-methoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) oxymethyl] -imidazo [4,5-b] pyridin-5-ylcarboxamide 308 mg (1.0 mmol) 1-methyl-2 - [(4-cyanophenyl) oxymethyl] -5-carboxy-imidazo [4,5-

The b] -pyridine was suspended in 5 ml of dimethylformamide and mixed with 303 mg (3.0 mmol) of N-methylmorpholine and 321 mg (1.0 mmol) of O- (benzotriazol-1-yl) -N, N, L ', N-tetramethyluronium tetrafluoroborate. After 10 min 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 h at room temperature, the reaction solution was added with stirring to ice water. After extraction with ethyl acetate three times, the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The resulting residue was chromatographed on silica gel with dichloromethane / ethanol (90: 1 to 25: 1).

Yield: 165 mg white powder (35% of theory), C _{2 S} H ₁₂ N ₆ O ₄ (407.50)

Melting point: 139-140 ° C.

h) N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidino-phenyl) oxymethyl] -imidazo [4,5-b] pyridin-5-yl-carboxamide

Prepared by reacting 140 mg (0.3 mmol) N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) -oxymethyl] -imidazo [4,5-] pyridin-5-yl] carboxamide with hydrogen chloride-saturated ethanol and ammonium carbonate / ethanol analogously to Example 1, g. The resulting product was purified by chromatography on silica gel with dichloromethane / ethanol (19: 1 to 4: 1).

Yield: 48 mg of white powder (36% of theory),

C ₂₇ H ₂₇ N ₇ O ₄ (501.57)

Mass Spectrum: (M + H) ⁺ = 502.

Example 9.

N-phenyl-N- (2-ethoxycarbonylethyl) -2 [N- (4-amidinophenyl) amino-methyl] -benzthiazole-5-carboxamide

a) 4-Fluoro-3-methoxyacetamidobenzoic acid ethyl ester

Solution of 2.8 g (15.3 mmol) of 3-amino-4-fluorobenzoic acid ethyl ester (See LSFosdick, AFDodds in J. Amer. Chem. Soc., 65, 2305 (1943)) and 1.56 ml (1.85 g of 17.0 mmol) methoxyacetyl chloride in 50 ml of chlorobenzene was stirred for 1 h at 50 ° C and then refluxed for 115 min. The solvent was then distilled in vacuo and the crude product obtained was purified by flash chromatography (silica gel; dichloromethane / ethanol = 100: 1). The initially desired oily compound solidifies within a few days.

Yield: 3.8 g (98% of theory),

R _f -value: 0.38 (silica gel; dichloromethane / ethanol = 19: 1) b) 2-Methoxymethylbenzthiazole-5-carboxylic acid ethyl ester

A mixture of 3.0 g (11.7 mmol) of 4-fluoro-3-methoxyacetamido-benzoic acid and 2.1 g (5.2 mmol) of Lawesson's reagent was heated for 6 hours in 90 ml of toluene under reflux, mixed again with 1.0 g of Lawesson's reagent and heated for another 6 h to 120 ° C. After replacing the solvent with xylene, it was heated for an additional 8 hours in an autoclave to 180 ° C. The solvent was then distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate / petroleum ether = 5:95) and purified again.

Yield: 2.1 g of yellow crystals (72% of theory),

R _f -value: 0.55 (silica gel; ethyl acetate / petroleum ether = 3: 7)

c) 2-methoxymethylbenzthiazole-5-carboxylic acid

A mixture of 2.1 g (8.36 mmol) of 2-methoxymethyl-benzthiazole-5-carboxylic acid ethyl ester and 16 ml of 2N sodium hydroxide was stirred in 60 ml of ethanol for 1 h at room temperature. The alcohol was then distilled, the crude product was dissolved in 20 ml of water, washed with 50 ml of diethyl ether and the aqueous phase was acidified with concentrated hydrochloric acid under ice-cooling. The precipitated beige-pink compound was filtered off with a suction filter, washed with water and dried.

Yield: 1.6 g (86% of theory),

R _f value: 0.12 (silica gel; dichloromethane / ethanol = 29: 1)

d) L1-phenyl-N- (2-ethoxycarbonylethyl) 2-methoxymethyl-benzthiazole-5-carboxamide

A suspension of 1.6 g (7.2 mmol) of 2-methoxymethylbenzthiazole-5-carboxylic acid in 60 ml of dichloromethane was mixed with 1.6 ml (22 mmol) of thionyl chloride and heated under reflux for 1 hour. The solid was dissolved after 20 minutes. After distillation of the liquid components, the crude product is further dissolved twice in dichloromethane, the solvent being distilled accordingly. The crude acid chloride thus obtained was dissolved in 50 ml of tetrahydrofuran, added dropwise to a mixture of 1.4 g (7.2 mmol) of N- (2-ethoxycarbonylethyl) aniline and 3.0 ml (21 mmol) of triethylamine in 50 ml of tetrahydrofuran and stirred overnight. at room temperature. The solvent was then distilled in vacuo, the residue was dissolved in 30 ml of dichloromethane, the solution was washed with water and dried with sodium sulfate. After distillation of the solvent and flash chromatography (silica gel; gradient: dichloromethane / ethanol 98.5: 1.5 to 80:20), the desired compound was isolated as a brownish oil.

Yield: 2.05 g (72% of theory),

R _f -value: 0.40 (silica gel; ethyl acetate / petroleum ether = 1: 1)

e) N-phenyl-N- (2-ethoxycarbonylethyl) -2- [N- (4-cyanophenyl) -aminomethyl] -benzthiazole-5-carboxamide

64588

A mixture of 2.05 g (5.14 mmol) of Ν-φβΗΗπ-Ν (2-ethoxycarbonyl-ethyl) -2-methoxymethyl-benzthiazole-5-carboxamide and 5.7 ml (5.7 mmol) of a boron tribromide solution in dichloromethane was dissolved in an additional 60 ml. dichloromethane and stirred for 16 h at room temperature. It is then washed with 40 ml of saturated sodium bicarbonate solution, the organic phase is dried with sodium sulfate and the solvent is distilled off. The crude N-phenyl-N- (2-ethoxycarbonylethyl) -2-bromo-methyl-benzthiazole-5-carboxamide (2.4 g) thus obtained was dissolved in 5.0 ml N, N-diisopropylethylamine and mixed with 0.64 g (5.4 mmol). After heating to 130 ° C for one hour, the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; gradient: ethyl acetate / petroleum ether = 1: 3 to 1: 1) to give an orange foam upon concentration of the eluates.

Yield: 1.1 g (44% of theory),

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

f) Ν-φβΗΗΠ-Ν- (2-ethoxycarbonylethyl) -2- [Ν- (4-amidinophenyl) -aminomethyl] -benzthiazole-5-carboxamide

1.1 g (2.27 mmol) Ν-φβΗΗΠ-Ν- (2-βτοκθΗcarbonylethyl) -2- (N- (4-cyanophenyl) -aminomethyl] -benzthiazole-5-carboxamide were stirred in 100 ml of hydrogen chloride-saturated ethanol for 5 h, first at 0 ° C and then at room temperature until starting material is detected by thin layer chromatography, then the solvent is distilled off at a maximum of 30 ° C, the oily residue is dissolved in 100 ml of absolute alcohol and mixed with 1.6 g (22 mmol) of ammonium carbonate After stirring at room temperature for 18 hours, the solvent was distilled off and the crude product was purified ca by flash chromatography (silisagel; gradient: water / methanol = 19: 1 to 4: 1). Concentration of the eluates afforded the desired compound as a white foam.

Yield: 0.77 g (63% of theory),

R _f value: 0.19 (silica gel; dichloromethane / ethanol = 3: 7)

C 'H ₂₇ NO ₃ S (501.60)

Mass Spectrum: (M + H) ⁺ = 502.

Example 10.

N-phenyl-N (2-carboxyethyl) -2- [74- (4-amidinophenyl) aminomethyl] -benzthiazole-5carboxamide 0.45 g (0.84 mmol) N-ββΗΗΠ-Ν (2-ethoxycarbonylethyl) -2- [N- (4-amidinophenyl) ) -aminomethyl] -benzthiazole-5-carboxamide was dissolved in 15 ml ethanol, mixed with 2 ml 2N sodium hydroxide% and stirred at room temperature for 4 h. It was then acidified with 3 ml of 2N hydrochloric acid and the solvent distilled. The resulting crude material was dissolved in 5 ml of dichloromethane / ethanol (2: 1) and separated by filtration from insoluble sodium chloride. Distillation of the solvent gave the desired compound as a yellow foam.

Yield: 0.26 g (67% of theory),

R _f value: 0.47 (silica gel; methanol / 5% aqueous sodium chloride solution = 6: 4) C ₂₅ H ₂₃ N ₅ O ₃ S (473.55) Mass spectrum: (M + H) ⁺ = 474 Example 11.

N- (2-pyridyl) N - (2-methoxycarbonylethyl) -2- [N- (4-amidinophenyl) -aminomethyl] -benzthiazol-5-ylcarboxamide dihydrochloride

Obtained similarly to Example 9 from N (2-pyridyl) -N (2-methoxycarbonylethyl) -2 [N- (4-cyanophenyl) aminomethyl] -benz-thiazol5-ylcarboxamide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Yield: 68% of theory, C ₂ 5 ^H 2 <N ₆ O ₃ S (488.57)

R _f value: 0.13 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum: (M + Well = 489. Example 12.

N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -2- [2- (4-amidinophenyl) -ethyl] -benzthiazol-5-ylcarboxamide dihydrochloride

Prepared similar to Example 9 from N (2-pyridyl) -N- (ethoxycarbonylmethyl) -2- [2 (4-cyanophenyl) ethyl] -benzthiazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 95% of theory,

R _f -value: 0.20 (silica gel; methylene chloride / ethanol = 4: 1 few drops of acetic acid

ESA Mass Spectrum: (M + HF = 488. Example 13.

N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -2- [L- (4-amidinophenyl) -aminomethyl] benzthiazol-5-ylcarboxamide dihydrochloride

Obtained similarly to Example 9 from N (2-pyridyl) -N (ethoxycarbonylmethyl) -2- [B1 (4-cyanophenyl) aminomethyl] -benz-thiazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 68% of theory, ^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)

ESA Mass Spectrum: (M + Well = 489 Example 14.

N- (2-pyridyl) -1H- (hydroxycarbonylmethyl) -2- [N- (4-amidinophenyl) -aminomethyl] benzthiazol-5-ylcarboxamide dihydrochloride

Obtained similarly to Example 10 from N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -2 [T4- (4-amidinophenyl) aminomethyl] -benz-thiazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

Yield: 90% of theory,

C ₂ 3H ₂₀ N ₆ O3S (460.52)

Rf value:

ESA - mass spectrum: (M + OU = 461 (N + Na) ⁺ = 483 (M + 2Na) ^{+ +} = 253

Example 15.

N-phenyl-N- (2-ethoxycarbonylethyl) -2 [N- (4-amidinophenyl) -] N-methyl-aminomethyl] - benzthiazol-5-ylcarboxamide hydrochloride

a) Ν-φβΗΗπ-Ν- (2-ethoxycarbonylethyl) 2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] benzthiazol-5-ylcarboxamide dihydrochloride

Prepared similarly to Example 9e from 4cyanophenyl-N-methylaniline and Ν-φβΗΗΠ-Ν- (2ethoxycarbonylethyl) -2-methoxy-methyl-benzthiazole-5-carboxamide

Yield: 57% of theory,

Rf value: 0.46% (silica gel; dichloromethane / ethanol = 19: 1)

b) b} -phenyl-N- (2-ethoxycarbonylethyl) 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzthiazol-5-ylcarboxamide hydrochloride

Prepared similarly to Example 9 from Νphenyl-N- (2-ethoxycarbonylethyl) -2- [N- (4-cyanophenyl) -N-methylaminomethyl] -benzthiazol-5ylcarboxamide, ethanol and ammonium carbonate.

Yield: 73% of theory,

C ^ N ^ S (515.64)

Rf value: 0.29 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum; (M + OU = 516.

Example 16.

N-phenyl-1- {1- (2-hydroxycarbonylethyl) 2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzthiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 10 from N-phenyl-N- (2-ethoxycarbonylethyl) -2- [N- (4-amidinophenyl) -N-methylamino-methyl] -benzthiazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 96% of theory, C ₂₆ H ₂₅ N ₅ O ₃ S (487.58)

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

ESA mass spectrum: (M + HU = 488 (M + 2Na) ^{+ +} = 266.5 Example 17.

N-phenyl-N- (2-ethoxycarbonylethyl) -2 [(4-amidinophenyl) -thiomethyl] -benzthiazole-5-ylcarboxamide hydrochloride

Prepared similarly to Example 9 from N-phenyl-N- (2-ethoxycarbonylethyl) -2 - [(4-cyanophenyl) -thiomethyl] -benzthiazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 61% of theory,

C ₂₇ H ₂₅ N ₄ 0 ₃ S ₂ (518.66)

Rf value: 0.27 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum: (M + HF = 519.

Example 18

N-phenyl-N- (2-hydroxycarbonylethyl) -2 - [(4-amidinophenyl) -thiomethyl] -benzthiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 10 from N-phenyl-N- (2-ethoxycarbonylethyl) -2 - [(4-amidinophenyl) -thiomethyl] -benzthiazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 95% of theory, ^C 25 ^H 22 ^N AS ₂ (490.61)

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

ESA mass spectrum: (M + H = 491 (M + Na) ⁺ = 513

Example 19.

Phenyl-No (ethoxycarbonylmethyl) -223

64588 [N- (4-Amidinophenyl) -amino-methyl] -benzthiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 9 from N-phenyl-L- (ethoxycarbonylmethyl) -2- [N- (4-cyanophenyl) -aminomethyl] -benzthiazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 82% of theory, C ₂₆ H ₂₅ N ₅ O ₃ S (487.58) N -value: 0.21 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum: (M + Well = 488.

Example 20.

N-phenyl-L- (hydroxycarbonylmethyl) 2- [N- (4-amidinophenyl) -aminomethyl] -benzthiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 10 for phenyl-N- (2-ethoxycarbonylmethyl) -2- [L- (4-amidinophenyl) -aminomethyl] -benzthiazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 75% of theory, C ₂₄ H ₂₁ N ₅ O ₃ S (459.53)

Rf value: 0.14 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum: (M + Nu = 460 (M + 2Na) ⁺ - 482 Example 21.

N-phenyl-N- (2-ethoxycarbonylethyl) -2 [2- (4-amidinophenyl) -ethyl] -benzothiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 9 from N-phenyl-N- (2-ethoxycarbonylethyl) -2- [2- (4-cyanophenyl) -ethyl] -benzthiazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 80% of theory, C _2g H _2g N ₄ 0 ₃ S (500.62)

Rf value: 0.30 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum: (M + Well = 501. Example 22.

N-phenyl-N- (2-hydroxycarbonylethyl) 2- [2- (4-amidinophenyl) -ethyl] -benzthiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 10 from N-phenyl-N- (2-ethoxycarbonylethyl) -2- [2- (4-amidinophenyl) -ethyl] -benzthiazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 77% of theory,

C ^ N ^ S (472.57)

Rf value: 0.18 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA Mass Spectrum: (M + Well = 473 (M + Na) ⁺ = 495 (M + H + Na) ⁺⁺ = 259

Example 23.

N- (n-propyl-N- (2-ethoxycarbonylethyl) -2- [N- (4-amidinophenyl) -aminomethyl] benzthiazol-5-ylcarboxamide hydrochloride

Prepared similarly to Example 9 from N (n-propyl) -N- (2-ethoxycarbonylethyl) -2- [N (4-cyanophenyl) -aminomethyl] -benzthiazole-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 83% of theory,

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)

ESA Mass Spectrum: (M + H = 468 (2M + H) ⁺ = 935

Example 24

N- (η-propyl) -N- (2-hydroxycarbonylethyl) -2- [N- (4-amidinophenyl) -aminomethyl] benzthiazol-5-ylcarboxamide hydrochloride

Obtained similarly to Example 10 from b1- (n-propyl) -N- (2-ethoxycarbonylethyl) -2 [N- (4-amidinophenyl) -aminomethyl] -benzthiazol-5-ylcarboxamide hydrochloride and sodium hydroxide. Yield: 75% of theory,

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)

ESA mass spectrum: (M + H &lt; ⁺ &gt; = 440 (2M + H) ⁺ = 231.6

Example 25

N-Phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidino-phenyl) -aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

a) N-phenyl-L1- (2-ethoxycarbonylethyl) -

4-methylamino-3-nitrobenzamide

To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitro-benzoyl chloride and 22.3 g (0.115 mol) of L- (2-ethoxycarbonylethyl) aniline in 300 ml of THF were added dropwise with stirring 13.1 g (0.13 mol) of triethylamine at room temperature. temperature for 15 min. After stirring for 2 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 20 ml of dichloromethane each time, the organic extract was washed with 200 ml of 2N hydrochloric acid and twice with 300 ml of water and dried over sodium sulfate. The solvent was then distilled and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluent: petroleum ether / ethyl acetate = 2: 1).

Yield: 35.0 g (82% of theory),

Re-value: 0.28 (silica gel; dichloromethane / ethanol = 50: 1).

b) N-phenyl-N- (2-ethoxycarbonylethyl) -

3-amino-4-methylamino-benzamide

12.1 g (0.0326 mol) of Ν-φβΗΗΠ-Ν- (2-β-oxicarbonylethyl) -4-methylamino-3-nitrobenzamide are hydrogenated in 300 ml of ethanol and 150 ml of dichloromethane with about 4 g of palladium / carbon (10% en) at room temperature. and a hydrogen pressure of 5 bar. The catalyst was then filtered off and the filtrate concentrated. The crude product thus obtained is used without further purification.

Yield: 10.6 g (95% of theory),

1 _D -value: 0.19 (silica gel; dichloromethane / ethanol = 50; 1).

c) N-phenyl-L- (2-ethoxycarbonylethyl) 1-methyl-2- [L- (4-cyano-phenyl) -aminomethyl] benzimidazol-5-yl carboxamide

6.17 g (0.035 mol) of N- (4-cyanophenyl) glycine and 5.68 g (0.035 mol)

N, N'-Carbonyldiimidazole was heated in refluxed 300 ml of THF for 30 min, then 10.6 g (0.032 mol) of N-phenyl-N- (2-ethoxycarbonylethyl) -3-amino-4-methylamino was added -benzamide and refluxed for a further 5 hours. The solvent was then distilled off, the residue was dissolved in 150 ml of glacial acetic acid and heated at reflux for one hour. The glacial acetic acid was then distilled off in vacuo, the residue was sealed in about 300 ml of dichloromethane, the solution was washed twice with about 150 ml of water each, and then dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g silica gel; eluent: dichloromethane with 1 -2% ethanol).

Yield: 8.5 g (57% of theory),

F _f -CTofiHocT: 0.51 (silica gel; dichloromethane / ethanol = 19: 1).

d) L1-phenyl-14- (2-ethoxycarbonylethyl) 1-methyl-2- [L1- (4-cyano-phenyl) -aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

1.2 g (2.49 mmol) of phenyl-L- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide are stirred in 100 ml of saturated ethanol hydrochloric acid. 6 h at room temperature. It was then evaporated in vacuo to dryness, the residue was dissolved in 100 ml of ethanol, 2.5 g (26 mmol) of ammonium carbonate were added and stirred at room temperature overnight. After distillation of the solvent, the crude product obtained was purified by column chromatography (100 g silica gel; eluent: dichloromethane / ethanol = 4: 1). Concentration of the eluates gave the desired compound as a white amorphous solid.

Yield: 1.10 g (83% of theory),

Ff value: 0.18 (silica gel; dichloromethane / ethanol = 4: 1).

C ₂₈ H ₃₀ N ₆ O ₃ xHC1 (498.6)

ESA mass spectrum: (M + H / = 499 (M + 2H) ^{+ +} = 250 (Μ + H + Na) ^{+ +} = 261 Example 26.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-methyl-2- [N- (4-amidino-phenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide

Mixture of 300 mg (0.56 mmol) N-phenyl-N- (2-ethoxycarbonyl-ethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazole-5-ylcarboxamide hydrochloride, 15 ml ethanol, 4 ml water and 120 mg (3.0 mmol) sodium hydroxide was stirred for two hours at room temperature. It is then diluted with about 20 ml of water and the acetic acid monitored slightly acidified. The crystallized product was filtered off, washed with water and dried at 60 ° C in vacuo.

Yield: 250 mg (95% of theory),

C ₂₆ H ₂₆ N ₆ O ₃ (470.5)

ESA mass spectrum: (M + H = 471 (M + H + Na) ^{+ +} = 247 (M + 2Na) ⁺⁺ = 258.

64588

Example 27

N- (p-propyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidino-phenyl) -thiomethyl] benzimidazol-5-ylcarboxamide hydrochloride

a) N- (n-propyl) -N- (2-ethoxycarbonylethyl) -4-methylamino-3-chloroacetamido-benzamide

Solution of 1.8 g (5.9 mmol) N- (η-προpyl) -N [- (2-ethoxy-carbonylethyl) -3-amino-4methylamino-benzamide [preparation analogous to N-phenyl-N- (2-ethoxycarbonylethyl) -3-Amino-4-ethylaminobenzamide], 1.1 g (6.8 mmol) of N, N'-carbonyldiimidazole and 0.65 g (6.9 mmol) of chloroacetic acid in 75 ml of THF were stirred for one hour at room temperature. The solvent was then distilled 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) yellow oil,

Rf value: 0.58 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1).

b) N- (n-propyl) -1H- (2-ethoxycarbonylethyl) -2-chloromethyl-1-methylbenzimidazol-5-ylcarboxamide

1.6 g (4.3 mmol) of N- (η-προπΗπ) -Ν- (2-ετοκω-carbonylethyl) -4-methylamino-3-chloroacetamido-benzamide were heated in 25 ml of acetic acid at 100 ° C for 30 min. The solvent was then distilled, the crude product was dissolved in 40 ml of methylene chloride / ethanol (9: 1) and washed with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated.

