CZ200147A3 - Benzimidazoles, process of their preparation and use as medicaments - Google Patents

Abstract

The present invention relates to novel benzimidazoles of the general formula I wherein Ra to Rc, A, Ar, and B are specific for their tautomers, stereoisomers, mixtures, precursors, and derivatives thereof carboxyl groups contain negatively under physiological conditions a charged group, and salts thereof, especially physiologically acceptable salts with inorganic or organic acids; bases that demonstrate valuable properties. General compounds the formulas i, where R0 is cyanoacid, are valuable intermediates for the production of the remaining general compounds of formula (I), and compounds of formula (I) wherein Rc is amidine group, show valuable pharmacological properties properties, especially antithrombotic effects.

Description

Benzimidazoles, their production and use as a medicament

Technical field

The present invention relates to benzimidazoles of formula I wherein R _a to R _c ,

A, Ar and B are as defined in claim 1, their tautomers, their stereoisomers, their mixtures, their precursors, their derivatives which contain negatively charged λ in place of the carboxy group under physiological conditions

and the salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids or bases, which show valuable properties. Compounds of formula I wherein R _c is cyano are valuable intermediates for the preparation of the remaining compounds of formula I, and compounds of formula I wherein R _c is amidino as set forth in claim 1 exhibit valuable pharmacological properties, particularly antithrombotic effects.

SUMMARY OF THE INVENTION

The present invention relates to benzimidazoles of formula I,

R

N

their tautomers, stereoisomers, mixtures, precursors, derivatives containing a negatively charged group under physiological conditions, and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, which exhibit valuable properties.

Compounds of formula (I) wherein R @ _c is cyano are valuable intermediates in the preparation of other compounds of formula (I) and compounds of formula (I) wherein R @ _c is one of the following amidino groups and tautomers, stereoisomers, mixtures, precursors, derivatives containing a negatively charged group under physiological conditions, and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids, and their stereoisomers demonstrate valuable pharmacological properties, in particular antithrombotic effects.

Accordingly, the present invention relates to novel compounds of the above general formula (I) and to their manufacture, to medicaments containing pharmacologically active compounds, to their manufacture and use.

In the above general formula I means

Ar is a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, a trifluoromethyl, a C 1-3 alkyl or alkoxy group, a thienylene, a thiazolylene, a pyridinylene, a pyrimidinylene, a pyrazinylene or a pyridazinylene optionally substituted with a C 1-3 alkyl group;

A C 1-3 - alkylene group,

B an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, or an imino group substituted with a C 1-3 alkyl group in which the alkyl moiety may be mono- or disubstituted with a carboxy group,

R _and RrCO-C 5-8 -cycloalkyl, where it is

R1-C1-3-alkoxy, amino, C1-4-alkylamino or di- (C1-4-alkyl) -amino, in which the alkyl moiety may be substituted by carboxy,

A 4- to 7-membered cycloalkylenimino or cycloalkenylenimino group which may be substituted with one or two

C 1-3 -alkyl, wherein one alkyl substituent may be simultaneously substituted by hydroxy-, C 1-3 -alkoxy, carboxy-, carboxy-C 1-6 -alkyl. _3- alkoxy-, carboxy-C 1-3 -alkylamino-, N- (C 1-3 -alkyl) -N- (carboxy-C 1-3 -alkyl) amino, carboxy-C 1-3 -alkylamino-carbonyl, N- (C 1-3 -alkyl) -N- (carboxy-C 1-3 -alkyl) aminocarbonyl, carboxy-C 1-3 -alkylaminocarbonylamino,

- (C 1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonylamino, 3- (C 1-3 -alkyl) -3- (carboxy- (1-3-alkyl) -aminocarbonylamino or 1, 3-di- (C ₃ -alkyl) - 3 - (carboxy-C1-3 -alkyl) aminocarbonyl-amido,

4- to 7-membered cycloalkyleneimino substituted with hydroxy;

A 5- to 7- membered cycloalkyleneimino group optionally substituted Cv ₃ -alkyl, where through two adjacent carbon atoms of a phenyl ring condensed group morflino, piperazino, N- (C-i_ ₃ alkyl) piperazino, pyrrolino, 3,4- dehydro-piperidino or pyrrol-1-yl, R ₂ -CX-C 3-5 -cycloalkyl, wherein

R ₂ is optionally phenyl, naphthyl or monocyclic 5- or

A 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group optionally contains an imino group substituted with

A C 1-3 alkyl group, an oxygen or sulfur atom or one or two nitrogen atoms and the above alkyl substituent may be substituted by carboxy, carboxy-C 1-3 -alkoxy, carboxy-C 1-3 -alkylamino or N- (C 1-6 -alkyl); ₃ -alkyl) -carboxy-C 1-3 -alkylamino, and

X is an oxygen atom, C 1-3 -alkylamino, C 1-3 alkoxyimino, C 1-3 -alkylhydrazino, di- (C ₃ -alkyl) hydrazine, c _{2. 4-} alkanoyl-hydrazino, N- (C 1-3 alkyl) -C ₂ . ₄ -alkanoylhadrazino or

C 1-3 -alkylidene which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety substituted by a carboxy group, a C _1-3 -alkyl- or a C _{3 group} . ₅ cycloalkyl substituted by imidazole or imidazolone, in which the imidazole ring may be substituted by phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, the substituents being the same or different and one of the above alkyl substituents may be simultaneously substituted by carboxy or in the 2 or 3 position by amino,

C 2-4 alkanoylamino, C 1.3 alkylamino, N- (C _2.4 alkanoyl) - C _{4th The 3-} alkylamino or di- (C _1-3 -alkyl) -amino and imidazolone ring may be substituted by a C _1-3 -alkyl group, wherein the alkyl substituent may be substituted by a carboxy group or at the 2 or 3 position by an amino group,

C ₂ .4 alkanoylamino, C ₃ -alkylamino, N- (C ₂ -4 -alkanoyl) -C ₃ -alkylamino or di- (C ₃ -alkyl) -amino and, additionally to the above-mentioned imidazole and imidazolone cycle can via two adjacent carbon atoms to condense a pyridine ring, an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two C _1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by a carboxy group, a C 1-4 -alkyl group, which is substituted by • 9

- 6 98 9

C 1-3 -alkyl-Y 1 -C 1-3 -alkyl, HOOC-C 1-3 -alkyl-Y 1 -C 1-3 -alkyl, tetrazolyl-C 1-3 -alkyl-Y ₂ , R ₃ NR 4 - or R 3 NR 4 -C 1-3 - alkyl and isoxazolidinyl optionally substituted with C 1-3 -alkyl, pyrrolinocarbonyl, 3,4-dehydropiperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy-, aminocarbonyl-C _1-3 -alkylaminocarbonyl-, di- (C 1-3 -alkyl) - aminocarbonyl- or

4- to 7-membered cycloalkylenimino-carbonyl, wherein the cycloalkylenimine moiety of the previously mentioned groups is substituted with one or two C 1-3 -alkyl groups and at the same time the alkyl moiety or alkyl substituent of the above-mentioned C 1-3 -alkylaminocarbonyl, di- (C _1-3) -alkyl) -aminocarbonyl or cycloalkylenimino-carbonyl groups substituted by carboxy and the remaining hydrogen atoms may be replaced, in whole or in part, by a fluorine atom in which

R ₃ represents hydrogen or optionally C 1-3 -alkyl substituted with carboxy and

R ₄ is hydrogen, C 1-3 -alkyl-Y ₁ -C 1-3 -alkyl-Y ₂ , carboxyC 1-3 -alkyl-Y ₁ -C 1-3 -alkyl-Y ₂ , C 1-3 -alkyl-Y ₂ or carboxyCl -3-alkyl-Y ₂ ;

R 3 and R 4 together with the intervening nitrogen atom are 4- to 7-membered cycloalkyleneimino substituted with carboxy, O-3-alkyl or carboxy-C _1-3 -alkyl, where

- 7 ··· ··· ···

Vazbuι carbon-carbon bond, oxygen atom, sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH- group;

Y ₂ carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO-, wherein the carbonyl group is -NH-CO- group connected to the nitrogen atom R3NR4- groups and in the definition of the radicals Y1 and Y2 occurring imino groups can be substituted with C 1-3 -alkyl or carboxy-C 1-3 -alkyl, C 1-3 -alkyl or C 3-5 -cycloalkyl substituted with R 5 NR 6, where

R ₅ is hydrogen, C 1-3 alkyl, C 5-7 cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl; and

R ₆ is O 1-3 -alkyl, carboxy-C 1-6 -alkyl; _3- alkyl or carboxy-C 1-6 alkyl; ₃ alkylcarbonyl,

Cm -alkyl which is substituted by C ₂ -4 -alkynoyl or _C5-.7 cykloalkynoyl a chlorine, bromine or iodine-substituted C 1-3 -alkyl,

R _b is a hydrogen atom or a C 1-3 alkyl group a

R _{c is} cyano or optionally an amidine group substituted with one or two C 1-3 -alkyl groups.

• ·

In defining the abovementioned residues, said carboxy groups may be replaced by a group which can be converted in-vivo to a carboxy group, or under physiological conditions with a negatively charged group, or in defining the abovementioned residues, said amino and imino groups may be substituted inter alia in-vivo removable residue. Such groups are described, for example, in WO98 / 46576 and N.M.Nielson et al. in International Journal of Pharmaceutics 39, 75-85 (1987).

A group that is converted in-vivo to a carboxy group is, for example, a hydroxymethyl group, an alcohol-esterified carboxy group, wherein the alcohol moiety is preferably ββ -alkanol, phenyl-C 1. ₃ -alkanol, C ₃ . ₉ cycloalkanol, wherein the C ₅ -8 -cykloalkynol may subsequently be substituted by one or two C ₃ alkyl groups, C _5. -Cykloalkynol _8, wherein the methyl group is replaced in the 3 or 4 position by an oxygen atom or alternatively a group C ₃ -alkyl, phenyl-C i_ ₃ -alkyl, phenyl-C ₃ -alkoxycarbonyl or C ₂ -6 alkanoyl substituted imino group and the cycloalkynol moiety may be substituted with one or two C _1-3 -alkyl groups, C ₄ . ₇ cycloalkenol, C ₃ . ₅ -alkenol, a phenyl-C ₃ -s -alkenol C _{3rd 5} -alkinol or phenyl-C ₃ -s alkynol with an indication that no binding of carbon atom with an oxygen atom which forms a double or triple bond, C _{3rd 3-} cycloalkyl-C _1-3 -alkanol, bicycloalkanol having a total of 8 to 10 carbon atoms, which may be substituted by one or two C _1-3 -alkyl groups, 1,3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of formula

R _d = CO-O- (R _e CR f) -OH, where they are

R _{d is} a C 1-6 group. _3- alkyl, C 5-7 -cycloalkyl, phenyl- or phenyl-C 1-6 alkyl; _3- alkyl •

- 8 ·· · «··

R _e is hydrogen, C 1-3 -alkyl, C 5-7 -cycloalkyl, or phenyl and

Rf is hydrogen or C 1-3 -alkyl, under physiological conditions a negatively charged group means tetrazo-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C 1-6 alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C 1-6 -alkylsulfonylamino, C 1-6 -alkylsulfonylamino, C 1-6 -alkylsulfonylamino perfluoro-C- | ₆ -alkylsulfonylaminocarbonyl, and an in-vivo leaving group imino or amino means a hydroxy group, an acyl group such as a benzoyl group optionally mono- or disubstituted with a fluorine, chlorine, bromine or iodine atom, a C 1-3 -alkyl or a C 1-3 -alkoxy group, the substituents may be the same or different, pyridinoyl or C 1-6 -alkynoyl as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl, 3,3,3-trichloropropionyl or alkyloxycarbonyl, C 1-6 -alkoxycarbonyl or C 1-6 -alkylcarbonyloxy wherein the hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxykarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexydecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloretylkarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, terc.butylkarbonyloxy, pentylcarbonyloxy, hexylcarbonyl-oxy octylkarbonyloxy, nonylkarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy, phenyl-C 1-6 -alkoxycarbonyl such as benzyloxycarbonyl, phenylethoxy · ♦ ·· <··

- 10 - ......... · * ··· carbonyl or phenylpropoxycarbonyl, 3-aminopropionyl, in which the amino group may be mono- or disubstituted

Whose. ₆ alkyl or C3-7 cycloalkyl group and the substituents may be identical or different, C 1-3 _{-alkylsulfonyl-C2} -4 -alkoxycarbonyl, C |. _{3 -alkoxy-C2} -4 -alkoxycarbonyl, R _d -CO-O- (R _d CR _f) -O-CO, C. ₆ alkyl-CO-NH- (R _g CR _h) -O-CO or

C 1-6 -alkyl-CO-O- (R g CR _h ) - R _g CR _h ) -O-CO, wherein R _d to R _{f are} as defined above,

_Rg and Rh may be the same or different and represent hydrogen atoms or C1-3 -alkyl groups.

Further, the previously defined saturated alkyl and alkoxy groups containing more than 2 carbon atoms also include their branched isomers such as isopropyl, tert-butyl, isobutyl, and the like.

Important compounds are compounds of formula Ia

where

A represents a C 1-3 -alkylene group,

B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C 1-3 alkyl group in which the alkyl moiety may be mono- or disubstituted by a carboxy group;

- 12 4 4 4

4 ·

4 ·

4 · 444 ·

R _a represents a group R 1 -CO-C 3-5 -cycloalkyl where it is

R _{4 is} a C 1-3 -alkoxy, amino, -alkylamino or di- (C _1-4 -alkyl) amino group in which the alkyl moiety may be substituted by a carboxy group,

A 4- to 7- membered cycloalkylenimino or cycloalkenylenimino group which may be substituted with one or two C 1-3 alkyl groups, wherein the alkyl substituent may be simultaneously substituted with hydroxy, -alkoxy, carboxy, carboxy-C 1-3 -alkoxy, carboxy-C 1-6 . _3- alkylamino, N- (C _1-3 -alkyl) -N (carboxy-C 1-3 -alkyl) -amino, carboxy-C-1-3-alkylamino-carbonyl, N- (C _1-3 -alkyl) -N - (carboxy-C _1-3 -alkyl) -aminocarbonyl, carboxy-C 1-3 -alkylaminocarbonylamino, 1- (C 1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) -aminocarbonylamino, 3- (C 1-6 -alkyl) -aminocarbonylamino; _3- alkyl) -3- (carboxy-C 1-3 ₎

-alkyl) aminocarbonylamino or 1,3-di- (C 1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) aminocarbonylamino,

4- to 7- membered cycloalkyleneimino substituted with hydroxy

A 5- to 7-membered cycloalkylenimine group optionally substituted with a C 1-3 -alkyl group wherein the phenyl ring, the morpholino, piperazino, N- (C _1-3 -alkyl) -piperazino, pyrrolino, 3, is fused over two adjacent carbon atoms , 4-dehydropiperidino or pyrrol-1-yl,

- 12 φφ φ

φ • φ φ

φ φ φ φ · · · • • • φ φ

• R ₂ represents a -C ₂ -C ₃ -C 5 -cycloalkyl group where it is

R 2 is a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted with a C 1-3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group in optionally substituted C 1-3 an alkyl group, an oxygen atom, a sulfur atom or one or two nitrogen atoms and d and the above alkyl substituent may be substituted by carboxy, carboxy-C 1. _3- alkoxy, carboxy-C _1-3 -alkyl amino or N- (C 1-3 -alkyl) -carboxy-C 1-6 alkyl; ₃ -Alkylamino a

X an oxygen atom, a C1-3 -alkylimino, 0 ^ 3 alkoxyimino, C 1-3 -alkylhydrazino, di- (C ₃ -alkyl) hydrazine, c _2. -Alkynoyl _4-hydrazino, N- (C ₃ -alkyl) -C ₂ .4 -alkanoylhydrazino or C1-3 - alkyiidenová which may be alkyl or alkanoyl groups, or part of the alkyl and alkanoyl moieties are substituted by carboxy, C represents a group 3-alkyl or C 3-5 -cycloalkyl substituted by imidazole or imidazolone, wherein the imidazole ring may be substituted by phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C _1-3 -alkyl groups, wherein the substituents may be be the same or different and one of the above alkyl substituents may be simultaneously substituted with a carboxy group or in the 2 or 3 position by a group 9

- 14 - «♦ · · * ····». ...

amino, C 2-4 alkanoylamino, C 1-3 -alkylamino, N- (C ₂ -4 -alkanoyl) -C 1-3 -alkylamino or di- (C ₃ -alkyl) -amino and the imidazolone ring may be substituted by C i_ ₃ -alkyl, while the alkyl substituent may be substituted with carboxy or in 2 or 3 position by amino, c _{2. 4-} alkylamino or di- (C _1-3 -alkyl) -amino and furthermore, in the above imidazole and imidazolone ring, a phenyl or pyridine ring may be fused via two adjacent carbon atoms, imidazolidin-2,4-dion-5-yl which may be substituted by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by a carboxy group, means a C 1-4 -alkyl group which is substituted by a group

C 1-3 -alkyl-Y-Cd-3 -alkyl, HOOC-C 3 -alkyl-Y-C ₃ -alkyl, tetrazolyl-CD.3 _-alkyl-Y2, R3NR4 or NR ₃ R ₄ with -C ₃ -alkyl and isoxazolodino-1-yl-carbonyl optionally substituted with C 1-3 -alkyl, pyrrolinocarbonyl, 2,3-dehydropipridinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C 1-3 -alkylaminocarbonyl-, di- (C 1 -) ( _3- alkyl) -aminocarbonyl or a 4- to 7-membered cycloalkylenimino-carbonyl group, wherein in the above groups the cycloalkylenimine moiety is substituted with one or two C 1-3 -alkyl groups and at the same time the alkyl moiety or alkyl substituent of the above-mentioned C 1-3 groups -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl or groups · «000 ·

0 0 ··· ··

, The cycloalkyleneiminocarbonyl substituted by carboxy, and the remaining hydrogen atoms of the C _1-4 alkyl group may be replaced wholly or partially by fluorine atoms, where

R ₃ is hydrogen or C 1-3 -alkyl optionally substituted by carboxy; and

R ₄ is hydrogen, C 1-3 -alkyl-Y-Ci.3 alkyl-Y ₂ karboxyC1-3 -alkyl-Y-CV3 -alkyl-Y _2, C 1-3 -alkyl-Y ₂ or carboxy-C1 -3-alkyl-Y ₂ ;

R ₃ and R ₄ together with the intervening nitrogen atom are a 4- to 7-membered cycloalkyleneimino group optionally substituted by carboxy, C 1-3 -alkyl or carboxy-C 1-3 alkyl, wherein

Znamená · \ represents a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or

-NH-CO-NH- a

Y ₂ represents a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the group R ₃ NR ₄ and, under the definitions of Y ₁ and Y ₂ , imino groups substituted with C 1-3 -alkyl or carboxy-C 1-3 -alkyl, means C 1-3 -alkyl or C 3-5 -cycloalkyl substituted with R 5 NR 6, where they represent:

- 15 • 9 9 • 9 9

9 9 9 9 9 9 9 9 9 9999 9

R ₅ is hydrogen, C 1-3 -alkyl, C 5-7 -cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl; and

R _{6 is} a C 1-3 -alkyl, carboxy-C 1-3 -alkyl or carboxy-C 1-3 alkylcarbonyl group, means a C 1-3 -alkyl group which is substituted with

C 2-4 -alkynoyl or C 5-7 -cycloalkynoyl and C 1-3 -alkyl substituted by chlorine, bromine or iodine,

R _b represents a hydrogen atom or a C 1-3 -alkyl group a

R _c is cyano or amidino, which may be substituted by hydroxy, one or two C 1-3 -alkyl groups, one or two C _1-8 -alkoxycarbonyl groups, wherein in the definition of the abovementioned radicals said carboxy, amino and imino groups may be inter alia substituted in-vivo cleavable moiety, tautomers, stereoisomers, and salts thereof.

Particularly preferred compounds of formula (Ia) above are those in which the C1-3 -alkylene group is 99 9999 99. 99 · ·

-16- ·· ·

B represents an oxygen atom, a methylene, imino or N- (C _1-3 -alkyl) imino group in which the alkyl moiety may be substituted by a carboxy group,

_And R is C ₃ .s -cycloalkyl group substituted in the 1-position residue R-CO wherein R

R a C ₃ -alkoxy, amino, CV ₄ -alkylamino or di- (C ₁ _ ₄ -alkyl)

-amino in which the alkyl moiety may be substituted with a carboxy group,

A 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by a hydroxy group, C 1-7. _3- alkoxy, carboxy, carboxy-C 1-6 alkyl; ₃ -alkoxy, carboxy-CV ₃ -alkylamino, N- (C ₃ -alkyl) -N- (carboxy-C ₃ -alkyl) -amino, carboxy-C ₃ alkylaminocarbonyl, N- (C _3.1 alkyl ) -N- (carboxy-C _1-3 -alkyl) aminocarbonyl, carboxy-C _1-3 -alkylaminocarbonylamino, 1- (C _1-3 -alkyl) -3- (carboxy-C _1-3 alkyl) -aminocarbonylamino or 1,3 -di- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonylamino,

A 5- to 7-membered cycloalkyleneimino group optionally substituted with a C _1-3 -alkyl group on which the phenyl ring, the morpholino, piperazino, N- (C _1-3 -alkyl) -piperazino pyrrolino, 3,4- dehydro-piperidino or pyrrol-1-yl,

·· ··· « ·· • 9 • · - * • · • · 9 · • a * · · • · • • 9 · «· • 9 ·· ♦ · ·· »9

represents a C 3-5 -cycloalkyl group substituted in the 1-position by a radical R 2 -CX, where it is

R ₂ is phenyl, naphthyl or a monocyclic 5- or 6-membered heteroaryl group optionally substituted with C 1-3 -alkyl, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group in optionally substituted C 1-3 - alkyl, oxygen or sulfur or imino optionally substituted by C 1-3 -alkyl and oxygen or sulfur or one or two nitrogen atoms and the above-mentioned alkyl substituent may be substituted by carboxy, carboxy-C 1-3 -alkoxy, carboxy-C 1 .3 alkylamino- or N- (Ci. ₃ alkyl), carboxy-Ci-3 alkylamino, and

X is an oxygen atom, a C 1-3 -alkylimino, a C 1-3 -alkoxyimino or a C 1-3 -alkylidene which may be substituted by a carboxy group in the alkyl or alkoxy moiety, means a C 1-3 -alkyl group substituted in the 1-position by imidazole or imidazolone, the ring may be substituted with phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, wherein the substituents may be the same or different and one of the above alkyl substituents may be substituted with a carboxy group or in 2 or 3 position by amino, C2-4 -alkynoylamino, C1-3 -alkylamino, N- (C ₂ -4 -alkynoyl) -C ₃ -alkylamino or di- (C ₃ -alkyl) -amino and · The imidazolone ring may be substituted with a C 1-3 -alkyl group, wherein the alkyl substituent may be substituted with a carboxy group or in the 2- or 3-position of the amino, C 2-4 -alkanoylamino, C 1-3 -alkylamino, N- ( C ₂ -alkanoylj _4-C ^ -alkylamino or a di- (Ci_3-alkyl) -amino and can be further on the above imidazole and imidazolone cycle through two adjacent carbon atoms of the phenyl or pyridine fused cycle represents imidazolidine-2,4- dion-5-yl, which may be substituted with one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted with a carboxy group, means a C 1-4 -alkyl group which is substituted in the 1-position by a group

R 3 NR 4 or R 3 NR 4 -C 1-3 -alkyl and pyrrolinocarbonyl, 2,3-dehydropiperidinocarbonyl, imidazol-1-ylcarbonyl, carboxy, aminocarbonyl, isoxazolidin-1-ylcarbonyl, or a 4- to 7-membered cycloalkyleneiminocarbonyl group, of the above-mentioned groups substitutes the cycloalkylenimine moiety, and at the same time the alkyl moiety or the alkyl substituent of the above-mentioned group may be substituted (carboxy), di- (C 1-3 -alkyl) aminocarbonyl, or cycloalkyleniminocarbonyl substituted with carboxy; ·····················

4Π ········

- fy - ·· · ·· ········

The C 1-4 -alkyl groups may be wholly or partially replaced by the fluorine atoms where they are

R ₃ is hydrogen or C 1-3 -alkyl substituted in optionally with carboxy; and

R ₄ is hydrogen, C 1-3 -alkyl-Y ₂ or carboxy-C ₃ -alkyl-Y _2, or

R 3 and R 4 together with the intervening nitrogen atom are a 4- to 7-membered cycloalkyleneimino group substituted in the 1-position optionally with a carboxy, C 1-3 -alkyl or carboxy-C 1-3 -alkyl group, wherein

Y ₂ represents a carbon-nitrogen bond or a carbonyl-, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the group R 3 NR 4, and by definition of the residue Y _{2 the} existing imino groups may be substituted C 1-3 -alkyl or carboxy-C 1-3 -alkyl, means a C 1-3 -alkyl- or C _{3 group} . _5- cycloacyl substituted at the 1-position with R ₅ NR ₆ where they are

R ₅ is hydrogen, C 1-3 -alkyl, C 5-7 -cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl; and

R ₆ is C 1-3 -alkyl, carboxy-C 1-6 -alkyl; _3- alkyl or carboxy-C _1-3 alkylcarbonyl;

9,999,9999 9,999,999 means 9-3,999,999,99 represents a C 1-3 alkyl group which is substituted by a C 2-4 alkanoyl or a C 5-7 group. cycloalkanoyl and C 1-3 -alkyl substituted with chlorine, bromine or iodine,

R _b represents a C 1-3 -alkyl group a

R _c is an amidino group optionally substituted with 2,2,2-trichloroethoxycarbonyl, C 1-8 -alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl, the benzoyl moiety being mono- or disubstituted with fluorine, chlorine, bromine or iodine atoms with C 1-3 -alkyl or (C 1-3 -alkoxy and substituents may be the same or different, their C 1-3 -alkanol ester, their tautomers, stereoisomers, and salts thereof).