Yield: 1.5 g (100% of theory) of brown oil,

R _f -CTofiHOCT: 0.63 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1).

c) b1- (p-propyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) thiomethyl] benzimidazol-5-ylcarboxamide

A mixture of 1.5 g (4.1 mmol) N- (η-προπππ) L 1- (2-ethoxycarbonyl-ethyl) -2-chloromethyl-1 methylbenzimidazol-5-ylcarboxamide and 0.65 g (4.8 mmol) of p-cyanothiophenol was heated in 10 ml. dimethylformamide and 10 ml diisopropylethylamine at 100 ° C for one hour. The solvent was then distilled in vacuo, the crude product was dissolved in 30 ml of ethyl acetate, washed with 30 ml of water and purified after concentration by flash chromatography (silica gel; methylene chloride / ethanol = 49: 1 to 19: 1).

Yield: 1.5 g (79% of theory) of brown oil,

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

i) N- (n-propyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidinophenyl) -thiomethyl] benzimidazol-5-ylcarboxamide hydrochloride

1.4 g (3.01 mmol) of N- (η-προπΗπ) -N- (2ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) -thiomethyl] -benzimidazol-5-ylcarboxamide are stirred in 50 ml of hydrogen chloride saturated with ethanol 5 h first at 0 ° C, later at room temperature, until no more than the starting material is detected by thin layer chromatography. The solvent was then distilled at a maximum of 30 ° C in the water bath, the oily residue was dissolved in 40 ml of absolute ethanol and mixed with 2.8 g of ammonium carbonate. After 18 h, 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).

Yield: 1.3 g (83% of theory) of a light beige solid,

Re-value: 0.29 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5).

C ₂₅ H ₃₁ N ₆ O ₃ S (481.62) ESA Mass Spectrum: (M + H / = 482 Example 28).

N- (n-propyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2 - [(4-amidinophenyl) thiomethyl] benzimidazol-5-ylcarboxamide hydrochloride

0.52 g (1.0 mmol) N- (η-προπΗπ) -N- (2ethoxycarbonylethyl) -1-methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-yl-carboxamide hydrochloride was dissolved in 15 ml of ethanol , mixed with 5 ml of 2N sodium hydroxide solution and stirred at room temperature for 2 hours. Then 5 ml of water are added, the alcohol is distilled off and acidified with concentrated hydrochloric acid. The water was distilled in vacuo and the crude product was dissolved in 5 ml of ethanol and filtered off with insoluble sodium chloride. Distillation of the solvent gave the title compound as a white solid.

Yield: 0.43 g (88% of theory),

R _f - (cToftHOCT: 0.19 (silica gel; ethyl acetate 26

64588

1-methyl-2 - [(4-cyanophenyl) -oxymethyl] -benzimidazol-5-ylsulfonamide

532 mg (3.0 mmol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mmol) of N, N-carbonyldiimidazole were dissolved in 40 ml of THF and heated at reflux for 15 min. 700 mg (2.24 mmol) of N-methyl-N- (1-methylpiperidin-4-yl) -3amino-4-methylamino-benzenesulfonamide were then added and heated for 8 hours. It was then concentrated and the oily residue thus obtained was heated in 30 ml of glacial acetic acid for one hour under reflux. The glacial acetic acid was distilled off, the residue was mixed with about 30 ml of water and basified with concentrated ammonia, and the solution was extracted three times with about 20 ml of dichloromethane each. The organic phases are dried and concentrated. The product thus obtained is used without further purification.

Yield: 400 mg (39% of theory),

C ₂₃ H ₂₇ N ₅ O ₃ S (453.6)

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

f) Ν-ΜβΤΗΠ-Ν- (1-methylpiperidin-4-yl) 1-methyl-2 - [(4-amidinophenyl) -oxymethyl] -benzimidazol-5-ylsulfonamide hydrochloride

Prepared analogously to Example 25 d from 400 mg of N-methyl-N- (1-methylpiperidin-4-yl) -1-methyl-2 - [(4-cyanophenyl) -oxymethyl] benzimidazol-5-ylsulfonamide with ethanol hydrochloric acid and ammonium carbonate.

Yield: 370 mg (83% of theory), ^C A ^N 6 ° 3 ^S ( ⁴ 7θ · 6)

ESA mass spectrum: (M + HU = 471 (M + 2H) ⁺⁺ = 236

Example 33.

Ν-ΜβτΗΠ-Ν-φβΗΗπ-1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-ylsulfonamide hydrochloride

Prepared analogously to Example 32 from N-methyl-N-phenyl-1-methyl-2 - [(4-cyanophenyl) oxymethyl] benzimidazol-5-ylsulfonamide, ethanol and ammonium carbonate.

Yield: 46% of theory,

C ₂₃ H ₂₃ N ₅ O ₃ S (449.5) ESA mass spectrum: (M + Well = 450 (M + H + methanol) ⁺ = 482 (M + 2H) ⁺⁺ = 223

Example 34

B1- (3-ethoxycarbonyl-n-propyl) -N-phenyl-1-methyl-2 - [(4-amidinophenyl) oxymethyl] benzimidazol-5-ylsulfonamide hydrochloride

Prepared analogously to Example 32 of N- (3-ethoxycarbonyl) -n-propyl-N-phenyl-methyl-2 - [(4-cyanophenyl) -oxymethyl] -benzimidazol-5-ylsulfonamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 57% of theory, ς, Η ,, Ν, Ο, β (549.7) ECA Mass Spectrum: (M + Well = 550 Example 35.

1-methyl-2 - [(3-amidinophenyl) oxymethyl] -benzimidazol-5-ylsulfonylpyrrolidide hydrochloride

Prepared analogously to Example 32 from 1-methyl-2 - [(3-cyanophenyl) oxymethyl] -benzimidazol-5-ylsulfonylpyrrolidide hydrochloride, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 71% of theory, C ₂₀ H ₂₃ N ₅ O ₃ S (413.5) ECA mass spectrum: (M + H = 414 Example 36).

N-phenyl-L4- (3-methoxycarbonylpropyl) -1-methyl-2- [2- (4-amidino-phenyl) ethyl] benzimidazol-5-ylcarboxamide dihydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -1-methyl-2- [2- (4-cyanophenyl) -ethyl] -benzimidazol-5-ylcarboxamide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Yield: 83.5% of theory,

Rf value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1). C ₂₉ H _{3 |} N ₅ O ₃ (497.6)

ESA mass spectrum: (M + H = 498 (M + H + Na) ⁺⁺ = 260.7 Example 37.

N-phenyl-N- (3-hydroxycarbonylpropyl) -1-methyl-2- [2- (4-amidino-phenyl) ethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from N-phenyl-N- (3-methoxycarbonylpropyl) -1methyl-2 - [(4-amidinophenyl) amino-methyl] -benzimidazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

Yield: 92% of theory,

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

C ₂₈ H ₂₉ N ₅ O ₃ (483.6)

EKA mass spectrum: (Μ + Well = 484 (M + Na) ⁺ = 506 (Μ + Η + Na) ⁺⁺ . = 253.7

Example 38

L1-phenyl-N- (3-ethoxycarbonylpropyl) 1-methyl-2- (N- (4-amidino-phenyl) aminomethyl] benzimidazol-5-ylcarboxamide dihydrochloride

a) L1-phenyl-N- (3-tert-butyloxycarbonylpropyl) -1-methyl-2-N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide

Obtained analogously to Example 25c from N- (4-cyanophenyl) -glycine and N-φβΗΗΒ-N- (3-tert-butyloxycarbonylpropyl) -3-amino-4methylamino-benzamide.

Yield: 65% of theory, N-value: 0.17 (silica gel; dichloromethane / methanol = 19: 1).

b) N-phenyl-N-C3-ethoxycarbonylpropyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide dihydrochloride

Prepared in analogy to Example 25d of N-phenyl-L- (3- tert-butyloxycarbonylpropyl) -1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 68% of theory,

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

C ₂ , H ₃₂ N ₆ O ₃ (512.6)

EKA mass spectrum: (M + H = 513 (M + H + Na) ⁺ . = 268 Example 39.

N-phenyl-1 N- (3-hydroxycarbonylpropyl) -1-methyl-2- [N- (4-amidino-phenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from N-phenyl-N- (3-ethoxycarbonylpropyl) -1 methyl-2- [N- (4-amidinophenyl) amino-methyl] benzimidazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

Yield: 73.5% of theory, ^C : DD ° ₃ (484.6)

EKA mass spectrum: (M + H) ⁺ = 485 (M + 2H) ⁺⁺ = 243 (M + H + Na) ⁺⁺ = 254

Example 40

N-phenyl-N- (ethoxycarbonylmethyl) -1-methyl-2- [2- (4-amidino-phenyl) ethyl] -benzimidazol-5-ylxarboxamide hydrochloride Prepared analogously to example 25d of b1-phenyl-N- (ethoxycarbonylmethyl) ) -1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazole-

5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 73% of theory, 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.

N-phenyl-N- (hydroxycarbonylmethyl) 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 of N-phenyl-N- (ethoxy-carbonylmethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 97% of theory, C ₂₆ H ₂₅ N _S O ₃ (455.5)

EKA mass spectrum: (M + Well = 456 (M + Na) ⁺ = 478 (M + 2Na) ⁺⁺ = 250.6

Example 42.

N-phenyl-N- (ethoxycarbonylmethyl) -1 methyl-2 - [(4-amidino-phenyl) oxymethyl] -benzimidazol-5-ylcarboxamide hydrochloride Prepared analogously to example 25d of N-phenyl-L1- (ethoxycarbonylmethyl) -methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 76% of theory, 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

N-phenyl-N- (hydroxycarbonylmethyl) 1-methyl-2 - [(4-amidino-phenyl) oxymethyl] benzimidazol-5-ylcarboxamide hydrochloride Prepared analogously to example 26 of N-phenyl-N- (ethoxy-carbonylmethyl) 1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 58% of theory, C ₂₅ H ₂₃ N ₅ O ₄ (457.5)

64588

EKA mass spectrum: (Μ + H / = 458 (Μ + Na) ⁺ = 480 (Μ + 2Na) ~ = 251.6

Example 44

N-phenyl-L- (ethoxycarbonylmethyl) -1-methyl-2- [N- (4-amidino-phenyl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (ethoxycarbonylmethyl) -1-methyl2- [N- (4-cyanophenyl) amino-methyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 74% of theory,

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

C ₂₇ H ₂₈ N ₆ ° 3 (484.6)

ESA Mass Spectrum: (M + H = 485 (M + H + Na) ⁺⁺ - 254

Example 45

N-phenyl-L-hydroxycarbonylmethyl) -1-methyl-2- [N- (4-amidino-phenyl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Obtained analogously to Example 26 from N-phenyl-N- (ethoxy-carbonylmethyl) -1-methyl2- [b1- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 84% of theory, C ₂₅ H ₂₄ N ₆ O ₃ (456.5)

ESA Mass Spectrum: (M + Nu = 457 (M + Na) ⁺ - 479 (M + 2NaF - 251

Example 46

N- (4-pyrimidyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidino-phenyl) oxymethyl] -benzimidazol-5-yl] carboxamide hydrochloride

Prepared analogously to Example 25d of N- (4-pyrimidyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) oxymethyl] benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol ammonium carbonate .

Yield: 14% of theory, C ₂₆ H ₂₇ N ₇ O ₄ (501.6)

Mass Spectrum: (M + H) ⁺ = 502 Example 47.

N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -1-methyl-2 - [(4-amidinophenyl) oxymethyl] benzimidazol-5-ylcarboxamide dihydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -1H- (2-ethoxycarbonylmethyl)

1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 44% of theory,

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

^€ 26 ^Η 26 ^Ν 6θ4 (486.5)

ESA mass spectrum: M + HU = 487 (M + 2H) ⁺⁺ - 244 (Μ + H + Na) ⁺⁺ = 255

Example 48

N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 of N- (2-pyridyl) -N- (ethoxycarbonylmethyl) 1-methyl-2 - [(4-amidinophenyl) oxymethyl] benzimidazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

Yield: 85% of theory, ^C 2 <H ₂₂ N ₆ O ₄ (458.5)

ESA mass spectrum: (M + HU = 459 (M + Na) ⁺ = 481 (M + 2Na) ⁺⁺ = 252

Example 49

B1- (2-pyridyl) -14- (ethoxycarbonylmethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide dihydrochloride

a) N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -1-methyl-2- [N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 25c of N- (4-cyanophenyl) -glycine and N- (2-pyridyl) N- (ethoxycarbonylmethyl) -3-amino-4-methylamino-benzamide.

Yield: 24% of theory,

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

b) N- (2-pyridyl) -1H- (ethoxycarbonylmethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide dihydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (ethoxycarbonylmethyl) 1-methyl-2- [N- (4-cyanophenyl) amino-methyl] benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 70% of theory,

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

tat / ethanol / ammonia = 50: 45: 5).

C _m H ₂₇ N ₅ O ₃ S (453.3 / 57)

ESA mass spectrum: (Μ + HU = 454 (Μ + Na) ⁺ = 476.

Example 29.

N- (2-methylpropyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 27 from L- (2-methylpropyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) -thiomethyl] benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid , ethanol and ammonium carbonate.

Yield: 83% of theory, C ₂₅ H ₃₁ N ₆ O ₃ S (495.65) N -value: 0.30 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5).

ESA Mass Spectrum: (M + Well = 496 Example 30.

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 27 from N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) -thiomethyl] -benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 90% of theory,

C ^ N ^ S (515.64)

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

ESA Mass Spectrum: (M + H = 516 (M + H + Na) ⁺⁺ = 269.7 Example 31.

N-phenyl-N (2-hydroxycarbonylethyl) 1-methyl-2 - [(4-amidinophenyl) -thiomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 28 from N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [(4-amide inophenyl) -thiomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide

Yield: 76% of theory,

C ₂₆ H ₂₅ N ₅ O ₃ S (487.58)

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

ESA mass spectrum: (M + H = 488 (M + Na) ⁺ = 510

Example 32

N- (1-methylpiperidin-4-yl) -N-methyl-1 methyl-2 - [(4-amidino-phenyl) -oxymethyl] -benzimidazol-5-ylsulfonamide hydrochloride

a) N- (1-methylpiperidin-4-yl) N - methyl-

4-chloro-3-nitrobenzene-sulfonamide

To a solution of 2.2 ml (15 mmol) of 1-methyl-4-methylaminopiperidine in 60 ml of pyridine was added ice-cold 3.8 g (15 mmol) of 4-chloro-3-nitrobenzenesulfonyl chloride in portions. The mixture is then stirred for 2 hours under cooling, evaporated to dryness, the residue is mixed with 50 ml of water and alkalinized with vigorous stirring by the addition of concentrated ammonia. The precipitated crude product was filtered 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 C1N ₃ O ₄ S (347.8)

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

b) Ν-ΜβτΗπ-Ν- (1-methylpiperidin-4-yl) -

4-methylamino-3-nitrobenzene sulfonamide

1.6 g (4.6 mmol) of methyl-N- (1-methylpiperidin-4-yl) -4-chloro-3-nitrobenzenesulfonamide were mixed with 30 ml of a 40% solution of methylamine and stirred in a closed flask for 4 hours at room temperature. It is then diluted with about 40 ml of water, the precipitated crude product is filtered off, 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) Ν-ΜβΝπ-Ν- (1-methylpiperidin-4-yl) -

3-amino-4-methylamino-benzene-sulfonamide

1.5 g (4.6 mmol) of methyl-N (1-methylpiperidin-4-yl) -4-methylamino-3-nitrobenzenesulfonamide were dissolved in 100 ml of methanol and hydrogenated at room temperature and 5 bar hydrogen catalytically (10 palladium on carbon). The catalyst was then filtered off and the filtrate concentrated. The oily product thus obtained is used without further purification.

Yield: 1.4 g (100% of theory),

C, ₄ H _M N ₄ O ₂ S (312.4)

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

d) Ν-ΜβτΗΠ-Ν- (1-methylpiperidin-4-yl) 27

C ₂₆ H ₂₇ N ₇ O ₃ (485.6)

EKA mass spectrum: (Μ + OU = 486 (Μ + 2Η) ⁺⁺ = 243.7 (Μ + Η + Na) ⁺⁺ = 254.6

Example 50

B1- (2-pyridyl) -1H- (hydroxycarbonylmethyl) -1-methyl-2-p4- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -1 methyl-2- [N- (4-amidinophenyl) amino-methyl] benzimidazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

Yield: 91% of theory, C ₂₄ H ₂₃ N ₇ O ₃ (457.5)

ESA Mass Spectrum: (M + Well = 458 (M + Na) ⁺ = 480 (M + 1 Na) ⁺⁺ = 251.7

Example 51

N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26d from N- (2-pyridyl) -N- (ethoxycarbonyl methyl) -1 methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 90% of theory, N-value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1).

C ₂₇ H ₂₈ N ₆ O ₃ (484.5)

ESA mass spectrum: (M + H = 485 (M + 2H) ⁺⁺ = 243 (M + H + Na) ⁺⁺ = 254

Example 52

B1- (2-pyridyl) -N- (hydroxycarbonylmethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -1 methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

Yield: 89% of theory, ^C 25 ^H 2? W ⁴⁵⁶ · *)

ESA mass spectrum: (M + HU = 457 (M + Na) ⁺ = 479 Example 53.

N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [N- (4-amidino-phenyl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared in analogy to Example 25d of Phenyl-N (2-ethoxycarbonylethyl) -1-methyl-2- (4- (cyanophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide, methanolic 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)

ESA mass spectrum: (M + H = 485 (M + 2H) ⁺⁺ = 243 (M + H + Na) ⁺⁺ = 254

Example 54.

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2 - [(4-amidino-phenyl) oxymethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) oxymethyl] -benzimidazol-5-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 79.5% of theory, ^C ₂₈ H ₂₉ N ₅ O ₄ (499.6)

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

ESA mass spectrum: (M + HU = 500.0 (M + H + Na) * ^4. = 261.7 Example 55.

N-phenyl-N (2-hydroxycarbonylethyl) 1-methyl-2 - [(4-amidino-phenyl) oxymethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared in analogy to Example 26 from N-βββπ-N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidinophenyl) oxymethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 82% of theory, C ₂₆ H ₂₅ N ₅ O ₄ (471.5)

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

ESA mass spectrum: (M + HU = 472 (M + H + Na) ⁺⁺ = 247.6 (M + Na) ⁺ = 494 (M + 2Na) ⁺ = 258.6

Example 56.

N- (2-methylphenyl) -N- (2-ethoxycarbonylmethyl) -1-methyl-2- [2- (2-amidinothiophen-5yl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

a) N- (2-methylphenyl) -N- (2-ethoxycarbonyl) -1-methyl-2- [2- (2-cyanothiophen-5yl) ethyl] -benzimidazol-5-ylcarboxamide

64588

Prepared analogously to Example 25c from 3- (2-cyanothiophen-5-yl) -propionic acid and N- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) -3-amino-4-methylamino-benzamide.

Yield: 18% of theory,

Rf value: 0.66 (silica gel; dichloromethane / methanol = 9: 1).

B) N- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (2-amidinothiophen-5yl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of L1- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [2- (2-cyanothiophen-5-yl) ethyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 53% of theory, yield (504.6)

Rf value: 0.22 (silica gel; dichloromethane / methanol = 5: 1).

ESA mass spectrum: (M + H &lt; + &gt; = 505 (M + H + Na) ⁺⁺ = 264

Example 57

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [2- (2-amidinothiophen-5yl) ethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 98% of theory,

C ₂₄ H ₂₄ N ₆ O ₃ S (476.5)

ESA Mass Spectrum: (M + Well = 477 (M + Na) ⁺⁺ = 499 (M + 2H) ⁺⁺ = 239

Example 58.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [14- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

a) b1- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 25c of N- (4-cyanophenyl) -glycine and N- (2-pyridyl) N- (2-ethoxycarbonylethyl) -3-amino-4-methylamino-benzamide.

Yield: 61% of theory,

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

b) N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2-N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-cyanophenyl) amino-methyl] benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 71% of theory, C ₂₇ H ₂₉ N ₇ ° 3 (499-6)

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

ESA Mass Spectrum: (M + HU = 500 (M + H + Na) ⁺⁺ = 261.8 (M + 2H) ⁺⁺ = 250.8

Example 59

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- | N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [L- (4-amidinophenyl) amino-methyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide .

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

ESA mass spectrum: (M + HU = 472 (M + H + Na) ⁺⁺ . = 247.6 (M + 2H) ⁺⁺ = 236.7 (M + 2Na) ~ = 258.6

Example 60.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-ylcarboxamide hydrochloride

a) N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 149a from 3- (4-cyanophenyl) -propionic acid and N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -3amino-4-methylamino-benzamide.

Yield: 22% of theory,

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

b) N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 85% of theory,

C ₂₈ H ₃₀ N ₆ O ₃ (498.6) N -value: 0.30 (silica gel; dichloromethane / methanol = 5: 1).

ESA mass spectrum: (M + HU = 499 (M + H + Na) ⁺⁺ = 261

Example 61

N- (2-pyridyl) -1H- (2-hydroxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-ethoxycarboxylethyl) 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 97% of theory,

C ₂₆ H ₂₆ N ₆ O ₃ (470.5)

ESA Mass Spectrum: (M + Well = 471 (M + H + Na) ⁺⁺ = 247 (M + Na) ⁺ = 493

Example 62

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [2- (4-amidino-phenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazole-

5-ylcarboxamide, ethanol 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).

ESA Mass Spectrum: (M + H = 498 (M + 2H) ⁺⁺ = 249.8 Example 63.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-methyl-2- [2- (4-amidino-phenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from L1-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 71% of theory, ^C 2 ₇ H ₂₇ N ₅ O ₃ (469.6)

ESA mass spectrum: (M + H = 470 (M + H + Na) ⁺⁺ = 246.6 (M + Na) ⁺ = 492 (Μ + 2H) '* = 235.6

Example 64.