Particularly preferred compounds of formula I are those in which:

A is methyl,

B represents an oxygen atom or an imino group,

R _a represents a cyclopropyl group at the 1-position substituted by a radical R 1 -CO, wherein

- 21 · · · · · · · · · · · · ·

R 1 represents a pyrrolidino or piperidine group optionally substituted by a methyl or ethyl group in which the methyl or ethyl moiety may be substituted by a carboxy, carboxy-C 1-3 -alkoxy, carboxy-C 1 group. _3- alkylamino or N- (C 1-3 -alkyl) -carboxy-C 1-3 -alkylamino, means a cyclopropyl group at the 1-position substituted by a radical R ₂ -CX, wherein

R ₂ represents a phenyl, pyridyl, pyrazolyl group optionally substituted by C 1-3 -alkyl and

X represents an oxygen atom, a C 1-3 -alkoxyimino or a C 1-3 -alkylidene group which are substituted by a carboxy group in the alkyl or alkoxy moiety, means the -alkyl group at the 1-position substituted by an imidazole group in which the imidazole ring may be substituted by phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, wherein the substituents may be the same or different and one of the above alkyl substituents may be simultaneously substituted by carboxy or in the 1 or 3 position by amino , C ₂ . ₄ alkanoylamino, C 1-3 -alkylamino, N- (C ₂ .4 alkanoyl) -C ₃ -alkylaminonebo di- (C 3 -alkyl) -amino, wherein additionally can be in the aforementioned imidazole cycles through two adjacent carbon atoms fused to the phenyl or pyridine ring,

Means a C 1-2 -alkyl group which is substituted in the 1-position by a benzimidzolon-1-yl group, wherein the imidazolone ring may be substituted by a methyl or ethyl group optionally substituted by a carboxy group, a methyl or ethyl group which is substituted at the 1-position

R3NR4 or R3NR4-C1-3 alkyl, and di- (C ₃ - alkyl) aminocarbonyl, isoxazolidin-1-yl- carbonyl, piperidinocarbonyl or pyrrolidinocarbonyl optionally substituted in the C 1-3 -alkyl group, wherein the above-mentioned groups may be alkyl part or an alkyl substituent substituted with a carboxy group, where they are

R ₃ is hydrogen or C 1-3 -alkyl substituted with carboxy case,

R ₄ is hydrogen, C 1-3 -alkyl-Y ₂ or carboxy-C 1-3 alkyl-Y2 or

R ₃ and R 4 together with the intervening nitrogen atom are a 4- to 7-membered cycloalkylenimine group substituted in an optionally carboxy group, wherein

Y ₂ represents a carbon-nitrogen bond, a carboxyl group or an imino group optionally substituted by a C 1-3 -alkyl group,

23 represents a C 1-2 alkyl group substituted at the 1-position with R 5 NR 6 where they are

R ₅ is pyridinyl, phenylcarbonyl or phenylsulfonyl;

R _{6 is} a C 1-3 alkyl or carboxy-C 1-3 alkyl, n-propyl substituted in the 3-position by a chlorine atom and in the 1-position a cyclopentylcarbonyl, represents a cyclopropyl group substituted in the 1-position by a cyclopentylamino group and a nitrogen atom by carboxy-C 1. _3- alkylcarbonyl,

R b represents a methyl group and

R _c is an amidino group optionally substituted

CYs-alkoxycarbonyhacetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl, and in particular those compounds of formula Ia in which methyl is methyl

- 24 ♦ · · · · · · · · · · · · · · · · ·

Β represents an imino group

R _a represents a cyclopropyl group at the 1-position substituted by a radical R 1 -CO, wherein

R 1 represents a pyrrolidino or piperidino group optionally substituted by methyl or ethyl, wherein the methyl or ethyl moiety may be substituted by carboxy, carboxyC 1-3 -alkoxy, carboxy-C-1-3-alkylamino- or N- (C 1-3 -alkyl) carboxy-C 1-3 -alkyloamino, means a cyclopropyl group substituted in the 1-position with the radical R ₂ -CX, wherein

R ₂ represents a phenyl, pyridyl, or pyrazolyl optionally substituted by C 1-3 -alkyl and

X represents an oxygen atom, a C 1-3 -alkoxyimino group, or an alkyl group

C 1-3 alkylidene substituted in the alkyl or alkoxy moiety by carboxy means a C 1-2 alkyl substituted in the 1-position by an imidazole group in which the imidazole ring may be substituted by 1 to 3 methyl groups or two methyl and one ethyl group, wherein one of the aforementioned methyl or ethyl substituents may be simultaneously substituted with a carboxy group,

• 9 9 9 9 9 99 99 9 99 99 99 99 99 25 - ·· · .........

represents a methyl or ethyl group substituted in the 1-position by a group

R 3 NR 4 or R 3 NR 4 -CH 2 and di- (C 1-3 -alkyl) -aminocarbonyl, pyrrolidinecarbonyl or piperidinocarbonyl optionally substituted with C 1-3 -alkyl, wherein for the above groups the alkyl moiety or alkyl substituent may be substituted with a carboxy group where they represent

R3 is a hydrogen atom or a C1-3-alkyl group substituted in an optionally carboxy group,

R ₄ is C _1-3 -alkyl-Y ₂ or carboxy-C ₁ . _3- alkyl-Y ₂ wherein

Y ₂ represents a carbon-nitrogen bond, a carbonyl group or an imino group substituted with a C 1-3 -alkyl group,

R _b represents a methyl group a

R _c is an amidino group optionally substituted with C 6 -alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl; 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9

99 9 99 9999, with particular preference given to the aforementioned compounds of the general formula I, in which the residue R _and in the 5-position, their C 1-3 -alkanol ester, their tautomers, stereoisomers and their salts.

For example, the following are mentioned as more important compounds:

(a) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -cyclopropyl] benzimidazole, (b) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- {1 - [(pyridin-2-yl) - (carboxymethyloxyimino) methylene] cyclopropyl] benzimidazole, (c) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2) (d) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- {1- [2- (2-carboxyethyl) -carboxyethylamino] -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole; pyrrolidin-1-yl-carbonyl] -cyclopropyl} -benzimidazole, (e) 2- (4-Amidinofenzlaminomethyl) -1-methyl-5- [2 - (- 2-carboxyethyl) -4,5-dimethyl-imidazole-1 (methyl) -benzimidazole (f) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-ylcarbonyl) ethyl] benzimidazole; · Νΐί; * Λ · τ; vx's · - ' ^: j ν ·· Χ; Χ ·

(g) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole and their C1.3 alkanolester, their N- (C1-6-alkoxycarbonyl) -, N-benzyloxycarbonyl- and N-benzoyl-amidines, their tautomers, stereoisomers and their salts.

According to the invention, the compounds of the formula I are obtained according to known processes, for example according to the following processes:

(a) For the preparation of a compound of the general formula I in which R _c represents a cyano group:

Cyclization of the compound of formula (II), which in this case is formed in the reaction mixture,

(ii) where

R _a , R b, Ar, A and B are defined as indicated at the beginning, Z 1 and Z ₂ , which may be the same or different, are amino, hydroxy or mercapto groups optionally substituted by C 1-6 alkyl groups or Z 1 and Z ₂ together represent oxygen or sulfur, NH • e · ·· 99 · 99 99 · 9 • 9

9

- 29 9 9 9 9 9

Is optionally substituted with 1 to 3 carbon atoms, alkylenedioxy or alkylenedithio of 2 or 3 carbon atoms.

The cyclization is carried out, as appropriate, in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzol, chlorobenzol, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or excess acylating agent to be used. compounds of the formula II, e.g. in the corresponding nitrile, anhydride, acid halides, ester or amide, for example at temperatures between 0 and 250 ° C, preferably at the boiling point of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, acid sulfuric, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N, N-dicyclohexylcarbodiimide or optionally also in the presence of a base such as potassium ethylate or potassium tert-butylate. However, the cyclization can also be carried out without a solvent and / or without a condensing agent.

However, the reaction is particularly preferably carried out in such a way that the compound of the formula II is produced in the reaction mixture by reduction of the corresponding o-nitro compound, optionally in the presence of a carboxylic acid of the formula

HO - CO - A - B - Ar - CN (III) where

Ar, A and B are defined as initially indicated by acylating the corresponding amino compound formed in the reaction mixture.

• 4,444

4

b) For the preparation of a compound of formula I, wherein R _a is R ₂ -CX'-C 3-5 cycloalkylene, wherein R ₂ is as defined at the beginning, and X 'is one of the imino radicals which have been Started for X:

Reaction of a compound of formula (IV),

Rb (IV), where

R b, R c, Ar, A and B are defined as initially indicated, and R _a 'is R ₂ -CO-C 3 _-5 -cycloalkyl, wherein R ₂ is defined as initially indicated, s with an amine of formula

H ₂ X '(V) where

X 'is one of the imino residues that was initially listed for X.

The reaction is preferably carried out in a solvent such as methanol / toluene, ethanol, isopropanol or xylene and, if appropriate, in the presence of a dehydrating agent such as a molecular filter, sodium sulfate or calcium chloride, optionally in the presence of a base such as triethylamine at temperatures between 50 and 100 ° C. preferably at the boiling point of the reaction mixture.

- 30 • 99 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 • 9 9 9 9 9

c) Κ producing a compound of formula I wherein R _a is a R2-CX-C _3-5 cycloalkylene group, wherein R ₂ is as defined initially and X "is an alkylidene radical initially listed for X :

Reaction of a compound of formula (IV),

(IV), where

R b, R _c , Ar, A and B are deinated as indicated at the beginning, and R _a 'represents a R 2 -CO-C 3-5 - cycloalkylene group, wherein R ₂ is defined as mentioned at the beginning, s a phosphone of general formula

Z ₃ - HX (VI) where

X 1 is an alkylidene radical which has been mentioned initially for X and Z ₃ is triphenylphosphono- or (C 1 -C 4 -alkoxy) phosphono such as triethoxyphosphono.

The reaction is preferably carried out under a shielding gas in a solvent such as tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or dimethyl sulfide in the presence of a base such as potassium tert-butylate, sodium methylate or hydride

sodium at temperatures between -25 and 50 ° C, preferably at temperatures between -15 and room temperature.

d) To produce a compound of formula I wherein R _c is an amidino group which may be substituted with one or two C 1-3 alkyl groups:

Reaction of a compound of formula (VII) formed in a reaction mixture,

(VII), where

R _a , R b, Ar, A and B are defined as initially indicated by a

Z ₄ is an alkoxy or aralkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy or an alkylthio or aralkylthio group such as methylthio, ethylthio, n-propylthio or benzylthio, with an amine of the formula

HR ₇ NR ₈ (Vlil), where

R ₇ and R 8, which may be the same or different, represent a hydrogen atom or a C 1-3 -alkyl group,

99 · 9 9

9 9 • 9

9 9

9

- 32 • 9 ·

• 9 • 9 • 9

9 9

9999

9

9 or its salts.

The reaction is carried out, as appropriate, in a solvent such as methanol, ethanol, npropanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, with an amine of formula (VIIIa) or the corresponding acid addition salt. for example, ammonium carbonate or ammonium acetate.

The compound of formula (VII) is obtained, for example, by reacting the corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting the corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as is methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, preferably at 20 ° C, or by reaction of the corresponding nitrile with hydrogen sulfide as appropriate in a 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 corresponding alkyl or aralkyl halide.

e) For the preparation of a compound of formula I wherein R _a is an imidazoline-2,4-dion-5-yl group which may be substituted with one or two C _1-3 alkyl groups, wherein the alkyl substituent may be simultaneously substituted with carboxy- or C 1-6 -alkyl. _3- acoxycarbonyl:

····

44

4 4 4

4 4

4 4

9

- 34 • 4 · • 4 4

4 4

4 · 4 4

4 • 9949

4

4

Cyclization of a compound of formula (IX) formed in the reaction mixture,

Ar-CN (ix) where

R b, Ar, A and B are as defined at the beginning, and R a is an aminocarbonylamino group which is substituted at the 3-position with a C 1-3 alkoxycarbonyl-C 1-3 -alkyl group.

The reaction is preferably carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at 20 ° C.

(f) For the preparation of a compound of formula I wherein R _c is hydroxyamino:

Reaction of the nitrile of formula (X),

• «

where

R _a . Rb, Ar, A and B are defined as indicated at the beginning with hydroxylamine or its salts.

The reaction proceeds as appropriate in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran, tetrahydrofuran / water, dioxane or dioxane / water at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 150 ° C.

g) For a compound of formula I wherein R _a contains a carboxy group and R _c is defined as stated in the beginning, or R _and is defined as stated in the beginning, and R _c denotes an amidino group substituted by hydroxy or one or two C1 -3-alkyl groups:

Compound of formula (XI),

(XI), where

R _b , Ar, A and B are as defined at the beginning, and R _a 'and R _c ' have the same meanings as R _a and R _c mentioned at the beginning, that R _a contains a carboxyl-convertible group by hydrolysis, by acid or base treatment, by thermolysis or by hydrogenolysis and R _c is defined as above or R _c is an amidino-convertible group, in which case hydroxy is substituted or

- 35 • 4 · 4 · 4 ·· 44 44 • 4 4444 444

44 444 444 444 444 • 44 ·· · 44 4 444 44 444 by one or two C 1-3 -alkyl groups, by hydrolysis by acid or base, thermolysis use or hydrogenolysis, and R _is defined as stated in the beginning, is converted by hydrolysis , treatment of a compound of formula (I) with an acid or base, thermolysis or hydrogenolysis, wherein R _a contains a carboxy group and R _c is daffinated as indicated at the beginning, or R _a is defined as stated at the beginning and R _c represents aimidino group optionally substituted by hydroxy or by one or two C 1-3 alkyl groups.

A carboxyl-converting group is, for example, a carboxyl group protected by a protective group and its functional derivatives, e.g. unsubstituted and substituted amide, ester, thioester, trimethylsilyl ester, orthoester or iminoester, which are converted by hydrolysis to carboxyl groups, its tertiary alcohol ester, for example, a tert-butyl ester which is converted by carboxylic acid or thermolysis into a carboxyl group, and an ester thereof with an aralkanol, for example a benzyl ester which is converted to a carboxyl group by hydrogenolysis.

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

^: ň- ~ ''

• · · · · · • · · • · · * • · · · • · · · · · · • · · * · · • · · ·· · ·· • · · ·

If the compound of formula (XI) contains, for example, a tert-butyl or tert-butyloxycarbonyl group, 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. in an inert solvent such as methylene chloride, chloroform, benzol, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or also thermally optionally in an inert solvent such as methylene chloride chloroform, benzene, toluene, tetrahydrofuran or diaoxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvent used, for example at temperatures between 40 and 120 ° C.

If the compound of formula (XI) contains, for example, a benzyloxy or benzyloxycarbonyl group, they may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, for example at room temperature, and a hydrogen pressure of from 1 to 5 bar.

h) For the preparation of a compound of formula (I) wherein R _c is an imidino group which is substituted with one or two C 6 -alkyloxycarbonyl groups or an in vivo leaving group:

Reactions of the compound of formula (XII) ·· ··········

R _b where

R _a , R b, Ar, A and B are as defined at the beginning and R _c "represents an amidino group with a compound of the general formula

Z ₅ -R ₉ (XIII), wherein R ₉ is a C 1-6 -alkoxycarbonyl or acyl residue of one of the in vivo cleavable residues at the beginning of said and

Z 5 is a nucleofusion leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a p-nitrophenyl group.

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

With a compound of formula (XIII) wherein Z5 is a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as

,, ^ ίΥΐώ · ^;

· »» © 99

9 9 9 9 9

9

- 38 • · · ·

Methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethylsulfoxide optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butylate or N-ethyldiisopropylamine at temperatures between 0 and 60 ° C.

According to the invention, we obtain a compound of the general formula (I) which contains a group (R 3 NR 4) -C 1-3 alkyl in which at least one of the radicals R 3 or

R4 is hydrogen, it can be subsequently converted with the corresponding isocyanate or carbamoyl halide into the corresponding urea compound of formula (I) and / or if a compound of formula (I) containing an NH2-C1-3 alkyl group is obtained convert the corresponding acrylic acid to the corresponding 2- (C 1-3 -alkyloxycarbonyl) -ethyl compound of formula (I) and / or to obtain a compound of formula (I) containing a (R ₃ NR 4) -C 1-3 alkyl group wherein R 3 and R ₄ are hydrogen, it can be subsequently converted by the corresponding dihaloalkane to the corresponding compound of formula (I), wherein R 3 and R ₄ together with the intervening nitrogen atom represent a 4- to 7-membered cycloalkyleneimino group, and / or when a compound of formula (I) wherein R _c is an amidino group is obtained, it can be subsequently converted by reaction with a haloacetic acid derivative and by hydrolysis and decarboxylation to the corresponding amidino compound substituted with one or two methyl groups, and / or to give a compound of formula (I) wherein R c is a hydroxyamidine group, it may subsequently be converted by catalytic hydrogenation to the corresponding amidino compounds and / or φ φ ι

By obtaining a compound of formula (I) wherein R _a contains a carboxy group, it can be subsequently converted by esterification to the corresponding ester.

The subsequent preparation of the corresponding urea compound of formula (I) is carried out according to the purpose with the corresponding isocyanate or carbamoyl chloride preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50 ° C, preferably at room temperature.

The subsequent preparation of the corresponding compound 2- (C 1-3 -alkyloxycarbonyl) -ethyl is carried out by the corresponding acrylic ester preferably in a solvent such as methanol, ethanol or isopropanol at temperatures between 50 and 100 ° C, preferably at the boiling point of the reaction mixture.

The subsequent preparation of the corresponding 4- to 7-membered cycloalkylenimine compound of formula (I) is carried out by the corresponding dihalogenalkane preferably in a solvent such as methanol, ethanol or isopropanol in the presence of a base such as sodium carbonate at temperatures between 50 and 100 ° C, preferably at boiling point. of the reaction mixture.

The subsequent alkylation is carried out, as appropriate, in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium iodide or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or tertiary organic a base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously serve as solvents, or optionally in the presence of silver carbonate; or

- 40 - ......

silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.

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

The additional esterification is carried out with the corresponding alcohol as appropriate in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzol / tetrahydrofuran or dioxane, preferably in excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or dehydration. agents, for example, in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, phosphorous pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylamine Ν'-carbonyldiimidazole- or Ν, Ν'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylic acid, optionally in the presence of a base such as potassium carbonate,

N-ethyl-diisopropylamine or Ν, Ν-dimethylamino-pyridine, as appropriate, at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, or the corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium iodide or potassium iodide, and preferably in the presence of a base such as sodium carbonate or potassium carbonate, or in the presence of a tertiary organic base such as N-ethyl-41-

diisopropylamine or N-methylmorpholine, which may also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, preferably at temperatures between -10 and 80 ° C.

In the above reactions, optionally, reactive groups such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, the hydroxy protecting group is trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl, and the carboxyl protecting group is trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl; as amino-, alkylamino- or imino-protecting group, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl for amino are furthermore phthalyl.

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

• 42 · _ 42 - ........

The cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl moiety, however, takes place, for example, hydrogenolytically with, for example, hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid. 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.

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

The cleavage of the 2,4-dimethoxybenzyl residue, however, preferably takes place in trifluoroacetic acid in the presence of anisole.

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

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

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

The starting compounds of the formulas (II) to (XIII) used, which are known in the literature, are obtained by methods known in the literature, but their preparations are nevertheless described in the examples.

For example, the chemistry of compounds of formula III is described by Jack Robinson in J. Chem. Soc.1941, 744, benzimidazoles by Katritzka and Rees in Comprehesive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, by Schaumann in Hetarane III, Organic Chemistry Methods (Houben- Weyl), 4th edition, Thieme, Stuttgart 1993.

The compound of formula II is obtained, for example, by acylation of the corresponding diamino compound with the corresponding reactive derivative of the compound of formula III, compounds of formulas IV, VII, IX, X, XI and XII are obtained by cyclization of the corresponding substituted compound according to process a) and subsequent reduction of the nitro group. in the phenyl moiety and subsequent acylation, amidation and / or halogenation.

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

Thus, for example, the obtained compounds of the formula I which occur in racemates can be separated according to known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1071) into their optical antipodes and compounds. of the formula I with at least 2 asymmetric

Carbon atoms based on their physicochemical differences and known methods, for example by chromatography and / or fractional crystallization, to their diastereomers which are possible when in racemic form , subsequently converted to the enantiomers as above.

The separation of the enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms with the racemic compound salts or derivatives such as esters or amides, in particular acids or their active derivatives or alcohols, the diastereomeric mixtures of salts or derivatives obtained by the process, for example because of different solubilities, whereby free antipodes can be released from the pure diastereomeric salts or derivatives by treatment with a suitable reagent.

Particularly common optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, campersulfonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol is, for example, (+) - or (-) - menthol, and an optically active acyl residue in amides is, for example, the (+) - or (-) - mentyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids here are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methylsulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

In addition, the novel compounds of the formula I thus obtained, if they contain a carboxy group, can optionally be subsequently converted by inorganic or organic bases into their salts, in particular for pharmaceutical use, into their physiologically acceptable salts.