N- (2-pyridyl) -N- (methoxycarbonylmethyl) -1-methyl-2- [N [- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide dihydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) N - (methoxycarbonylmethyl) 1-methyl-2- (4-cyanophenyl) amino-methyl] benzimidazol-5-ylcarboxamide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Yield: 73% of theory, C ₂₅ H ₂₅ N ₇ O ₃ (471.5)

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

ESA mass spectrum: (M + H = 472 (M + H + Na) ⁺⁺ = 247.8 Example 65.

N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) N- (2-methoxycarbonylethyl) 1-methyl-2- [N- (4-cyanophenyl) amino-methyl] benzimidazol-5-ylcarboxamide, methanolic 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 / methanol = 5: 1).

ESA mass spectrum: (M + H = 486 (M + H + Na) ** = 254.8

Example 66.

Ν-φβΗΗΠ-Ν- [2- (1H-tetrazol-5-yl) ethyl] 1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide hydrochloride

a) Ν-φεΗΗη-N- [2- (1H-tetrazol-5yl) ethyl] -1-methyl-2- [2- (4-cyanophenyl) ethyl] benzimidazol-5-ylcarboxamide

Prepared analogously to Example 25c from 3- (4-cyanophenyl) -propionic acid and N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -3-amino-4-methylamino-benzamide.

Yield: 67% of theory,

IR mass spectrum (KBr); characteristic bands at

3439.5 cm @ -1 (NH); 2235.5 cm- ¹ (C = H);

1631.6 spg ¹ (C = O)

b) N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-φββπ-N- [2- (1H-tetrazol-5-yl) ethyl] -1 methyl-2- [2- (4-cyanophenyl) ethyl] -benzimide

64588 Sol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 92% of theory,

C ₂₇ H ₂₇ N ₉ O (493.6)

ESA mass spectrum: (M + H / = 494 (M + Na) ⁺ = 516 (M + 2H) ⁺⁺ = 258.7

Example 67.

N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -1methyl-2-N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide and ethanol salt acid, ethanol and ammonium carbonate.

Yield: 29% of theory, C ₂₆ H ₂₆ N ₁₀ O (494.6)

ESA mass spectrum: (M + H / = 495 Example 68.

N- (2-pyridyl) -N- (2-n-hexyloxycarbonylethyl) -1-methyl-2- [L- (4-amide inophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

To about 30 ml of n-hexanol saturated with hydrogen chloride was added 0.60 ml (1.1 mmol) of N- (2-pyridyl) -N- (ethoxycarbonyl-ethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and stirred at room temperature for 19 h. The hexanol was then distilled in vacuo, the residue was stirred with 5 ml of 1N ammonia solution and concentrated again. The crude product thus obtained was purified by column chromatography (silica gel; dichloromethane / methanol = 5: 1).

Yield: 53% of theory,

C ₃ H ₃₇ N ₇ O ₃ (555.7) N -value: 0.36 (silica gel; dichloromethane / methanol = 5: 1).

ESA mass spectrum: (M + H / = 556

Example 69.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -Nmethylaminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

a) N- (2-pyridyl) N-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyanophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxamide

Obtained analogously to Example 25c from N (4-cyanophenyl) -N-methylglycine and N- (2-pyrrolidyl) N- (2-ethoxycarbonylethyl) -3-amino-4 methylamino-benzamide.

Yield: 71% of theory,

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

B) No. (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N - (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N (2-pyridyl) -N (2-ethoxycarbonylethyl) 1-methyl-2- (4- (cyanophenyl) N-methyl-aminomethyl] -benzimidazol-5-yl-carboxamide and ethanol salt acid, ethanol and ammonium carbonate.

Yield: 77% of theory, C _2g H ₃ , N ₇ O ₃ (513.6)

ESA mass spectrum: (M + H / = 514 (M + H + Na) ⁺⁺ = 268.7 Example 70.

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2-p4- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 26 of No. (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [14- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 66% of theory,

C ₂₆ H ₂₇ N ₇ O ₃ (485.6)

ESA mass spectrum: (M + H / = 486 (M + Na) ⁺ = 508 (M + 2Na) ⁺⁺ = 265.6

Example 71

B1-cyclopentyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) -ethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared in analogy to Example 25d of N-cyclopentyl-N (2-ethoxycarbonylethyl) 1-methyl-2- [2- (4-cyanophenyl) ethyl] -benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 65% of theory, C _2g H ₃₅ N ₅ O ₃ (489.6)

ESA Mass Spectrum: (M + Well = 490 Example 72.

N-cyclopentyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) -ethyl] benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 from Cyclopentyl-N (2-ethoxycarbonylethyl) 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzene34

64588

Yield: 85% of theory,

C ₂₅ H ₂₅ N ₇ O ₃ (471.5)

ESA mass spectrum: (M + HU = 472 (M + 2H) + = 236.6 (M + 2Na) ⁺⁺ = 258.6

Example 80

N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -N-methylaminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl- carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 64% of theory, C ₂₈ H ₃₁ N ₇ O ₃ (513.6)

ESA Mass Spectrum: (M + HF = 514 Example 81.

N- (3-pyridyl) -L- (2-hydroxycarbonylethyl) -1-methyl-2- [L1- (4-amidinophenyl) -L-methyl-aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 from L- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2-N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 70% of theory,

C ₂₆ H ₂₇ N ₇ O ₃ (485.6)

ESA mass spectrum: (M + HU = 486 (M + Na) ⁺ = 508 (M + 2Na) ⁺⁺ = 265.6

Example 82

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2-p4 [- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

a) N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-cyano-phenyl) -Nomethyl-aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 25c of N- (4-cyanophenyl) -N-methylglycine and N-phenyl-N- (2-ethoxycarbonylethyl) -3-amino-4-methylaminobenzamide

Yield: 71% of theory,

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

b) N-phenyl-N- (2-ethoxycarbonylethyl) 1-methyl-2- {1- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- {N- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid , ethanol and ammonium carbonate.

Yield: 74% of theory, ₂₉ n ₃ L ° 3 ( ⁵¹² · ⁶ )

ESA Mass Spectrum: (M + OU = 513 (M + H + Na) ⁺⁺ = 268 (M + 2H) ⁺⁺ = 257

Example 83

N- (phenyl) N - (2-hydroxycarbonylethyl) -1-methyl-2- | N- (4-amidinophenyl) -Nmethyl-aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 of N- (phenyl) -N (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidinophenyl) -Nmethyl-aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and sodium the basis.

Yield: 80% of theory,

C ₂₇ H ₂₈ N ₆ O ₃ (484.6)

ESA Mass Spectrum: (M + Well = 485 (M + H + Na) ⁺⁺ = 254 (M + Na) ⁺ = 507 (M + 2Na) ⁺ = 265

Example 84

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-ethyl-2- {N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-ethyl-2- [N (4-cyanophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid , ethanol and ammonium carbonate.

Yield: 85% of theory, C ₂₈ H ₃₁ N ₇ O ₃ (513.6)

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

ESA Mass Spectrum: (M + OU = 514 (Μ + Η + ΝβΓ = 268.6 (M + 2H) ⁺⁺ = 257.7

Example 85

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-ethyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide

Obtained analogously to Example 26 from N (2-pyridyl) -N (2-ethoxycarbonylethyl) 1-ethyl-2-p4- (4-amidinophenyl) -amino-methyl] midazol-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 89% of theory,

C _M H ₃₁ N ₅ O ₃ (461.6)

ESA Mass Spectrum: (M + Well = 462 (M + H + Nar = 242.6 (M + Na) ⁺⁺ = 484 (M + 2Na) ⁺⁺ = 231.6

Example 73

N-cyclopentyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [1 N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared in analogy to Example 25d of b1-cyclopentyl-b1- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-cyanophenyl) amino-methyl] benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 60% of theory, SACO, (490.6)

ESA Mass Spectrum: (M + HF = 491 Example 74.

N-cyclopentyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide

Obtained analogously to Example 26 from N-cyclopentyl-N- (2-ethoxycarbonylethyl) 1-methyl-2- [L- (4-amidinophenyl) amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 45% of theory,

C ₂₅ H ₃₀ N ₄ O ₄ (462.6)

ESA mass spectrum: (M + HU = 463 (M + H + Na) ⁺⁺ = 243 (M + Na) ⁺ = 485 (M + 2Na) ⁺⁺ = 254

Example 75

N- (2-pyridyl) -N- (2-ethoxycarbonylmethyl) -1-methyl-2- | 74- (4-amidinophenyl) -Nomethyl-aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N (2-pyridyl) -N- (2-ethoxycarbonylmethyl) 1-methyl-2- [74- (4-cyanophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 54% of theory,

C ₂₇ H ₂₉ N ₇ O ₃ (499.6)

ESA mass spectrum: (M + HU = 500 (M + 2H) ⁺⁺ = 250.7

Example 76

N (2-pyridyl) -N (hydroxycarboxylmethyl) -1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 26 of N (2-pyridyl) -N (ethoxycarbonyl methyl) -1 methyl-2- [14- (4-amidinophenyl) - N -methylaminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 68% of theory,

C ₂₅ H ₂ 5 ^N ₇ O ₃ < ⁴⁷¹ 5)

ESA Mass Spectrum: (M + Well = 472 (M + Na) ⁺ = 494 (M + 2Na) ~ = 258.6

Example 77

N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) -ethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N (3-pyridyl) -N (2-ethoxycarbonylethyl) 1-methyl-2- [2- (4-cyanophenyl) -ethyl] -benzimidazol-5-ylcarboxamide and ethanol 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).

ESA Mass Spectrum: (M + HF = 499 Example 78.

N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide dihydrochloride

Prepared analogously to Example 25d of N (3-pyridyl) -N (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] benzimidazol-5-ylcarboxamide and ethanol 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).

ESA Mass Spectrum: (M + HF = 500

Example 79

L1- (3-pyridyl) -L1- (2-hydroxycarbonylethyl) -1-methyl-2- | N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 from No. (3-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-ylcarboxamide dihydrochloride and sodium hydroxide.

benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 49% of theory,

C ₂₆ H ₂₇ N ₇ O ₃ (485.6)

ESA mass spectrum: (M + H = 486 (M + H + Na) ⁺⁺ = 254.6 (M + 2H) ⁺⁺ = 243.6 (M + 2Na) ⁺ = 265.7

Example 86

N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyano-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide and ethanol, hydrochloric acid, ethanol and ammonium carbonate.

Yield: 88% of theory,

C ₂₈ H ₂₉ FN ₆ O3 (516.6)

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

ESA Mass Spectrum: (M + H = 517 (M + H + Na) ⁺⁺ = 270 (M + 2H) ⁺⁺ = 259

Example 87

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

Prepared analogously to Example 26 from N- (2-fluorophenyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and sodium the basis.

Yield: 45% of theory,

C ₂₆ H ₂₅ FN ₆ O ₃ (488.5)

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

ESA Mass Spectrum: (M + well = 489 (M + H + Na) ⁺⁺ = 267 (M + 2H) ⁺⁺ = 256

Example 88

N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyano-phenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide and ethanol 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).

ESA mass spectrum: (M + H = 513 (M + H + Na) ⁺⁺ = 268

Example 89

N- (3-methylphenyl) -T4- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 from L- (3-methylphenyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 62% of theory, ^C 2 ₇ H ₂₈ FN ₆ O ₃ (484.6)

ESA Mass Spectrum: (M + Well = 485 (M + H + Na) ⁺⁺ = 254 (M + Na) ⁺⁺ = 507 (M + 2Na) ⁺⁺ = 265

Example 90.

N-phenyl-N- (2-ethoxycarbonylethyl) -1methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

1.1. g (2.06 mmol) Ν-φβΗΗπ-Ν- (2-β-oxicarbonylethyl) -1-methyl-2- [N- [4-amidinophenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride was dissolved in a mixture of 40 ml tetrahydrofuran 10 ml of water, then 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of n-hexyl ester of hydrochloric acid were added and stirred for 2 h at room temperature. The solvent was then distilled off, the residue was mixed with about 50 ml of saturated sodium chloride solution and the solution thus obtained was extracted three times with 20 ml of dichloromethane. The extracts were dried over sodium sulfate and concentrated. The crude material thus obtained was purified by column chromatography (100 g silica gel; dichloromethane + 5% ethanol).

Yield: 78% of theory, (626-8)

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

ESA mass spectrum: (M + HU = 627 (M + H + Na) ⁺⁺ = 325 (M + 2H) ⁺⁺ = 314

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Example 91

N-phenyl-N- (2-ethoxycarbonylethyl) -1methyl-2- [N- [4- (L-methoxy-carbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2 [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and methyl ester hydrochloric acid.

Yield: 41% of theory,

C ₃ oH ₃₂ N ₆ ° ₅ (556.6) N -value: 0.85 (silica gel; dichloromethane / ethanol = 4: 1)

ESA Mass Spectrum: (M + HU = 557 (M + H + Na) ⁺⁺ . = 290 (M + Na) ⁺⁺ = 579

Example 92.

N-phenyl-N- (2-methoxycarbonylethyl) -1 methyl-2- [N- [4- (1H-ethoxy-carbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 of N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-] carboxamide hydrochloride and ethyl ester of hydrochloric acid.

Yield: 62% of theory,

C ₃₀ H ₃₂ N ₆ O ₅ (556.6)

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

ESA Mass Spectrum: (M + OU = 557 (M + H + Na) ⁺⁺ = 290 (Μ + 2H) ⁺⁺ = 279

Example 93

N-Phenyl-N- (2-methoxycarbonylethyl) -1 methyl-2- [N- [4- (N-cyclohexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazole-

5-yl-carboxamide

Prepared in analogy to Example 90 of N-phenyl-L- (2-methoxycarbonylethyl) -1-methyl2- N- (4-amidinophenyl) amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and cyclohexyl ester of chlorochloride .

Yield: 25% of theory, ^C m ^H LOD610.7)

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

ESA Mass Spectrum: (M + well = 611 (Μ + 2H) ⁺⁺ = 306

Example 94

N-phenyl-L- (2-ethoxycarbonylethyl) -1methyl-2- [N- [4- [N- [2-methylsulfonyl] ethoxycarbonyl] amidino] phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from T4-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and 2- (methylsulfonyl) ) hydrochloric acid ethyl ester.

Yield: 66% of theory,

CANAS (648.8)

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

ESA Mass Spectrum: (M + HU = 649 (M + H + Na) ⁺⁺ = 336 (M + 2H) ⁺⁺ = 325

Example 95.

N-phenyl-N- (2-methoxycarbonylethyl) -1 methyl-2- [N- [4- (14-n-octyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazole-5-yl-carboxamide

Obtained analogously to Example 90 from N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [14- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and n-octyl hydrochloric acid ester.

Yield: 41% of theory, N, 0, (640.8)

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

ESA mass spectrum: (M + HU = 641 (M + Na) ⁺ = 663

Example 96

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [1- (4- (N-hydroxylamidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxamide

1.44 g (3.0 mmol) N-ββ-N- (2-β-oxicarbonylethyl) -1-3-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, 0.625 g (9.0 mmol) hydroxylamine hydrochloride and 0.425 g (4.0 mmol) sodium carbonate were dissolved in 80 ml of ethanol and refluxed for 7 h. An additional 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate were added, heated for a further 5 h and 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 thus obtained was purified by column chromatography (200 g silica gel, dichloromethane + 4% ethanol).

Yield: 39% of theory, ^C 2L <m (514.6)

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

ESA mass spectrum: (M + H / = 515 (M + Na) ⁺ = 537 (2M + H) ⁺ = 1029 (2M + Na) ⁺ = 1051

Example 97.

N-phenyl-T4- (2-methoxycarbonylethyl) -1 methyl-2- [b4- [4- (N-heptyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 of T4-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [L4- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and n-heptyl ester of hydrochloric acid.

Yield: 43% of theory,

C ₃₅ H ₄₂ N ₆ O ₅ (626.8)

Rf value: 0.40 (silica gel; dichloromethane / ethanol = 19: 1)

ESA Mass Spectrum: (M + H = 627 (M + H + Na) ⁺⁺ = 325 (M + Na) ⁺ = 649

Example 98

N-phenyl-N- (2-methoxycarbonylethyl) -1 methyl-2- [L- [4- (N-benzoyl-amidino) phenyl] aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 of N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [T4- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and benzoyl chloride.

Yield: 88% of theory, W & (588.7)

Rf-value: 0.37 (silica gel; dichloromethane / ethanol = 19: 1) 'H-NMR-spectrum (D ₆ -DMSO): 2.61 (t, 2H), 3.54 (s, H), 3.76 (s, H), 4.10 (t, 2H),

4.61 (d, 2H), 6. 83 (d, 2H), 7.05 to 7.55 (t, 12H), 8.03 (d, 2H), 8.25 (dd, 2H), 8.98 (s, 1H),

10.48 (s, 1H), 10.48 (s, 1H).

Example 99

N-phenyl-N- (2-methoxycarbonylethyl) -1 methyl-2- [N- [4- (1H-n-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and n-hexyl hydrochloric acid ester.

Yield: 54% of theory, <^ N, 0, (612.7)

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

ESA Mass Spectrum: (M + Well = 613 Example 100.

14-phenyl-N- (2-p-propyloxycarbonylethyl) -1-methyl-2- [N- [4- (N-p-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from N-phenyl-N- (2-n-propyloxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and n-hexyl ester hydrochloric acid.

Yield: 31% of theory,

C ₃₆ NL ₆ O ₅ (640.8),

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

ESA Mass Spectrum: (M + H = 641 (M + H + Na) ⁺⁺ = 332 (M + Na) ⁺ = 663 Example 101.

N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -N- (2-methoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and Hydrochloric acid ethyl ester.

Yield: 72% of theory,

C ₂₉ H ₃₁ N ₇ O ₅ (557.6)

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

ESA Mass Spectrum: (M + H = 558 (M + H + Na) ** = 290.8 (M + Na) ⁺ = 580

Example 102

N- (2-pyridyl) -1H- (2-methoxycarbonylethyl) -1-methyl-2- [N- [4- (N-octyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol5-yl-carboxamide

64588

Prepared analogously to Example 90 of L- (2-pyridyl) -L- (2-methoxycarbonylethyl) -1 methyl-2- [N- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and Hydrochloric acid n-octyl ester.

Yield: 57% of theory,

C ₃₅ H ₄₃ N ₇ O ₅ (641.8)

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

ESA mass spectrum: (M + HU = 642 (M + H + Na) ⁺⁺ = 332.8 (M + Na) ⁺ = 664

Example 103

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [B1- [4 - [(methoxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N (2-pyridyl) -N (2-ethoxycarbonylethyl) -1 methyl-2- | N- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and methyl ester of hydrochloric acid.

Yield: 48% of theory, ε ^, Ν, Ο, (557.6)

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

ESA mass spectrum: (M + HU = 558 (Μ + H + Na) ⁺⁺ = 290.7 (M + Na) ⁺ = 580

Example 104

N- (2-pyridyl) -N (2-hydroxycarbonylethyl) -1-methyl-2- {N- [4- (N-octyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

0.7 g (1.1 mmol) N- (2-methylphenyl) -N- (2-methoxycarbonylethyl) -1-ββΜπ-2- [N- [4- (Ν-η-κyloxycarbonylamidino) phenyl] -amino-methyl] -benzimidazole -5-yl-carboxamide was stirred in a mixture of 0.12 g (3.0 mmol) of sodium hydroxide, 5 ml of water and 10 ml of methanol for 1 h at room temperature. It is then diluted with 20 ml of water and adjusted to pH 6 with glacial acetic acid. About 5 ml of diethyl ether are added and stirred vigorously for 1 hour. The precipitated product is filtered off, washed with a little water and then with diethyl ether and dried.

Yield: 80% of theory,

C ₃ H ₄₁ N ₇ O ₅ (627.8)

ESA mass spectrum: (M + HU = 628 (M + H + NaF = 325.7 (M + Na) ⁺ = 650 (M + 2Na) ⁺⁺ = 337.7

Example 105.

N (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2-N- [4-N- (2-methylsulfonylethyloxycarbonyl) amidino] phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and 2- (Methylsulfonyl) ethyl ester of chloroformic acid.

Yield: 65% of theory, C ₃₁ H ₃₅ N ₇ O ₅ (649.7)

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

ESA Mass Spectrum: (M + Well = 650 (M + H + Na) ⁺⁺ = 336.6 (M + Na) ⁺ = 672 (M + 2Na) ⁺⁺ = 347.6

Example 106.

N (2-pyridyl) -N (2-methoxycarbonylethyl) -1-methyl-2- [N- [4- (N-p-butyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol5-yl-carboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -N (2-methoxycarbonylethyl) -1-methyl-2- {N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and n hydrochloric acid butyl ester.

Yield: 30% of theory, C ₃₁ H ₃₅ N ₇ O ₅ (585.7)

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

ESA Mass Spectrum: (M + H = 586 (M + H + Na) ⁺⁺ = 304.7 (Μ + 2H) ⁺⁺ = 293.7

Example 107.

N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- (N) [4- (N-n-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 of N (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2-N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and n- hydrochloric acid hexyl ester.

Yield: 51% of theory,

C ₃₃ H ₃₉ N ₇ O ₅ (613.7)

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

ESA mass spectrum: (M + H = 614 (M + H + Na) ⁺⁺ = 318.7 (M + 2H) ⁺⁺ = 307.6

Example 108.

N- (2-pyridyl) -1H- (2-methoxycarbonylethyl) -1-methyl-2- [N- [4- (N-heptyloscarbonylamidino) phenyl] -aminomethyl] -benzimidazol5-yl-carboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- {74- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and n-heptyl ester of chloroformic acid.

Yield: 21% of theory,

C ₃₄ H ₄₁ N ₇ O ₅ (627.8)

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

ESA mass spectrum: (M + H = 628 (M + H + Na) ** = 325.7 (M + 2H) ⁺⁺ = 314.7

Example 109.

N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- [14- [4- (N-pentyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and Chloroformic acid n-pentyl ester.

Yield: 66% of theory,

C ₃₂ H ₃₇ N ₇ O ₅ (599.7)

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

ESA Mass Spectrum: (M + Well = 600 (M + H + Na) ⁺⁺ = 311.7 (M + Na) ⁺ = 622

Example 110.

N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- [T4- [4- (N-nonyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol5-yl-carboxamide

Prepared in analogy to Example 90 from N- (2-pyridyl) -N- (2-methoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and hydrochloric acid p-nonyl ester.

Yield: 60% of theory,

C ₃₆ H ₄₅ N ₇ O ₅ (655.8)

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

ESA Mass Spectrum: (M + Well = 656 (M + H + Na) ⁺⁺ = 339.8 (M + Na) ⁺ = 678

Example 111

N- (2-pyridyl) -N (2-methoxycarbonylethyl) -1-methyl-2- [N- [4- (N-benzoylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from N (2-pyridyl) -N- (2-methoxycarbonylethyl) 1-methyl-2- (4- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and benzoyl chloride .

Yield: 62% of theory,

C ₃₃ H ₃₁ N ₇ O ₄ (589.7)

Rf value: 0.50 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + H 2 = 590 (M + Na) ⁺ = 612 Example 112.

N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -1-methyl-2- [N- [4- [nicotinoylamidino] phenyl] -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 of N (2-pyridyl) -N- (2-methoxycarbonylethyl) 1-methyl-2- {N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and nicotinoyl chloride.

Yield: 40% of theory,

C ₃₂ H ₃₀ N ₈ O ₄ (590.7)

Rf value: 0.47 (silica gel; dichloromethane / methanol = 9: 1)

ESA Mass Spectrum: (M + Well = 591 (M + H + Na) ⁺⁺ = 307 (M + Na) ⁺ = 613

Example 113.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [) N- [4- (N-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 of N (2-pyridyl) -1 N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and hydrochloric acid n-hexyl ester.

Yield: 51% of theory,

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C ₃₄ H ₄₁ N ₇ O ₅ (627.8)

Rf value: 0.53 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + H = 628 (M + H + Na) ⁺⁺ = 325.7 (M + 2H) ⁺⁺ = 314.7

Example 114

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [4- (N-octyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol5-yl-carboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and Hydrochloric acid n-octyl ester.

Yield: 57% of theory,

Sb ^H « ₅ X ₇ O ₅ (655.8)

Rf value: 0.46 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + H = 656 (M + H + Na) * ⁴ = 339.7 (M + 2H) ⁺⁺ = 328.7

Example 115.

N- (2-pyridyl) -N- (2-ethoxycarbonylmethyl) -1-methyl-2-N- [4- [N- (2-methylsulfonylethyloxycarbonyl) amidino] phenyl] -aminomethyl] benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -1methyl-2- [N (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and 2- (methyl -sulfonyl) hydrochloric acid ethyl ester.

Yield: 72% of theory,

C ₃₀ H ₃₃ N ₇ O ₇ S (635.7)

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

ESA mass spectrum: (M + H = 636 (M + H + Na) ⁺⁺ = 329.8

Example 116.

N- (2-pyridyl) -N-methoxycarbonylmethyl-1-methyl-2- [L- [4- (N-cyclohexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -L-methoxycarbonylmethyl-1-methyl-2- [1- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and cyclohexyl ester of hydrochloric acid.

Yield: 40% of theory,

C ₃₂ H ₃₅ N ₇ O ₅ (597.7)

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

ESA Mass Spectrum: (M + H = 598 (M + Na) ⁺ = 620

Example 117.

N- (2-pyridyl) N-ethoxycarbonylmethyl-1-methyl-2-N- [4-N-methoxycarbonylamidino) phenyl] -aminomethyl] -benzimidazole-5-yl-carboxamide

Prepared in analogy to Example 90 of N (2-pyridyl) -N-ethoxycarbonylmethyl-1 methyl-2- [N- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and hydrochloric acid methyl ester .

Yield: 62% of theory, C ₂₈ H ₂₉ N ₇ O ₅ (543.6)

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

ESA mass spectrum: (M + HU = 544 (M + H + Nap = 283.8 (M + Na) ⁺ = 566

Example 118.

N- (2-pyridyl) -Nomethoxycarbonylmethyl-1-methyl-2- [N- [4- [ethoxycarbonylamidino] phenyl] -aminomethyl] -benzimidazole-5-yl-carboxamide

Prepared in analogy to Example 90 of N (2-pyridyl) -N-methoxycarbonylmethyl-1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and hydrochloric acid ethyl ester.

Yield: 42% of theory,

C ₂₈ H ₂₉ N ₇ O ₅ (543.6)

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

ESA Mass Spectrum: (M + HF = 544 Example 119.

N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -1-Menw-2- [N- [4- (N-n-oxoalkylcarbonylamino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared in analogy to Example 90 of N- (3-pyridyl) -N (2-ethoxycarbonylethyl-1 methyl-2- (Y4- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and n- hydrochloric acid octyl ester.

Yield: 3.5% of theory,

C ₃₆ H ₄₅ N ₇ O ₅ (655.8)

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

ESA Mass Spectrum; (M + OU = 656 (M + 2H) ⁺⁺ = 328.7 Example 120.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [4- (N-p-hexyloxycarbonylamidino) phenyl] -N-methylaminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from N- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl- carboxamide hydrochloride and n-hexyl ester of hydrochloric acid.

Yield: 58% of theory,

C „H _4J N ₇ O ₅ (641.2)

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

ESA mass spectrum: (M + H = 642 (M + H + Na) ⁺⁺ = 332.7

Example 121.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [T <- [4- (N-octyloxycarbonylamidino) phenyl] -N-methylaminomethyl] -benzimidazol-5-yl- carboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- (N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl- carboxamide hydrochloride and chloroformic acid n-octyl ester.

Yield: 36% of theory, C ₃₇ H ₄₇ N ₇ O ₅ (669.8)

ESA mass spectrum: (M + HU = 670 (M + H + Na) ~ = 346.8 (Μ + 2H) ⁺⁺ = 335.6

Example 122.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [4- (N-butyloxycarbonylamidino) phenyl] -Nmethylaminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -L1 [- (2-ethoxycarbonylethyl-1-methyl-2- [14- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and n-butyl ester of hydrochloric acid.

Yield: 34% of theory,

C 'H ₃₉ N ₇ O ₅ (613.7)

ESA mass spectrum: (M + H = 614 (M + H + Na) ⁺⁺ = 318.7 (M + Na) ⁺ = 636 Example 123.

N- (2-pyridyl) -14- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [4- (1H-benzoylamidino) phenyl] -N-methylaminomethyl] -benzimidazole-5-yl-carboxamide

Prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl-1-methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and benzoyl chloride.

Yield: 63% of theory,

C ₃₅ H ₃₅₁ N ₇ O ₅ (617.7) ESA mass spectrum: (M + H 2 = 618 (M + H + Na) ⁺⁺ = 320.7 (M + Na) ⁺ = 640 Example 124.

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

a) 4-Chlorophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -ketone

8.4 g (40 mmol) of 3- (4-chlorobenzoyl) propionic acid were dissolved in 300 ml of THF and 5.8 g (120 mmol) of sodium hydride (50-60% suspension in paraffin oil) were added in portions. The mixture was then heated under reflux for 1.5 h, then 8.9 ml (60 mmol) were added dropwise.

1,5-diiodopentane and heated for 3 h. After cooling, the solution was poured under stirring in 200 ml of ice water, then the tetrahydrofuran was distilled in vacuo, the resulting aqueous solution was acidified with 2N hydrochloric acid and extracted three times with 150 ml of dichloromethane. The organic phase was dried and concentrated, and the crude product thus obtained was purified by column chromatography (500 g silica gel; eluent: dichloromethane with 1 -2% ethanol).

Yield: 6.2 g (55% of theory) of an oily product,

C ₁₅ H ₁₇ ClO ₅ (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 4-chlorophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -ketone are stirred at -5 to -10 ° C in portions of 80 ml of fuming nitric acid.

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It is then stirred for a further 10 min, then the solution is added with stirring in 200 ml of ice water, the precipitated precipitate is washed with water and dried.

Yield: 7.8 g (96% of theory),

C ₁₅ H ₁₆ C1NO ₅ (325.8)

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

c) 4-methylamino-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) ketone

7.8 g (23.9 mmol) of 4-chloro-3-nitrophenyl (1-hydroxycarbonyl-methyl-cyclohex-1-yl) ketone were stirred in 100 ml of 40% aqueous methylamine at room temperature for 14 h, after this is diluted with about 150 ml of water and slightly acidic pH is made with glacial acetic acid. The precipitated product was filtered off, washed with water and dried.

Yield: 7.1 g (93% of theory),

C ₁₆ H _m N ₂ O ₅ (320.4)

Rf value: 0.34 (silica gel; dichloromethane / ethanol -19: 1)

d) 4-methylamino-3-nitrophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone

4.9 g, (15 mmol) of 4-methylamino-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohexyl-yl) ketone was dissolved in 100 ml of tetrahydrofuran, 2.4 g (15 mmol) of N, N-carbonyldiimidazole were added and heated for 15 min. under reflux. The solvent was then evaporated, 30 ml of methanol was added and heated with stirring for 3 hours. After distilling the methanol, the crude product thus obtained was purified by column chromatography (250 silica gel; eluent: dichloromethane with 1 to 5% ethanol).

Yield: 2.4 g (48% of theory),

C _{| 7} H ₂₂ N ₂ O ₅ (334.4)

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

e) 3-amino-4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone

2.4g (7.2 mmol) of 4-methylamino-3-nitrophenyl- (1-methoxy-carbonylmethylcyclohex-1-yl) ketone was catalytically hydrogenated in 100 ml of methanol at room temperature and 5 bar of hydrogen pressure (10% palladium on carbon). The crude material thus obtained was further used without purification.

Yield: 2.1 g (96% of theory),

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

1) 3- (4-cyanophenyloxyacetylamino) -4methylaminophenyl- (1-methoxycarbonylmethylcyclohex-1-yl) ketone

620 mg (3.5 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of Γcarbonyldiimidazole were heated for 15 min in 50 ml of THF. 1.0 g (3.28 mmol) of 3-amino-4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -ketone are then added and the mixture is further boiled for 4 hours. The solvent was then evaporated and the crude material thus obtained was purified by column chromatography (150 g silica gel; eluent: dichloromethane with 0 to 2% ethanol).

Yield: 1.4 g (93% of theory), ^C 26 ^H 29 ^N 3 ° 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 were heated in reflux for 50 ml with glacial acetic acid. The glacial acetic acid was then distilled off, the residue was mixed with 20 ml of water and basified with concentrated ammonia. This solution was extracted three times with 20 ml of dichloromethane each, the organic extracts were dried and concentrated. The crude material thus obtained was purified by column chromatography (100 g silica gel; eluent: dichloromethane with 0 to 2% ethanol).

Yield: 700 mg (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

Prepared analogously to Example 25d of 700 mg (1.57 mmol) of 1-methyl-2- (4-cyanophenyloxymethyl) benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) ketone with ethanolic hydrochloric acid and ammonium carbonate .

Yield: 390 mg (50% of theory),

C ₂₇ H ₃₂ N ₇ O ₄ (476.6)

ESA Mass Spectrum: (M + H = 477

Ή-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), 7.25-7.40 (m, 3H), 7.56-7.75 (m, 2H), 7.90 (d. 2H), 9.20 (broad s, 4H) ppm.

Example 125.

1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-tert-butyl-ketone hydrochloride

Prepared in analogy to Example 25d of 1-methyl-2- | N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl-tert-butyl ketone, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 59% of theory, C ₂₁ H ₂₅ N ₅ O (363.5)

ESA Mass Spectrum: (M + H = 364 Example 126.

1-Methyl-2- {1- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl- (1-methylcyclopent-1-yl) ketone hydrochloride

Prepared analogously to Example 25d of 1-methyl-2- | N- (4-cyanophenyl) aminomethyl] benzimidazol-5-yl- (1-methylcyclopent-1-yl) ketone, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 63.5% of theory, C ₂₃ H ₂₇ N ₅ O (389.5),

ESA Mass Spectrum: (M + Well = 390 Example 127.

N-phenyl-N- (2-ethoxycarbonylethyl) -2 [(4-amidinophenyl) -sulfinylmethyl] -benzthiazol-5-ylcarboxamide hydrochloride

A solution of 0.15 g (0.27 mmol) of N-phenylH- (2-ethoxycarbonylethyl) -2 - [(4-amidinophenyl) -thiomethyl] -benzthiazol-5-ylcarboxamide hydrochloride in 10 ml of acetic acid was mixed with 0.09 ml (about 0.81 mmol ) 30% hydrogen peroxide solution and stirred at room temperature. After 4 days, another 0.18 ml of hydrogen peroxide solution was added and stirred for another 2 days. After removal of the solvent in vacuo, the crude material obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 10: 1 to 4: 1).

Yield: 58% of theory.

^С 27 ^Н 2бЧ ° Д (534.66)

Rf value: 0.24 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of acetic acid)

ESA mass spectrum: (M + HF = 535

Example 128.

N- (n-naphthyl) -N- (2-ethoxycarbonylmethyl) -1-methyl-2 - [(4-amidinophenyl) sulfonylmethyl] -benzimidazol-5-ylcarboxamide hydrochloride

A solution of 0.40 g (0.70 mmol) of N- (η-π-propyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4amidinophenyl) -thiomethyl] -benzimidazol-5-ylcarboxamide hydrochloride in 10 ml of formic acid mixed with 2 ml of 30% hydrogen peroxide solution and stirred at room temperature for 16 h. The solvent was then distilled off in vacuo to give the desired compound as a beige solid (contaminated with a small amount of N- (n-phenyl) -N (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-amidinophenyl) - sulfinylmethyl] -benzimidazole-5-yl-carboxamide hydrochloride.

Yield: 95% of theory.

C ₂₅ H ₃₁ N ₆ O ₅ S (513.62)

Rf value: 0.50 (silica gel; ethyl acetate / ethanol / 1N hydrochloric acid = 50: 45: 5)

ESA Mass Spectrum: (M + H = 514 Example 129.

N (phenyl) -N- (2-ethoxycarbonylethyl) -2 | N- (4-amidinophenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-ylcarboxamide hydrochloride

a) 5-Amino-6-chloronicotinic acid methyl ester

A solution of 1.08 g (5.00 mmol) of 6-chloro-5-nitronicotinic acid methyl ester (see AN Berrie, GT Newbold, FS Sppring 2590, 1951) in 25 ml of absolute ethanol is mixed sequentially with 0.53 ml. (29 mmol) of water, 3.2 g (57 mmol) of iron powder and 0.030 ml of concentrated hydrochloric acid and heated at reflux for 1 h. Once again, the same amounts of water, iron powder and hydrochloric acid were added and heated at reflux for 30 minutes. The precipitate which falls on cooling is filtered off, washed with water and the solvent is evaporated in vacuo.

Yield: 0.75 g (81% of theory) of a yellow-green solid.

Rf value: 0.31 (silica gel; ethyl acetate / petroleum ether = 1: 4)

C ₇ H ₇ C1N ₂ O ₂ (186.60)

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YEF mass spectrum: ΝΓ = 186 and 188 (chlorine isotopes)

b) 6-Chloro-5-methoxyacetamidonicotinic acid methyl ester

A solution of 0.75g (4.02 mmol) of 5-amino-6-chloronicotinic acid methyl ester and 0.43 g = 0.35 ml (4.5 mmol) of methoxyacetyl chloride in 20 ml of chlorobenzene was stirred for one hour at 110 ° C. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 100: 1), concentrated again in vacuo and then digested with petroleum ether.

Yield: 0.55 g (53% of theory) of a light yellow amorphous solid.

N -value: 0.33 (silica gel; ethyl acetate / petroleum ether = 1: 4)

c) 2-Methoxymethylthiazolo [5,4-b] pyridin-6-ylcarboxylic 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 was heated for 16 hours in 25 ml of xylene under reflux. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 100: 1) and concentrated again in vacuo.

Yield: 0.33 g (67% of theory) yellow amorphous solid.

Rf value: 0.52 (silica gel; ethyl acetate / petroleum ether = 1: 4)

d) 2-methoxymethylthiazolo [5,4-b] pyridin-6-ylcarboxylic acid

A mixture of 1.1 g (4.62 mmol) of 2-methoxy-methylthiazolo [5,4-b] pyridine-6-ylcarboxylic acid methyl ester and 9.2 ml of 2N sodium hydroxide in 50 ml of ethanol was stirred for 1 h at room temperature, then 9.2 was added ml of 2N hydrochloric acid, the alcohol is distilled and diluted with 20 ml of water. The aqueous phase was acidified with concentrated hydrochloric acid under ice-cooling, and the precipitated beige was filtered off, then washed with water and dried.

Yield: 1.03 g (100% of theory),

Rf value: 0.10 (silica gel; ethyl acetate / petroleum ether = 3: 7)

e) N-phenyl-N- (2-ethoxycarbonylethyl) -2 methoxymethyl-thiazolo [5,4-b] pyridin-6-ylcarboxamide

A suspension of 1.03 g (4.62 mmol) of 2-methoxymethyl-thiazolo- [5,4-b] pyridin-6-ylcarboxylic acid in 40 ml of methylene chloride was mixed with 1.6 g = 1.0 ml (13.5 mmol) of thionyl chloride and heated for 90 minutes under reflux, the solid being gradually dissolved. After distillation of the liquid components, the crude product was redissolved twice more in methylene chloride and concentrated again. The crude acid chloride thus obtained (1.2 g) was dissolved in 40 ml of tetrahydrofuran, added dropwise to a mixture of 0.94 g (4.86 mmol) of N- (2-ethoxycarbonylethyl) aniline and 2.1 ml (13.8 mmol) of triethylamine in 30 ml of tetrahydrofuran and stirred for 2 h at room temperature. It is then diluted with 200 ml of ethyl acetate, washed with 100 ml of a 14% solution of cooking salt and the organic phase is dried with 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: 1.57 g (87% of theory) of a yellow oil.

Rf value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1)

f) N- (phenyl) -T4- (2-ethoxycarbonylethyl) -2- [N- (4-cyanophenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-ylcarboxamide

Mixture of 1.54 g (3.85 mmol) of N-phenyl-N (2-ethoxycarbonylethyl) -2-methoxymethyl-thiazolo [5,4-b] pyridin-6-ylcarboxamide and 4.3 ml (4.3 mmol) of a one-molar solution of boron tribromide in methylene chloride was dissolved in another 30 ml of methylene chloride and stirred at room temperature for 5 hours. It is then washed with 40 ml of saturated sodium bicarbonate solution, the organic phase is dried with sodium sulfate and the solvent is distilled off. The crude product (1.9 g) was dissolved in 15.0 ml of N, N-diisopropylethylamine, mixed with 0.50 g (4.2 mmol) of 4-aminobenzonitrile and heated to reflux for 1 h. The solvent was then distilled in vacuo, the crude product was dissolved in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried with sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate / petroleum ether = 35:65 to

1: 1) and again concentrated in vacuo.

Yield: 0.45 g (24% of theory) yellow amorphous solid,

Rf value: 0.34 (silica gel; ethyl acetate / petroleum ether = 1: 1)

g) N- (phenyl) -N- (2-ethoxycarbonylethyl) -2- N- (4-amidino-phenyl) -aminomethyl] -thiazolo [5,4-b] pyridin-6-ylcarboxamide hydrochloride

0.39 g (0.803 mmol) N- (φβΗΗπ) -N- (2ethoxycarbonylethyl) -2- [N- (4-cyanophenyl) aminomethyl] -thiazolo [5,4-b] pyridin-6-ylcarboxamide was stirred in 40 ml of sat. with hydrogen chloride ethanol for 5 hours, first at 0 ° C and then at room temperature, until no longer starting material can be detected by thin layer chromatography. The solvent was then distilled at a maximum of 30 ° C in the water bath, the oily residue was dissolved in 40 ml of absolute ethanol and mixed with 0.5 g of ammonium carbonate. After 18 h, 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: 78% of theory, yellow foam,

C2 ₆ H ₂₆ N ₆ O ₃ S (502.60)

Rf value: 0.19 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of ethyl acetate)

ESA Mass Spectrum: (M + Well = 503

Example 130.

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2 - [(4-amidino-phenyl) -methylthio] -benzimidazol-5-ylcarboxamide hydrochloride) N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl- 2mercapto-benzimidazol-5-ylcarboxamide

A solution of 6.5 g (19 mmol) Ν-φβΗΗΠ-Ν (2-ethoxycarbonylethyl) -3-amino-4-methylamino-benzamide and 4.5 g (22.8 mmol) of N, N-thiocarbonyldiimidazole was dissolved under nitrogen in 100 ml of tetrahydrofuran , heated for 4 h to 90 ° C and allowed to stand at room temperature for 16 h. After removal of the solvent in vacuo, the crude product obtained was purified by flash chromatography (silica gel; petroleum ether / ethyl acetate = 100: 0 to 65:35).

Yield: 6.8 g (93% of theory) beige crystalline solid,

Rf value: 0.55 (silica gel; ethyl acetate)

b) N-phenyl-N- (2-ethoxycarbonylethyl) 1-methyl-2 - [(4-cyano-phenyl) -methylthio] -benzimidazol-5-ylcarboxamide

A solution of 1.30 g (3.4 mmol) of N-phenyl N- (2-ethoxy carbonyl ethyl) -1-meth-2-mercapto-benzimidazol-5-ylcarboxamide, 0.52 g (3.74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) 4-Bromomethylbenzonitrile in 40 ml absolute ethanol was stirred for 4 hours at 60 ° C and 16 hours at room temperature. The solvent was then distilled in vacuo, the crude product was dissolved in 30 ml of methylene chloride, washed with 40 ml of water and dried with sodium sulfate. After filtration and distillation of the solvent, the desired compound is obtained as a beige-white solid.