As stated at the outset, the novel compounds of the formula I and their salts have valuable properties. Thus, compounds of formula I wherein R _c is cyano are valuable intermediates to produce the remaining compounds of formula I, and compounds of formula I wherein R _c is the amidino group initially, and tautomers, stereoisomers, and physiologically acceptable salts thereof. have valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on thrombin or factor X _and influenced by action, for example thrombinin inhibiting or factor X _and - inhibiting effect, aPTT prolonging action and inhibiting effect on related proteases such as trypsin, urokinase factor VIIa, IX, XI and XII.

For example, the compounds

A = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] benzimidazole hydrochloride,

B = (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- {1 - [(piridin-2-yl) - (carboxymethyloxyimino) -methylene] -cyclopropyl} -benzimidazole hydrochloride,

C = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride, · ·· ··

- 46 D = 2- (4-amidinophenylaminomethyl) -1-methyl-5- {1- [2- (carboxyethyl) -pyrrolidin-1-ylcarbonyl] -cyclopropyl} -benzimidazole hydrochloride,

E = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole hydrochloride,

F = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride and

G = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole dihydrochloride investigated their effect on prolonging the aPPT period as follows:

Material: - Plasma, from human blood citrate,

- PTT reagents, Boehringer Mannheim (524298),

- Calcium solution (0,025 mol / l), Behring Werke, Marburg (OHR 056/57),

- Diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61),

- Bioamtic B10 coagulometer, Desaga, Wiesloch.

Design:

9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 999

Determination of aPPT time is performed on a Desaga Biomatic B10 coagulometer.

The test substance was added together with 0.1 ml human plasma citrate and 0.1 ml PTT reagents to test tubes. The sample is incubated at 37 ° C for 3 minutes. A coagulation reaction was started by the addition of 0.1 ml of calcium solution. By inserting the calcium solution and operating the instrument, time measurement is performed until the sample is precipitated. Samples to which DBA buffer was added were used as controls.

By definition, the effective concentration of the substance at which the aPPT time was doubled over the control was determined by the dose-response curve.

The following table contains the found values:

APTT substance (ED ₂ oo at pm)

AND

(B)

C

D

E

F

G

0.12

0.42

0.31

0.29

0.29

0.20

0.17

The compounds of the invention are well acceptable since no toxic side effects were observed at therapeutic doses.

 <. ^., ώ-ϊϊ, γί-ϊί ', -ςχ

- 48 • • 9,999,9999

99 «9 I 9 99 • · 99999 99 99

Because of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases such as the treatment of deep thrombosis of the leg vessels, to prevent reocclusion after bypass surgery or angioplasty (PT (C) A) and occlusion in peripheral arterial diseases such as pulmonary embolism, multiple intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke, and prevention of shunt occlusion. Further, the compounds of the invention are useful for antithrombotic support in thrombolytic treatment, such as rt-PA or streptokinase, for preventing long-term restenosis according to PA (C) A, for preventing metastasis and growth for coagulation-dependent tumors and fibrin-dependent inflammatory processes, e.g. treatment of pulmonary fibrosis.

The desired dosage required to achieve the corresponding effects is, as appropriate, at an intravenous dose of 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, and an oral dose of 0.1 to 50 mg / kg, preferably 0.3 to 30 mg / kg. 30 mg / kg, 1 to 4 times daily. Compounds of the formula I produced according to the invention, optionally in combination with other active ingredients, together with one or more inert customary carriers and / or solvents, for example, corn starch, milk sugar, raw sugar, microcristal cellulose, magnesium stearate, polyvinylpyrrolidone, acid citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, water / polaethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as hardened fat or suitable mixtures thereof, prepared in conventional galenic forms such as tablets, dragees , capsules, powder, suspensions or suppositories.

The following examples should illustrate the invention in more detail:

DETAILED DESCRIPTION OF THE INVENTION

···. <· ··· · ···· · * ·· ·· · · ·······

- 49 Example 1

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] -benzimidazole hydrochloride

A. 1- (4-Chloro-3-nitro-phenyl) -1-cyclopropanecarboxylic acid

To 350 ml of fuming nitric acid is gradually added at -25 ° C

50.0 g (0.21 mol) of 1- (4-chlorophenyl) -1-cyclopropanecarboxylic acid. The solution was stirred at -25 ° C for 15 minutes and then poured onto ice water. The precipitated product is filtered off with suction, washed with water and dried.

Yield: 58.5 g (95% of theory)

Rt value: 0.45 (silica gel; methylene chloride / methanol = 9.5: 0.5)

B. 1- (4-Methylamino-3-nitro-phenyl) -1-cyclopropanecarboxylic acid

20.0 g (0.083 mol) of 1- (4-chloro-3-nitro-phenyl) -1-cyclopropanecarboxylic acid and 100 ml of a solution of methylamine (40% in water) are heated in a pressure vessel at 80 ° C for 5 hours. Evaporate to dryness, dissolve in water and acidify with glacial acetic acid. The precipitated product is filtered off with suction, washed with water and dried.

Yield: 16.9 g (93% of theory),

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

C. 4- [1- (Pyrrolidin-1-yl-carbonyl) -cyclopropyl-2-nitro-N-methyl-aniline

2.4 g (0.01 mol) of 1- (4-methylamino-3-nitro-phenyl) -1-cyclopropanecarboxylic acid are dissolved in 50 ml of dimethylformamide and after addition of 3.2 g (0.01 mol) of o- ( benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 0.7g

- 50 9 · 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 (0.01 mol) pyrrolidine and 1.1 g (0.01 mol) of N-methylmorpholine were stirred at room temperature for 20 hours. The solvent was distilled off and the residue was chromatographed on silica gel, eluting with methylene chloride. The desired fractions were evaporated, taken up in ether, filtered off with suction and dried.

Yield: 1.8 g (61% of theory),

Rf value: 0.51 (silica gel; methylene chloride / methanol = 9: 1)

D. 4- [1- (Pyrrolidin-1-yl-carbonyl) -cyclopropyl-2-amino-N-methyl-aniline]

1.8 g (6.2 mmol) of 4- [1-pyrrolidin-1-yl-carbonyl) -cyclopropyl] -2-nitro-N-methylaniline are dissolved in 40 ml of methanol and 40 ml of methylene chloride and after addition of 0.4 g of palladium on charcoal (10%) was hydrogenated at room temperature for 4 hours. It is then filtered off from the catalyst and evaporated.

Yield: 1.6 g (100% of theory)

Rf value: 0.26 (silica gel; methylene chloride / methanol = 9: 1)

E. 4-Pyrrolidin-1-ylcarbonyl-cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline

Prepared in analogy to Example 1C from 4- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] -2-amino-N-methyl-aniline, o- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 66% of theory.

Rf value: 0.51 (silica gel; methylene chloride / methanol = 9: 1)

F. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl-4-benzimidazole

1.7 g (0.004 mol) of 4- [1- (pyrrolidin-1-yl-carbonyl) -cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline are heated in 7 ml of glacial acid

* 4 ·· »· • * 4 4 4 4 4 • · · 4 4 4 4 4 4 44 • 4 · 4 4 4 4 4 4 • 4 4 44 4444 44 44

acetic acid for 2 hours at reflux. The solvent was distilled off, the residue was dissolved in water and extracted with methylene chloride. The organic phase is dried, evaporated and subsequently chromatographed on silica gel, eluting with methylene chloride with the addition of 2-3% methanol.

Yield: 1.0 g (62% of theory),

Rf value: 0.49 (silica gel; methylene chloride / methanol = 9: 1)

G. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl) -carbonyl] cyclopropyl-benzimidazole hydrochloride

Dissolve 1.0 g (2.5 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole in 50 ml of saturated ethanolic hydrochloric acid and stir 5 hours at room temperature. The solvent was distilled off, the residue was dissolved in 50 ml of absolute ethanol, and 2.3 g (25 mmol) of ammonium carbonate was added. After 60 hours, evaporate to dryness at room temperature. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol (7: 1).

Yield: 700 g (62% of theory)

Rf value: 0.61 (silica gel; methylene chloride / methanol = 4: 1),

C ₂₄ H ₂₈ N ₆ O x HCl (416.54 / 453.0)

Mass Spectrum: (M + H) ⁺ = 417

In analogy to Example 1, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-methyl-piperidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 45% of theory

Rf value: 0.25 (silica gel; methylene chloride / methanol = 4: 1) ·· · · φ

9 9 ·· ·······

C ₂₆ H ₃₂ N ₆ O x HCl (444.59 / 481.05) Mass Spectrum: (M + H) ⁺ = 445 (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- ( piperidin-1-yl-carbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 57% of theory

Rf value: 0.23 (silica gel; methylene chloride / methanol = 4: 1)

C ₂₅ H ₃ N ₅ 0 x HCl (430,56 / 467,93)

Mass Spectrum: (M + H) ⁺ = 431 (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (4-methyl-piperazin-1-ylcarbonyl) -cyclopropyl] -benzimidazole- hydrochloride

Yield: 32% of theory

Rf value: 0.26 (silica gel; methylene chloride / methanol / ammonia = 2: 1: 0.25)

C ₂₅ H ₃₂ N ₇ O x HCl (445.58 / 482.04)

Mass Spectrum: (M + H) ⁺ = 446 (4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2,3-dihydroindolin-1-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 60% of theory.

Rf value: 0.34 (silica gel; methylene chloride / methanol = 4: 1)

C ₂₈ H ₂₃ N ₆ x HCl (464.58 / 501.04)

Mass Spectrum: (M + H) ⁺ = 465 (S) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) piperidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole -hydrochloride

• 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9 9. ............

Yield: 85% of theory

Rf value: 0.57 (silica gel; methylene chloride / methanol = 4: 1)

CaoHssNeCh x HCl (530.67 / 567.13)

Mass Spectrum: (M + H) ⁺ = 531 (6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - ((2-ethoxycarbonylethyl) pyrrolidin-1-ylcarbonyl) -cyclopropyl] -benzimidazole -hydrochloride

Yield: 60% of theory

CsgHseNeOs x HCl (516.64 / 553.10)

Mass Spectrum: (M + H) ⁺ = 517 (7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(N- (2-ethoxycarbonylethyl) -N-methylaminomethyl) -pyrrolidin-1-yl- carbonyl] -cyclopropyl] -benzimidazole hydrochloride

Yield: 65% of theory

C ₃₁ H ₄ 2N ₇ O3 x HCl (559.72 / 596.18)

Mass Spectrum: (M + H) ⁺ = 560 (M + 2H) ⁺⁺ = 280.6 (8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(2-ethoxycarbonylmethyloxymethyl) -pyrrolidine -1-yl-carbonyl] -cyclopropyl] -benzimidazole hydrochloride Yield: 61% of theory

Rf value: 0.20 (silica gel); methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)

C29H ₃₆ N ₆ O4 x HCl (532.66 / 569.11)

Mass spectrum: (M + H) ⁺ = 533 (M + 2H) ⁺⁺ = 267

- 54 φ Φ · · · · · · · · φ φ φ φ φ φ φ φ φ φ φ · · · ·

Example 2

2- (4-Amidinophenylaminomethyl) -1-methyl-5-1H-cyclopentylcarbonyl-3-chloro-propyl-benzimidazole hydrochloride

A. 4- [1- (Cyclopentylcarbonyl) -cyclopropin-chlorobenzol]

2.4 g (0.1 mol) of magnesium flakes are suspended in 10 ml of ether. After addition of iodine to the tip of the knife, 14.9 g (0.1 mol) of bromocyclopentane in 40 ml of ether is slowly added dropwise, starting at the beginning of the reaction with slight heating.

The solution was then heated under reflux for a further 30 minutes. Subsequently, a solution of 14.0 g (0.08 mol) of 1- (4-chlorophenyl) -1-cyclopropanecarbonitrile in 75 ml of ether was added and heated under reflux for 3 hours. The reaction solution was poured into ice water, adjusted to pH 3 with hydrochloric acid and extracted with ether. The organic extracts were dried and evaporated. The residue was chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (19: 1 and 15: 1).

Yield: 3.0 g (12% of theory),

Rf value: 0.58 (silica gel; petroleum ether / ethyl acetate = 4: 1)

B. 4- [1- (Cyclopentylcarbonyl) -cyclopropine-2-nitro-chlorobenzole Prepared in analogy to Example 1A from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -chlorobenzole and fuming nitric acid.

Yield: 87% of theory

_Rf value: 0.60 (silica gel; petroleum ether / ethyl acetate = 9: 1)

C. 4-ri- (Cyclopentylcarbonyl) -cyclopropine-2-nitro-N-methyl-aniline Prepared in analogy to example 1B from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] 9 · ···· · 9 ·

- 55 9 9 9

9,999,9999 99 ·

Of 2-nitro-chlorobenzole and an aqueous solution of methylamine.

Yield: 18% of theory

Rf value: 0.54 (silica gel; methylene chloride / ethanol = 19: 1)

D. 4- (Cyclopentylcarbonyl) -cyclopropin-2-ylamino-N-methyl-aniline

2.3 g (7.9 mmol) of 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2-nitro-N-methylaniline are dissolved in 125 ml of ethyl acetate and 25 ml of ethanol and hydrogenated after addition of 1.0 g of Raney nickel. 1.5 hours at room temperature. The catalyst is then filtered off and evaporated.

Yield: 2.0 g (98% of theory)

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

E. 4- [1- (Cyclopentylcarbonyl) -cyclopropyl] -2- (4-cyanophenomethylmethylcarbonylamino) -n-methyl-aniline

Manufactured in analogy to Example 1C from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2-amino-N-methyl-aniline, o- (benzotriazol-1-yl -) - N, N, Ν ', N'-tetramethyluroniumtetrafluoroborate , 4-cyano-phenyl-glycine and triethylamine in dimethylformamide. Yield: 96% of theory.

Rf value: 0.54 (silica gel; methylene chloride / ethanol = 19: 1)

F. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (cyclopentylcarbonyl) cyclopropyl] benzimidazole

Prepared in analogy to Example 1F from 4- [1- (cyclopentylcarbonyl) -cyclopropyl] -2- (4-cyanophenylaminomethylcarbonylamino) -N-methyl-aniline in glacial acetic acid.

• · 9 9 9 9 9 9 • · ·

- 56 ♦ · · · · 9 9 9 9

9,999,999,999,999

Yield: 53% of theory.

Rf value: 0.46 (silica gel; methylene chloride / ethanol = 19: 1)

G. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (1-cyclopentylcarbonyl-3-chloro-n-prop-4-benzimidazole hydrochloride)

Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) -1-methyl-5- (1-cyclopentylcarbonyl-3-chloro-n-propyl) -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 61% of theory.

C25H30CI N ₅ O x HCl (452.00 / 488.56)

Mass Spectrum: (M + H) ⁺ = 452/4 (CI)

Example 3 (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5-f-pyrrolidin-3-yl- (ethoxycarbonylmethylmethyloxvimino) -methylene-1-cyclopropene-benzimidazole hydrochloride

A. 1- [Pyridin-3-yl] -carbonyl-cyclopropyl-benzol

A solution of 21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether was added dropwise at -40 to -50 ° C to 100 ml of butyllithium (1.6 M in hexane) and then stirred at -40 for 20 minutes. Deň: 32 ° C. Subsequently, it is cooled to -60 ° C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropane-carbonitrile in 125 ml of ether is added dropwise. Then the reaction mixture was warmed to room temperature and stirred for 5 hours. To the suspension was added 20% hydrochloric acid and heated to 100 ° C for 30 minutes. After cooling, it was adjusted to pH 8 with 20% solution and extracted with ethyl acetate. The combined organic extracts were dried and evaporated. The residue was chromatographed on alumina eluting with petroleum ether / ethyl acetate (9: 1).

· ® ® ® ® ® - - - - - - - - - - - - - - - - - -

Yield: 14.0 g (46% of theory)

Rf value: 0.27 (alumina; petroleum ether / ethyl acetate = 9: 1).

B. 4- [1 - [[Pyridin-3-yl] -carbonyl] -cyclopropyl-1-nitrobenzol

Made analogously to Example 1A from 1 - [(pyridin-3-yl) -carbonyl] -cyclopropylbenzole and fuming nitrate.

Yield: 53.7% of theory.

Rf value: 0.29 (alumina; petroleum ether / ethyl acetate = 4: 1)

C. 4- [1-iPvridin-3-yl] -carbonyl-cyclopropaniline

Prepared in analogy to Example 2D from 4- [1- [pyridin-3-yl) -carbonyl] -cyclopropyl] nitrobenzol and Raney nickel in ethyl acetate / ethanol.

Yield: 94% of theory.

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

D. 4- [1- [Pyridin-3-yl] -carbonyl-1-cyclopropene-trifluoroacetvlaniline

8.0 g (33.5 mmol) of 4- [1- [pyridin-3-yl) -carbonyl] -cyclopropyl] -aniline are dissolved in 100 ml of chlorobenzol and, after addition of 15 ml of trifluoroacetic acid hydride, stirred at room temperature for 2 hours. Mp 110 ° C. The solvent was distilled off, the residue was stirred with petroleum ether / ether (9: 1), filtered off with suction and dried.

Yield: 10.0 g (88% of theory)

Rf value: 0.54 (silica gel; methylene chloride / ethanol = 19: 1)

E. 4- [1- (Pyridin-3-yl) -carbonyl] -cyclopropyl-2-nitro-trifluoroacetvlaniline ml conc. sulfuric acid and 16 ml of 65% nitric acid are added portionwise at -5 ° C to 1.7 g (5 mmol) of 4- [1 - [(pyridin-3-yl) -carbonyl] -cyclopropyl] -trifluoroacetylaniline. It is then stirred for 30 minutes without cooling, poured onto ice water and extracted with acetic acid ester. The organic extracts are

- 58 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (50: 1 and 25: 1). The desired fractions are evaporated, triturated with petroleum ether, aspirated and dried.

Yield: 1.2 g (75% of theory)

Rf value: 0.70 (silica gel; methylene chloride / ethanol = 19: 1)

F. 4- [1 - [(Pyridin-3-yl) -carbonyl-cyclopropyl] -2-nitro-N-trifluoroacetyl-N-methyl-aniline

1.15 g (3.0 mmol) of 4- [1- [pyridin-3-yl) -carbonyl] -cyclopropyl] -2-nitro-trifluoroacetylaniline are dissolved in 50 ml of acetone and after addition of 2.0 g of potassium carbonate and 0. 1.8 ml of methyl iodide was heated under reflux for two hours. The undissolved material was filtered off and the solution was concentrated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (1: 1 and 1: 4).

Yield: 0.88 g (75% of theory)

Rf value: 0.38 (silica gel; petroleum ether / ethyl acetate = 1: 1)

G. 4- [1 - [(Pyridin-3-yl) -carbonyl] -cyclopropyl-2-nitro-N-methyl-aniline

7.4 g (18.8 mmol) of 4- [1- [pyridin-3-yl) -carbonyl] -cyclopropyl] -2-nitro-N-trifluoroacetyl-N-methyl-aniline are stirred in 200 ml of 20% hydroxide. potassium hydroxide for two hours at 30 ° C. Subsequently, the organic phase is separated by dilution with isopropanol, 10.0 g of alumina are added and evaporated to dryness. The residue was chromatographed on alumina eluting with petroleum ether / ethyl acetate (4: 1 and 1: 1).

Yield: 2.6 g (47% of th.)

Rf value: 0.50 (silica gel; petroleum ether / ethyl acetate = 1: 1)

- 59 • 9 99 99 99

9

9 9 9 9 • 9 9

H. 4- [1 - [(Pyridin-3-yl) -carbonyl] -cyclopropyl-2-amino-N-methyl-aniline

Prepared in analogy to Example 2D from 4- [1 - [(pyridin-3-yl) -carbonyl] -cyclopropyl] -2-nitro-N-methyl-aniline and Raney nickel in ethyl acetate / ethanol.

Yield: 98% of theory.

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

I. 4- [1- (Pyridin-3-yl) -carbonyl] -cyclopropyl-2- (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline

Prepared in analogy to Example 1C from 4- [1- [pyridin-3-yl) -carbonyl] -cyclopropyl] 2-amino-N-methyl-aniline, o- (benzotriazol-1-yl) -N, Ν, Ν ' , N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 97% of theory

Rf value: 0.48 (silica gel; methylene chloride / ethanol = 19: 1)

2- (4-Cyanophenamidinomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) -carbonyl] cyclopropyl-benzimidazole

Prepared in analogy to Example 1F from 4- (pyridin-3-yl-carbonyl) -cyclopropyl-2- (4-cyanophenyl) -aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.

Yield: 76% of theory.

Rf value: 0.52 (silica gel; methylene chloride / ethanol = 19: 1)

L. (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- [pyridin-3-yl] - (carboxymethyl-oximino) -methylene-benzimidazole

1.6 g (4.0 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) carbonyl] benzimidazole, 3.0 g (12 mmol) of carboxymethoxylamine -hemihydrate, 0.84 ml triethylamine, 12 g molecular sieve 4A is heated in 80 ml methanol

- 60 φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ a a a a a a a a a a a a a a a a a a a a a 40 40 40 40 40 40 and 40 ml toluene 12 hours under reflux. It is then filtered off from the molecular sieve and evaporated. The residue is stirred with water, filtered off with suction and dried.

The crude product is chromatographed on silica gel, eluting with methylene chloride / ethanol / glacial acetic acid (25: 1: 0 and 8: 2: 0: 2). Yield: 0.9 g (49% of theory)

Rf value: 0.34 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2).

M. (E / Z) -2- (4-Aminophenophenylaminomethyl) -1-methyl-5-F1-1 (pyridin-3-yl) (ethoxycarbonylmethyloxvimino) -methylene-cyclopropene-benzimidazole hydrochloride

Prepared in analogy to Example 1G from (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl) - (ethoxycarbonylmethyloxyimino) -methylene] -cyclopropyl] benzimidazole and hydrochloric acid] of ammonium carbonate in ethanol. Yield: 60% of theory

Rf value: 0.28 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 1: 0.2)

C29H32N7O3 x HCl (525.62 / 562.09)

Mass Spectrum: (M + H) ⁺ = 526

In analogy to Example 3, the following compounds are obtained:

(1) (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [pyridin-2-yl] - (ethoxycarbonylmethyloxyimino) -methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield:

52% of theory

44 ·· • € 4 4444 444 ·· ····

Rf value: 0.21 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.2)

C29H31N7O3 x HCl (525.62 / 562.09)

Mass Spectrum: (M + H) ⁺ = 526 (2) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (ethoxycarbonylmethyloxyimino) -methylene] -cyclopropyl] - benzimidazole hydrochloride

Yield: 18% of theory

C30H32N6O3 x HCl (524.63 / 561.09)

Mass Spectrum: (M + H) ⁺ = 525 (M-H + HCl) + = 559/61 (Cl) (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (1-methylpyrazole) -5-ylcarbonyl) -cyclopropyl] -benzimidazole hydrochloride

Yield: 10% of theory.