Yield: 1.8 g (100% of theory),

Rf value: 0.64 (silica gel; ethyl acetate)

c) N-phenyl-N- (2-ethoxycarbonylethyl) 1-methyl-2 - [(4-amidino-phenyl) -methylthio] -benzimidazol-5-ylcarboxamide hydrochloride

1.5 g (3.0 mmol) of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2 - [(4-cyanophenyl) methylthio] benzimidazol-5-ylcarboxamide was stirred in 80 ml of hydrogen chloride-saturated ethanol for 6.5 hours. h at 0 ° C first and then at room temperature until no more starting material can be detected by thin layer chromatography. The solvent was then distilled at a maximum of 30 ° C in the water bath, the oily residue was dissolved in 80 ml of absolute ethanol and mixed with 1.0 g (10.5 mmol) of ammonium carbonate. After 18 h, the solvent was removed in vacuo and the crude product obtained was purified by flash chromatography (silica gel; methylene chloride / ethanol = 19: 1 to 10: 1).

Yield: 78% of theory, light beige solid,

C ₂₈ H ₂₉ N _s O ₃ S (515.63)

Rf value: 0.19 (silica gel; methylene chloride / ethanol = 4: 1 + a few drops of ethyl acetate)

ESA mass spectrum: (M + H = 516 (M + H + Na) ⁺⁺ = 269.7 (M + 2H) ⁺⁺ = 258.7

Example 131.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-methyl-2 - [(4-amidino-phenyl) -methylthio] -benzimidazol-5-ylcarboxamide hydrochloride

64588

Prepared analogously to Example 10 of N-phenyl-L4- (2-ethoxycarbonylethyl) -1-methyl-2 [(4-amidinophenyl) methylthio] -benzimidazole-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 57% of theory, C ₂₆ H ₂₅ N ₅ O ₃ S (487.58)

Rf value: 0.23 (reverse phase silica gel RP-8; methanol / 5% salt solution = 6: 4)

ESA Mass Spectrum: (M + H = 488 (M + Na) ⁺ = 510 (M + H + Na) ⁺⁺ = 255.6 Example 132.

N-propargyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-propargyl-N- (2-ethoxycarbonylethyl) -1methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 81% of theory, C ₂₅ H ₂₈ N ₆ O ₃ (460.6)

Rf value: 0.094 (silica gel; dichloromethane / ethanol = 4: 1)

ESA mass spectrum: (M + H = 461 (M + H + Na) ⁺⁺ = 242 (M + 2H) ⁺⁺ = 231 Example 133.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- [4- (L-p-hexyloxycarbonylamidino) phenyl] -ethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxamide hydrochloride and n Hydrochloric acid hexyl ester.

Yield: 72% of theory, C ₃₅ H ₄₂ N ₆ O ₅ (626.8)

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

ESA mass spectrum: (M + H 2 = 627 (M + Na) ⁺ = 649 Example 134.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- [4- (N-benzoylamidino) phenyl] -ethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 90 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxamide hydrochloride and benzoyl chloride .

Yield: 79% of theory, C ₃₅ H ₃₄ N ₆ O ₄ (602.7)

Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + HU = 603 (M + Na) ⁺ = 625

Example 135.

N- (2-pyridyl) N- (2-ethoxycarbonylethyl) -1-methyl-2- [2- [4- (N-nicotinoylamidino) phenyl] -ethyl] -benzimidazol-5-yl-carboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [2- (4-amidinophenyl) -ethyl] -benzimidazol-5-yl-carboxamide hydrochloride and nicotinoyl chloride.

Yield: 56% of theory, C ₃₄ H ₃₃ N ₇ O ₄ (603.7)

Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + HU = 604 (M + Na) ⁺ = 626 Example 136.

N-phenyl-N- (2-ethoxycarbonylethyl) -1-cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-L- (2-ethoxycarbonylethyl) -1-cyclopropyl-2- [N- (4-cyanophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 31% of theory,

C _M H ₆ O ₃ (524.6)

Rp value: 0.40 (silica gel; dichloromethane / methanol = 5: 1)

ESA mass spectrum: (M + HU = 525 (M + H + Na) ⁺⁺ = 274 (M + 2H) ⁺⁺ = 263

Example 137.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 of N-phenyl-N (2-ethoxycarbonylethyl) -1-cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide. Yield: 64% of theory,

C ₂₈ H ₂₈ N ₆ O ₃ (496.6)

ESA Mass Spectrum: (Μ + Hy = 497 (Μ + Η + NaF = 260 (Μ + Na) ⁺ = 519 (Μ + 2Na) ⁺⁺ = 271

Example 138.

N-phenyl-L- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidinophenyl) -N- (n-butyl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyanophenyl) -N (n-butyl) -aminomethyl] -benzimidazol-5-yl- carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 31% of theory,

C ₃₂ H ₃₈ N ₆ O ₃ (554.7)

ESA Mass Spectrum: (M + Well = 555 (M + H + Na) ⁺⁺ - = 289 (M + 2H) ⁺⁺ = 278

Example 139.

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidino-2-chlorophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared in analogy to Example 25d of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- {1- (4-cyano-chlorophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 82% of theory, C ₂₈ H ₂₉ C1N ₆ O ₃ (533.1) ECA mass spectrum: (M + HU = 533/5 (M + H + Na) ⁺⁺ = 278/9

Example 140.

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- [4- (n-octyloxycarbonylamidino) phenyl]) -aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of T4-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -amino-methyl] benzimidazol-5-yl-carboxamide hydrochloride and n-octyl hydrochloric acid ester.

Yield: 34% of theory,

C ₃₇ H ₄₆ N ₆ O ₅ (654.8)

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

ESA mass spectrum: (M + HU = 655 (M + H + Na) ⁺⁺ = 339 (M + Na) ⁺ = 677

Example 141.

N-phenyl-N (2-ethoxycarbonylethyl) -1-methyl-2- {N- (4-amidino-2-ethylphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N (2-ethoxycarbonylethyl) -1-methyl-2- {1- (4-cyano-2-ethylphenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 61% of theory, ^C ₃ ^H ₃ ^N ° ₃ (526.6)

ESA Mass Spectrum: (M + Well = 527 (M + H + NaF = 275 (M + 2H) ⁺⁺ = 264

Example 142.

N-benzyl-1-methyl-2- {4- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N-benzyl-1-methyl-2- [14- (4-cyanophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 63% of theory,

C ₂₄ H ₂₄ N ₆ O (412.5)

Rf value: 0.76 (silica gel; dichloromethane / ethanol = 4: 1)

ESA Mass Spectrum: (M + H = 413 Example 143.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [4- (4- (2- (2-ethoxyethoxy) ethyloxy) carbonylamidino) phenyl] -aminomethyl] -benzimidazole-5 -carboxamide

Prepared analogously to Example 90 of N (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- {74- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-ylcarboxamide hydrochloride and ester hydrochloric acid and diethylene glycol monoethyl ether.

Yield: 43% of theory,

C ₃₄ H ₄₁ N ₇ O ₇ (659.8)

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

ESA mass spectrum: (M + h = 660 (M + H + Na) ⁺⁺ = 341.7 Example 144.

N (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -1-methyl-2-N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylcarbox49

64588 Samide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-cyanophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide, ethanol, hydrochloric acid, ethanol and ammonium carbonate.

Yield: 60% of theory.

C ₂₆ H ₃₀ N ₈ O ₃ (502.6)

Rf value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1)

ESA Mass Spectrum: (M + Well = 503 (M + H + Nap = 263 (M + 2H) ⁺⁺ = 252

Example 145.

N-phenyl-N- (2-ethoxycarbonylethyl) -3methyl-2 - [(4-amidinophenyl) -thiomethyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride

Prepared analogously to Example 1 of N-phenyl-N- (2-methoxycarbonylethyl-3-methyl2 - [(4-cyanophenyl) thiomethyl] -imidazo [4,5b] pyridin-6-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 88% of theory,

C ₂₇ H ₂₈ N ₆ O ₃ S (516.63)

Rf value: 0.23 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA mass spectrum: (M + HU = 517 (M + H + Na) ⁺⁺ = 270

Example 146.

L1-phenyl-N- (2-ethoxycarbonylethyl) -3methyl-2- [1- (4-amidinophenyl) -aminomethyl] imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride

Prepared analogously to Example 1 of N-phenyl-N- (2-methoxycarbonylethyl-3-methyl-

2- | T4- (4-cyanophenyl) aminomethyl] -imidazo [4,5-

B) pyridin-6-ylcarboxamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 82% of theory,

C ₂₇ H ₂₉ N ₇ O ₃ (499.58)

Rf value: 0.20 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA Mass Spectrum: (M + HU = 500 (M + H + Na) ⁺⁺ = 261.7 Example 147.

N-phenyl-L1- (2-hydroxycarbonylethyl) -

3-methyl-2 - [(4-amidinophenyl) -thiomethyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride

Prepared analogously to Example 2 from N-phenyl-N- (2-ethoxycarbonylethyl-3-methyl-2 [(4-amidinophenyl) thiomethyl] -imidazo [4,5b] pyridin-6-ylcarboxamide hydrochloride and sodium hydroxide).

Yield: 88% of theory, ^C A ^N A ^S ( ⁴⁸⁸ · ⁵⁶ )

Rf value: 0.21 (silica gel; ethyl acetate / ethanol / ammonia: = 50: 45: 5)

ESA mass spectrum: (M + HU = 489 (M + Na) ⁺ = 511 Example 148.

N-phenyl-N- (2-hydroxycarbonylethyl-

3-methyl-2- {1- (4-amidinophenyl) -aminomethyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride

Prepared analogously to Example 2 of N-phenyl N - (2-ethoxycarbonylethyl-3-methyl2- [T4- (4-amidinophenyl) amino-methyl] -imidazo [4,5-b] pyridin-6-ylcarboxamide hydrochloride and sodium hydroxide .

Yield: 80% of theory,

C ₂₅ H ₂₅ N ₇ O ₃ (471.52)

Rf value: 0.19 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA Mass Spectrum: (M + Well = 472 (M + Na) ⁺ = 494 (M + 2Na) ~ = 258.6

Example 149.

N-phenyl-N (2-ethoxycarbonylethyl) -1-methyl-2- | 14- (4-amidinophenyl) -aminomethyl] benzimidazol-5-ylsulfonamide hydrochloride

a) N-phenyl-N- (2-ethoxycarbonylethyl) 1-methyl-2- N- (4-cyanophenyl) -aminomethyl] benzimidazol-5-ylsulfonamide

2.54 g (6.2 mmol) of Ν-φβΗΗΠ-Ν- (2-6toxicarbonylethyl) -3-nitro-4-methylaminobenzenesulfonamide were hydrogenated at room temperature and 5 bar of hydrogen pressure on palladium / charcoal (10%) in a mixture of 75 ml of ethanol and 75 ml of dichloromethane. The crude N-phenyl-N- (2-ethoxycarbonylethyl) -3-amino-4-methylaminobenzenesulfonamide thus obtained was dissolved without purification in 30 ml of phosphoroxychloride, then 1.1 g (6.2 mmol) of (4-cyanophenyl) glycine was added and the mixture was heated 2 h under reflux. After cooling to room temperature, the reaction mixture was cooled in about 70 ml of water to decompose the excess phosphorus oxychloride. The solution thus obtained was neutralized with solid sodium carbonate and extracted three times with 30 ml of ethyl acetate. After evaporation of the solvent, the crude product was purified by column chromatography (100 g silica gel; eluent: cyclohexane / ethyl acetate = 2: 3).

Yield: 860 mg (26.8% of theory),

Melting point: 188-191 ° C

C ₂₇ H ₂₇ N ₅ O ₃ S (517.6)

Rf value: 0.52 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + H = 518 (M + Na) ⁺ = 540

b) N-phenyl-N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-ylsulfonamide hydrochloride

Prepared in analogy to Example 25d of N-phenyl-1 N- (2-ethoxycarbonylethyl) -1-methyl-2- {N - (4-cyanophenyl) -aminomethyl] -benzimidazol-5-ylsulfonamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 87% of theory,

C ₂₇ H ₃₀ N ₆ O ₄ S (534.6)

Rf value: 0.13 (silica gel; dichloromethane / ethanol = 9: 1)

ESA mass spectrum: (M + H = 535 (M + H + Na) ⁺⁺ = 279 Example 150.

N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [14- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylsulfonamide hydrochloride

Prepared analogously to Example 25d of N- (1-methyl-pyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5 -lsulfonamide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 38% of theory,

C ₂₅ H _{3 ()} N ₈ O ₄ S (538.6)

Rf value: 0.09 (silica gel; dichloromethane / ethanol = 9: 1)

ESA Mass Spectrum: (M + H = 539 Example 151.

1-Methyl-2- | N- (4-amidinophenyl) -aminomethyl] -5- (2,3-dihydroindol-1-ylsulfonyl) benzimidazole hydrochloride

Prepared analogously to Example 25d of 1-methyl-2- [T4- (4-cyanophenyl) -aminomethyl] 5- (2,3-dihydroindol-1-ylsulfonyl) -benzimidazole and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 15% of theory, ^C 24 ^H 24 ^N 6 ^O ₂ ^S ( ⁴⁶⁰ · ⁶ )

Rf value: 0.36 (silica gel; dichloromethane / ethanol = 4: 1)

ESA Mass Spectrum: (M + Well = 461 Example 152.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-methyl-2-p4- (4-amidinophenyl) -aminomethyl] benzimidazol-5-ylsulfonamide

Obtained analogously to Example 26 from N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [L- (4-amidinophenyl) -amino-methyl] benzimidazol-5-ylsulfonamide hydrochloride and sodium hydroxide.

Yield: 24% of theory,

C ₂₅ H ₂₆ N ₆ O ₄ S (506.6)

Rf value: 0.55 (reverse phase RP-18 silica gel; methanol / 5% sodium chloride solution = 3: 2)

ESA Mass Spectrum: (M + Well = 507 (M + Na) ⁺ = 529 (M + 2Na) ⁺⁺ = 276

Example 153.

1-Methyl-2- {1- (4-amidinophenyl) -aminomethyl] -5- (5-isoindolin-2-ylsulfonyl) -benzimidazole hydrochloride

Prepared analogously to Example 25d of 1-methyl-2- [T4- (4-cyanophenyl) -aminomethyl] 5- (isoindolin-2-ylsulfonyl) -benzimidazole and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 33% of theory,

C ₂₄ H ₂₄ N ₆ O ₂ S (460.6)

Rf value: 0.32 (silica gel; dichloromethane / ethanol = 4: 1)

ESA mass spectrum: (M + HF = 461

Example 154.

N-phenyl-N- (2-ethoxycarbonylethyl) -2 [2- (4-amidinophenyl) -ethyl] -quinazolin-7-ylcarboxamide hydrochloride

a) 4-methyl-3-nitrobenzoic acid ethyl ester

To a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulfuric acid at 5 ° C and stirring was added dropwise 4.9 g (0.03 mol) of ethyl p-tolyl acid and stirred for 1 h while cooling in an ice bath. After warming to room temperature, it is poured onto ice water and extracted with ethyl acetate. The organic extracts were washed with sodium hydrogencarbonate solution, dried and evaporated.

Yield: 5.7 g (90% of theory),

64588

Rj 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 dimethylacetal and 2 ml of dimethylformamide were heated at 140 ° C for 3 h with stirring. The solvent was then distilled off and the crude material thus obtained was used without further purification.

Yield: 1.2 g (100% of theory),

Rf value: 0.54 (silica gel; ethyl acetate / cyclohexane = 1: 1)

c) 4-Formyl-3-nitrobenzoic acid methyl ester

4- (2-Dimethylaminovinyl) -3-nitrobenzoic acid methyl ester (4.8 mmol) was dissolved in 120 ml of THF / water (1: 1) and stirred for 20 h at room temperature after the addition of 3.0 g (14.3 mmol) of sodium metaperiodate. temperature. The suspension is 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, eluting with ethyl acetate / cyclohexane (1: 3).

Yield: 0.6 g (63% of theory),

Rf value: 0.63 (silica gel; ethyl acetate / cyclohexane = 1: 1)

d) 3-amino-4-formylbenzoic acid methyl ester

To a solution of 25 ml of ethanol / ethyl acetate / 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 iron powder and 0.01 ml of concentrated hydrochloric acid and, with stirring, it is heated to reflux for 15 min. The iron was then separated, the solution 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-formylbenzoic acid methyl ester

1.0 g (5.6 mmol) of 3amino-4-formylbenzoic acid methyl ester and 1.1 g (5.6 mmol) of 4-cyanophenylpropionyl chloride were dissolved in 50 ml of methylene chloride and stirred for 24 h after addition of 0.7 g (5.6 mmol) of N-ethyldiisopropylamine. temperature. It is then extracted with sodium hydrogen carbonate solution, the combined organic extracts are dried and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate / cyclohexane (1: 3).

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 h. The solution was then distilled, the residue was chromatographed on silica gel, eluting with methylene chloride containing 0 to 1% methanol.

Yield: 0.35 g (62% of theory),

Rf value: 0.38 (silica gel; ethyl acetate / cyclohexane = 1: 1)

g) 2- [2- (4-cyanophenyl) ethyl] quinazoline-

7-carboxylic acid

0.3 g (0.94 mmol) of 2 [2- (4-cyanophenyl) ethyl] quinazoline-7-carboxylic acid methyl ester was dissolved in 4.7 ml of lithium hydroxide solution and 4 ml of THF and stirred at room temperature for 3 h. Then 4.7 ml of 1N hydrochloric acid was added and stirred for 30 min. The precipitate was filtered off with a suction filter, washed with water and dried.

Yield: 0.30 g (100% of theory),

Rf value: 0.1 (silica gel; ethyl acetate / cyclohexane = 1: 1)

h) N-phenyl-N- (2-methoxycarbonylethyl) -2- [2- (4-cyanophenyl) -ethyl] -quinazoline-7-ylcarboxamide

0.4 g (1.3 mmol) of 2- [2- (4-cyanophenyl) ethyl] -quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred for 60 min at 50 ° C. The thionyl chloride was then distilled off, the residue was dissolved in methylene chloride and mixed with 0.24 g (1.3 mmol) of methyl ester.

3- (N-Phenylamino) propionic acid and 22 ml (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 h at room temperature. After evaporation in vacuo, the solvent is chromatographed on silica gel and eluted with methylene chloride containing 1% methanol.

Yield: 230 mg (37% of theory),

Rf value: 0.64 (silica gel; methylene chloride / methanol = 9: 1)

i) N-phenyl-N- (2-ethoxycarbonylethyl) -2 [2- (4-amidinophenyl) -ethyl] -quinazolin-7-ylcarboxamide hydrochloride

230 mg (0.5 mmol) Ν-φβΗΗΠ-Ν- (2-Δβοκωcarbonylethyl) -2- [2- (4-cyanophenyl) -ethyl] quinazolin-7-ylcarboxamide was stirred for 8 h at room temperature in 30 ml of saturated ethanol hydrochloric acid. . It was then evaporated to dryness in vacuo, the residue dissolved in 20 ml of ethanol, mixed with 0.5 g (5.0 mmol) of ammonium carbonate and stirred at room temperature overnight. After evaporation of the solvent, the crude material is chromatographed on silica gel and eluted with methylene chloride / ethanol (4: 1).

Yield: 100 mg (39% of theory),

Rf value: 0.5 (silica gel; methylene chloride / methanol = 4: 1)

C ₂₉ H ₂₉ N ₅ O ₃ (495.59)

ESA Mass Spectrum: (M + H / = 496 Example 155.

N- (1-methylpyrazol-4-yl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-ylsulfonamide

Prepared analogously to Example 26 of 14- (1-methylpyrazol-4-yl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-ylsulfonamide hydrochloride and sodium hydroxide.

Yield: 95% of theory,

C _M H ₂₆ N ₈ O ₄ S (510.6)

Rf value: 0.53 (reverse phase RP-18 silica gel; methanol / 5% sodium chloride solution)

ESA Mass Spectrum: (M + H / = 511 (M + Na) ⁺ = 533 (M + 2Na) ⁺⁺ = 278

Example 156.

N- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (3-amidinopyridin-6-yl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

a) b4- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) -3 - [(N-tert-butoxycarbonylamino) -acetylamino] -4-methylamino-benzamide

19.2 g (0.11 mol) of N-tert-butyloxycarbonylglycine were dissolved in 175 ml of dimethylformamide and mixed with 35.2 g (0.11 mol) of O-benzotriazol-1-yl-N, N ', N' -tetramethyluronium tetrafluoroborate, 11.0 g of triethylamine and 34.2 g (0.10 mol) of N- (2-pyridyl) -1 N- (2-ethoxycarbonylethyl) -3-amino-4-methylaminobenzamide and stirred at room temperature for 2.5 h. The reaction solution was then mixed with 5 l of ice water and stirred for 2 h. The resulting gray precipitate was filtered off with suction, washed with water, dried and recrystallized from ethyl acetate with activated charcoal.

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) 14- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- (N-tert-butoxycarbonylaminomethyl) -benzimidazol-5-yl-carboxamide

10.0 g (0.02 mol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -3 - [(N-tert-butoxycarbonylamino) -acetylamino] -4methylaminobenzamide was dissolved in 50 ml of glacial acetic acid and heated under reflux for 1 h. refrigerator. The solvent was then distilled, the residue was mixed with ice water and the pH was adjusted to 8 by the addition of 2N ammonia. After extraction with ethyl acetate three times, the combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the crude material is chromatographed on silica gel, eluting first with methylene chloride, then with methylene chloride / ethanol (50: 1) and (25: 1). The desired fractions were combined and evaporated.

Yield: 5.85 g (61% of theory),

0,, 11,, 14.0, (481.6)

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

c) N- (2-pyridyl) -L1- (2-ethoxycarbonylethyl) -1-methyl-2-aminomethyl-benzimidazole53

64588

5-yl-carboxamide trifluoroacetate

4.81 g (0.10 mol) of N- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- (1H-tert-butoxycarbonyl-aminomethyl) -benzimidazol-5-ylcarboxamide was dissolved in 25 ml of methylene chloride, mixed with 5 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. The solvent was then distilled off and the residue was mixed with ether. The resulting crystals were filtered off, washed with ether and dried.