C24H25N7O x HCl (427.51 / 463.97)

Mass Spectrum: (M + H) ⁺ = 428 (M + H + HCl) + = 464/6 (Cl) (4) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [ 1 - [(1-Methyl-pyrazol-5-yl) - (ethoxycarbonylmethyloxyimino) -methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 80% of theory

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)

C ₂₈ H ₃₂ N8O ₃ x HCl (528,63 / 565,08) • 4 * 4

9 9 9 9 9

9 9 9 9 9 9

- 62 - ..... .... .. ·

Mass Spectrum: (M + H) ⁺ = 529 (5) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl- (3-ethoxycarbonyl-n-propyloxyimino)] ) -methylene] -benzimidazole dihydrochloride Yield: 47% of theory

Rf value: 0.06 (silica gel; methylene chloride / methanol = 9: 1)

C ₃₂ H ₃ 6N ₆ O ₃ x HCl (552.69 / 625.60)

Mass Spectrum: (M + H) ⁺ = 553

Example 4 (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (f) -pyridin-2-yl) (carboxymethyloxvimino) -methylene-cyclopropene-benzimidazole hydrochloride

150 mg of (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl- (ethoxycarbonyl-methyloxyimino) -methylene] -cyclopropyl] -benzimidazole hydrochloride and 2.5 ml of 2N sodium hydroxide was stirred in 10 ml of ethanol for 5 hours at room temperature, the alcohol was distilled off and the residue was adjusted to pH 5 with hydrochloric acid. The crystalline product was filtered off with suction, washed with water and dried.

Yield: 46% of theory

Rf value: 0.10 (silica gel; methylene chloride / ethanol / glacial acetic acid = 8: 2: 0.1)

C ₂₇ H ₂₇ N ₇ O ₃ x HCl (497.58 / 534.05)

Mass Spectrum: (M + H) ⁺ = 498 (M + Na) ⁺ = 520

- 63 9 9 9 9 9 9 9 9 9 9 · 9 9 9 9 9 99 99 90 9

In analogy to Example 4, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) -piperidin-2-ylcarbonyl] -cyclopropyl] -benzimidazole hydrochloride

Yield: 94% of theory.

Rf value: 0.57 (reverse phase RP 18; methanol / 5% sodium chloride solution = 3: 2)

C28H34N6O3 x HCl (502.62 / 539.08)

Mass Spectrum: (N + H) ⁺ = 503 (M + Na) ⁺ = 525 (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1- (pyrroplidine-) 1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 98% of theory.

Rf value: 0.73 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 2)

C26H33N7O3 x HCl (491,60 / 564,54)

Mass Spectrum: (M + H) ⁺ = 492 (M + 2H) ⁺⁺ = 247 (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-carboxypropionylamino) 1- (ethoxycarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 98% of theory

Rf value: 0.70 (RP 8; methanol / 5% sodium chloride solution = 1: 2)

CasHsoNsOsX HCI (494.55 / 531.05)

Mass Spectrum: (M + H) ⁺ = 495 (2M + H) ⁺ = 989

·· • • ···· • · • · • • ·· • • ·· • · • ·· • 9 • • • • • · • • • • • ·· • ··

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) methyl] benzimidazole hydrochloride

Yield: 87% of theory

C24H29N7O3 x HCl (463.54 / 500.04)

Mass Spectrum: (M + H) ⁺ = 464 (M + 2H) ⁺ = 232.6 (5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (2-carboxyethyl) - pyrrolidin-1-yl-carbonyl] -cyclopropyl] -benzimidazole hydrochloride

Yield: 94% of theory.

C ₂₇ H32N ₆ O ₃ x HCl) 488.59 / 525.05)

Mass Spectrum: (M + H) ⁺ = 489 (M + Na) ⁺ = 511 (6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -1- (pyrrolidine- 1-yl-carbonyl) -methyl] -benzimidazole hydrochloride Yield: 49% of theory,

C25H29N7O4 x HCl (491.55 / 528.01)

Mass Spectrum: (M + H) ⁺ = 492 (M + H + Na) ⁺⁺ = 257.7 (7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 (carboxymethylcarbonylamino-1-) (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride Yield: 92% of theory

C ₂₆ H ₃₁ N7O _4x HCl (505,58 / 542,04)

65 = 506

Mass Spectrum: (M + H) ⁺ (M + H + Na) ⁺⁺ (8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-carboxymethyl-imidazoline-2,4- dion-5-yl) -benzimidazole hydrochloride

Yield: 88% of theory.

C22H33N7O4 x HCl (449.47 / 485.94)

Mass Spectrum: (M + H) ⁺ = 450 (M + 2Na) ⁺⁺ = 247.7 (9) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [( pyridin-3-yl) - (carboxymethyloxyimino) -methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 54% of theory

C27H27N7O3 x HCl (497.56 / 534.09)

Mass Spectrum: (M + H) ⁺ = 498 (M + Na) ⁺ = 520 (10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (N- (2-carboxyethyl)) -N-Methyl-aminomethyl) -pyrrolidin-1-yl-carbonyl] -cyclopropyl] -benzimidazole hydrochloride

Yield: 100% of theory.

C29H37N7O3 x HCl (531.66 / 568.12)

Mass Spectrum: (M + H) ⁺ = 532 (MH) + = 530 (11) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (2-carboxyethyl) -N- (29,999) · · 9 9999 99 • 99 99 999 λλ · · · 99 99

- ΟΌ - 99 9 99 9900 99

-pyridyl) aminomethyl] -benzimidazole hydrochloride Yield: 91% of theory

C25H27N7O2 x HCl457.54 / 493.96)

Mass spectrum: (M + H) ⁺ = 458 (12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (N-benzosulfonyl-N-carboxymethyl-aminomethyl) -benzimidazole hydrochloride Yield: 84% of theoretical yield

CssHaeNgCUS x HCl (506.59 / 543.06)

Mass Spectrum: (M + H) ⁺ = 507 (13) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) benzimidazol-1-ylmethyl] benzimidazole hydrochloride Yield 76% of theory

C27H27N7O2 x HCl (481.56 / 518.05)

Mass Spectrum: (M + H) ⁺ = 482 (M + 2H) ²⁺ = 242 (M + Na) ⁺ = 504 (M + H + Na) ²⁺ = 253 (M-H + 2Na) ⁺ = 526 ( M + 2Na) ²⁺ = 264 (14) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (2-methyl-4-carboxyimidazol-1-ylmethyl) benzimidazole hydrochloride Yield: 61% theoretical yield

C ₂₂ H23N ₇ O ₂ x HCl (417.47 / 453.92) • ·

- 67 Mass Spectrum: (M + H) ⁺ = 418 (15) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [3- (3-carboxy-n-propyl) -benzimidazol-2-one-1 -yl-methyl] -benzimidazole hydrochloride

Yield: 86% of theory

C ₂₈ H ₂₉ N ₇ O ₃ x HCl (511.59 / 548.04)

Mass Spectrum: (M + H) ⁺ = 512 (M + Na) ⁺ = 534 (M + H + Na) ²⁺ = 267.7 (M + 2 N a) ²⁺ = 278.8

(16) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [3- (2-carboxyethyl) imidazo [4,5-b] pyridin-2-one-1-ylmethyl] benzimidazole hydrochloride

Yield: 83% of theory

C ₂ 6H ₂₆ N ₈ O ₃ x HCl (498.55 / 535)

Mass Spectrum: (M + H) ⁺ = 499 (M + Na) ⁺ = 521 (M-H) ' = 497 (2M-H) = 995

(17) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole hydrochloride

Yield: 68% of theory

Rf value: 0.70 (reverse phase RP 8; methanol / 5% sodium chloride solution = 6: 4)

C ₂₅ H ₂ N ₇ O ₂ x HCl (459,56 / 496,01)

Mass Spectrum: (M + H) ⁺ = 460 99 99 999

- 68 - • 9 9 9 · 9 9 99,999 9 9 9 (M + Na) ⁺ = 482 (M + H + Na) ²⁺ = 241

(18) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- [phenyl] - (carboxymethyloxyamino) -methylene] -cyclopropyl] -benzimidazole dihydrochloride

Yield: 70% of theory

C ₂ 8H ₂ 8N ₆ O ₃ x HCl (496.57 / 569.5)

Mass Spectrum: (M + H) ⁺ = 497 (MH) + = 495 (19) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl)] 1- (Carboxymethylidene) -methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 37% of theory

Rf value: 0.45 (reverse phase RP 8; methanol / 5% sodium chloride solution = 6: 4)

C ₂₇ H ₂₆ N ₆ O 2 x HCl (466,55 / 503,0)

Mass Spectrum: (M + H) ⁺ = 467 (20) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(1-methylpyrazol-5-yl) - (carboxymethyloxyimino) -methylene] -cyclopropyl] -benzimidazole hydrochloride

Yield: 30% of theory

Rf value: 0.25 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1)

C ₂ 6H ₂₈ N ₈ O ₃ x HCl (500.58 / 537.03)

Mass Spectrum: (M + H) ⁺ = 501 · 9 9 · · 9 ·

(MH +) = 499 (M + Cl) ⁺ = 535/537 (Cl) (21) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl -5- [1- [phenyl- (3-carboxy-n-propyloxyimino) -methylene] -cyclopropyl] -benzimidazole dihydrochloride

Yield: 37% of theory

Rf value: 0.35 (reverse phase RP 8; 5% sodium chloride / methanol = 3: 2)

C30H32N6O3 x HCl (524.64 / 597.55)

Mass Spectrum: (M + H) ⁺ = 525

Example 5

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) aminomethyl] benzimidazole hydrochloride

A. 5- (4-chlorophenyl) imidazoline-2 _l four-dione

15.0 g (0.11 mol) of 4-chlorobenzaldehyde, 51.3 g (0.53 mol) of ammonium carbonate and 7.6 g (0.12 mol) of potassium cyanate are stirred in 150 ml of water and 150 ml of methanol for 18 hours at room temperature. temperature 55 ° C. The solvent was distilled off, the residue was dissolved in water and extracted with ethyl acetate. The combined organic extracts were dried and evaporated. Yield: 8.6 g (38% of theory),

Melting point: 215 ° C

B. 5- (4-Chloro-3-nitro-phenyl) -imidazolidine-2,4-dione

Made analogously to Example 1A from 5- (4-chlorophenyl) -imidazolidine-2,4-dione and fuming nitric acid.

- 71 ·· 4 4 9 4

Yield: 52% of theory

Rf -value:

0.63 (silica gel: methylene chloride / methanol = 9: 1)

C. 4-Chloro-3-nitro-phenvlalanine hydrochloride

560 mg (2.2 mmol) of 5- (4-chloro-3-nitro-phenyl) -imidazolidine-2,4-dione are heated in 20 ml of dilute hydrochloric acid for 24 hours at reflux. The solvent was distilled off, the residue was dissolved in water, filtered from insoluble residues and evaporated. The residue is dissolved three times in ethanol, evaporated to dryness, mixed with ether, filtered off with suction and dried.

Yield: 380 mg (65% of theory)

Melting point: 186 ° C

D. 4-Chloro-3-nitro-N-tert-butyloxycarbonyl-phenylalanine

5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine hydrochloride are dissolved in 50 ml of dioxane and 25 ml of water and, after addition of 5.5 ml (39.1 mmol) of triethylamine and 4.8 g. (21.3 mmol) of di-tert-butyl dicarbonate was stirred at room temperature for 18 hours. It is then diluted with 0.5 M potassium hydrogen sulphate solution and extracted with ethyl acetate. The combined organic extracts were dried and evaporated.

Yield: 6.3 g (100% of theory),

Rf value: 0.20 (silica gel; methylene chloride / methanol = 9: 1)

E. 2- (4-Chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone

Prepared in analogy to Example 1C from 4-chloro-3-nitro-N-tert-butyloxycarbonylphenylalanine, o- (benzotriazol-1-yl) -N, N, Ν ', Ν'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl-di- isopropylamine in tetrahydrofuran.

Yield: 68% of theory.

Melting point: 203 ° C • ·

- 71 F. 2- (4-Methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone

Prepared in analogy to Example 1B from 2- (4-chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone and methylamine solution.

Yield: 76% of theory.

Rf value: 0.33 (silica gel; cyclohexane / ethyl acetate = 1: 1)

G. 2- (4-Methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidin-1-yl-ethanone

Made analogously to Example 1D from 2- (4-methylamino-3-nitrophenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone and palladium on activated carbon in methylene chloride / ethanol.

Yield: 100% of theory.

Rf value: 0.12 (silica gel; cyclohexane / ethyl acetate = 1: 1)

H. 2- [4-Methylamino-3- (4-quinophenylaminomethylcarbonylamino) -phenyl] -2-tert-butoxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone Prepared in analogy to Example 1C from 2- (4-methylamino-3-aminophenyl) -2-tert.

butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone, o- (bezotriazol-1-yl) -N, N, Ν ', N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in tetrahydrofuran.

Yield: 100% of theory.

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

2- ^{(4-Kyanofenvlaminometyl,)} -1-methyl-5- | 1- (pyrrolidin-1-yl-carbonyl) - 72 ·· ···· and "·· · • · · · · · ···

aminomethyl-1-benzimidazole

Prepared in analogy to Example 1F from 2- [4-methylamino-3- (4-cyanophenylamino-methylcarbonylamino) -phenyl] -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -ethanone in glacial acetic acid.

Yield: 30% of theory.

Rf value: 0.19 (silica gel; methylene chloride / methanol = 9.5: 0.5)

K. 2- (4-Amino-phenylaminomethyl) -1-methyl-5-ri- (pyrrolidin-1-ylcarbonyl) aminomethyl-benzimidazole hydrochloride Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) -1-methyl- Of 5- [1- (pyrrolidin-1-yl-carbonyl) -aminomethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 27% of theory.

C22H27N7O x HCl (405,50 / 441,96)

Mass Spectrum: (M + H) ⁺ = 406

In analogy to Example 5, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N-acetyl-aminomethyl] -benzimidazole hydrochloride

Yield: 29% of theory.

C24H29N7O2 x HCl (447.54 / 484.54)

Mass Spectrum: (M + H) ⁺ = 448 (2) 2- (4-Aminophenyl (aminomethyl) -1-) methyl 5- [1- (pyrrolidin-1-yl-carbonyl) -N- (2-ethoxycarbonylethyl) -N-methyl-aminomethyl] -benzimidazole hydrochloride

Yield: 74% of theory.

C ₂ 8H ₃ 7N ₇ O ₃ x HCl (519.65 / 556.11)

Mass Spectrum: (M + H) ⁺ = 520 (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (ethoxycarbonylmethyl) aminomethyl] benzimidazole -hydrochloride

Yield: 76% of theory.

C ₂₆ H ₃₃ N ₇ O ₃ x HCl (491.59 / 528.05)

Mass Spectrum: (M + H) ⁺ = 492 (M + 2H) ⁺⁺ = 246.7 (4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl)] -N, N-di- (ethoxycarbonylmethyl) aminomethyl] -benzimidazole hydrochloride

Yield: 51% of theory.

C ₃ H ₃₉ N ₇ 05 X HCl (577,68 / 614,14)

Mass Spectrum: (M + H) ⁺ = 578 (M + Na) ⁺ = 600 (5) 2- (4-Aminophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N - (ethoxyacarbonylmethylcarbonyl) -aminomethyl] -benzimidazole hydrochloride

Yield: 29% of theory.

C ₂ 7H ₃₃ N ₇ O ₄ x HCl (519.60 / 556.06)

Mass Spectrum: (M + H) ⁺ = 520

(M + 2H) ⁺⁺ = 260.7 (6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) -N- (2-ethoxycarbonylethyl) aminomethyl -benzimidazole hydrochloride

Yield: 84% of theory.

C27H35N7O3 x HCl (505.62 / 542.62)

Mass Spectrum: (M + H) ⁺ = 506 (M + 2H) ⁺ = 253.7

Example 6

2- (4-Arnidinophenylaminomethyl) -1-methyl-5- [1- (N) - (2-ethoxycarbonylmethyl) amino] -1- (pyrrolidin-1-yl) -carbonyl-ethylH-benzimidazole hydrochloride

A. 5- (4-Chior-3-nitro-phenyl) -5-methyl-imidazolidine-2,4-dione

To 50 ml of fuming nitric acid at -25 ° C to -35 ° C was added portionwise 10.0 g (4.45 mmol) of 5- (4-chloro-phenyl) -5-methyl-imidazolidine-2,4 -dion. After 45 minutes, the reaction mixture was poured into ice water at -25 ° C to -20 ° C. The crystalline product is filtered off with suction, washed with water and dried.

Yield: 10.5 g (100% of theory),

Melting point: 173-178 ° C

Rf value: 0.30 (silica gel; cyclohexane / ethyl acetate = 1: 1)

B. 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid

10.5 g (0.044 mol) of 5- (4-chloro-4-nitro-phenyl) -5-methyl-imidazolidine-2,4-dione are heated in 200 ml of dioxane and 700 ml of 6N hydrochloric acid for 5 days under reflux. . Evaporate the solution, dilute the residue with water and extract with ethyl acetate.

9 <99 9 9 9 with acetate. The aqueous phase is evaporated, toluene is added and evaporated to dryness. The residue is mixed with ether, filtered off with suction and dried.

Yield: 6.8 g (63% of theory),

Rf value: 0.24 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1)

C. 2-tert-Butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid

Prepared in analogy to Example 5D from 2-amino-2- (4-chloro-3-nitrophenyl) -propionic acid, pyrocarbonic acid di-tert-butyl carbonate and triethylamine in dioxane.

Yield: 9.6 g (100% of theory),

Rf value: 0.31 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 2)

D. 2- (4-Chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone

Prepared in analogy to Example 1C from 2-tert-butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid, o- (benzotriazol-1-yl) -N, N, Ν ', N'-tetramethyluroniumtetrafluoroborate, pyrrolidine and N-methylmirpholine in dimethylformamide.

Yield: 94% of theory.

Rf value: 0.11 / silica gel; cyclohexane / ethyl acetate = 1: 1)

E. 2- (4-Methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1

- (pyrrolidin-1-yl) -propanone

Prepared in analogy to Example 1B from 2- (4-chloro-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone and a solution of methylamine in dimethylformamide at 160 ° C.

- 76 * © © © © © 76 76 76 76 76 76 76 76 9 9 9 9 9 9

8 «© · · ···»

Rf value: 0.79 (silica gel; acetic acid / ethanol = 9: 1)

F. 2- (4-Methylamino-3-amino-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidin-1-yl-propanone

Prepared in analogy to Example 1D from 2- (4-methylamino-3-nitro-phenyl) -2-tert.

butyloxycarbonyl-amino-1- (pyrrolidin-1-yl) -propanone and palladium on activated carbon / hydrogen in methanol.

Yield: 100% of theory.

Rf value: 0.63 (silica gel; ethyl acetate / ethanol = 9: 1)

G. 2- [4-Methylamino-3- (4-cyanophenylaminomethylcarbonylamino) -phenyl] -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone Prepared in analogy to Example 1C from 2- (4-methylamino-3-amino- phenyl) -2-tert.

butyloxy-carbonylamino-1- (pyrrolidin-1-yl) -propanone, o- (benzotriazol-1-yl) -N,

N, Ν ', Ν'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and N-methylmorpholine in dimethylformamide.

Yield: 37% of theory.

Rf value: 0.47 (silica gel; ethyl acetate)

H. 2- (4-Cyanophenylaminomethyl) -1-methyl-5-ri- (N-tert-butyloxycarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) ethyl-benzimidazole

Prepared in analogy to Example 1F from 2- [4-methylamino-3- (4-cyanophenylaminoethylcarbonylamino) -phenyl] -2-tert-butyloxycarbonylamino-1- (pyrrolidin-1-yl) -propanone and glacial acetic acid.

Yield: 60% of theory.

Rf value: 0.37 (silica gel; ethyl acetate)

9 «9 ·

9 9 9 9 9

99 * 99 <99

-7-7 999,999 99

- I f · ·· * 99 9999 99 9

I. 2- (4-Cyanophenylaminomethyl) -1-methyl-5-β-amino-1- (pyrrolidin-1-carbonyl) -ethyl-benzimidazole

1.3 g (2.3 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] - The benzimidazole is dissolved in 20 ml of dioxane and stirred at room temperature for two hours after addition of 40 ml of dilute hydrochloric acid. Ice was added to the solution, basified with ammonia and extracted with ethyl acetate. The combined organic extracts were dried and evaporated.

Yield: 0.9 g (98% of theory),

Rf value: 0.14 (silica gel; ethyl acetate / ethanol = 9: 1)

K. 2- (4-Cyanophenylaminomethyl) -1-methyl-5-1H-N - (2-ethoxycarbonylethyl) aminol-1- (pyrrolidin-1-yl-carbonyl) ethyl-benzimidazole

Dissolve 0.4 g (1.04 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole in 10 ml ethanol, and after addition of 0.3 ml (2.7 mmol) of ethyl acrylate, it is stirred at 95 ° C for 24 hours. The solvent was distilled off, and the residue was chromatographed on silica gel, eluting with methylene chloride / ethanol (20: 1 and 4: 1).

Yield: 0.16 g (31% of theory),

Rf value: 0.26 (silica gel; ethyl acetate / ethanol = 9: 1)

L. 2- (4-Amidinophenylaminomethyl) -1-methyl-5-r- N - (2-ethoxycarbonylethyl) amino-1- (pyrrolidine-1-ylcarbonyl) ethyl 1-benzimidazole hydrochloride Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- [N- (2-ethoxycarbonylethyl) amino] -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole and hydrochloric acid of ammonium carbonate in ethanol Yield: 96% of the theoretical yield,

C ₂ 8H ₃₇ N ₇ O 3 x HCl (519.65 / 556.11)

Mass Spectrum: (M + H) ⁺ = 520 · 9999 ♦ 9

- 78 9 9 9 9 9 9 9 9

9,999,999 (9 + 9) (M + Na) ⁺ = 542

In analogy to Example 6, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonylpropionyl-amino) -1-ethoxycarbonyl-ethyl] -benzimidazole hydrochloride

Yield: 69% of theory.

C27H34N6O5 x HOl (522.62 / 555.08)

Mass Spectrum: (M + H) ⁺ = 523 (M + H + Na) ⁺⁺ = 273 (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylcarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 95% of theory.

C28H35N7O4 x HCl (533.64 / 570.10)

Mass Spectrum: (M + H) ⁺ = 534 (M + Na) ⁺ = 556 (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonylpropionylamino) -1 - ( pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 20% of theory.

C ₂₉ H37N ₇ O4 x HCl (547.66 / 584.12)

Mass Spectrum: (M + H) ⁺ = 548 (M + H + Na) ⁺⁺ = 285.7.9 (4) 2- [4-Amidinophenyl-N- (2-ethoxycarbonylethyl) aminoethyl] 1-Methyl-5- [1-dimethylamino-1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 91% of theory.

C30H41N7O3 x HCl (547, 71 / 584.17)

Mass Spectrum: (M + H) ⁺ = 548 (MH) + = 546 (5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) 1- (dimethylaminocarbonyl) ethyl] -benzimidazole hydrochloride

Yield: 40% of theory.

Rf value: 0.60 (reverse phase RP 8; 5% sodium chloride / methanol = 1/1)

C26H35N7O3 x HCl (493.63 / 530.08)

Mass Spectrum: (M + H) ⁺ = 494, (M-H + 2HCl) - = 564/566/568 (Cl ₂ ) (6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride

Yield: 77% of theory.

Rf value: 0.40 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C27H35N7O3 x HCl (505.63 / 542.08)

Mass Spectrum: (M + H) ⁺ = 506 (7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylamino) -1- (N-ethyl-N-methylaminocarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 85% of theory

9 9 9 9 9 ·

9 9 9 • 99 9 * 99

9 9 9 9 9 9999 99 9

9 9 99 9 • 9 ·

9 · 9 9

9 * 9

80 Rf value: 0.44 / silica gel; methylene chloride / ethanol = 9: 1)

C27H37N7O3 x HCl (507.64 / 544.14)

Mass Spectrum: (M + H) ⁺ = 508 (M + Cl) + = 542/4 (Cl) (8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (methoxycarbonylmethylamino) - 1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole hydrochloride

Yield: 99% of theory.