Yield: 3.15 g (68% of theory), ςΗ ₂₃ Ν ₅ Ο, (381.4)

Rf value: 0.18 (silica gel; methylene chloride / ethanol = 9: 1)

d) N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (3-cyanopyridin-6-yl) aminomethyl] -benzimidazol-5-yl-carboxamide

1.5 g (3.25 mmol) of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2-aminomethylbenzimidazol-5-yl-carboxamide trifluoroacetate were stirred in 10 ml of N-ethyldiisopropylamine and heated for 15 min at 100 °. S. After the 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 20 ml of water, the pH was adjusted to 4 by the addition of 1N hydrochloric acid and extracted 3 x with ethyl acetate. The combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the crude material is chromatographed on silica gel, eluting first with methylene chloride, then with methylene chloride / ethanol (25: 1) and (19: 1). The desired fractions were combined and evaporated.

Yield: 1.05 g, (61% of theory),

C ₂₆ H 2 _J N ₇ O ₃ (483.6)

Mass Spectrum: (M + H) ⁺ = 484

e) N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (3-amidinopyridin-6-yl) aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- [L- (3-cyanopyridin-6-yl) -aminomethyl] -benzimidazol-5-yl- carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 38% of theory,

C ₂₈ H ₂₈ N ₈ O ₃ (500.6)

Mass Spectrum: (M + H) ⁺ = 501

Example 157.

N-Phenyl-N- (2-methoxycarbonylethyl) -1 methyl-2- [N- (4-amidinophenyl) -aminomethyl] indol-5-ylcarboxamide hydroiodide

a) N-phenyl-N- (2-methoxycarbonylethyl) -4-nitrobenzamide

16.7 g (0.1 mol) of 4-nitrobenzoic acid was dissolved in 50 ml of thionyl chloride and 3 drops of dimethylformamide were refluxed for 1 h. After distilling the solvent in vacuo, the crude material was dissolved in 150 ml of THF and added dropwise to a solution of 18 g (0.1 mol) of L- (2-methoxycarbonylethyl) aniline in 250 ml of THF and 42 ml (0.3 mol) of triethylamine. After stirring for 1 h at room temperature, it was diluted with 250 ml of ethyl acetate and washed twice with 200 ml of 14% sodium chloride solution. After distillation of the solvent and chromatography (silica gel: methylene chloride), a yellow oil was isolated which slowly solidified.

Yield: 32.6 g (100% of theory),

Rf value: 0.37 (silica gel; methylene chloride / ethanol = 50: 1)

b) N-Phenyl-N- (2-methoxycarbonylethyl) -4-aminobenzamide g (67 mmol) N-phenyl-N- (2-methoxycarbonylethyl) -4-nitrobenzamide in 500 ml methanol is hydrogenated with 2 g of 10% palladium on charcoal at 3 bar hydrogen pressure for 3 h. After filtration and distillation, the solvent was washed with 100 ml of ether and the white crystalline product was further reacted directly.

Yield: 18.6 g (94% of theory),

Rf value: 0.70 (silica gel; methylene chloride / ethanol = 19: 1)

c) N-phenyl-L- (2-methoxycarbonylethyl) -2-methyl-3-thiomethylindol-5-ylcarboxamide

26.8 g (91 mmol) Ν-φβΗΗΠ-Ν- (2-Μβτοκsicarbonylethyl) -4-aminobenzamide was dissolved in 500 ml of methylene chloride, cooled to 70 ° C and mixed with freshly prepared tert-butyl hypochlorite (MJ) for 30 min. Mintz et al., Organic Synthesis, Coll. Vol. 5, 184).

It was stirred at -70 ° C for 2 h, then 9.46 g (91 mmol) of methylthioacetone in 40 ml of methylene chloride was added dropwise over 10 min and stirred for 1.5 h. Then 12.7 ml (9.1 g, 91 mmol) of triethylamine in 25 ml of methylene chloride were added. It is allowed to stand at -78 ° C for 30 min and then slowly warmed to room temperature overnight. After washing twice with 50 ml of water each, the organic phases were separated and dried with sodium sulfate. Removal of the solvent in vacuo after purification by chromatography (silica gel: ethyl acetate / petroleum ether = 2: 8 to 3: 7) gave a white amorphous substance.

Yield: 24.1 g (69% of theory),

Rf value: 0.58 (silica gel; ethyl acetate / petroleum ether = 1: 1) ^C ₂₁ ^H 22 ^N 2 ^O 3 ^S < ³⁸² · ⁴⁹ )

Mass Spectrum: (M) ⁺ = 382

d) L1-phenyl-N- (2-methoxycarbonylethyl) -1-tert-butoxydicarbonyl-2-methyl-indol-5-ylcarboxamide

8.9 g (23 mmol) of N-phenyl-N- (2-methoxycarbonylethyl) -2-methyl-3-thiomethyl-indol-5-ylcarboxamide was dissolved in 600 ml of ethanol, mixed with about 150 mg of Raney-nickel and stirred for 2 h at room temperature (similar to PG Gassman et al., Organic Synthesis Coll. Vol. 6,601). It is then filtered and the solvent is removed in vacuo. The crude material thus obtained (8 g) was dissolved in 200 ml of absolute tetrahydrofuran, mixed with 150 mg of dimethylaminopyridine and 6.84 g (32 mmol) of pyrocarbonic acid di-tert-butyl ester and stirred for 2.5 h at 50 ° C. The solvent was then distilled off in vacuo and the crude material was purified by chromatography (silica gel, ethyl acetate / petroleum ether = 1: 4).

Yield: 10.0 g (98% of theory),

Rf value: 0.40 (silica gel; ethyl acetate / petroleum ether = 3: 7)

e) N-phenyl-N- (2-methoxycarbonylethyl) -2- [L- (4-cyanophenyl) -aminomethyl] -indole5-ylcarboxamide

3.5 g (8 mmol) of N-phenyl-N- (2-methoxycarbonylethyl) -1-tert-butoxycarbonyl-2-methyl-indol-5-ylcarboxamide were dissolved in 80 ml of tetrachloromethane, mixed with 1.5 g (8.4 mmol) of N bromosuccinimide and 20 ml azobis-isobutyronitrile and refluxed for 2.5 h.

The still warm solution was then filtered, the resulting filtrate washed with sodium hydrogen carbonate solution and dried with sodium sulfate. After distilling the solvent, the crude material was dissolved in 30 ml of N-ethyldiisopropylamine, mixed with 1.0 g (8 mmol).

4-Aminobenzonitrile and refluxed for 2.5 h. The solvent was distilled off in vacuo and the resulting residue was purified by chromatography (silica gel: ethyl acetate / petroleum ether = 1: 4 to 1: 1).

Yield: 1.1 g (30% of theory),

Rf value: 0.21 (silica gel; ethyl acetate / petroleum ether = 1: 1)

1) N-phenyl-N- (2-methoxycarbonylethyl) 1-methyl-2- [N- (4-thiocarbamoyl) phenyl) aminomethyl] -indol-5-ylcarboxamide

1.5 g (3.3 mmol) of N-phenyl-L- (2-methoxycarbonylethyl) -2- [N- (4-cyanophenyl) aminomethyl] -indol-5-ylcarboxamide was dissolved in 60 ml of xylene, mixed with 0.45 g (3.3) mmol) of potassium carbonate and 0.5 ml (3.3 mmol) of p-toluenesulfonic acid methyl ester and refluxed for 4 hours. Once again, the same amounts of potassium carbonate and p-toluenesulfonic acid methyl ester were added and refluxed overnight. Filter and wash with acetone. After concentrating the filtrate thus obtained, the resulting residue was purified by chromatography (silica gel: ethyl acetate / petroleum ether = 1: 4 to 2: 3). The resulting N-methylated indole (yield: 0.64 g, 41% of theory) was dissolved in 20 ml of pyridine and mixed with 0.67 ml (1.37 mmol) of triethylamine. Hydrogen sulphide was then passed into the solution thus obtained. After 4.5 days, nitrogen was bubbled through the reaction solution for 30 minutes, the solvent was distilled off and the resulting residue was purified by chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 98: 2).

Yield: 0.30 g (43% of theory),

C ₂₈ H _M N ₄ O ₃ S (500.62)

ESA-Mass Spectrum: (M + H) f = 501 (M + Na) ⁺ = 523

g) N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -indol-5-ylcarboxamide hydroiodide

0.30 g (0.60 mmol) N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [N- (4-thiocarbamo)

64588 yl) phenyl) aminomethyl] -indol-5-yl-carboxamide was dissolved together with 0.75 ml (12 mmol) of methyl iodide in 20 ml of acetone and stirred at room temperature for 2 h. The solvent was then distilled and the crude product was stirred with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of methylene chloride at 40 ° C for 20 h. The solvent was distilled off in vacuo and the resulting residue was purified by chromatography (silica gel; methylene chloride / ethanol = 9: 1 to 4: 1).

Yield: 55% of theory,

C ₂ , H ₂₉ N ₅ O ₃ S (483.58)

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 4: 1 + 1 drop of ethyl acetate)

ESA-Mass Spectrum: (M + H / = 484 Example 158.

B1-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidinophenyl) -aminomethyl] thieno [2.3- d] imidazol-5-ylcarboxamide hydrochloride

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 diethyl ether was cooled to 0 ° C and 22.5 g (0.62 mol) of hydrogen chloride gas was introduced over a period of 1 hour. the end crystallizes out the reaction product. For complete precipitation, mix with 130 ml of diethyl ether and colorless needles filtered.

Yield: 66.4 g (86% of theory),

Melting point: 117-118 ° C.

b) 4-hydroxymethyl-2-methoxymethylimidazole

A mixture of 30.6 g (0.20 mol) iminoethyl ester of methoxyacetic acid hydrochloride, 18 g (0.20 mol) of 1,3-dihydroxyacetone and 200 ml of liquid ammonia was heated for 3 hours in an autoclave with a stirrer at a pressure of 27 bar to 68 ° C (according to: R. Dziuronetal. Arch. Pharm., 307, 1974, S.470). The ammonia was then removed and 200 ml of methylene chloride were added. The precipitated white precipitate was filtered off and washed with methylene chloride. The filtrate was concentrated and the resulting residue was purified by chromatography (alumina; methylene chloride / ethanol = 90:10 to 85:15).

Yield: 26.7 g (94% of theory),

Rf value: 0.43 (silica gel; methylene chloride / ethanol = 9: 1)

C ₆ H ₁₀ N ₂ O ₂ (142.20)

Mass Spectrum: (M) ⁺ = 142

c) 4-hydroxymethyl-2-methoxymethyl-1 methylimide azole 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 was heated in 100 ml of dimethylformamide for 4 h to 50 ° C (according to I. Sinclair et al., J. Med. Chem., 29, 1986, 261). The solvent was then distilled in vacuo and the crude product was purified by column chromatography (aluminum oxide; methylene chloride / ethanol = 99: 1 to 95: 5).

Yield: 6.1 g (78% of theory, 1: 1 mixture of both isomers),

Rf value: 0.32 (silica gel; methylene chloride / ethanol = 19: 1)

d) 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methylimidazole

1: 1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methylimidazole and

5-hydroxymethyl-2-methoxymethyl-1-methylimidazole as well as 7.3 g (55 mmol) of N-chlorosuccinimide were heated in 48 ml of ethylene glycol monoethyl ether and 70 ml of dioxane for 10 h at 50 ° C. The solvent was then distilled in vacuo and the crude product was purified by chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 90:10).

Yield: 3.4 g (36% of theory),

Rf value: 0.40 (silica gel; methylene chloride / ethanol = 19: 1)

e) 5-chloro-4-formyl-2-methoxymethyl1-methylimidazole

3.4 g (18 mmol) of 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methylimidazole were dissolved in 100 ml of methylene chloride and mixed with manganese dioxide (2 x 6.0 g, 0.14 mol in total) for 2 hours. After 4 h, the inorganic component was filtered off, the solvent was removed and the resultant was used 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-methoxymethylthieno [2,3-b] -imidazol-5-ylcarboxylic acid ethyl ester

To a freshly prepared solution of sodium ethanolate (391 mg, 17 mmol sodium) in 15 ml ethanol was added dropwise 1.9 ml (2.1 & 17 mmol) of thioglycolic acid ethyl ester. After stirring at room temperature for 1 h, 1.6 g (8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methylimidazole in 20 ml of absolute ethanol was added and heated to 80 ° C (according to B., Iddon et al., J. Chem. Soc. Perkin Trans. I, 1987, 1457). After 5 h the solvent was distilled off, the residue was dissolved 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 then the combined organic phases were dried with sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by column chromatography (aluminum oxide; methylene chloride).

Yield: 1.0 g (46% of theory),

Rf value: 0.48 (silica gel; methylene chloride / ethanol = 50: 1)

C _h H ₁₄ N ₂ O ₃ S (254.31)

ESA-Mass Spectrum: (M + H = 255 (M + Na) ⁺ = 277

g) 1-methyl-2-methoxymethylthieno [2,3-b] imidazol-5-yl-carboxylic acid

To a solution of 0.90 g (3.54 mmol) of 1-methyl-2-methoxymethylthieno [2,3-b] -imidazol-5-ylcarboxylic acid ethyl ester in 30 ml of ethanol was added dropwise 5 ml of sodium hydroxide and stirred for 2 h at room temperature. temperature. The solvent was then distilled in vacuo, the residue was dissolved in 5 ml of water and washed with 10 ml of diethyl ether. The aqueous phase was acidified with 6 ml of 2N hydrochloric acid, cooled to 0 ° C and the precipitated crystals were filtered off.

Yield: 0.50 g (63% of theory),

Rf value: 0.21 (silica gel; methylene chloride / ethanol = 9: 1 + a few drops of acetic acid)

C ₉ H ₁₀ N ₂ O ₃ S (226.26)

ESA-Mass Spectrum: (M) ⁺ = 226

h)> 1-Phenyl-L- (2-methoxycarbonylethyl) -1-methyl-2-methoxy-methyl-thieno [2.3b] imidazol-5-ylcarboxamide

A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxy-methylthieno [2.3-b] -imidazol-5-ylcarboxylic acid in 20 ml of methylene chloride was combined 2.0 ml (3.2 g, 27 mmol) of thionyl chloride and heated for 60 min under reflux, the solid being gradually dissolved. After distillation of the liquid components, the crude product was dissolved 2x in methylene chloride. The solvent was again removed, the crude acid chloride was dissolved in 20 ml of tetrahydrofuran and added dropwise to a mixture of 0.42 g (2.3 mmol) N- (2-ββοκicarbonylethyl) aniline and 0.92 ml (6.6 mmol) triethylamine in 30 ml tetrahydrofuran. After stirring at 50 ° C for 16 h, 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) N-phenyl-L1- (2-methoxycarbonylethyl) 1-methyl-2- (L1-4-cyanophenylaminomethyl) -thieno [2,3 ^] imidazol-5-ylcarboxamide

To a solution of 0.73 g (1.88 mmol) of N-phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2-methoxymethyl-thieno [2.3 ^] -imidazol-5-ylcarboxamide in 30 ml of methylene chloride was added dropwise at 5 ° C 2.9 ml (2.9 mmol) 1-molar solution of boron tribromide in methylene chloride. After stirring at room temperature for 16 h, it is washed with 20 ml of saturated sodium bicarbonate solution, the organic phase is separated, dried with sodium sulfate and filtered. The filtrate was combined with 14 ml of N-ethyldiisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile. The methylene chloride was then distilled in vacuo, the resulting residue was heated at 50 ° C for 1 hour and then the residual solvent was distilled in vacuo. Chromatography (silica gel; methylene chloride / ethanol = 99: 1 to 97: 3) gave a yellow oil which gradually solidified.

Yield: 0.37 g (42% of theory),

Rf value: 0.29 (silica gel; methylene chloride / ethanol = 50: 1 + a few drops of ammonia)

)) N-phenyl-N- (2-ethoxycarbonylethyl) -1methyl-2- [N- (4-amidinophenyl) -aminomethyl] thieno [2.3-0] imidazol-5-ylcarboxamide hydrochloride

0.38 g (0.80 mmol) N-N-β-N- (2-N-oxicarbonylethyl) -1-methyl-2- (E4-4-cyano-phenylaminomethyl) -thieno [2.3 ^] imidazol-5-ylcarbonyl

64588 boxamide was stirred in 40 ml of hydrogen chloride saturated with ethanol for 5 hours first at 0 ° C, then at room temperature, until no more starting material could be detected by thin layer chromatography. The solvent was then distilled at a maximum of 28 ° C in the water bath, the oily residue was dissolved in 40 ml of absolute ethanol and mixed with 1.1 g of ammonium carbonate. 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)

Yield: 57% of theory, ^C A ^N 6 ° 3 ^S ( ⁵⁰⁴ · ⁶² )

Rf value: 0.21 (silica gel; methylene chloride / ethanol = 4: 1+ a few drops of acetic acid)

ESA Mass Spectrum: (M + HU = 505 (M + H + Na) ⁺⁺ = 264 Example 159.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-methyl-2- [T4- (4-amidinophenyl) -aminomethyl] thieno [2.3-0] imidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 2 from N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2H- (4-amidinophenyl) -amino-methyl] -thieno [2.3 <1] imidazol-5-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 85% of theory, C ₂₄ H ₂₄ N ₆ O ₃ S (476.56)

Rf value: 0.36 (reverse phase silica gel RP-8; methanol + 5% solution of cooking salt)

ECA mass spectrum: (M + HU = 477 (M + Na) ⁺ = 499 (M + 2Na) ⁺⁺ = 250 Example 160. N-Phenyl- N (2-ethoxycarbonylethyl) -1 methyl-3- N- (4 -amidinophenyl) -thiomethyl] quinoxalin-2-one-6-ylcarboxamide hydrochloride

a) N-phenyl-N (2-methoxycarbonylethyl) 1-methyl-3- N- (4-cyanophenyl) -thiomethyl] quinoxalin-2-one-6-ylcarboxamide

A solution of 2.5 g (7.6 mmol) N-φβΗππ-Ν (2-methoxycarbonylethyl) -3-amino-4-methylaminobenzamide and 2.4 g (9.6 mmol) of 3- (4-cyanophenyl) thio-2-oxopropionic acid ethyl ester heated in 50 ml of ethanol to reflux for 30 min. After removal of the solvent, the crude product obtained is purified by chromatography (silica gel; methylene chloride).

Yield: 1.6 g (40% of theory),

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

b) N-phenyl-N- (2-ethoxycarbonylethyl) -

1- methyl-3-N- (4-amidinophenyl) -thiomethyl] quinoxalin-2-one-6-ylcarboxamide hydrochloride

Prepared analogously to Example 1 from N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-

3- | N- (4-cyanophenyl) -thiomethyl] -quinoxaline-

2- on-6-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 23% of theory,

C ₂₈ H ₂₇ N ₅ O ₄ S (543.64)

Rf value: 0.25 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA mass spectrum: (M + HU = 544 (M + Na) ⁺ = 566 Example 161.

N-phenyl-N (2-ethoxycarbonylethyl) -3methyl-2- [2- (4-amidinophenyl) -ethyl] imidazo [1,2-a] pyridin-7-ylcarboxamide hydrochloride

a) Phenyl-No (2-ethoxycarbonylethyl) -

3-methyl-2- [2- (4-cyanophenyl) -ethyl] imidazo [1,2-a] pyridin-7-ylcarboxamide

1.4 g (4.6 mmol) of 3-methyl-2- [2- (4-cyanophenyl) -ethyl] imidazo [1,2-a] pyridin-7-ylcarboxylic acid (obtained from 4-bromo- (4-cyanophenyl) -1- penten-3-one and 2-aminopyridine-4-carboxylic acid methyl ester according to Y. Katsura et al., Chem. Pharm. Bull., 1992, 40, 1424-1438) were suspended in 15 ml of thionyl chloride and heated 1 h to boil until completely dissolved. After distillation of the thionyl chloride, the acid chloride, without further purification, was dissolved in 15 ml of pyridine and 1.0 g (5.2 mmol) of N (2-ethoxycarbonylethyl) aniline was added at 0 ° C. After 1 h, the solvent was distilled off, the residue was dissolved in 30 ml of methylene chloride, washed with 15 ml of 1N hydrochloric acid and dried with sodium sulfate. Distillation of the solvent and chromatography (silica gel; methylene chloride / ethanol = 0 to 2%) gave a brown oil.

Yield: 1.48 g (64% of theory),

Rf value: 0.73 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1)

b) Phenyl-No (2-ethoxycarbonylethyl) 58

3-methyl-2- [2- (4-amidinophenyl) -ethyl] imidazo [1,2-a] pyridin-7-ylcarboxamide hydrochloride

Prepared analogously to Example 1 of No. phenyl-No. (2-ethoxycarbonylethyl) -3-methyl-

2- [2- (4-cyanophenyl) -ethyl] imidazo- [1,2-a] pyridin-7-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 62% of theory,

C ₂₉ H ₃₎ N ₅ O ₃ (497.60)

Rf value: 0.23 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA Mass Spectrum: (M + Well = 498 Example 162.

N-phenyl-N- (2-hydroxycarbonylethyl) -

3-methyl-2- [2- (4-amidinophenyl) -ethyl] -imidazo [1,2-a] pyridin-7-ylcarboxamide hydrochloride

Prepared analogously to Example 2 from N-phenyl-N- (2-ethoxycarbonylethyl) -3-methyl2- [2- (4-amidinophenyl) -ethyl] -imidazo [1.2a] pyridin-7-ylcarboxamide hydrochloride and sodium hydroxide.

Yield: 92% of theory, ^C ₂₇ H ₂₇ N ₅ O ₃ (469.55)

Rf value: 0.19 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)

ESA mass spectrum: (M + HU = 470 (M + Na) ⁺ - 492 (M + 2H) ⁺⁺ = 235.7 (M + H + Na) ⁺⁺ = 246.7 (M + 2Nar = 257.7

Example 163.

N-Phenyl-N [(N-ethoxycarbonylethyl-N-methyl) -2-aminoethyl] -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-ylcarboxamide dihydrochloride

Prepared analogously to Example 25d of N, N-methyl-N - [(N-ethoxyphenyl) -N-methyl) -2-aminoethyl] -1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] benzimidazole-5- ilcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 80% of theory,

C ₃₁ H ₃₇ N ₇ O ₃ (555.7)

Rf value: 0.24 (silica gel; dichloromethane / methanol = 4: 1)

ESA Mass Spectrum: (M + Well = 556 (M + H + Na) ⁺⁺ = 289.8 (M + 2H) ⁺⁺ = 278.8

Example 164.