Rf value: 0.21 (silica gel- · methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C26H33N7O3 x HCl (491,60 / 528,05)

Mass Spectrum: (M + H) ⁺ = 492 (M-H + HCl) - = 526/8 (Cl) (M-H + 2HCl) - = 562/4/8 (Cl ₂ ) (9) 2- ( 4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N, N-bis (ethoxycarbonylmethyl) amino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride Yield: 65% of theory,

Rf value: 0.35 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C31H41N7O5 x HCl (591.72 / 628.17)

Mass Spectrum: (M + H) ⁺ = 592 (M-H + HCl) - = 626/8 (Cl) (M-H + 2HCl) - = 662/4/6 (Cl ₂ )

4 4 4 4 4 '4 4' 4 4 4 4 4 4 4 4. 81 - ......... ”* (10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) 1- (isoxazolidin-1-ylcarbonyl) ethyl] -benzimidazole hydrochloride

Yield: 9% of theory

Rf value: 0.50 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C26H33N7O4 x HCl (507.60 / 544.05)

Mass Spectrum: (M + H) ⁺ = 508 (11) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-ethylamino) 1- (isoxazolidin-1-yl-carbonyl) - ethyl] -benzimidazole hydrochloride (12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (N-methyl-N-ethylaminocarbonyl) ethyl] -benzimidazole dihydrochloride

Yield: 58% of theory.

Rf value: 0.70 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C26H35N7O3 x 2 HCl (493.62 / 566.52)

Mass Spectrum: (M + H) ⁺ = 494 (M + HCl-H) - = 528/30 (Cl) (13) 2- (4-Amidinophenylaminomethyl) 1-methyl-5- [1 - ((N, N) -diethoxycarbonylmethyl-amino) -1- (N-methyl-N-ethylaminocarbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 30% of theory.

_Rf value: 0.40 (reverse phase RP 8; methanol / 5% saline solution = 3: 2)

C30H41N7O5 x 2 HCl (579.71 / 652.62)

Mass Spectrum: (M + H) ⁺ = 580 · 9 · 9 9 9 9 9

9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

9 99 9900 99

82 (M-H) - = 578 (14) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylamino) -1- (piperidinocarbonyl) ethyl] benzimidazole dihydrochloride

Yield: 82% of theory.

Rf value: 0.60 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C ₂₈ H ₃₇ N ₇ O ₃ x 2 HCl (519.65 / 592.75)

Mass Spectrum: (M + H) ⁺ = 520 (M-H + HCl) - = 534/6 (Cl) (M-H + 2HCl) - = 590/2/4 (Cl ₂ ) (15) 2- ( 4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (diethylaminocarbonyl) ethyl] benzimidazole dihydrochloride

Yield: 88% of theory.

Rf value: 0.60 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C ₂₇ H ₃₇ N ₇ O ₃ x 2 HCl (507.64 / 580.56)

Mass Spectrum: (M + H) ⁺ = 508 (M-H + 2HCl) - = 578/580/582 (Cl ₂ ) (16) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- ( ethoxycarbonylmethyl-methylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 46% of theory.

Rf value: 0.43 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid)

C28H37N7O3X 2HC1 (519.65 / 592.56)

Mass Spectrum: (M + H) ⁺ = 520 (M + Cl) + = 554/6 (Cl) (17) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol-5-yl) -methylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole dihydrochloride (18) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (3-ethoxycarbonyl-propylamino) - 1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 95% of theory.

Rt value: 0.50 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C29H39N7O3 x 2 HCl (533.68 / 606.58)

Mass Spectrum: (M + H) ⁺ = 534

Example 7

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1-1H-cyclopentyl-N- (3-ethoxycarbonyl-propionyl) -amino-cyclopropene-benzimidazole hydrochloride

A. 4 - ((1-tert-Butoxycarbonylamino) -cyclopropyl) -2-nitro-N-methyl-aniline

15.0 g (63.5 mmol) of 4 - ((1-carboxy) cyclopropyl) -2-nitro-N-methyl-aniline and 17.6 ml (127 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and at a temperature of At 0 ° C, 8.3 g (76 mmol) of ethyl chloroformate were added. After one hour, 0.75 g of tetrabutylammonium bromide was added at room temperature. A solution of 6.3 g (96 mmol) of sodium azide in 20 ml of water is then added dropwise. After i '' Í ΥΛΑ—. ^ -.

Dilute the solution at 0 ° C with water for one hour and extract with ethyl acetate. The organic extracts are dried and evaporated. The residue was dissolved in 200 ml of tert-butanol and heated at reflux for two hours. The solvent was evaporated, the residue was chromatographed on silica gel and eluted with methylene chloride.

Yield: 15.5 g (77% of theory),

Rf value: 0.83 (silica gel) methylene chloride / methanol = 9.5: 0.5)

B. 4 - ((1-Amino) -cyclopropvl) -2-nitro-N-methyl-aniline hydrochloride

15.5 g (0.05 mol) of 4 - [(1-tert-butyloxycarbonylamino) -cyclopropyl] -2-nitro-N-methylaniline are dissolved in 50 ml of ethanol and 50 ml of ethanolic hydrochloric acid and stirred for 7 hours at room temperature. . The solvent was distilled off, the residue was mixed with ether, filtered off with suction and dried.

Yield: 98% of theory.

Rf value: 0.44 (silica gel; methylene chloride / methanol = 9.5: 0.5)

C. 4-N- (1-cyclopentyl-amino) -cyclopropyl-2-nitro-N-methyl-aniline

12.0 g (0.05 mol) of 4 - [(1-amino) -cyclopropyl] -2-nitro-N-methyl-aniline hydrochloride are dissolved in 500 ml of tetrahydrofuran and after addition of 4.1 g (0.05 13.6 g (0.064 mol) of sodium triacetoxyborohydride are added in portions, diluted with sodium bicarbonate solution at room temperature and extracted with ethyl acetate, and the organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with ethyl acetate / cyclohexane (1: 1).

Rf value: 0.56 (silica gel; methylene chloride / methanol = 9.5: 0.5)

D. 4- [1- (N- (3-Ethoxycarbonylpropionyl) -N-cyclopentyl-amino) -cycloprop-2-nitro-N-methyl-aniline]

1.0 g (3.6 mmol) of 4 - [(1-cyclopentylamino) -cyclopropyl] -2-nitro-N-methyl-aniline is dissolved in 30 ml of tetrahydrofuran and after addition of 0.45 g (4.4 mmol) triethylamine was added 0.65 g (4.4 mmol) of ethyl succinate chloride and stirred for four hours at room temperature. It is then diluted with ethyl acetate and sodium bicarbonate solution, the organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with ethyl acetate / cyclohexane (1: 1).

Yield: 1.3 g (90% of theory),

Rf value: 0.46 (silica gel; ethyl acetate / cyclohexane = 1: 1)

E. 4- [1- (N- (3-Ethoxycarbonylpropionyl) -N-cyclopentyl-amino) -cyclopropyl-2-amino-N-methyl-aniline

Prepared in analogy to Example 1D from 4- [1- (N- (3-ethoxycarbonylpropionyl) -N-cyclopentylamino) -cyclopropyl] -2-nitro-N-methyl-aniline and palladium on activated carbon / hydrogen in methylene chloride / ethanol.

Yield: 100% of theory.

Rf value: 0.18 (silica gel; ethyl acetate / cyclohexane = 1: 1)

F. 4- [1- (N- (3-ethoxycarbonylpropionyl) -N-cyclopentyl-amino) -cyclopropyl] -2- (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline

Prepared in analogy to Example 1C from 4- [1- (N- (3-ethoxycarbonylpropionyl) -N-cyclopentyl-amino) -cyclopropyl] -2-amino-N-methyl-aniline, o- (benzotriazol-1-yl) -N , N, Ν ', N'-tetramethyluronium terafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 96% of theory.

Rf value: 0.54 (silica gel; methylene chloride / methanol = 9.5: 0.5)

G. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1H-N-cyclopentyl-N- (3-ethoxycarbonylpropionyl) D-aminol-cyclopropylH-benzimidazole ·· ····

Prepared in analogy to Example 1F from 4- [1- (N- (3-ethoxycarbonyl-propionyl) -N-cyclopentylamino) -cyclopropyl] -2- (4-cyanophenyl) -aminomethylcarbonylamino-N-methylaniline in glacial acetic acid.

Yield: 52% of theory.

Rf value: 0.81 / silica gel; methylene chloride / methanol = 9: 1)

H. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1H-N-cyclopentyl-N- (3-ethoxycarbonylpropionyl) -amino-cycloprop-1H-benzimidazole hydrochloride Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) 1-Methyl-5- [1- [N-cyclopentyl-N- (3-ethoxycarbonylpropionyl) -amino] -cyclopropyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol (yield: 36% of theory),

CsoHssNeOs x HCl (530.68 / 567.14)

Mass Spectrum: (M + H) ⁺ = 531

Example 8

2- (4-Amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-ethoxycarbonylmethylimidazoline-2,4-dione-5-yl) -benzimidazole hydrochloride

A. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino-carbonylamino) -1- (pyrrolidine-1-yl-carbonyl) -ethyl] -benzimidazole

Dissolve 1.0 g (2.5 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole in 10 ml of dimethylformamide and after addition of 0.9 ml (7.9 mmol) of ethyl isocyanatoacetate, it is stirred at room temperature for 45 minutes. The solution is poured onto ice water, crystalline.

• I * ·

- 87> tf · ·

• * · • · · · Ί _# f «·>

The product is aspirated and dried. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol / ammonia (20: 1: 0.01 and 10: 1: 0.01)

Rf value: 0.77 (silica gel; methylene chloride / ethanol / ammonia = 9: 1: 0.01)

B. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3-ethoxycarbonylmethylimidazolin-2,4-dion-5-yl) -benzimidazole hydrochloride Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) 1-Methyl-5- [1- (ethoxy-carbonylmethylaminocarbonylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol. Yield: 68% of theory.

C24H27N7O4 x HCl (477.52 / 513.99)

Mass Spectrum: (M + H) ⁺ = 478

Example 9

2- (4-Amidinophenylaminomethyl) -1-methyl-5-N- (2-pyridyl) -N- (2-ethoxycarbonyl-4-ethyl-amino) benzimidazole hydrochloride

A. 4- (2-tert-Butyloxycarbonyl-ethyl) -2- (pyridyl-aminomethyl) -2-nitrochlorobenzole

13.4 g (0.053 mol) of 4-chloro-3-nitrobenzyl bromide and 11.8 g (0.053 mol) of 2-tert. butyloxycarbonylethylamino-pyridine was stirred in 80 ml of N-ethyl-diisopropylamine for 3 hours at 90 ° C. The solution was evaporated, the residue was chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (8: 2 and 7: 3).

• 9 ····

99 9 9

- 88 • · • 9

9 • 9 9 9

9 ·· • 9

9 • 9 • 9 • 9 • 9 • 9 • 99

Yield: 8.2 g (40% of theory),

Rf value: 0.64 (silica gel; petroleum ether / ethyl acetate = 8: 2)

B. 4- (2-tert-Butyloxycarbonyl) -2- (pyridinomethyl) -2-nitro-N-methyl-aniline

Prepared in analogy to Example 1B from 4- (2-tert-butyloxycarbonylethyl) -2- (pyridylaminomethyl) -2-nitro-chlorobenzole and methylamine solution.

Yield: 20% of theory.

Rf value: 0.65 (silica gel; methylene chloride / ethanol = 9: 1)

C. 4- (2-tert-Butyloxycarbonyl) -2- (pyridinomethyl) -2-amino-N-methyl-aniline

1.6 g (4 mmol) of 4- (2-tert-butyloxycarbonylethyl) -2- (pyridinylaminoethyl) -2-nitro-N-methylaniline are dissolved in 200 ml of methanol and, after addition of 2 g of Raney nickel, 1 ml of hydrazine- hydrate. The solution was stirred at room temperature for 30 minutes and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (95: 5).

Yield: 1.2 g (82% of theory);

Rf value: 0.33 (silica gel; methylene chloride / ethanol = 9: 1)

D. 2- (4-Cyanophenylaminomethyl) -1-methyl-5-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -aminoethoxybenzimidazole

Prepared in analogy to Example 1C from 4- (2-tert-butyloxycarbonylethyl) -2 (pyridylaminomethyl) -2-amino-N-methyl-aniline, o- (benzotriazol-1-yl) -N, Ν, Ν ', N' tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine in tetrahydrofuran and glacial acetic acid.

Yield: 72% of theory.

Rf value: 0.36 (silica gel; methylene chloride / ethanol = 9: 1)

89- 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (2-pyridyl) -N- (2-ethoxycarbonylethyl-D-aminomethyl) -benzimidazole hydrochloride Prepared in analogy to Example 1G from 4 - [(5 - (2-tert-Butyloxycarbonylethyl) -2-pyridylaminomethyl-1-methyl-benzimidazol-2-yl) -methylamino] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 59% of theory.

C27H31N7O2 x HCl (485.59 / 522.1)

Mass Spectrum: (M + H) ⁺ = 486

In analogy to Example 9, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (ethoxycarbonylmethyl) benzolsulfonylaminomethyl] benzimidazole hydrochloride

Yield: 53% of theory.

C2 ₇ H ₃ N ₆ O ₄ S x HCl (534,64 / 571,1)

Mass Spectrum: (M + H) ⁺ = 535 (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- (N-methylphenylcarbonylamino-methyl)] benzimidazole hydrochloride

Yield: 42% of theory.

C25H26N6O x HCl (426.53 / 462.96)

Mass Spectrum: (M + H) ⁺ = 427

Example 10

V -: - _{; -;} rpSMrtA5 ^

- 90 2- (4-Amidinophenylaminomethyl) -1-methyl-5-yl-2-methyl-benzimidazol-1-yl} -methoxy-benzimidazole hydrochloride

A. 1- (4-Chloro-3-nitrobenzyl) -2-methylbenzimidazole

Made analogously to Example 9A from 2-methylbenzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulfoxide.

Yield: 78% of theory.

Ci ₅ H ₁₂ CIN ₃ O ₂ (301.7)

Mass Spectrum: M ⁺ = 301/303

B. 1- (4-Methylamino-3-nitrobenzyl) -2-methylbenzimidazole

Made analogously to Example 1B from 1- (4-chloro-3-nitrobenzyl) -2-methylbenzimidazole and methylamine.

Yield: 96% of theory.

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

C. 1- (4-Methylamino-3-aminobenzyl) -2-methylbenzimidazole

Made analogously to Example 1C from 1- (4-methylamino-3-nitrobenzyl) -2-methylbenzimidazole and hydrogen / Raney nickel.

Yield: 100% of theory.

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

D. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- (2-methyl-benzimidazol-1-yl) methyl-benzimidazole

A mixture of 1.94 g (11.0 mmol) of N- (4-cyanophenyl) glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole was heated in 80 ml of absolute tetrahydrofuran for 15 min.

9 9 9999 99 9 99 99 • 9 9 9999 999 99 99 99 999

999 999 9999 •• 9,999,999 _, 99,999,999,999 9

After adding 2.7 g (10.46 mmol) of 1- (4-methylamino-3-aminobenzyl) -2-methylbenzimidazole, the mixture was further heated under reflux for 16 hours. Subsequently, the solution is evaporated to dryness, 80 ml of glacial acetic acid are added to the residue and heated under reflux for 1 hour. It is then evaporated to dryness again, 50 ml of water are added to the residue, and the mixture is then basified with concentrated ammonia (ca. pH 10). The crystallized product is filtered off with suction, washed with a little water and dried.

Yield: 4.1 g (96% of theory),

Rt -value:

0.30 (silica gel; methylene chloride / ethanol = 19.1)

C ₂₅ H ₂ 2N ₆ (406.5)

Mass Spectrum: M ⁺ = 406

E. 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-benzimidazol-1-yl) -methyl] -benzimidazole hydrochloride

Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) -1-methyl-5 - [(2-methyl-benzimidazol-1-yl) -methyl] -benzimidazole and hydrochloric acid / ammonium carbonate.

Yield: 59% of theory.

C ₂₅ H25N ₇ x HCl (423.5 / 459.9)

Mass spectrum: (M + H) ⁺ = 424 (M + 2H) ⁺ = 217.7

In analogy to Example 10, the following compounds are obtained:

(1) 2- (4-Amidinophenyloxymethyl) -1-methyl-5 - [(imidazol-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 30% of theory.

- 92 C ₂₀ H ₂₀ N ₆ O x HCl (360.4 / 396.9)

Mass Spectrum: (M + H) ⁺ = 361 (M + 2H) ²⁺ = 181 (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (imidazol-1-yl) ethyl] -benzimidazole hydrochloride

Yield: 70% of theory.

C ₂ H ₂₃ N ₇ x HCl (363,46 / 410)

Mass Spectrum: (M + H) ⁺ = 374 (M + 2H) ²⁺ = 187.6 (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethyl-4-methyl) -imidazol-1-yl) -ethyl] -benzimidazole dihydrochloride

Yield: 18% of theory.

C ₂₄ H ₂₉ N ₇ x HCl (415.55 / 488.46)

Mass Spectrum: (M + H) ⁺ = 416 (M + 2H) ²⁺ = 208.7 (4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 [(2-ethyl-4-methyl-imidazole- 1-yl) -methyl] -benzimidazole dihydrochloride

Yield: 36% of theory.

C ₂₃ H ₂₇ N ₇ x 2HCl (401.52 / 437.97)

Mass Spectrum: (M + H) ⁺ = 402 (M + 2H) ²⁺ = 201.7 (5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [N- (pyridin-2-yl) - N-methylaminomethyl-benzimidazole dihydrochloride

9 9,999 9 9 9 9 9 9

9 9 9 9 9

Yield: 78% of theory.

C23H25N7 x 2HCI (399.5 / 435.95)

Mass Spectrum: (M + H) ⁺ = 400 (M + 2H) ²⁺ = 200.6 (6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-ethoxycarbonyl-ethyl)) -benzimidazol-1-yl) -methyl] -dihydrochloride

Yield: 61% of theory.

C29H31N7O2 x HCl (509.62 / 546.07)

Mass Spectrum: (M + H) ⁺ = 510 (M + 2H) ²⁺ = 255.7 (M + H + Na) ²⁺ = 266.7 (7) 2- (4-Amidinophenylaminomethyl) -1-methyl- 5 - [(imidazol-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 35% of theory.

C20H21N7 x HCl (359.44 / 395.89)

Mass Spectrum: (M + H) ⁺ = 360 (M + 2H) ²⁺ = 180.6 (8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-acetyl-amino- ethyl) -4,5-dimethyl-imidazol-1-yl) -methyl] -benzimidazole dihydrochloride

Yield: 42% of theory.

C26H ₃₂ N ₈ O x 2 HCl (472.6 / 545.51)

Mass Spectrum: (M + H) ⁺ = 473 (M + 2H) ²⁺ = 237.

(M + H + Na) ²⁺ = 248 (9) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2- (2-aminocarbonyl-ethyl) -4,4-dimethyl-imidazole-1- yl) -methyl] -benzimidazole dihydrochloride

Yield: 68% of theory.

C ₂₅ H ₃ O ₈ 0 x 2 HCl (458.6 / 531.51)

Mass Spectrum: (M + H) ⁺ = 459 (M + 2H) ²⁺ = 230 (10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(2-methyl-4-ethoxycarbonyl-imidazole-1) -yl) -methyl] -benzimidazole hydrochloride

Yield: 34% of theory.

C24H27N7O2 x HCl (445.53 / 481.98)

Mass Spectrum: (M + H) ⁺ = 446 (M + 2H) ²⁺ = 223.5 (M + H + Na) ²⁺ = 234.5 (11) 2- (4-Amidinophenylaminomethyl) -1-methyl- 5 - [(3- (3-Ethoxycarbonyl-n-propyl) -benzimidazol-2-one-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 58% of theory.

C ₃ o H ₃₃ N ₇ 0 ₃ x HCl (539,64 / 576,09)

Mass Spectrum: (M + H) ⁺ = 540 (M + H + Na) ²⁺ = 281.7 (12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(3- (2-ethoxycarbonyl- ethyl) -imidazol [4,5-b] pyridin-2-on-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 29% of theory.

- 95 -. ......

C28H30N8O3 x HCl (526.6 / 593.05)

Mass Spectrum: (M + H) ⁺ = 527 (M + 2H) ²⁺ = 264 (M + H + Na) ²⁺ = 275 (13) 2- (4-Arnidinophenylaminomethyl) -1-methyl-5 - [( 2-Phenyl-imidazol-1-yl) -methyl] -benzimidazole hydrochloride

Yield: 58% of theory.

C ₂₆ H ₂₅ N ₇ x HCl (435.54 / 472)

Mass Spectrum: (M + H) ⁺ = 436 (M + Na) ⁺ = 218.6 (14) 2- (4-Amidinophenylaminomethyl) -1-methyl-5 - [(4,5-dimethyl-2- (2)) -ethoxy-carbonylethyl) -imidazol-1-yl) -methyl] -benzimidazole dihydrochloride

Yield: 52% of theory.

C ₂₇ H ₃₃ N ₇ O ₂ x HCl (487.61 / 560.52)

Mass Spectrum: (M + H) ⁺ = 488 (M + 2H) ²⁺ = 244.6

Example 11

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-acetidin-1-yl) -1- (pyrrolidin-1-yl) -carbonyl-ethoxy-benzimidazole hydrochloride

9 9 9 9 9 9 9 9 9 99 99 999

A. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (2-tert-butoxycarbonyl-acetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole

0.8 g (1.86 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidin-1-ylcarbonyl) ethyl] benzimidazole and 1.65 g (5.5 mmol) of t-butyl 2,4-dibromobutyrate was dissolved in 5 ml of ethanol, 0.2 g (1.86 mmol) of sodium carbonate was added and stirred under nitrogen for 30 hours at 55 ° C. After cooling, the white precipitate was filtered off and washed with ethanol. The filtrate was evaporated, the residue was chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate / ethanol / ammonia (20: 1: 0.01). The desired fractions were purified and evaporated.

Yield: 0.44 g (44% of theory) as a mixture of diastereomers,

C ₃ H 38 N ₆ O ₃ (542.69)

Mass Spectrum: (M + H) ⁺ = 543

B. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-acetidin-1-yl) -1- (pyrrolidin-1-ylcarbonyl) -diethyl-benzimidazole hydrochloride (mixture of diastereomers) )

Made analogously to Example 1G from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (2-tert-butyl-oxycarbonyl-acetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) - ethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol. Yield: 12% of the theoretical yield,

C ₂ 9H37N ₇ O ₃ x HCl (531.66 / 568.12)

Mass Spectrum: (M + H) ⁺ = 532 (M + H + HCl) ² * = 568/70 (Cl)

Example 12 (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyridin-3-yl) ethoxycarbonylmethylmethylene) -methylene] -cyclopropane- benzimidazole hydrochloride

A. (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyridin-3-yl) -ethoxycarbonyl-methylidene) -methylene-cycloprop-1H-benzimidazole

897 mg (4.0 mmol) of phosphonoacetic acid triethyl ester are dissolved after argon in 30 ml of tetrahydrofuran. At -15 ° C, 449 mg (4.0 mmol) of tert. potassium butylate. After 30 minutes, 815 mg (2.0 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (pyridin-3-ylcarbonyl) cyclopropyl] -benzimidazole was added portionwise and stirred overnight at room temperature. The solution was then heated at reflux for 6 hours and concentrated. Sodium chloride solution was added to the residue and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel, eluting with dichloromethane with 5% ethanol. The desired fractions were concentrated, the residue was treated with ether, filtered off with suction and dried.

Yield: 365 mg (38% of theory).

B. (E / Z) -2- (4-Aminophenophenylaminomethyl) -1-methyl-5- [1,1-f (pyridin-3-yl) -ethoxycarbonyl-methylidene) -methylene | -cyclopropyl-benzimidazole hydrochloride

Made analogously to Example 1G from (E / Z) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-3-yl -) - ethoxycarbonylmethylidene) -methylene] -cyclopropyl] -benzimidazole and hydrochloric acid] ammonium carbonate in ethanol. Yield: 58% of theory.

C29H30N6O2 x HCl (494.60 / 531.05)

Mass Spectrum: (M + H) ⁺ = 495

In analogy to Example 12, the following compounds are obtained:

9

(1) (E / Z) -2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) -ethoxycarbonylmethylidene] -methylene [-cyclopropyl] -benzimidazole hydrochloride

Yield: 72% of theory.

C29H30N6O2 x HCl (494.60 / 531.05)

Mass Spectrum: (M + H) ⁺ = 495

Example 13

2- (4-Amidinophenylaminomethyl) -1-methyl-5-ri- (2-carboxy-acetidin-1-yl) -1- (pyrrolidin-1-ylcarbonyl) -ethyl 1-benzimidazole hydrochloride (diastereomers)

200 mg (0.35mmol) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonyl-acetidin-1-yl) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole hydrochloride is dissolved in 30 ml of 6N hydrochloric acid and stirred at room temperature for 13 hours. The reaction mixture was evaporated with the addition of toluene, the residue was mixed with acetone / ether, filtered off with suction, washed with ether and dried.

Yield: 200 mg (less than 100% of theory, containing ammonium chloride),

C27H33N7O3 x HCl (503.62 / 540.07)

Mass Spectrum: (M + H) ⁺ = 504

In analogy to Example 13, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1 (dimethylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 91% of theory.

- 99 «« ·· ♦ · · · ·

Rf value: 0.75 (reverse phase; 5% sodium chloride / methanol = 1: 1)

C ₂₄ H ₃₁ N7O _3x HCl (465,56 / 502,01)

Mass Spectrum: (M + H) ⁺ = 466 (M-H + 2HCl) - = 537/539 (Cl ₂ ) (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino)) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole dihydrochloride

Yield: 70% of theory.

_Rf value: 0.51 (reverse phase, 5% salt solution / methanol = 3: 2)

C ₂₅ H ₃ iN ₇ O ₃ x 2 HCl (477.57 / 550.48)

Mass Spectrum: (M + H) ⁺ = 478 (3) (E / Z) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - [(pyridin-2-yl) carboxymethylidene] methylene ] -cyclopropyl] -benzimidazole hydrochloride Yield: 65% of theory,

C ₂₇ H ₂₆ N ₆ O ₂ x HCl (466.55 / 503.0)

Mass Spectrum: (M + H) ⁺ = 467 (M + Cl) ⁺ = 501/503 (Cl) (4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylamino) ) -2- (Pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole dihydrochloride

Yield: 99% of theory.

Rf value: 0.55 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C ₂₈ H ₃₅ N7O ₄ x 2 HCl (533.64 / 606.64)

Mass Spectrum: (M + H) ⁺ = 534.

- 100 -

(MH) - = 532 (M-H + HCl) - = 568/70 (Cl) (5) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1 - (N-ethyl-N-methylaminocarbonyl) -ethyl] -benzimidazo-dihydrochloride Yield: 75% of the theoretical yield,

Rf value: 0.54 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C25H33N7O3X2 HCl (479.59 / 552.59)

Mass Spectrum: (M + H) ⁺ = 480

Example 14

2- [4- (N-hexyloxycarbonylamidino) -phenylaminomethyl-1-methyl-5- [1- (2-ethoxycarbethoxy) -1- (dimethylaminocarbonyl) -ethyl] -benzimidazole

Dissolve 1.5 g (2.8 mmol) of 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- / 2-ethoxycarbonylethylamino) -1- (diethylaminocarbonyl) ethyl] benzimidazole hydrochloride in 14 ml Water (55 ml) tetrahydrofuran, 2.0 g of potassium carbonate and 1.0 ml (6 mmol) of hexyl chloroformate were added and stirred at room temperature for 4 hours. After the solvent was removed in vacuo, the residue was treated with brine and extracted three times with methylene chloride. The combined organic phases were washed with water, dried over magnesium sulphate and evaporated. The crude product is purified on silica gel, eluting with methylene chloride with 2 to 7.5% ethanol. The uniform fractions were purified, evaporated, dissolved in ethyl acetate and petroleum ether was added. The resulting solid is filtered off with suction, washed with petroleum ether and dried.

Yield: 0.8 g (43% of theory),

9 999

- 101 C ₃₃ H ₄ 7N ₇ O ₅ (621.79)

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 19: 1)

Mass Spectrum: (M + H) ⁺ = 622 (M + Na) ⁺ = 644

Example 15

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole hydrochloride

A. 2- (4-Chloro-phenyl) -3-hydroxy-2-methyl-propionic acid methyl ester

To a solution of 8.1 mL of diisopropylamine (85 mmol) in 20 mL of tetrahydrofuran at -78 ° C was added dropwise 35 mL of a 1.6 molar solution of n-butyllithium in hexane (61 mmol). Subsequently, a solution of 10.0 g (50 mmol) of methyl 2- (4-chlorophenyl) -propionate in 30 ml of tetrahydrofuran was added dropwise at -78 ° C. Gaseous formaldehyde is then introduced into the reaction mixture at -20 ° C for 30 minutes. After addition of 5% citric acid and glacial acetic acid, it is extracted with ethyl acetate. The organic phases were washed with 1N sulfuric acid, water, saturated sodium carbonate solution and common salt solution and dried over magnesium sulfate. The crude product was purified on silica gel eluting with cyclohexane / ethyl acetate (19: 1; 9: 1; 4: 1; 1: 1 and 0: 1). The combined fractions were purified and evaporated.

Yield: 9.7 g (84% of theory) of a yellow oil,

Rf value: 0.25 (silica gel; petroleum ether / ethyl acetate 4: 1)

B. 2- (4-Chloro-phenyl) -3-hydroxy-2-methyl-propionic acid

Made analogously to Example 4 from 2- (chlorophenyl) -3-hydroxy-2-methyl-propionic acid methyl ester and sodium hydroxide in ethanol.

·· ···· 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

- 102 - ·· · ·· .......

Yield: 83% of theory.

Rf value: 0.55 (silica gel; acetic acid ester (cyclohexane 2: 1 + glacial acetic acid))

C. 2- (4-Chloro-3-nitro-phenyl) -2-methyl-3-nitrooxy-propionic acid

Made analogously to Example 1A from 2- (4-chlorophenyl) -3-hydroxy-2-methylpropionic acid and nitric acid.

Yield: 90% of theory.

Melting point: 129-132 ° C

C ₁₀ H ₉ CIN ₂ O ₇ (304.64)

D. 2- (4-Chloro-3-nitro-phenyl) -2-methyl-3-hydroxy-propionic acid

Prepared in analogy to Example 6 from 2- (4-chloro-3-nitro-phenyl) -3-nitrooxy-2-methylpropionic acid and 6N hydrochloric acid in dioxane.

Yield: 98% of theory.

C ₁₀ Hi ₀ CINO ₅ (259.65)

Mass Spectrum: (MH) - = 258/60 (Cl) (2M-H) · = 517/9 (Cl ₂ )

E. 2- [4- (N-Benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-propionic acid

Made analogously to Example 1B from 2- (4-chloro-3-nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.

Yield: 81% of theory.

C ₁₈ H ₂₀ CIN ₂ O ₅ (344.37)

Mass Spectrum: M ⁺ = 344

- 103 • 0 ······

000 0 0 0 0 0

000 0 0 · · 0 · • 0 · 0

F. 2-4- ^{(N-benzyl-methylamino,)} -3-nitro-phenyl-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one

Prepared in analogy to Example 1C from 2- [4- (N-benzyl-methyl-amino) -3-nitro-phenyl] -3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.

Yield: 96% of theory.

C ₂₂ H ₂₇ N ₃ O ₄ (397.48)

Mass Spectrum: M ⁺ = 398 (M + Na) ⁺ = 420

G. 2- [4- (N-Benzyl-methylamino) -3-nitro-phenyl-2-methyl-3-methanesulfonoyl-1-pyrrolidin-1-yl-propan-1-one

To a solution of 1.2 g (3.0 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propane-1 In 20 ml of tetrahydrofuran, 1.3 ml (9.3 mmol) of triethylamine are added at room temperature. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonyl chloride was added dropwise at 2-5 ° C. After 2 hours at room temperature, the precipitate formed is filtered off with suction and the filtrate is evaporated. The crude product reacts further without purification.

Yield: 1.4 g (98% of theory).

H. 2-F4- (N-Benzyl-methylamino) -3-nitro-phenyl-2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one

To a solution of 1.4 g (2.9 mmol) of 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3-methanesulfonyloxy-1-pyrrolidin-1-yl-propane- 1-one in 10 ml of dimethylformamide was added 20 ml of a 40% aqueous methylamine solution and heated at 100 ° C for 70 minutes. After cooling, ice water was added to the reaction mixture and extracted with ethyl acetate. The organic phases are washed with water and brine, dried and evaporated over magnesium sulphate. The crude product was purified on silica gel, eluting with ethyl acetate / ethanol (10: 1, 9: 1, 4: 1 + 1% conc. Ammonia). The combined fractions were purified and evaporated.

Yield:

740 mg (61% of theory). _n . ··· ··· ··

- j U4 - ····

Rf value: 0.45 (silica gel; methylene chloride / ethanol 9: 1 + 1% conc. Ammonia)

I. 2- [4- (Benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3- (N-methoxycarbonylmethylcarbonyl-methylamino) -1-pyrrolidin-1-yl-propan-1-one

Prepared in analogy to Example 7D from 2- [4- (N-benzyl-methyl-amino) -3-nitro-phenyl] 2-methyl-3-methylamino-1-pyrrolidin-1-yl-propan-1-one and malonic acid methyl ester chloride.

Yield: 84% of theory.

Rf value: 0.65 (silica gel; ethyl acetate / ethanol 9: 1 + ammonia)

C ₂ 7H ₃ 4N ₄ O6 (510.60)

Mass Spectrum: (MH) - = 509 (M + Na) ⁺ = 533

J. 2- (4-Methylamino-3-amino-phenyl) -2-methyl-3- (N-methoxycarbonylmethyl-carbonylmethylamino) -1-pyrrolidin-1-yl-propan-1-one

Prepared in analogy to Example 1D from 2- [4- (N-benzyl-methyl-amino) -3-nitro-phenyl] 2-methyl-3- (N-methoxycarbonylmethylcarbonyl-methylamino) -1-pyrrolidin-1-ylpropan-1 -one and hydrogen / palladium on activated carbon.

Yield: 100% of theory.

Rf value: 0.40 (silica gel; ethyl acetate / ethanol 9: 1 + 1% conc. Ammonia)

C ₂ H 30 N ₄ 04 (390.49)

Mass Spectrum: M ⁺ = 390

K. 4- [2- (3- (N-N-methoxycarbonylmethylcarbonyl-methylamino)) - 2-methyl-1-PVrolidin-1-yl-propan-1-one-2-yl] -2 (4-cyano-phenyl) - aminomethyl- 105 -

-carbonylamino-N-methyl-aniline

Made analogously to Example 1E from 2- (4-methylamino-3-aminophenyl) -2-methyl-3- (N-methoxycarbonylmethylcarbonyl-methylamino-1-pyrrolidin-1-yl-propan-1-one and o- ( benzotriazol-1-yl) -N, Ν, Ν ', N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.

Yield: 95% of theory.

Rf value: 0.35 (silica gel; ethyl acetate / ethanol 9: 1 + 1% conc. Ammonia)

L. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethyl-carbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yn-benzimidazole

Prepared in analogy to Example 1F from 4- [2- (3- (N-methoxycarbonylmethylcarbonylmethylamino)) - 2-methyl-1-pyrrolidin-1-yl-propan-1-one-2-yl] -2- (4-canophenyl) ) aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.

Yield: 47% of theory.

Rf value: 0.20 (silica gel; ethyl acetate / ethanol = 9: 1)

C ₂ 9H ₃₄ N ₆ O4 (530.63)

Mass Spectrum: (M + H) ⁺ = 531 (M + Na) ⁺ = 553

M. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yn-benzimidazole hydrochloride

Prepared in analogy to Example 1G from 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1 (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole and hydrochloric acid. ammonium carbonate in ethanol. Yield: 65% of theory.

- 106 9 99

Rf value: 0.30 (silica gel; methylene chloride / methanol = 4: 1 + glacial acetic acid)

C3OH39N7O4 x HCl (561.69 / 598.19)

Mass Spectrum: (M + H) ⁺ = 562 (M + Cl) + = 569/8 (Cl)

In analogy to Example 15, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methoxy-calbonylmethyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl) -benzimidazole hydrochloride

Yield: 89% of theory.

Rf value: 0.35 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C28H37N7O3 x HCl (519.66 / 556.11)

Mass Spectrum: (M + H) ⁺ = 520 (M-H + HCl) - = 554/6 (Cl) (2) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylamino) 1- [2- (Pyrrolidinocarbinyl) -prop-2-yl] -benzimidazole acetate

Yield: 45% of theory.

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2 + 1% ethyl acetate)

C29H37N7O4 x CH ₃ COOH (547.66 / 607.71)

Mass Spectrum: (M + H) ⁺ = 548 (MH +)

•. • i:? ·:. ·: -: - • 9

** ** · ** · · · · · · · · · · · · · · · · · · · · · · · ·

-107- .........

(M-H + CH 3 COOH) - = 606 (3) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (N-methyl-ethylaminocarbonyl) -prop-2- yl] -benzimidazole hydrochloride (4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylmethylamino) -2- (N-methyl-N-ethylaminocarbonyl) -prop-2-yl] (5) 2- (4-Amidinophenylaminomethyl) -2-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (piperidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride (6) ) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylsulfonylmethylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride (7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methoxycarbonylmethyl-carbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole acetate

Yield: 72% of theory.

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2 + 1% glacial acetic acid)

C29H37N7O4 x CH ₃ COOH (547.66 / 607.71)

Mass Spectrum: (M + H) ⁺ = 548 (MH) + = 546

- 108 (8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-ethoxycarbonylethylcarbonylamino) -2- (pyrrolidinocarbonyl) prop-2-yl] benzimidazole hydrochloride (9) 2- ( 4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylsulfonylamino) -2- (pyrrolidinecarbonyl) -prop-2-yl] -benzimidazole hydrochloride

Yield: 14% of theory.

Rf value: 0.20 (silica gel; methylene chloride / ethanol = 8: 2)

C ₂₈ H37N ₇ O ₅ S x HCl (583.65 / 620.17)

Mass Spectrum: (M + H) ⁺ = 584 (M + Na) ⁺ = 606 (10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol-5-yl) methylcarbonylamino- 2-Pyrrolidinocarbonyl) prop-2-yl] -benzimidazole hydrochloride (11) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) 2- (pyrrolidinocarbonyl) prop-2-yl] -benzimidazole dihydrochloride

Yield: 40% of theory.

C ₂₈ H ₃₇ N ₇ O ₃ x 2 HCl (519.65 / 592.26)

Mass Spectrum: (M + H) ⁺ = 520 (M + Na) ⁺ = 542 (M + HCOO) ' = 564 (M + Cl) ' = 554

• ·

- 109 ·· ·

Example 16

2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (isoxazolidin-1-yl) carboxy] -ethoxy-benzimidazole hydrochloride

Made by hydrolyzing 2- (4-amidinophenylaminomethyl) -1-methyl-6- [1- (ethoxycarbonylmethylamino) -1- (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride with sodium hydroxide in ethanol .

Yield: 90% of theory.

Rf value: 0.65 (reverse phase RP 8; methanol / 5% sodium chloride solution = 3: 2)

C24H29N7O4 x HCl (479.54 / 515.99)

Mass Spectrum: (M + H) ⁺ = 480

In analogy to Example 16, the following compounds are obtained:

(1) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylamino) -1 (isoxazolidin-1-ylcarbonyl) ethyl] benzimidazole hydrochloride (2) 2- ( 4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1 (N-methyl-N-ethylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 93% of theory.

Rf value: 0.40 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C24H31N7O3 x HCl (465.47 / 502.02)

Mass Spectrum: (M + H) ⁺ = 466 (M + Cl-H) - = 500/2 (Cl) 9

(4) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole -hydrochloride Yield: 90% of the theoretical yield,

Rf value: 0.55 (reverse phase RP 8; methanol / 5% table salt = 4: 6)

C27H33N7O4 x HCl (519.61 / 556.06)

Mass Spectrum: (M + H) ⁺ = 520 (MH) + = 518 (S) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylmethylamino) -2- (N-ethyl- (6) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylcarbonyl-methylamino) -2- (N-ethyl-methylaminocarbonyl) -prop methylaminocarbonyl) -prop-2-yl] -prop-2-yl -2-yl] -benzimidazole hydrochloride (7) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylcarbonylmethylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazole- (8) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylsulfonylmethylamino) -2- (pipridinocarbonyl) prop-2-yl] -benzimidazole hydrochloride (9) 2- (4) -Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (piperidinocarbonyl) -ethyl] -benzimidazole hydrochloride Yield: 81% of theory.

Rf value: 0.40 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C ₂ 6H33N ₇ O ₃ (491.60 / 528.05)

Mass Spectrum: (M + H) ⁺ = 492 (MH) + = 490 (10) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxyethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole hydrochloride (11) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylsulfonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] - benzimidazole hydrochloride (12) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1 (diethylaminocarbonyl) ethyl] benzimidazole hydrochloride

Yield: 70% of theory.

Rf value: 0.50 (reverse phase RP 8; methanol / 5% sodium chloride solution = 1: 1)

C25H33N7O3 x HCl (479.59 / 516.05)

Mass Spectrum: (M + H) ⁺ = 480 (MH) - = 478 (M-H + HCl) - = 514/516 (Cl) (13) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [ 1- (Carboxymethylamino) -2 (pyrrolidinocarbonyl) prop-2-yl] -benzimidazole dihydrochloride

Yield:

Rf -value

22% of the theoretical yield,

0.50 (reverse phase RP 8; 5% sodium chloride / methanol = 1: 1)

-11299 9999 • 1 «

C26H33N7O3X HCl (491,60 / 564,51)

Mass Spectrum: (M + H) ⁺ = 492 (MH) + = 490 (14) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylmethylamino) -1- (pyrrolidinocarbonyl) ethyl 4-Benzimidazole dihydrochloride

Rf value: 0.48 (reverse phase RP 8; 5% sodium chloride / methanol = 3: 2)

C26H33N7O3 x 2 HCl (491,60 / 564,51)

Mass Spectrum: (M + H) ⁺ = 492 (MH) + = 490 (15) 2- (4-Amidinophenylaminomethyl) -1-methyl- [1- (3-carboxypropylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole -dihydrochloride

Yield: 82% of theory.

Rf value: 0.73 (reverse phase; 5% sodium chloride / methanol = 1: 1)

C27H35N7O3x2 HCI (505.63 / 578.54)

Mass Spectrum: (M + H) ⁺ = 506

Example 17

2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole • 9 9 9 9

A suspension of 1.4 g (2.4 mmol) of 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride in 5 ml of N of ethyl-diisopropylamine and 2 ml of diethylformamide were added to 1.5 g (6 mmol) of 4-nitrophenyl benzoate to give a clear solution upon heating. After two hours, the solution was evaporated in vacuo at 120 ° C, the residue dissolved in dichloromethane after cooling and purified on silica gel, eluting first with dichloromethane, then dichloromethane / ethanol (50: 1, 25: 1, 18: 1). The combined fractions were purified, evaporated, mixed with water, filtered off with suction and dried.

Yield: 0.7 g (49% of theory),

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

C34H39N 704 (609.73)

Mass Spectrum: (M + H) ⁺ = 610 (M + Na) ⁺ = 632 (MH) + = 608

In analogy to Examples 14 and 17, the following compounds are obtained:

(1) 2- [4- (N-n-hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 53% of theory,

Rf value: 0.35 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃ 4H47N7O5 (633.79)

Mass Spectrum: (M + Na) ⁺ = 656 (MH) + = 632

- 114 ....... ·

9 ··· 9 · 9

999 (2) 2- [4- (N-n-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1 (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 46% of theory.

Rf value: 0.43 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₆ H ₅ iN ₇ O5 (661.84)

Mass spectrum: (M + Na) ⁺ = 684 (MH) + = 660 (3) 2- [4- (N-hexyloxycarbonyl-amidino) -phenylaminomethyl) -1-methyl-5- [1- (methoxycarbonylmethylamino)] -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole (4) 2- [4- (Nn-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] - benzimidazole Yield: 32% of theory,

Rf value: 0.27 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₅ H ₄ 9N ₇ O ₅ (647.82)

Mass Spectrum: (M + Na) ⁺ = 670 (MH) + = 646 (S) 2- [4- (N-hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonylmethylamino) -2 - (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 52% of theory.

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

C ₃ 7H ₅₁ N ₇ O ₆ (689.85)

Mass Spectrum: (M + H) ⁺ = 690

4

4 ····

115 4

4444 (MH) - (M + Na) ⁺ (M + HCl-H) - = 688 = 712 = 724/26 (Cl) (6) 2- [4- (N-octyloxycarbonyl-amidino) -phenylaminomethyl) -1 -methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole (7) 2- [4- (N-hexyloxycarbonylamidino) -phenylaminomethyl] -1-methyl -5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 21% of theory.

Rf value: 0.55 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₆ H ₄ 9N ₇ O ₆ (675.83)

Mass Spectrum: (M + H) ⁺ = 676 (M + Na) ⁺ = 698 (M + HCl-H) - = 724/26 (Cl) (8) 2- [4- (N-octyloxycarbonylamidino) - phenylaminomethyl) -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole (9) 2- [4-N-phenylcarbonylamidino) -phenylaminomethyl] - 1-Methyl-5- [1- (methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 34% of theory,

Rf value: 0.55 (silica gel; methylene chloride / ethanol = 9: 1 + 1% ammonia)

C ₃ 3H37N ₇ O4 (595.70) ·· ··· 9 9 99 9 9 • · · ♦ ··· 9

9 9 9 9 9 9 9 9

- 117 - ...........

Mass Spectrum: (MH) - = 594 (M + Na) ⁺ = 618 (10) 2- [4- (N-isopropyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino)] -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 66% of theory.

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃ 4H ₄₅ N7O ₆ (647.77) Mass Spectrum: (M + H) ⁺ = 648 (M-H) ' = 646 (M + Na) ⁺ = 670

(11) 2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 23% of theory.

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C37H43N7O5 (665.79)

Mass Spectrum: (M + H) ⁺ = 666 (MH) + = 664 (M + Na) ⁺ = 688 (M + H + Cl) ⁺ = 700/2 (Cl) (12) 2- [4- (N) -phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxy-carbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

- 117 ·· · · © 4> · 4 ·· ····

Yield:

Rf -value:

67% of the theoretical yield,

0.6% (silica gel: methylene chloride / ethanol = 9: 1)

C ₃₆ H4 ₁ N ₇ O ₅ (651.76) Mass Spectrum: (M + H) ⁺ = 652 (M-H) ' = 650 (M + Na) ⁺ = 674

(13) 2- [4- (N-butyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 45% of theory.