Phenyl-N- [N - hydroxycarbonylethyl] methyl) -2-aminoethyl] -1-methyl-2- (4- (4-amidinophenyl) -aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from Ν-φβΗΗΠ-Ν - [(Ν-βτοκθΗΚ3ρ6θΗΗΠβτΗΠ-Ν-Μβethyl) -2-aminoethyl] -1-methyl-2- | 14- (4-amidinophenyl) -aminomethyl] benzimidazole-5- ilcarboxamide dihydrochloride and sodium hydroxide.

Yield: 79% of theory, C ₂₉ H ₃₃ N ₇ O ₃ (527.6)

Rf value: 0.43 (reverse phase silica gel RP-18; methanol / 5% salt solution = 6: 4)

ESA mass spectrum: (M + H = 528 (M + H + Na) ⁺⁺ = 275.6 (M + 2H) ⁺⁺ = 264.6

Example 165.

N-phenyl-N- (3-hydroxy-n-propyl) -1methyl-2- {N - (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride

Obtained from Ν-φβΗΗΠ-Ν- (3-6βΗ3θΗloxy-n-propyl) -1-methyl-2- | N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride by hydrogenation over palladium / carbon (10%) at 5 bar hydrogen pressure and at room temperature.

Yield: 61% of theory, ^C ₂₆ H ₂₈ N ₆ O ₂ (456.6)

Rf value: 0.70 (reverse phase silica gel RP-18; methanol / 5% salt solution = 9: 1)

ESA mass spectrum: (M + H &lt; + &gt; = 457 (M + H + Na) ⁺⁺ = 240

Example 166.

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- | N- [4- (N-hexyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazol-5-yl-carboxamide

Prepared in analogy to Example 26 of No. (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2 - [N- [4 - [[2- (N-hexyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazol-5-yl] carboxamide dihydrochloride sodium hydroxide.

Yield: 97% of theory,

C ₃₂ H ₃₇ N ₇ O ₅ (599.7)

Rf value: 0.22 (silica gel; dichloromethane / methanol = 9: 1)

ESA Mass Spectrum: (M + Well = 600 (M + H + Na) ⁺⁺ = 311.7 (M + 2H) = 300.8

64588 (Μ + 2Na) ⁺⁺ = 322.8

Example 167.

N-phenyl-L4- (3-hydroxy-p-propyl) -1-methyl-2- [N- [4- (N-p-hexyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 165 of N-phenyl-N- (3-benzyloxy-n-propyl) -1-methyl-2- (S) - [4- (N-p-hexyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazole-5- ilcarboxamide by catalytic debenzylation.

Yield: 26% of theory, SAND (584.7)

January _d -value: 0.39 (silica gel; dichloromethane / ethanol = 9: 1)

ESA Mass Spectrum: (M + HU = 585 (M + H + Na) ⁺⁺ = 304 (M + Na) ⁺ = 607

Example 168.

N- (3-fluorophenyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide and ethanol salt 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)

ESA mass spectrum: (M + H = 517 (M + H + Na) ⁺⁺ = 270

Example 169.

N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- | N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (4-fluorophenyl) -L- (2-ethoxycarbonylethyl) -1-methyl-2- [14- (4-cyanophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide and ethanol salt acid, ethanol and ammonium carbonate.

Yield: 90% of theory, C ₂₈ H ₂₉ FN ₆ O ₃ (5I6.6)

Rf value: 0.29 (silica gel; dichloromethane / methanol = 5: 1)

ESA mass spectrum: (M + HU = 517 (M + H + Na) ⁺⁺ = 270

Example 170

N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 of N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [T4- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide .

Yield: 97% of theory, ^with L ^p H ° 3 ( ⁴⁸⁸ · ⁵ )

Rj value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1)

ESA Mass Spectrum: (M + OU = 489 (M + Na) ⁺ = 511 (M + 2Na) ⁺⁺ = 267

Example 171

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

Prepared analogously to Example 26 from N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- {1- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide .

Yield: 89% of theory, C ₂₆ H ₂₅ FN ₆ O ₃ (488.5)

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

ESA Mass Spectrum: (M + Well = 489 (M + Na) ⁺ = 511 (M + 2Na) ⁺⁺ = 267

Example 172

N-phenyl-N- (2-ethoxycarbonylethyl) -1 methyl-2- {74- (4-amidino-2-methoxyphenyl) aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-cyano-2-methoxyphenyl) -aminomethyl] benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid , ethanol and ammonium carbonate.

Yield: 89% of theory,

C ₂₉ H ₃₂ N ₆ O ₄ (528.6)

And _d- value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1)

ESA mass spectrum: (M + HU = 529 (M + H + Na) ⁺⁺ = 276 (Μ + 2H) ⁺⁺ = 265

Example 173

N (2-pyridyl) -N (2-ethoxycarbonyl) -1-methyl-2- [N- [4- (1H-4-ethylbenzoylamidino) phenyl] -aminomethyl] benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and 4-ethylbenzoyl chloride .

Yield: 64% of theory,

C ₃₆ H ₃₇ N ₇ O ₄ (631.7)

Rf value: 0.78 (silica gel; dichloromethane / methanol = 9: 1)

ESA Mass Spectrum: (M + H = 632 (M + H + Na) ⁺⁺ = 327.8 (M + Na) ⁺ = 654

Example 174.

B1- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazol5-yl-carboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [b4- (4-amidinophenyl) aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and benzyl ester. hydrochloric acid.

Yield: 64% of theory,

C ₃₅ H ₃₅ N ₇ O ₅ (633.6)

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

ESA mass spectrum: (M + H / = 634 (M + H + Na) ⁺⁺ = 328.8 (M + Na) ⁺ = 656

Example 175.

N-phenyl-N- (2-hydroxycarbonylethyl) 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 from N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2-P4- (4-amidino-2-methoxyphenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide .

Yield: 71% of theory.

C ₂₇ H ₂₈ N ₆ O ₄ (500.6)

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

ESA Mass Spectrum: (M + OU = 501 (M + Na) ⁺ = 523 (M + 2Na) ⁺⁺ = 273

Example 176

N- (2-pyridyl) -1H- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-cyano-2-methoxyphenyl) -aminomethyl] benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 67% of theory,

C ₂₈ H ₃₁ N ₇ O ₄ (529.6)

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

ESA Mass Spectrum: (M + Well = 530 Example 177.

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- | T4- (4-amidino-2-methoxyphenyl) -aminomethyl] benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 from N- (2-pyridyl) -L4- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (4-amidino-2-methoxyphenyl) aminomethyl] benzimidazol-5-yl-carboxamide hydrochloride and sodium hydroxide.

Yield: 78% of theory, ^^ 0, (501.6)

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

ESA mass spectrum: (M + H / = 502 Example 178.

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazol-5-yl-carboxamide

Prepared analogously to Example 104 from N- (2-pyridyl) -1 N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- [4- (N-benzyloxy-carbonylamidino) phenyl] -aminomethyl] benzimidazole-5- ilcarboxamide and sodium hydroxide.

Yield: 62% of theory,

C ₃₃ H ₃₁ N ₇ O ₅ (605.7)

Rf value: 0.26 (silica gel; dichloromethane / methanol = 9: 1)

ESA mass spectrum: (M + H / = 606 (M + Na) ⁺ = 628 (M - H + 2Na) ⁺ = 650 (M + 2H) ⁺⁺ = 303.8 (M + H + Na) ~ = 314.8 (M + 2NaF = 325.7

Example 179

L1-phenyl-N- (3-benzyloxy-n-propyl) -1 methyl-2- [N- (4-amidinophenyl) -aminomethyl] benzimidazol-5-yl-carboxamide hydrox61

64588 loride

Prepared analogously to Example 25 from N-phenyl-L-C3-benzyloxy-n-propyl) -1-methyl2- [74- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 61% of theory,

C ₃₃ H ₃₄ N ₆ O ₂ (546.7)

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

ESA mass spectrum: (M + H / = 547 (M + H + Na) ⁺⁺ = 285 Example 180.

14-Phenyl-T4- (3-benzyloxy-n-propyl) -1-methyl-2- [N- [4- (N-p-hexyloxycarbonylamidino) phenyl] -aminomethyl] benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N-phenyl-N- (3-benzyloxy-n-propyl) -1-methyl2- [N- (4-amidinophenyl) -amino-methyl] -benzimidazol-5-yl-carboxamide hydrochloride and hydrochloric acid phexyl ester.

Yield: 73% of theory,

C ^ NA (674.9)

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

ESA mass spectrum: (M + H / = 675 (M + H + Na) ** = 349 (M + Na) ⁺ = 697 (M + K) ⁺ = 713

Example 181

N (2-pyridyl) -N (2-ethoxycarbonylethyl) -3-methyl-2- [2- (4-amidinophenyl) ethyl] imidazo [1,2-a] pyridin-7-ylcarboxamide hydrochloride

Prepared analogously to Example 1 of N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -3methyl-2- [2- (4-cyanophenyl) ethyl] -imidazo [1.2a] pyridin-7-ylcarboxamide hydrochloride and ethanol, hydrochloric acid, ethanol and ammonium carbonate.

Yield: 53% of theory,

C _M H ₃₀ N ₆ O ₃ (498.59)

Rf value: 0.42 (silica gel; ethyl acetate / ethanol / ammonia: = 50: 45: 5)

ESA mass spectrum: (M + H / = 499 (M + 2Na) ⁺⁺ = 272 (M + H + Na) ** = 261 (M + 2H) ⁺⁺ = 250

Example 182

N- (2-pyridyl) N - (2-hydroxycarbonylethyl) -1-methyl-2- [N- (3-amidinopyridin-6 yl) -aminomethyl] benzimidazol-5-yl-carboxamide

Prepared analogously to Example 26 from N (2-pyridyl) -N (2-hydroxycarbonylethyl) -1-methyl-2- N- (3-cyanopyridin-6-yl) aminomethyl] benzimidazol-5-yl-carboxamide and sodium the basis.

Yield: 40% of theory,

C ₂₄ H ₂₄ N ₈ O ₃ (472.9)

Rf value: 0.67 (reverse phase silica gel RP-8; methanol / 5% solution of cooking salt = 1: 1)

ESA Mass Spectrum: (M + H = 473 Example 183.

N- (2-pyridyl) -No [2- (methanesulfonylaminocarbonyl) ethyl] -1-methyl-2- [T4- [4- (4-hydroxylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

a) No. (2-pyridyl) N - [2- (methanesulfonylaminocarbonyl) ethyl] -1-methyl-2- [N- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide

2.0 g (4.5 mmol) N- (2-methylphenyl) -1- (2-hydroxycarbonylethyl) -1-methyl-2- [14- (4-cyanophenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide and 0.73 g (4.7 mmol) Carbonyldiimidazole was dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide and stirred at room temperature for 30 min and at 90 ° C for 2 h. In parallel, 0.55 g (5.8 mmol) of methanesulfonamide and 0.28 g (5.8 mmol) of sodium hydride in 15 ml of dimethylformamide were suspended and stirred at room temperature for 2 h. This suspension was then added at room temperature to the tetrahydrofuran solution. After 12 h at room temperature, 50 ml of water were added and the pH was adjusted to 6.8. The solution was extracted 4x with methylene chloride, the combined organic phases were dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel (methylene chloride / ethanol (40: 1)). The desired fractions are combined and concentrated.

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) N- (2-pyridyl) N - [2- (methanesulfonylaminocarbonyl) ethyl] -1-methyl-2- [N- [4- (N-hydroxylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide

Prepared analogously to Example 96 of N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) ethyl] -1-methyl-2- | N- (4-cyanophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide and hydroxylamine.

Yield: 27% of theory, C ₂₆ H ₂₈ N ₈ O ₅ S (564.6)

Rf value: 0.75 (silica gel; dichloromethane / ethanol = 7: 3 + 1% glacial acetic acid)

ESA Mass Spectrum: (M + Well = 565 (M + Na) * = 587

Example 184

T4- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (5-amidinothiazol-2yl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (5-cyanothiazol-2-yl) -aminomethyl] benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Example 185.

N- (2-pyridyl) -1H- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (5-amidinothiazol-2yl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 26 from N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- (N- (2-amidinothiazol-2-yl) aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride and sodium the basis.

Example 186.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [2-amidinopyrazin-5-yl] aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride

Prepared analogously to Example 25d of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) 1-methyl-2- [N- (2-cyanopyrazin-5-yl) -aminomethyl] benzimidazol-5-ylcarboxamide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Yield: 19% of theory,

C ₂₅ H ₂₇ N ₉ O ₃ (501.6)

Rf value: 0.28 (silica gel; dichloromethane / methanol = 4: 1 + 1% glacial acetic acid)

ESA mass spectrum: (M + H 2 = 502 (M + H + Na) ** = 262.5

Example 187.

N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2 - [N- (2-amidinopyrazin-5yl) aminomethyl] benzimidazol-5-ylcarboxamide

Prepared analogously to Example 26 from N (2-pyridyl) -L- (2-ethoxycarbonylethyl) 1-methyl-2- (2- (2-amidinopyrazin-5-yl) -aminomethyl] benzimidazol-5-ylcarboxamide hydrochloride and sodium hydroxide .

Yield: 11% of theory.

C ₂₃ H ₂₃ N ₉ O ₃ (473.5)

Rf value: 0.55 (reverse phase silica gel RP-8; 5% solution of cooking salt / methanol = 6: 4)

ESA Mass Spectrum: (M + H = 474 (M + Na) * = 496.6 Example 188.

N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -

1- methyl-2- [2- [4-N-n-hexyloxycarbonylamidino) phenyl] ethyl] benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 from N-ΗΗββπ-N- [2- (1H-tetrazol-5-yl) ethyl] -1 methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-ylcarboxamide and the hydrochloric acid n-hexyl ester.

Example 189.

N-phenyl-N (ethoxycarbonylethyl) -1-methyl-2- | N- (2-methoxy-4-n-pentoxycarbonylidinophenyl] aminomethyl] benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- {1- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and n-pentyl hydrochloric acid ester.

Yield: 53% of theory,

C ₃₅ H ₄₂ N ₆ O ₆ (642.7)

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

ESA Mass Spectrum: (M + H = 643 (M + H + Na) ** = 333.4 Example 190.

1-Phenyl- (2-ethoxycarbonylethyl) -1methyl-2- (4-n-heptyloxycarbonylamidino-

2-methoxyphenyl] aminomethyl] -benzimidazol5-ylcarboxamide

Prepared analogously to Example 90 of N-phenyl-N- (2-ethoxycarbonylethyl) -1-methyl-2- | N- (4-amidino-2-methoxyphenyl) -amino

64588 methyl] -benzimidazol-5-ylcarboxamide hydrochloride and hydrochloric acid n-heptyl ester.

Yield: 68% of theory,

C ₃₇ H ₄₆ N ₆ O ₆ (670.8) N -value: 0.56 (silica gel; dichloromethane / ethanol = 9: 1)

ESA mass spectrum: (M + H / = 671 (M + H + Na) ⁺⁺ = 347.4

Example 191.

N- (2-pyridyl) -B4- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (4-ethoxycarbonylamidino2-methoxyphenyl] aminomethyl] -benzimidazol-5ylcarboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -1 N- (2-ethoxycarbonylethyl) -1 methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and hydrochloric acid ethyl ester.

Yield: 43% of theory,

C ₃₁ H 'N ₇ O ₆ (601.7)

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

ESA mass spectrum: (M + H / = 602 (M + H + Na) ⁺⁺ = 312.8 Example 192.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (2-methoxy-4-p-pentoxycarbonylamidinophenyl] aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared analogously to Example 90 of N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1 methyl-2- N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hydrochloride and n-pentyl ester of hydrochloric acid.

Yield: 72% of theory,

C ₃₄ H ₄₁ N ₇ O ₆ (643.7)

Rf value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1)

ESA mass spectrum: (M + HF = 644 (M + H + NaF = 333.9

Example 193.

N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- (2-methoxy-4-n-heptyloxycarbonylamidinophenyl] aminomethyl] -benzimidazol-5-ylcarboxamide

Prepared in analogy to Example 90 of N- (2-pyridyl) -1 N- (2-ethoxycarbonylethyl) -1 methyl-2- [4- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide hyd hydrochloric acid rochloride and n-heptyl ester.

Yield: 55% of theory, C ₃₆ H ₄₅ N ₇ O ₆ (671.8)

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

ESA mass spectrum: (M + H &lt; + &gt; = 672 (M + H + NaF = 347.9 Example 194.

Dry ampoule with 75 mg of active substance per 10 ml

Composition:

active substance 75.0 mg mannitol 50.0 mg water for injection ad 10.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. The reconstitution of the solution for administration is made with water for injection.

Example 195

Dry ampoule with 35 mg of active substance per 2 ml

Composition:

active substance 35.0 mg mannitol 100.0 mg water for injection ad 2.0 ml

Preparation:

The active substance and mannitol are dissolved in water. After filling, freeze-dried. The reconstitution of the solution for administration is made with water for injection.

Example 196.

50 mg tablet active ingredient Composition:

(1) active substance 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mg

215.0 mg

Preparation:

The ingredients 1, 2 and 3 are mixed and granulated with an aqueous solution of 4. The dried granulate is mixed with 5. From this mixture, tablets are biplanar, double sided and with a dividing line on one side. Tablet diameter: 9 mm.

Example 197. 1 candle contains: 350 mg tablet of the active substance active substance 100.0 mg Composition: polyethylene glycol (1) active substance 350.0 mg (M.G. 1500) 600.0 mg (2) milk sugar 136.0 mg 5 polyethylene glycol (3) corn starch 80.0 mg (M.G. 6000) 460.0 mg (4) polyvinylpyrrolidone 30.0 mg polyethylene sorbitan mono- (5) magnesium stearate 4.0 stearate 840.0 mg

2000.0 mg

600.0 mg

Preparation:

Ingredients 1, 2 and 3 are mixed and mixed.

Claims (15)

nullified with an aqueous solution of 4. To the dried granulate is added by mixing 5. From this mixture compressed tablets, biplanar, double-sided and with a dividing line on one side. Tablet diameter: 12 mm. Example 198. 50 mg capsules of active substance (1) active substance 50.0 mg (2) corn starch dried 58.0 mg (3) milk sugar spray 50.0 mg (4) magnesium stearate 2.0 mg 160.0 mg Preparation: (1) is triturated with (3) and added to a mixture of (2) and (4) with vigorous mixing. This powder mixture is filled into hard gelatin capsules, size 3, with a capsule filling machine. Example 199 Capsules with 350 mg of active substance (1) active substance 350.0 mg (2) corn starch dried 46.0 mg (3) milk sugar pulverized 30.0 mg (4) magnesium stearate 4.0 mg 430.0 mg 1. Disubstituted bicyclic heterocyclic compounds of general formula R _a -A-Het-B-Ar-E (I) in which A represents a carbonyl or sulfonyl group attached to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of Het, at these parts cannot contain the group R, B means an ethylene group in which the methylene group, which is bonded either to the radical Het or Ar, can be replaced by an oxygen or sulfur atom, with one sulfinyl, sulfonyl, carbonyl or -NR] group, R] represents hydrogen atom or C _{| A 6-} alkyl group, E means cyano or R _b NH-C (= NH) -pyrene, in which R _b represents a hydrogen atom, a hydroxy group, a C, _3- alkyl group, or an in-moiety, Ar represents an optionally fluorine, chlorine or bromine atoms, by trifluoromethyl, C] ₃ alkyl or C] ₃ alkoxy substituted phenylene or naphthylene group, an optionally in the carbon skeleton by C _{f 3} alkyl substituted tienilenova, tiazolilenova, piridinilenova, a pyrimidinylene, pyrazinylene or pyridazinylene group, Het means a bicyclic heterocycle of formula Preparation: (1) is triturated with (3) and added to a mixture of (2) and (4) with vigorous mixing. This powder mixture is filled into hard gelatin capsules, size 6Be 0, with a capsule filling machine. Example 200. Suppositories with 100 mg of active substance45 in which X represents a nitrogen atom and Υ represents an oxygen or sulfur atom or one optionally substituted C, _6- alkyl or C _3-7 -cycloalkyl group with a nitrogen atom, in which one or two more do not65 64588 Angular methine groups in the phenyl moiety of the preceding bicyclic heterocycle may be replaced by one nitrogen atom, or X represents optionally a radical R, a substituted methine group, wherein R 1 is as defined above, and Y represents an optionally substituted C _1-6 alkyl group or a C _3-7 cycloalkyl group substituted with a nitrogen atom, or Het represents a group of the formulas Rj is defined as above, Z represents an oxygen or sulfur atom, one of the radicals D or G represents a nitrogen atom and the other of the radicals D or G represents a methyl group, and R _a represents a C _1-6 alkyl group, one optionally substituted by a C _3- alkyl group substituted with C _{3 7} a -cycloalkyl group, the C ₁₃ -alkyl group being optionally substituted by a carboxyl group or by a group which may be converted in vivo to a carboxyl group, or an R ₂ NR ₃ -pyrene, in which R ₂ represents a C _1-4 alkyl group which may be substituted with a carboxyl, Cj ₆ -alkiloksikarbonilna, benzyloxycarbonyl, C _{t 3} -alkilsulfonilaminokarbonilna, fenilsulfonilaminokarbonilna, trifluorosulfonilamino-, trifluorosulfonilaminokarbonilna or 1H-tetrazolyl group, a hydroxyl, phenyl -Cj ₃ -alkoxy, carboxy-C! _3- alkylamino-, C _1-3 -alkoxycarbonyl-C _1-3 -alkylamino-, N- (C _1-3 -alkyl) carboxy-C _1-3 -alkylamino- or N- (C _1-3 -alkyl) -C 1! N -alkoxycarbonyl-C! _{A 3-} alkylamino group substituted with a C ₂ '-alkyl group, wherein in said groups the adjacent to the nitrogen atom the α-carbon atom cannot be substituted, or one optionally substituted with a C _1-3 alkyl group substituted by a piperidinyl group, and R ₃ represents a hydrogen atom, a C _1-6 alkyl group, optionally a C _1-3 alkyl group substituted with a C _3-7 cycloalkyl group, one C _3-6 alkenyl or C _3-6 alkynyl group, wherein the unsaturated moiety cannot be directly linked to the nitrogen atom of the R ₂ NR ₃ -pyrene, optionally with a fluorine, chlorine or bromine atom, with a C _1-3 -alkyl or C _1-3 -alkoxy group substituted phenyl group, one optionally with a C _1-3 -alkyl substituted benzyl group, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl First, pyridazinyl, pyrrolyl, thienyl or imidazolyl group, or R ₂ and R ₃ together with the nitrogen atom between them optionally represent a carboxylic or C 1-6 -alkoxycarbonyl group substituted by a 5- to 7-membered cycloalkenylamino group to which one phenyl ring, their tautomers, their stereoisomers may be further condensed , mixtures thereof and salts thereof. Disubstituted bicyclic heterocyclic compounds of general formula I according to claim 1, wherein the formula A means one with a benzo, pyrido, pyrimido-, pyrazino-, pyridazino- or thiopart of the radical Het bonded carbonyl or sulfonyl group, furthermore, said portions may not contain the group R, B means an ethylene group in which a methylene group, which is bonded to either the radical Het or Ar, may be replaced by one oxygen or sulfur atom, with one sulfinyl, sulfonyl, carbonyl or NR1 group, Rj represents a hydrogen atom or _{L 4} -alkyl group, E denotes an _{R b NH-C (= NH} ) -rpyna, in which Rh represents a hydrogen atom, a hydroxyl group, a _3- alkyl group or an in vivo leaving group, Ar represents an optionally fluorine, chlorine or bromine atom or by a trifluoromethyl, C ₍₃ -alkyl or ₃ -alkoxy-substituted phenylene group, an optionally in the carbon skeleton by Cj ₃ alkyl substituted tienilenova, tiazolilenova, piridinilenova, pirimidinilenova, pirazinilenova or a pyridazinylene group, Het means a bicyclic heterocycle- in which X represents a nitrogen atom and Y represents an oxygen or sulfur atom or one optionally substituted C _1-6 alkyl or C _3-7 cycloalkyl group with an additional one or two non-angular methine groups in the phenyl moiety of the previous bicyclic heterocycle may be replaced by one nitrogen atom, or X represents an optionally substituted radical R _{1 with a} methyl group, wherein R 1 is as defined above, and Y represents an optionally substituted C _1-6 alkyl or C _3-7 cycloalkyl group substituted with a nitrogen atom, or Het means a group of the formulas R] is defined as above, Z represents an oxygen or sulfur atom, one of the radicals D or G represents a nitrogen atom and the other of the radicals D or G represents a methyl group, and R _a represents a C _(6- alkyl group, one optionally substituted by a C _(3- alkyl group substituted by C) _{A 37-} cycloalkyl group, the C _1-3 -alkyl group being optionally substituted by a carboxyl group or by a group that can be converted in vivo to a carboxyl group, or an R ₂ NR ₃ -pyrene, in which R ₂ represents a ₄ alkyl group which may be substituted with a carboxyl, C -alkiloksikarbonilna, benzyloxycarbonyl, C ₃ -alkilsulfonilaminokarbonilna, fenilsulfonilaminokarbonilna, trifluorosulfonilamino-, trifluorosulfonilaminokarbonilna or 1H-tetrazolyl group, a hydroxyl, phenyl With! ₃ -alkoxy, carboxy-C ^ ₃ -alkylamino, C ₃ alkoxycarbonyl-C! _3- Alkylamino-, N- (C ₃ -alkyl) carboxy-C, _3- alkylamino- or N- (C ₃ -alkyl) C, _3- alkoxycarbonyl-C _1-3- alkylamino group substituted with a C _2-4 alkyl group, such as in said groups, the carbon atom adjacent to the nitrogen atom may not be substituted, or optionally substituted by a piperidinyl group with a C _1-3 alkyl group, and 64588 R ₃ represents a hydrogen atom, a (C _1-3 alkyl group, optionally a C _3-6 alkyl group substituted with a C _3-7 cycloalkyl group, a C _3-6 alkenyl or -alkynyl group, wherein the unsaturated moiety cannot be directly bonded to the nitrogen atom of the R ₂ NR ₃ -pyrrole, optionally with a fluorine, chlorine or bromine atom, with a ( _3- alkyl or / _3- alkoxy group substituted phenyl group, one optionally with a C _1-3 alkyl group substituted with benzene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimid nonyl, pyrazinyl, pyridazinyl, imidazolyl group or a piperidinyl group, or R ₂ and R ₃ together with the nitrogen atom between them optionally represent a carboxylic or C ₁ -alkoxycarbonyl group substituted by a 5- to 7-membered cycloalkylenimino group to which a phenyl ring, their tautomers, their prodrugs may be further condensed , their double prodrugs, their stereoisomers and their salts. Disubstituted bicyclic heterocyclic compounds of the general formula I according to claim 1, wherein the formula A means one with a benzo, pyrido, pyrimido -, - pyrazino-, pyridazino- or thiopart of the Het bonded carbonyl or sulfonyl group, furthermore the above-mentioned moieties may not contain the group R _p B means an ethylene group in which the methylene group which is bound to the radical Ar can be replaced by an oxygen or sulfur atom or by a -NR 1 -pyrrole, wherein R 1 represents a hydrogen atom or a C ₁ -C ₆ alkyl group, E denotes one R _b NH-C - (= NH) -pyrene in which Rh represents a hydrogen atom, hydroxyl, C] ₉ -alkoxycarbonyl, cyclohexyloxycarbonyl, _phenyl-C1-3 -alkoxycarbonyl, benzoyl, p-C _{| 3} -alkilbenzoilova or pyridinoyl group, the ethoxy moiety in the 2-position of the previous C ₁₉ -alkoxycarbonyl the group may be further substituted by one C _1-3 alkylsulfonyl or 2 (C ₃ alkoxy) ethyl group, Ar means one optionally chlorine atom, one methyl, ethyl or methoxy group substituted 1,4-phenylene group or one 2,5-thienylene group, Het represents 1 - (/ _3-alkyl) -2,5-benzimidazolilenova, 1-cyclopropyl-2,5-benzimidazolilenova, 2,5-benztiazolilenova, 1 - (/ _3-alkyl) -2,5-indolilenova, 1 - (( _3- alkyl) -2,5-imidazo [4,5-b] -pyridinylene, 3- (C, _3- alkyl) -2,7-imidazo [1,2-a] pyridinylene, or 1 - (/ ₃ - alkyl) -2,5-thieno [2,3-b] imidazolylene group and R _a represents an I / NR ₃ -pyrene in which R ₂ represents a (N-alkyl) group which may be substituted by one carboxyl, C _1-6 alkyloxycarbonyl, benzyloxycarbonyl, C, _3- alkylsulfonylaminocarbonyl or 1 H -tetrazol-5-yl group, one by hydroxyl, benzyloxy-, carboxy ( _3- Alkylamino- / _3- alkoxycarbonyl- / _3- alkylamino-, N - (( _3- alkyl) -carboxy- / _3- alkylamino- or N- (C ₃ -alkyl) -C ₁₃ -alkoxycarbonyl-C, _{A 3-} alkylamino group substituted with a C ₂ 'alkyl group, and in the said groups the α-carbon atom adjacent to the nitrogen atom cannot be substituted, I / represents a C _3-7 cycloalkyl group, one propargyl group, wherein the unsaturated moiety cannot be directly bonded to the nitrogen atom of the f / NR 1 group, optionally a fluorine or chlorine atom, to a methyl or methoxy group substituted phenyl group, optionally a methyl group substituted with a pyrazolyl, pyridazolyl or pyridinyl group, or R ₂ and R ₃ together with the nitrogen atom between them optionally represent a carboxylic or / '-alkoxycarbonyl group substituted by a 5- to 7-membered cycloalkyleneimino group to which one phenyl ring, their tautomers, their stereoisomers and their salts. Disubstituted bicyclic heterocyclic compounds of the general formula I according to claim 1, wherein the formula A means one with the benzo, pyrido or thieno moiety of the radical Het bonded carbonyl or sulfonyl group, furthermore the moieties mentioned above may not contain the group Rp B stands for an ethylene group in which the methylene group attached to the radical Ar can be replaced by one oxygen or sulfur atom or by a -NR 1 -pyrrole such as Rj represents a hydrogen atom or a methyl group, E denotes one R _b NH-C - (= NH) -pyrene in which R _b represents a hydrogen atom, hydroxyl, C] ₉ -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C] ₃ -alkilbenzoilova or nicotinoyl group, the ethoxy moiety in the 2-position of the previous C ₁₉ -alkoxycarbonyl group may be further substituted with a C] ₃ -alkilsulfonilova or 2- (C ₃ alkoxy) ethyl group, Ar means one optionally chlorine atom, one methyl, ethyl or methoxy group substituted 1,4-phenylene group or one 2,5-thienylene group, Het stands for 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo [4,5- B] -pyridinylene, 3-methyl-2,7-imidazo [1,2-a] pyridinylene or 1-methyl-2,5-thieno- [2.3b] imidazolylene group and R _a means one R ₂ NR ₃ -rpyna in which R ₂ represents one C _(3- alkyl group which may be substituted by one carboxyl, C _1-6 alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1 H-tetrazol-5-yl group, one by hydroxyl, benzyloxy-, carboxy-C _3- alkylamino-, C 1 -alkoxycarbonyl-C, _3- alkylamino-, N- (C ₁ -alkyl) -carboxy-C _1-3 alkylamino- or N- (C ₃ -alkyl) -C] ₃ -alkoxycarbonyl-C, _3- alkylamino group substituted by a C _2-3 -alkyl group, whereas in said groups the α-carbon atom adjacent to the nitrogen atom cannot be substituted, R ₃ represents a propargyl group wherein the unsaturated moiety cannot be directly bonded to the nitrogen atom of the R 6 R 6 group, optionally a fluorine or chlorine atom, a methyl or methoxy group substituted phenyl group or pyridinyl group, their tautomers, their stereoisomers and their salts. 5. Disubstituted bicyclic heterocyclic compounds of the general formula I according to claim 1, wherein the formula A means one with the benzo or thieno moiety of the Het radical linked carbonyl group, B means an ethylene group in which the methylene group bound to the radical Ar can be replaced by an -NR 1 group, wherein R represents a hydrogen atom or a methyl group, E denotes one R _b NH-C - (= NH) -pyrene in which R _b represents a hydrogen atom, a hydroxyl, C ₉ -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C ₃ -alkylbenzoyl or nicotinoyl group, the ethoxy moiety in the 2-position of the foregoing C 1 ₉ alkoxy group being additionally substituted with one methylsulfonyl or 2-ethoxyethyl group, Ar means one optionally substituted with a methoxy group 1,4-phenylene group or one 2,5-thienylene group, Het means a 1-methyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno [2.3b] imidazolylene group, and R _a means one R ₂ NR ₃ -rpyna in which R ₂ represents a C _1-3 alkyl group which may be substituted by one carboxyl, C 1-6 alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, one by hydroxyl, benzyloxy, carboxy-C _{( 3-} alkylamino-, C 1-6 -alkoxycarbonyl-C] _3- alkylamino-, N- (C _(3- alkyl) -carboxy-C, _3- alkylamino- or N- (C] _3- alkyl) -C ₁₃ -alkoxycarbonyl A -C, _3- alkylamino group substituted with a C _2-3 -alkyl group, and in said groups the α-carbon atom adjacent to the nitrogen atom cannot be substituted, R ₃ represents a fluorine atom optionally substituted phenyl group or 2-pyridinyl group, their tautomers, their stereoisomers and their salts. 6. Compounds of general formula I: (a) N-phenyl-L4- (2-carboxyethyl) -2- [N (4-amidinophenyl) -amino-methyl] -benzthiazole- 5-carboxamide, (b) 14-phenyl-L4- (2-hydroxycarbonylethyl) -2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -benzthiazol-5-ylcarboxamide, 64588 (c) N-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, (d) N-phenyl-N - (3-hydroxycarbonylpropyl) -1-methyl-2-N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, (e) N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -1 -methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, (f) N- (2-pyridyl) -L4- (2-hydroxycarbonylethyl) -1-methyl-2- [ 2- (2-amidinothiophen-5-yl) ethyl] -benzimidazol-5-yl-carboxamide, (g) T4- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4 -amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, (h N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [2- (2-amidinophenyl) ethyl] benzimidazol-5-yl-carboxamide, (i) N-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-yl-carboxamide, (j) N-phenyl-N- [2- (1H-tetrazol-5yl) ethyl] -1-methyl-2- [2- (4-amidinophenyl) ethyl] benzimidazol-5-yl-carboxamide, (k) N-phenyl-N- [2- (1H-tetrazol-5yl) ethyl] -1 -methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, (1) N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [ N- (4-amidinophenyl) -methylaminomethyl] -benzimidazol-5-yl-carboxamide, (m) L1- (3-pyridyl) -L1- (2-hydroxy) bonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -L-methylaminomethyl] -benzimidazol-5-yl-carboxamide, (n) L1-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -L4-methylaminomethyl] -benzimidazol-5-yl-carboxamide, (o) N-phenyl-N - [(N-hydroxycarbonylethyl-14-methyl) -2-amino-ethyl] -1 -methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazole-5-yl-carboxamide, (p) b1- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- ( 4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, (q) N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) - aminomethyl] -benzimidazol-5-yl- carboxamide, (d) N-phenyl-N- (2-hydroxycarbonyl) -1-methyl-2- [T4- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, (s ) B1- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide, (t) N- phenyl-N- (2-methoxycarbonylethyl) -1-methyl-2- [T4- (4-amidinophenyl) -aminomethyl] -indol-5-yl-carboxamide, (i) b4-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -thieno [2,3-b] imidazol-5-yl-carboxamide, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and ehni salts. 7. L1-phenyl-N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxamide, its prodrugs, its double prodrugs and its salts. 8. N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxamide, its prodrugs, its double prodrugs, and its salts. 9. N- (2-Pyridyl) -1H- (2-hydroxycarbonylethyl) -1-methyl-2- [N- (4-amidino-2-methoxyphenyl) -aminomethyl] -benzimidazol-5-ylcarboxamide, its prodrugs, its double prodrugs and its salts. 10. N1- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -1-methyl-2- [N- [4- (1H-p-hexyloxycarbonylamidino) phenyl] -aminomethyl] -benzimidazol-5-yl-carboxamide and salts thereof. 11. Physiologically acceptable salts of the compounds according to claims 1 to 10, characterized in that E represents one R _b NH-C (= NH) -pyrene. A medicament comprising a compound according to at least one of claims 1 to 10, wherein E represents one R _b NH-C (= NH) group or salt according to claim 11 optionally together with one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 10, in which E represents an R _b NH-C (= NH) group or salt according to claim 11 for the preparation of a medicament with the effect of extending thrombin time, with the effect of inhibiting thrombin and related serine proteases. A method for the preparation of a medicament according to claim 12, wherein the non-chemical route is a compound according to at least one of claims 1 to 10, wherein E represents one R _b NH-C (= NH) -pyrene or salt according to claim 11 is embedded in one or more inert carriers and / or diluents. A process for the preparation of the compounds according to claims 1 to 11, characterized in that a) for the preparation of a compound of general formula I, in which E represents R _b NH-C (= NH) group, wherein R _b represents one hydrogen atom, one hydroxyl group or a C _1-3 alkyl group optionally in the reaction mixture obtained compound of the general formula RA-Het-B-Ar-C (= NH) -Z ₁ (II) in which A, B, Ar, Het and R _a are as defined in claims 1 to 10, and Z represents an alkoxy-, aralkoxy-, alkylthio or aralkylthio group, reacts with one amine of the general formula H ₂ NR _b '(III) in which R / represents one hydrogen atom, one hydroxyl or a C ₃ -alkyl group, or b) for the preparation of a compound of general formula I wherein R _a -A-pyrene and E are as defined in claims 1 to 10, provided that the R _a -A-group contains a carboxyl group and E is defined, as in claims 1 to 10, or the I _a -A group is defined as in claims 1 to 10, and E represents NH ₂ -C (= NH) -rpyna, or the R 1 -A group contains a carboxyl group and E represents NH ₂ -C (= NH) -pyrene, a compound of the general formula R _a '-A-Het-B-Ar-C-E' (IV) in which A, B, Ar and Het are defined as in claims 1 to 10, and R _a '-A-rpyna and E' are given in claims 1 to 10 for R _a -A-rpynaTa and E ', provided that R _a ' -A-rpynaTa contains a group which, by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, can be converted to a carboxyl group, and E is as defined in claims 1 to 10, or E 'is a group which, by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, can be converted to NH ₂ -C (= NH) - rpyna, and R _a '-A-rpypata has mentioned in RETENTION 1 to 10 for R _a A-group, or a and _a '-A- group contains a group which, by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis can be converted into a carboxyl group, and E represents a group which, by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis, can be converted to NH ₂ -C (= NH) -pyrene, is converted by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to a compound of general formula I, in which I. _a -A-group and E are defined as in claims 1 to 10, provided And it is _a -A-group contains a carboxy group and E is defined as in claims 1 to 10, or R _a -A-rpynaTa is as defined in claims 1 to 10. meanings and E represents NH ₂ -C (= NH) -rpyna, or R _a -The group contains a carboxyl group and E represents NH ₂ -C (= NH) -rpyna, or c) for the preparation of a compound of the general formula I, wherein the I _a -A group contains one of the compounds of the general formula mentioned in the definition of the R _a -A group in claims 1 to 10 R _a- A-Het-B-Ar-E (V) in which B, E, Ar and Het are defined as in claims 1 to 10, and R _a- A-rpyna contains the claims mentioned in claims 1 to 10 for R _a -A-rpynaTa values, provided that the R 1 '- A-group contains a carboxyl group or a group which with alcohol may be converted to a corresponding ester group, reacts with an alcohol of the general formula HO-R ₇ (VI) in which R ₇ represents the alkyl moiety of one of the carboxylic groups mentioned in claims 1 to 10 for the in vivo leaving groups, with the exception of the R 1 -CO-O-1 R 1CR 5 -pyramine, or with its formamidacetals, or with a compound of the general formula Zj-R, (VII) in which R represents the alkyl moiety of one of the carboxylic groups mentioned in claims 1 to 10 for the in vivo leaving groups, except R ₆ -CO-O- (R ₅ CR ₆ ) - rpy 64588 watts, and Z ₂ represents a leaving group, or d) for the preparation of a compound of general formula I, in which R _b represents an in vivo leaving group, a compound of general 5 formula RA-Het-B-Ar-C (= NH) -NH ₂ (VIII) in which R _a , A, Het, B and Ar are as defined in claims 1 to 10, reacted with a compound of the general formula z ₂ -r "(IX) in which Rg denotes an in vivo leaving group and Z ₂ means a nucleofugal leaving group, or e) to obtain a compound of general formula I, in which B represents an ethylene group, in which one methylene group is replaced by a sulfinyl or sulfonyl 2θ group, a compound of the general formula R _a -A-Het-B'-Ar-E (X) wherein A, E, Ar, Het and R _a are as defined in claims 1 to 10 and B 'represents an ethylene group in which a methylene the group is replaced by a sulfenyl or sulfinyl group, oxidized, or f) to obtain a compound of general formula I wherein E is a cyano group and B is an ethylene group in which a methylene group which is bonded to either the Het group or the Ar group is replaced by an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NR 1 -pyrene compound of the general formula R _a -A-Het-U (XI) is reacted with a compound of the general formula V-Ar-CN (XII) in which the formulas R _a , A, E, Ar and Het are defined as in claims 1 to 10, one of the groups U or V represents one HO-, HS-, HOSO-, HOSO ₂ - or HNR, -rpyna, and 45 the other Z, CH ₂ -rpyna, wherein R 1 is as defined in claims 1 to 10, and Z represents a nucleofugal cleavage group, or g) for the preparation of a compound of the general formula I, in which E represents one cyano group and R _a - one R 1 NR 2 group, a compound of the general formula HA-Het-B-Ar-CN (XIII) in which A, B, Het and Ar are defined as in claims 1 to 10, is reacted with an amine of the general formula k, (XIV) in which R 1 and R ₃ are as defined in claims 1 to 10, or with its reactive derivatives, or h) for the preparation of a benzimidazolyl, benzthiazolyl or benzoxazolyl compound of the general formula I, in which B represents an ethylene group, a compound of the general formula wherein R _a , A and Y are defined as in claims 1 to 10 by reacting with a compound with general formula HO-CO-CH ₂ CH ₂ -Ar-E (XVI) in which Ar and E are as defined in claims 1 to 10, or with its reactive derivatives, or i) for the preparation of a quinoxalin-2-one compound of the general formula I a compound of the general formula in which R _a , R 1 and A are defined as in claims 1 to 10, is reacted with a compound of the general formula HO-CO-COCH ₂ -Ar-E, (XVIII) wherein Ar and E are as defined in claims 1 to 10, or with its reactive derivatives, or j) for the preparation of a compound of the general formula I, in which R 1 represents a C ₁ -C ₆ alkyl group which is substituted by one alkylsulfonylaminocarbonyl group, a compound of the general formula R _{2 '} NA-Het-B-Ar-E _R 1, (IXX) in which R 1, A, B, E and Het are as defined in claims 1 to 10 and R 4 represents one C | _{A 4-} alkyl group which is substituted by one carboxyl group or its reactive derivatives is reacted with a salt of a compound of the general formula C _t h-alkyl-SOj-NHj (XX) and, if necessary, removes the protecting group used during the reactions 5 Protection of reactive groups, and / or the compound of general formula I is separated then, if desired, of its stereoisomers, and / or the compound of formula (I) thus obtained is converted 10 into its salts, especially for pharmaceutical use, in its physiologically acceptable salts with an inorganic or organic acid or base.