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃ 4H45N ₇ O ₆ (647.77)

Mass Spectrum: (M + H) ⁺ = 648 (MH) - = 646 (M + Na) ⁺ = 670 (M-H + HCl) - = 682/4 (Cl) (14) 2- [4- (N) -ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethyl-methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 54% of theory.

Rf value: 0.40 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₃ H43N ₇ O ₆ (633.75) Mass Spectrum: (M + H) ⁺ = 634 (M-H) = 632 (M + Na) ⁺ = 656

·· ····

- 118 9 9 9 9

9999 99 999 (15) 2- [4- (N-ethyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (Ν-methoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole

Yield: 53% of theory.

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₂ H ₄ iN ₇ O ₆ (619.72) Mass Spectrum: (M + H) ⁺ = 620 (M-H) ' = 618 (M + Na) ⁺ = 642

(16) 2- [4- (N-pyridin-3-ylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonylmethylamino) -2- (pyrrolidinocarbonyl) -prop-2- yl] -benzimidazole

Yield: 16% of theory.

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₆ H ₄₂ N ₈ O ₅ (666.78)

Mass Spectrum: (M + H) ⁺ = 665 (M + Na) ⁺ = 689 (17) 2- [4- (N-butyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1 (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 52% of theory.

Rf value: 0.42 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₂ H ₄₃ N ₇ O ₅ (605.74)

Mass Spectrum: (M + H) ⁺ = 606 (M + Na) ⁺ = 628

- 119 00

0 0 0 0 9 • 0 0

0 0 0 0 0

0 0 00 00 * 0 0 0 0 0 0 0 0 0 00 00 00 00 00 0 00 (00) 0 = (MH) '= 604 (18) 2- [4- (N-ethyloxycarbonylamidino) -phenylaminomethyl] -1-ethyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 30% of theory.

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

C30N39N7O5 (577.68)

Mass Spectrum: (M + H) ⁺ = 578 (M + Na) ⁺ = 600 (MH) + = 576 (19) 2- [4- (N-benzyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1 - (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole Yield: 51% of the theoretical yield,

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₅ H ₄ iN ₇ O ₅ (639.75)

Mass Spectrum: (M + Na) ⁺ = 662 (MH) + = 638 (20) 2- [4- (N-pyridin-3-ylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1 - ( ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 84% of theory.

Rf value: 0.20 (silica gel; ethyl acetate / ethanol) C ₃₃ H ₃₈ N ₈ O ₄ (610.72) Mass Spectrum: (M + H) ⁺ = 611 (M-H) ' = 609 (M-HCOO) ' = 611

• · ·

- 120 a (a) a a a (21) 2- [4- (N-acetoxymethyloxycarbonylamidino) -phenylaminomethyl] - 1-Methyl-5- [1- (ethoxy-carbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 42% of theory.

_Rf value: 0.44 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₁ H ₃₉ N ₇ O ₅ (621.09)

Mass Spectrum: (M + Na) ⁺ = 644 (MH) + = 620 (22) 2- [4- (N- (2,2,2-trimethylethoxycarbonyl) -amino) -phenyl-aminomethyl] -1-methyl-5 - [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 73% of theory.

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

C ₃₀ H ₃₆ CIN ₇ ( ₅ )

Mass Spectrum: M ⁺ = 679/81/3 (Cl ₃ ) (M + Na) ⁺ = 702/4/6 (CI ₃ ) (M-H) ' = 678/80/2 (Cb)

Example 18

2- [4- (N-n-Octyloxycarbonylamidino) -phenylaminomethyl-1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) -ethylamine] benzimidazole

To a solution of 0.2 g (0.3 mmol) of 2- [4- (Nn-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) - (pyrrolidinocarbonyl) ethyl] - 121 of benzimidazole in 3 ml of tetrahydrofuran and 2.5 ml of ethanol was added 1.1 ml of 1N sodium hydroxide and stirred at room temperature for 4 hours. The reaction mixture was evaporated and 1 ml of 1N hydrochloric acid was added. After 12 hours, 2 drops of ammonia (33%) were added at room temperature, whereupon a pale yellow precipitate precipitated. After suctioning off the resulting solid, the filtrate was mixed with 1 ml of 1N hydrochloric acid and evaporated with the addition of toluene. The residue is mixed with acetone, filtered off with suction, washed with diethyl ether and dried.

Yield: 0.1 g (50% of theory),

Rf value: 0.35 (reverse phase RP 8; methanol / 5% sodium chloride solution = 2: 1)

C ₃ 4H ₄₇ N ₇ O5 (633.79)

Mass Spectrum: (M + H) ⁺ = 634 (M + H + Na) ⁺⁺ = 328.5

Example 19

2- [4- (N-Hydroxyamidino) -phenylaminomethyl-1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

To a suspension of 0.6 g (1.2 mmol) of 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole in 50 ml of ethanol is added 0 , 47 g (7.8 mmol) of hydroxylamine hydrochloride and 0.35 g (3.5 mmol) of sodium carbonate were heated at reflux for 17 hours. After cooling, the residue was filtered off, the filtrate was evaporated and diluted with water. After double extraction with dichloromethane, the combined organic phases are dried and evaporated. The crude product is purified on silica gel, eluting with dichloromethane / ethanol (19/1 and 7/1).

The uniform fractions are purified, evaporated, mixed with diisopropyl ether and dried.

• 9 9

9999 99 ·

- 122 Yield: 0.025 g (4% of theory),

Rf value: 0.68 (silica gel; methylene chloride / ethanol = 4: 1)

C ₂₇ H ₃₅ N ₇ O ₄ (521.62)

Mass Spectrum: (MH +) = 520 (M + Na) ⁺ = 544

Example 20

2- [4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] benzimidazole

A. 4- (5-Methyl-1H-oxydiazol-S-γ-D-phenylaminoacetic acid ethyl ester)

Prepared in analogy to Example 9A from 4- (5-methyl-1,2,4-oxadiazo-3-yl) -aniline and ethyl bromoacetate in N-ethyldiisopropylamine.

Yield: 78% of theory.

Rf value: 0.60 (silica gel; ethyl acetate / petroleum ether = 1: 1)

B. 4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylamino-acetic acid

Made analogously to Example 4 from 4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenylamino-acetic acid ethyl ester and sodium hydroxide in ethanol.

Yield: 75% of theory.

Rf value: 0.15 (silica gel; methylene chloride / ethanol = 9: 1)

C. 2- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylamino-methyl-1-methyl-5- [1-amino- (pyrrolidin-1-yl-carbonyl) -ethyl] -benzimidazole 9 9 9 9 9

• · 9 9 9 9

00 · · 9 9 9

- 123 - · * · ......

Prepared in analogy to Example 1E / F from 2- (4-methylamino-3-aminophenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidin-1-yl-propanone, 4- (5-methyl-1,2,4oxa- diazol-3-yl) -phenylamino-acetic acid and carbonylimidazole in tetrahydrofuran, followed by treatment with glacial acetic acid.

Yield: 34% of theory.

Rf value: 0.10 (silica gel; methylene chloride / ethanol = 9: 1)

D. 2- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) -phenylamino] -methyl-1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Prepared in analogy to Example 11 from 2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenylaminomethyl] -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) ethyl] -benzimidazole, isopropyl bromoacetate and potassium carbonate in isopropanol / methylene chloride.

Yield: 42% of theory.

Rf value: 0.69 (silica gel; methylene chloride / ethanol = 9: 1)

E. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (isopropoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl-benzimidazole acetate

Prepared in analogy to Example 1D from 2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) - ethyl] -benzimidazole and hydrogen / palladium (10% on activated carbon) in ethanol / glacial acetic acid.

Yield: 69% of theory.

Rf value: 0.30 (silica gel; methylene chloride / ethanol = 7: 3)

F. 2- [4- (N-Phenylcarbonylamidino) -phenylamino-methyl-1-methyl-5- [1- (isopropoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -1H-124-benzimidazole

Prepared in analogy to Example 17 from 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (isopropyl-oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole acetate and 4-nitrophenyl benzoate in N-ethyldiisopropylamine -dimethylformamide.

Yield: 26% of theory

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₅ H4N ₇ O ₄ (623.75)

Mass Spectrum: (M + Na) ⁺ = 646 (MH) + = 622

In analogy to Example 20, the following compounds are obtained:

(1) 2- [4- (N-phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-butyloxycarbonyl-methylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole (2) 2- [ 4- (N-Phenylcarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (2-phenylethyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole (3) 2- [4- (N-hexyloxycarbonylamidino) -phenylaminomethyl -1-Methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 40% of theory.

Rf value: 0.45 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃₅ H ₄₉ N ₇ O ₅ (647.82) • · • ·

- 125 -

Mass Spectrum: (M + H) ⁺ = 648 (M-H) ' = 646 (M + Na) ⁺ = 670

(4) 2- [4- (N-n-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1 - ((pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 31% of theory.

Rt value: 0.48 (silica gel; methylene chloride / ethanol = 9: 1)

C37H ₅₃ N ₇ O5 (675.88)

Mass Spectrum: (M + H) ⁺ = 674 (M + Na) ⁺ = 698 (5) 2- [4- (N- (2,2,2-trichlorethyloxycarbonyl) -amino) -phenylaminomethyl] -1-methyl- 5- [1- (Isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole

Yield: 43% of theory.

Rf value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1)

C ₃ H ₃₈ Cl ₃ N ₇ O ₅ (695.05)

Mass Spectrum: (MH) = 692/694/696/698 (Cl ₃ ) (6) 2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-propyl-oxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benzimidazole

Yield: 70% of theory.

Rf value: 0.35 (silica gel; ethyl acetate / ethanol = 9: 1)

C ₅ H 41 N ₇ O ₄ (623.76) Mass Spectrum: (M + H) ⁺ = 624

- 126 (MH) - = 622 (M + HCOO) - = 668 (7) 2- [4- (N-octyloxycarbonylamidino) -phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

Yield: 53% of theory.

Rf value: 0.39 (silica gel; ethyl acetate / ethanol = 9: 1)

C ₃₇ H ₅₃ N ₇ O ₅ (675.88)

Mass Spectrum: (M + H) ⁺ = 676 (M + Na) ⁺ = 698 (MH) + = 674

Example 21 (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1 (pyrrolidino-carbonyl) ethyl-benzimidazole hydrochloride

A. 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid ethyl ester

A mixture of 28 g (0.11 mol) of 2-amino-2- (4-chloro-3-nitrophenyl) -propionic acid in 200 ml of 5.6N ethanolic hydrochloric acid was heated at reflux for 36 hours. After evaporation of the solvent, the residue is taken up in 300 ml of ethyl acetate and 300 ml of saturated sodium hydrogen carbonate solution are added. The organic phase is washed twice with saturated sodium hydrogen carbonate solution and once with water, dried over sodium sulphate and evaporated.

Yield: 21.1 g (68% of theory) of a light brown oil.

1- '· / /

B. (R) - (+) - 2-Amino-2- (4-chloro-4-nitro-phenyl) -propionic acid ethyl ester

17.33 g (63.6 mmol) of 2-amino- (4-chloro-3-nitro-phenyl) propionic acid ethyl ester are dissolved in 247 ml of isopropanol and 207 ml of methanol and 9.54 g (63.6 mmol) are added. L - (+) - tartaric acid. The reaction mixture was heated to 100 ° C to give a clear solution. The solution is cooled to 27 ° C over 3 hours, the precipitate formed is filtered off with suction, washed with ethanol and dried. Subsequently, the resulting solid (21.5 g) was dissolved in 400 ml of ethyl acetate and 400 ml of saturated sodium bicarbonate solution was added. After extraction and phase separation, the organic phase is washed with water, dried and evaporated.

Yield: 7.68 g (44.4% of theory) of a pale yellow oil, [.alpha.] D @ ²⁰ = + 4.38 DEG (ethyl acetate);

HPLC-analysis: ee-value> 98.6%

C. (R) - (-) - 2-Amino-2- (4-chloro-3-nitro-phenyl) -propionic acid

Prepared in analogy to Example 4 from (R) - (+) - 2-amino-2- (4-chloro-3-nitro-phenyl) -propionic acid ethyl ester and sodium hydroxide in tetrahydrofuran. Yield: 63% of theory, [.alpha.] D @ ²⁰ = - 59.6 DEG (methanol / water 1: 1)

D. (R) -2-tert-Butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid

Prepared in analogy to Example 5D from (R) - (-) - 2-amino-2- (4-chloro-3-nitrophenyl) propionic acid and di-tert-butyl dicarbonate of pyrocarbonate and triethylamine in dioxane.

Yield: 100% of theory.

E. (R) -2-tert-butyloxycarbonylamino-2- (4-methylamino-3-nitrophenyl) propionic acid 9 9 9 9 9

128 Prepared in analogy to Example 1B from (R) -2-tert-butyloxycarbonylamino-2- (4-chloro-3-nitro-phenyl) -propionic acid and methylamine.

Yield: 69% of theory.

F. (R) -2- (4-Methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone

Prepared in analogy to Example 1C from (R) -2-tert-butyloxycarbonylamino-2- (4-methylamino-3-nitro-phenyl) -propionic acid, pyrrolidine carbonyldiimidazole in tetrahydrofuran.

Yield: 96% of theory.

G. (R) -2- (4 (Methylamino-3-amino-phenyl)) - 2-tert-butoxycarbonylamino-1-pyrrolidino-propanone

Prepared in analogy to Example 1C from (R) -2- (4-methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone and hydrogen / palladium on activated carbon in methanol.

Yield: 99% of theory.

H. (R) -2- (Cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) -ethyl] -1-benzimidazole

Made analogously to Example 1C / 1F from (R) -2- (4-methylamino-3-nitro-phenyl) -2-tert-butyloxycarbonylamino-1-pyrrolidino-propanone, 4-cyanophenylglycine, carbonyldiimidazole in tetrahydrofuran and subsequent ring closure in glacial acetic acid.

Yield: 100% of theory.

- 129 I. (R) -2- (4-Quanophenylaminomethyl) -1-methyl-5-β-amino-1- (pyrrolidinocarbonyl) ethyl-benzimidazole

Prepared in analogy to Example 6I from (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and 6N hydrochloric acid in dioxane.

Yield: 76% of theory.

K. (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl)]

-amino) -1- (pyrrolidinocarbonyl) -ethyl-benzimidazole Prepared in analogy to Example 6K from (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) - ethyl] -benzimidazole and iodoacetate / potassium carbonate in acetone.

Yield: 75% of theory.

L. (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl-aminol-1-pyrrolidinocarbonyl) -ethyl] -benzimidazole hydrochloride Prepared in analogy to Example 1G from (R) -2- (4) (cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] -benzimidazole and hydrochloric acid / ammonium carbonate in ethanol (yield: 95% of theory).

M. (R 1 -R 4 -Aminidinophenylaminomethyl-1-methyl-S-1-carboxymethylamino) -1- (pyrrolidinocarbonyl) -ethoxy-benzimidazole hydrochloride Prepared in analogy to Example 4 from (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole and sodium hydroxide in ethanol.

Yield: 100% of theory.

- 130 ·· · · · ·

C ₂₅ H ₃₁ N ₇ O ₃ x 2 HCl (477.57 / 550.5)

Mass Spectrum: (M + H) ⁺ = 478 (M-H + HCl) - = 512/514 (Cl) (M-H + 2HCl) - = 448/550/552 (Cl ₂ )

Example 22

Dry ampoule with 75 mg of active substance per 10 ml

Ingredients:

Active substance

Mannitol

Water for injection purposes

75.0 mg 50.0 mg ad 10.0 ml

Production:

The active substance and mannitol are dissolved in water. After filling, it is freeze-dried. Dissolution to the required solution is followed by water for injection purposes.

Example 23

Dry ampoule with 35 mg of active substance in 2 ml

Ingredients:

• 00 ·

- 131

Active substance 35.0 mg Mannitol 100.0 mg Water for injection purposes ad 2.0 ml Production: The active substance and mannitol are dissolved in water. After filling it is freeze-dried. Dissolve to the required solution with water for injection purposes.

Example 24

Tablet with 50 mg of the active substance

Ingredients:

(D Active substance 50.0 mg (2) Milk sugar 98.0 mg (3) Cornstarch 50.0 mg (4) Polyvinylpyrrolidion 15.0 mg (5) Magnesium stearate 2,0 mq

215.0 mg

Production:

(1), (2) and (3) are mixed and granulated with an aqueous solution (4). (5) is added to the dry granulate. Tablets are compressed from this mixture with a double facet and a dividing line on one side. Tablet diameter: 9 mm • 4 • 4 • 444

- 132 ·· 4 · 5 ·

4 5 «· 4

4

Example 25

Tablet with 350 mg of the active substance

Ingredients:

(1) Active substance 350.0 mg (2) Milk sugar 136.0 mg (3) Cornstarch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4,0 mq

600.0 mg

Production:

(1), (2) and (3) are mixed with the aqueous solution (4) and granulated. (5) is added to the dry granulate. Tablets are compressed from this mixture with a double-faced facet dividing the score on one side. Tablet diameter: 12 mm

Example 26

Capsules containing 50 mg of the active substance

Ingredients:

··

- 133 ··· ♦ * · ·

(1) Active substance 50.0 mg (2) Dried corn starch 58.0 mg (3) Powdered milk sugar 50.0 mg (4) Magnesium stearate 2, P.ma. 160.0 mg

Production:

(1) is mixed with (3). To this mixture is added a mixture of (2) and (4) with vigorous stirring. This powder mixture is filled into a size 3 gelatin capsule on a filling machine.

Example 27

Capsules with 350 mg of the active substance

Ingredients:

(1) Active substance 350.0 mg (2) Dried corn starch 46.0 mg (3) Powdered milk sugar 30.0 mg (4) Magnesium stearate 4,0 mq

430.0 mg

Production:

(1) is mixed with (3). To this mixture is added a mixture of (2) and (4) with vigorous stirring. This powder mixture is filled on a filling machine into size 0 gelatin capsules.

♦ · <► ♦ ·

Example 28 Suppositories with 100 mq of active ingredient 1 suppository contains: Active substance 100.0 mg Polyethylene glycol (M.G. 1500) 600.0 mg Polyethylene glycol (M.G. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mq

000.0 mg

Production:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40 ° C the milled active ingredient is dispersed homogeneously in the melt. Cool to 38 ° C and pour into slightly pre-cooled suppository molds.

Claims (13)

Patent claims What is claimed is: 1. A compound of the formula (I) EMI3.0 wherein they are Ar is a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, a trifluoromethyl group, a C 1-6 alkyl group; _3- alkyl or C 1-6 alkyl; _{A 3-} alkoxy group, optionally a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group substituted in the C1-hydrocarbon structure; _3- alkyl, A is C-. _3- alkyl, B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C _1-3 alkyl group in which the alkyl moiety may be mono- or disubstituted by carboxy. • ♦ • · ► ···! ♦ · ···· -136R _a represents R 1 -CO-C ₃ . _{A 5-} cycloalkyl group wherein it is R f is -alkoxy, amino, C _1-4 -alkylamino or di-C 1-4 -alkyl) -amino, in which the alkyl moiety may be substituted by carboxy, a 4- to 7-membered cycloalkylenimino or cycloalkenylimino group which may be substituted with one or two Whose. _3- alkyl groups, wherein the alkyl substituent may be simultaneously substituted with hydroxy, C 1-3 -alkoxy, carboxy, carboxy-C _1-3 -alkoxy, carboxy-C _1-3 -alkylamino, N- (C _1-3 -alkyl) -N- ( carboxy-C _1-3 -alkyl) amino, carboxy-C 1-3 -alkylaminocarbonyl, N-C 1-8 -alkyl-N-carboxy-C 1-8 -alkyl-aminocarbonyl, carboxy-C _1-3 -alkylaminocarbonylamino, 1-carboxylic acid - (C _1-3 -alkyl) -3- (carboxyC _1-3 -alkyl) -aminocarbonylamino, 3- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) aminocarbonylamino or 1,3 -di- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonylamino, 4- to 7-membered cycloalkylenimino substituted with hydroxy, 5- to 7-membered cycloalkylenimino optionally substituted with C _1-3 -alkyl a group to which the phenyl ring is fused via two adjacent carbon atoms, a morpholino-, piperazino-, N- (C _1-3 -alkyl) -piperazino-, pyrrolino-, 3,4-dehydro-piperidino- or pyrrol-1- yl, • 9 represents R 2 -CX-C 3-5 -cycloalkyl, wherein R ₂ represents a phenyl, naphthyl or a monocyclic 5 or 6 membered heteroaryl substituted by C 1-3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms, five-membered heteroaryl group contains an imino group optionally substituted with 1-3 an alkyl group, an oxygen or sulfur atom, or an imine group optionally substituted by a C 1-3 -alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms, and the aforementioned alkyl substituent may be substituted by carboxy, carboxy-C-1-3 -alkoxy, carboxy-C 1-3 -alkylamino or N- (C _1-3 -alkyl) -carboxy-C 1-3 -alkylamino, and X represents an oxygen atom, a C 1-3 -alkylamino group, a C 1-3 alkoxyimino, a C 1-3 -alkylhydrazino, a di- (C _1-3 -alkyl) -hydrazino, C2-4 -alkanoylhydrazino, N- (Cl. ₃ alkyl) -C 2-4 -alkanoylhydrazino or C1-3 -alkylideno which may be alkyl or alkanoyl part of a carboxy substituted C1-3 alkyl- is a group or a C3- 5-cycloalkyl substituted with an imidazole or imidazolone group, wherein the imidazole ring may be substituted with a phenyl or carboxy group and one or two C 1-3 alkyl groups or one, two or three C 1-3 alkyl groups, wherein the substituents may be the same or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or in 2 or 3 position by amino, C 2-4 alkanoylamino, C _"3 -alkylamino, N- (C ₂ -4-CF--alkanoyQ with -alkylamino or di- ( The C _1-3 -alkyl) -amino, ··· imidazolone ring may be substituted by a C 1-3 -alkyl group, wherein the alkyl substituent may be substituted by a carboxy group or at the 2 or 3 position by an amino-, C 2-4 -alkano group ylamino-, C 1-3 -alkylamino, N- (C ₂ .4-alkanoyl-C. ₃ -alkylamino or di- (C. _3- alkyl) -amino, and additionally, the phenyl ring, imidazolidin-2,4-dion-5-yl, may be fused over two adjacent carbon atoms of the above imidazole and imidazolone ring, which may be substituted by one or two C- | . _3- alkyl groups, wherein the alkyl substituent may be simultaneously substituted with a carboxy group, is a C 4 -C 4 alkyl group which is substituted with a C 1-6 alkyl group. _3- alkyl-Y 1 -C 1. ₃ -alkyl, HOOC-C ₃ -alkyl-Y-C ₃ alkyl, tetrazolyl-C ₃ -alkyl-Y _2, R ₃ NR ₄ or R ₃ NR 4 C ₃ -alkyl and izoxazolidinylkarbonylovou group optionally substituted by C- |. _3- alkyl, pyrrolinocarbonyl, 3,4-dehydro-piperidino-carbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C 1-6 -benzyl; _3- alkylamino-carbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, or a 4- to 7-membered cycloalkylene-iminocarbonyl group, wherein in the aforementioned groups the jecycloalkylenimine moiety is substituted by one or two C _1-3 -alkyl groups and at the same time may be an alkyl moiety or an alkyl substituent of the above C 1-6 alkyl group; _3- alkylaminocarbonyl, (C1-C4-alkyl) -aminocarbonyl or cycloalkylenimino-carbonyl substituted with carboxy, and the remaining hydrogen atoms - 139 · · 4 * 4 * 4 4 4 4 4 · The &quot; 4444 &quot; may be replaced wholly or partially by the fluorine atoms where they are R ₃ is hydrogen or C 1-6 alkyl; _{A 3-} alkyl group optionally substituted by a carboxy group; and R ₄ is hydrogen, a C _"3 -alkyl-YIC-1-3 -alkyl-Y _2, carboxy-C ₃ -alkyl-Y-C 1-3 -alkyl-Y _2, C ₃ -alkyl-Y ₂ or carboxy-C _1-3 -alkyl-Y ₂ or R ₃ and R ₄ together with the nitrogen atom in the middle of the 4- to 7-membered cycloalkylenimine group optionally substituted with a carboxy group, C 1-6 alkyl; _3- alkyl or carboxy-C _1-3 -alkyl, wherein they are Yf a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NHa group Y _{2 is} a carbon-nitrogen bond or a carbonyl, sulfonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked by a nitrogen atom R _{3 of the} NR ₄ -group, and in the definition of Y 1 and Y ₂ may be imino groups additionally substituted with C 1-3 -alkyl or carboxy-C 1-4 -alkyl, means C _1-3 -alkyl or C ₃ . _5- cycloalkyl substituted with R ₅ NR _{4 '} , where they are - 140 R ₅ is hydrogen, C 1-3 -alkyl, C _{5. 7-} cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl; and R ₆ is C 1-3 -alkyl, carboxy-C 1-6 -alkyl; ₃ -alkyl or carboxy-C ₃ -alkyl-carbonyl denotes a C 1-3 -alkyl group which is substituted by C ₂ -4 -alkanoyl or C5-7 -cykloalkanoyl a chlorine, bromine or iodine, R _b represents a hydrogen atom or a C 1-3 -alkyl group a R _c represents a cyano or amidino group optionally substituted by one or two C 1-3 -alkyl groups, their tautomers, stereoisomers, mixtures thereof, precursors, derivatives which contain a negatively charged group under physiological conditions and salts thereof. 2. Benzimidazoles of the general formula Ia wherein: • -141 -: A represents a C 1-3 -alkylene group, B represents an oxygen or sulfur atom, a methylene, carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted A C 1-3 -alkyl group in which the alkyl moiety may be mono- or disubstituted with a carboxy group, R _a is R 1 -CO-C 3-5 - cycloalkyl, where R is R1 is C1-3-alkoxy, amino, C1-4-alkylamino or di- (C1-4-alkyl) -amino, wherein the alkyl moiety may be substituted by carboxy, A 4- to 7-membered cycloalkylenimino group or a cycloalkenylimino group which may be substituted by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by hydroxy, C 1-3 -alkoxycarboxy, carboxy-C 1-6 -alkyl. _3- alkoxy, carboxy-C _1-3 -alkylamino, N- (C _1-3 -alkyl) -N- (carboxy-C 1-3 -alkyl) aminocarboxy-C 1-6 alkyl; _3- alkylaminocarbonyl, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkyl) aminocarbonyl, carboxy-C 1-6 alkyl; _3- alkylaminocarbonylamino, 1- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) aminocarbonylamino, 3- (C _1-3 -alkyl) -3- (carboxy-C 1-3 -alkyl) - aminocarbonylamino or 1,3-di (C 1-6 -alkyl) -3- (carboxy-C _1-3 -alkyl) aminocarbonylamino, 4- to 7-membered cycloalkyleneimino substituted by hydroxy; A 5- to 7-membered cycloalkyleneimino group optionally substituted with a C _1-3 alkyl group, and to which the phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C _1-3 ) group alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl means R ₂ -CX-C ₃ . _{A 5-} cycloalkyl group wherein R ₂ represents a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl optionally substituted A C _1-3 alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted with a C _1-3 -alkyl group, an oxygen or sulfur atom or an imido group optionally substituted with C 1-6 alkyl; _{A 3-} alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted by a carboxy, carboxy-C _1-3 -alkoxy, carboxy-C _1-3 -alkylamino or N- (C _{1-3 )} alkyl group; alkyl) -carboxy-C _1-3 -alkylamino, and X represents an oxygen atom, a C _1-3 -alkylimino group, a C _1-3 -alkoxyimino-C 1 group. _3- alkylhydrazino, N- (C _1-3 -alkyl) -C ₂ . _{A 4-} alkanoylhydrazino or C 1-3 -alkylidene group which may be substituted by a carboxy group in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moiety means a C _1-3 -alkyl or a C _{3 group} . _5- cycloalkyl substituted by imidazole- or imidazolone, wherein / • 9 - 143 The imidazole cycle may be substituted with a group of: - - - - - - - - - phenyl or carboxy or one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, wherein the substituents may be the same or different and one of the above alkyl substituents may be substituted by carboxy or in the 2 or 3 position amino, _C2 -4 -alkanoylamino-, C1-3 -alkylamino, N- (C _{2 4} -alkanoyl) -C 1-3 -alkylamino or di- (C ₃ -alkyl) -amino, and the imidazolone ring may be substituted with C 1-3 -alkyl, wherein the alkyl substituent may be substituted by carboxy or in the 2 or 3 position by amino, C ₂ . ₄ alkanoylamino, C 1-3 -alkylamino, N- (C ₂ -4 -alkanoyl) -C 3 -alkylamino or di- (C ₁ _ ₃ alkyl) amino, and additionally may be on the above-mentioned imidazole and imidazolone a phenyl or pyrrolidine ring means an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by a carboxy group, C 1-4 -alkyl which is substituted by C 1-3 -alkyl-Y-C 1-3 -alkyl, HOOC-C 1-3 -alkyl-Y-C 1-3 -alkyl, tetrazolyl-C _1-3 -alkyl-Y ₂ -, R 3 NR 4 - or R 3 NR 4 -C 1-3 -alkyl and Λ Λ Λ · · · · · - 144 - ·· · ...... isoxazolidin-1-yl-carbonyl optionally substituted with C 1-3 -alkyl, pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, -alkylaminocarbonyl, di- (C _1-3) -alkyl) aminocarbonyl or a 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein in the above groups, the cycloalkylenimine moiety is substituted with one or two C 1-6 alkyl. ₃ -alkyl groups, whilst the alkyl moiety or alkyl substituent in the above groups C ₃ alkylaminocarbonyl, di-fC ^ -alkyl) aminocarbonyl or cykloalkyleniminokarbonyl may be substituted by carboxy, and the remaining hydrogen atoms _V4 C -Alkyl groups may be totally or partially replaced by fluorine atoms where they are R ₃ is hydrogen or C 1-6 alkyl; _3- alkyl optionally substituted with carboxy; and R ( ₄₎ is hydrogen; _3- alkyl-YiCi. _3- alkyl-Y ₂ , carboxy-C 1-6 alkyl; ₃ -alkyl-Y ₁ -C ₁ _ ₃ -alkyl-Y _2, C ₃ -alkyl-Y ₂ or carboxy-C. _3- alkyl-Y ₂ ; R ₃ and R ₄ together with the nitrogen atom in the center of the 4- to 7-membered cycloalkyleneimino group optionally substituted by carboxy, C _1-3 -alkyl- or carboxy-C _1-3 -alkyl, where they represent a carbon-carbon bond, an oxygen atom, a sulfenyl, sulfinyl, sulfonyl, -NH-, -NH-CO- or -NH-CO-NH- a Y ₂ a carbon-nitrogen bond or a carbonyl, sulfonyl, imino-, or -NH-CO- group, wherein the carbonyl group The -NH-CO- group is linked by the nitrogen atom of the R3NR4 group, and the imino groups in the definition of the residues Y1 and Y2 may be additionally substituted with a C1-3-alkyl or carboxy-C1 group. ₃ -alkyl, represents C 1-3 alkyl or C _3-5 cycloalkyl substituted with NR ₅ R ₆ -group, wherein mean R ₅ is hydrogen, C 1-3 -alkyl, C 5-7 -cycloalkyl, phenylcarbonyl, phenylsulfonyl or pyridinyl; and R 6 is C 1-3 -alkyl, carboxy-C 1-6 -alkyl; _3- alkyl or carboxy-C 1-6 alkyl; _3- alkylcarbonyl means a C _1-3 -alkyl group which is substituted by a group C 2-4 -alkanoyl or C 5-7 -cycloalkanoyl and a C 1-3 -alkyl group substituted by a chlorine, bromine or iodine atom, R b represents a hydrogen atom or a C 1-3 -alkyl group and R _c is cyano or amidino, which may be substituted by hydroxy, one or two C 1-3 -alkyl groups, one or two C _1-8 -alkoxycarbonyl groups, wherein in the definition of the abovementioned radicals the carboxy, amino and imino groups may be, inter alia, substituted in vivo leaving group, tautomers, stereoisomers and salts thereof. - 146 ·· · · · · · · · · · Φ · · ······ · · · The benzimidazoles of formula Ia according to claim 2, wherein A represents a C 1-3 -alkylene group, B represents an oxygen atom, a methylene, imino or N- (C _1-3 -alkyl) imino group, wherein the alkyl moiety may be substituted by a carboxy group, R _a represents a C 3-5 -cycloalkyl group substituted at the 1-position R 1 -CO-radical where they are R 1 is C-1-3-alkoxy, amino, C 1-4 -alkylamino or di- (C 1-4 -alkyl) -amino, wherein the alkyl moiety may be substituted with a carboxy group, A 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted by a hydroxy, C 1-3 -alkoxy, carboxy, carboxy-C 1-3 -alkoxy group, carboxy-C ₃ alkylamino, N- (C _3.1 -alkyl) -N- (carboxy-C 3 -alkyl) -amino, carboxy-C |. _3- alkylaminocarbonyl, N- (C _1-3 -alkyl) -N- (carboxy-C 1-3 -alkyl) aminocarbonyl, carboxy-C 1-3 -alkylaminocarbonylamino, 1- (C _1-3 -alkyl) -3- (carboxy) -C 1-3 alkyl-aminocarbonylamino, 3- (C _1-3 -alkyl) -3- (carboxy-C _1-3 -alkyl) -aminocarbonylamino or 1,3-di- (C _1-3 -alkyl) -3- (carboxy-C 1-3 alkyl) -aminocarbonylamino, 9 - 147 • 99 99 99 9 9 9 9 9 9 9 9 9 A 5- to 7-membered cycloalkyleneimino group optionally substituted with a C 1-3 -alkyl group, and to which the phenyl ring, the morpholino, piperazino, N- (C _1-3 -alkyl) -piperazino, pyrrolino, 3,4, is fused via two adjacent carbon atoms -dehydro-piperidino or pyrrol-1-yl means a cycloalkyl group substituted at the 1-position of the R ₂ -CX-radical, wherein R ₂ represents a phenyl, naphthyl or a monocyclic 5 or 6 membered heteroaryl group optionally substituted -alkyl, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms, five-membered heteroaryl group contains an imino group optionally substituted by C1-3 -alkyl an oxygen or sulfur atom or an imino group optionally substituted by a C 1-3 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and the aforementioned alkyl substituent may be substituted by carboxy, carboxy-C _1-3 -alkoxy, carboxy-C 1-3 - alkylamino or N- (C 1-3 -alkyl) -carboxy-C 1-3 -alkylamino, and X represents an oxygen atom, a C 1-3 -alkylimino, a C 1-3 -alkoxyimino or a C 1-3 -alkylidene which may be substituted in the alkyl or alkoxy part by a carboxy group, means a C 1-3 -alkyl group substituted in the 1-position by an imidazole or imidazolone group where - 148 · 9 · 9 · 9 9 · 9 · 9 9 9 9 99 99 9 9 9 9 99 99 The imidazole ring may be substituted by phenyl or carboxy and by one or two C 1-3 -alkyl groups. groups or by one, two or three C1-3 -alkyl groups, wherein the substituents may be the same or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or in 2 or 3 position by amino, _C2 -4 alkanoylamino, C1 .3 alkylamino, N- (C ₂ -4 - -alkanoyl) -C 1-3 -alkylamino or di- (C ₃ -alkyl) -amino, and the imidazolone ring may be substituted by C 1-3 -alkyl, wherein the alkyl substituent It may be substituted with carboxy or in position 2 or 3 amino, c _{2. 4} - alkanoylamino, C 1-3 -akylamino, N- (C _4.2 -alkanoyl) -C. _3- alkylamino- or di- (C _1-3 -alkyl) -amino, and additionally, in the above imidazole and imidazolone ring, a phenyl or pyridine ring may be fused via two adjacent carbon atoms, imidazoline-2,4-dione-5 -yl, which may be substituted by one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be substituted by a carboxy group, means a C 1-4 -alkyl group which is substituted in the 1-position by R 3 NR 4 or R 3 NR 4 -C 1-3 alkyl and pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, C 1-3 alkylaminocarbonyl, di- (C _1-3 -alkyl) aminocarbonyl, isoxazolidin-1-yl-carbonyl or 4- to 3-carboxylic acid; 7-member • · · · -149 - · .. ·: · .. ·.: .. cycloalkyleniminocarbonyl, wherein for the above groups, the cycloalkylenimine moiety may be substituted with one or two C 1-3 -alkyl groups and at the same time the alkyl moiety or alkyl substituent of the above-mentioned C 1-3 -alkylaminocarbonyl, di- (C 1-3 -alkyl) aminocarbonyl or cycloalkyleniminocarbonyl be substituted by carboxy, and the remaining hydrogen atoms of the C 1-4 -alkyl group may be wholly or partially replaced by fluorine atoms, where R @ ₃ is hydrogen or C1-3 -alkyl optionally substituted by carboxy; R ₄ is hydrogen, C 1-3 -alkyl-Y ₂ or _{carboxy-Ci-3-alkyl-2} or Y R ₃ and R ₄ together with the nitrogen atom in the center of the 4- to 7-membered cycloalkyleneimino group substituted in the 1-position by carboxy, C 1-3 -alkyl or carboxy-C 1-3 -alkyl, Y _{2 is} a carbon-nitrogen bond or a carbonyl-, iminone or -NH-CO- group, wherein the carbonyl group of the group -NH-CO- is linked to the nitrogen atom R3NR4 group, and imino group may be in the definition of the radical Y ₂ additionally substituted with C 1-3 -alkyl or carboxy-C ^ -alkyl, represents C 1-3 -alkyl or C 3-5 - cycloalkyl substituted at the 1-position with R 5 NR 6, where they are • - 150 «* 150 150 · 150 150 150 150 150 150 150 150 R ₅ is hydrogen, C 1-3 -alkyl, C ₅ .7 cycloalkyl, phenylcarbonyl, phenyl, pyridinyl or sulphonyl and R 6 is C 1-3 -alkyl, carboxy-C 1-6 -alkyl; _3- alkyl or carboxy-C 1-4 -alkylcarbonyl means a C 1-3 -alkyl group which is substituted by a C 2-4 -alkanoyl or C _{5 group} . _7- cycloalkanoyl and a chlorine, bromine or iodine atom, R b represents a C _1-3 -alkyl group and R _c is an amidino group optionally substituted with 2,2,2-trichloroethoxycarbonyl, C 1-8 -alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl, wherein the benzoyl moiety may be mono- or disubstituted with fluorine, chlorine, bromine or iodine, with C1. The 3-alkyl- or C 1-3 -alkoxy and substituents may be the same or different, their C 1-3 -alkanol ester, their tautomers, stereoisomers and their salts. 4. A compound according to claim 2, wherein: A is methyl, B represents an oxygen atom or an imino group, - 151 • · · · · · · · · · · · · · · R a represents a cyclopropyl group substituted at the 1-position with the radical R 1 -CO-, wherein R 1 represents a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group, wherein the methyl or ethyl moiety may be substituted by a carboxy, carboxy-C _1-3 -alkoxy, carboxy-C- group. _3- alkylamino or N- (C _1-3 -alkyl) -carboxy-C 1-3 -alkylamino, means a cyclopropyl group substituted in the 1-position by R ₂ -CX, wherein R ₂ represents a phenyl, pyridyl, pyrazolyl group optionally substituted with C 1-3 -alkyl and X represents an oxygen atom, a C 1-3 -alkoxyimino or a C 1-3 -alkylidene group which are substituted by a carboxy group in the alkyl or alkoxy moiety, means a C _1-2 -alkyl group substituted by an imidazole group in the 1 position, wherein the imidazole cycle may be substituted by phenyl or carboxy and one or two C 1-3 -alkyl groups or one, two or three C 1-3 -alkyl groups, wherein the substituents may be the same or different and one of the above alkyl substituents may be simultaneously substituted by carboxy or in the 2 or 3 position with an amino group - 150 - ......... _C2 -4 - alkanoylamino, C 1-3 -alkylamino, N- (C ₂ -4 -alkanoyl) -C. _3- alkylamino or di- (C _1-3 -alkyl) -amino, wherein the phenyl or pyridine ring can additionally be fused to the above imidazole cycles via two adjacent carbon atoms, represents a C 1 group. _2- alkyl substituted at the 1-position by a benzimidazolon-1-yl group, wherein the imidazolone ring may be substituted by a methyl or ethyl group, which may optionally be substituted by a carboxy group, means a methyl or ethyl group substituted at the 1-position by a group R3NR4 or R3NR4-C1-3-alkyl group and a di- (C ₃ -alkyl) aminocarbonyl, isoxazolidin-1-ylcarbonyl, pyrrolidinocarbonyl or piperidinocarbonyl group optionally substituted by C1-3 alkyl, wherein the alkyl moiety or alkyl substituent may be substituted for the above groups with a carboxy group, where they are R ₃ is hydrogen or C 1-6 alkyl; _3- alkyl optionally substituted with carboxy; and R ₄ is hydrogen, C 1-3 -alkyl-Y ₂ - or carboxy-C. _3- alkyl-Y ₂ ; 4 4 4 · 4 4 4 444 444 4444 4 4 444 44 - 154 - · * · ........ R ₃ and R 4 together with the nitrogen intermediate the 4- to 7-membered group cykloalkylenimino optionally substituted by carboxy, wherein Y ₂ represents a carbon-nitrogen bond, a carbonyl group or an imino optionally substituted with a C 1-6 -alkyl group, means a C 1-6 group. _2- alkyl substituted at the 1-position with R 5 NR 6, where they are R ₅ is pyridinyl, phenylcarbonyl or phenylsulfonyl; R ₆ is C 1-3 -alkyl or carboxy-C 1-6 -alkyl; _3- alkyl, means the n-propyl group substituted at the 3-position with a chlorine atom and which is substituted at the 1-position by a cyclopentylcarbonyl group, represents a cyclopentyl group substituted at the 1-position by a cyclopentylamino group and substituted at the nitrogen by carboxy-C 3- alkylcarbonyl, R _b is methyl and amidino is substituted with C 1-8 -alkoxy - 154 4 «« 4 ·· • · 4 · 444 4 4 4 4 4 4 4 4 4 44, 444 44 4 carbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl, their C 1-3 -alkanol ester, their tautomers, stereoisomers and their salts. The benzimidazoles of formula Ia according to claim 2, wherein A is methyl, B represents an imino group, R _a represents a cyclopropyl group substituted at the 1-position by R 1 -CO, where R 1 represents a pyrrolidino or piperidino group optionally substituted by methyl or ethyl, and wherein the methyl or ethyl moiety may be substituted by carboxy, carboxy-C 1-3 -alkoxy, carboxy-C 1. _3- alkylamino or N- (C _1-3 -alkyl) -carboxy-C 1-3 -alkylamino, means a cyclopropyl group substituted in the 1-position by R ₂ -CX, where R ₂ is phenyl, pyridyl, pyrazolyl optionally substituted with C 1-3 -alkyl and 99 9 - 155 tf 10 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 98 9 9 9 9 9 9 9 X is oxygen, -alkoxyimino or C 1-3 -alkylideno substituted in the alkyl or alkoxy moiety by carboxy means C 1-2 -alkyl substituted in position by imidazole, and wherein the imidazole ring may be substituted by 1 to 3 methyl or two methyl groups and one ethyl group, wherein one of the above methyl or ethyl substituents may be simultaneously substituted by carboxy, is methyl or ethyl substituted at the 1-position by R3NR4 or R3NR4-CH2 and di- (C1-3- alkyl) -aminocarbonyl, pyrrolidinocarbonyl or piperidinocarbonyl optionally substituted with C 1-3 -alkyl, wherein the alkyl moiety or alkyl substituent of the above groups may be substituted with a carboxy group where R ₃ is hydrogen or C 1-3 -alkyl optionally substituted with carboxy; and R ₄ is C 1-3 -alkyl-Y ₂ - or carboxy-C 1-3 -alkyl-Y ₂ wherein Y2 represents a carbon-nitrogen bond, a carbonyl group or an imino optionally substituted by a C1-3-alkyl group, - 156 • © © · · © © · · © · · · © © · · «© · © ·· · Rb is methyl and R _c is an amidino group optionally substituted C 1-8 -alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl, their C 1-3 -alkanol ester, their tautomers, stereoisomers and their salts. The benzimidazoles of formula I according to at least one of claims 1 to 5, wherein the residue R _a stands in the 5-position, their tautomers, stereoisomers and their salts. 7. The following compounds of formula Ia: (a) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl] benzimidazole, (b) (E / Z) -2- (4-amidinophenylaminomethyl) - 1-Methyl-5- [1 - [(pyridin-2-yl) - (carboxymethyl-oxyimino) -methylene] -cyclopropyl] -benzimidazole, (c) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (2-carboxy-ethylamino) -1- (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole, 00 00 0 00 00 00 000 000 00 0 00 00 000 000 000 00 - 157 (d) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- [2- (carboxyethyl) -pyrrolidin-1-ylcarbonyl] -cyclopropyl] -benzimidazole, (e) 2- (4) (Amino-phenylaminomethyl) -1-methyl-5- [2- (2-carboxyethyl) -4,5-dimethyl-imidazol-1-ylmethyl] -benzimidazole, (f) 2- (4-Amidinophenylaminomethyl) -1-methyl- 5- [1- (carboxymethylamino) -1- (pyrrolidin-1-ylcarbonyl) ethyl] -benzimidazole and (g) 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (N-methylcarboxymethylcarbonylaminomethyl) ) -1-methyl- (pyrrolidin-1-yl-carbonyl) -ethyl] benzimidazole, and their C ₃ -alkanolester their N- (C _8.1 alkoxycarbonyl) - N-benzyl-N enzyloxykarbonyla amidino, their tautomers, stereoisomers and their salts. 8. 2- (4-Amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrroidin-1-ylcarbonyl) ethyl] -benzimidazole, its C _1-3 alkanol ester and its N - (C _1-8 -alkoxycarbonyl) -, N -benzyloxycarbonyl- and N -benzoylamidine, its tautomers, stereoisomers and salts thereof. Physiologically acceptable salts of the compounds according to claims 1 to 8, wherein R _c represents one of the amidino groups mentioned in claims 1 to 8. Medicament comprising a compound according to at least one of claims 1 to 8, wherein R _c represents one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9 in addition to optionally one or more inert carriers and / or solvents. 9 * 999 · 9 · 99 99 9 9 9 · 9 9 - 158 ··· 999,999 · * ♦ 99,999 99,999 Use of a compound according to at least one of claims 1 to 8, wherein R _c represents one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, for the manufacture of a medicament having a thrombin delayed effect, thrombin inhibitory effect and related inhibitory effect. serine proteases. A method for the manufacture of a medicament according to claim 10, characterized in that the compound according to at least one of claims 1 to 8, wherein R _c is one of the amidino groups of claims 1 to 8, or the salt according to claim 9 is incorporated into one or more inert carriers and / or solvents. A process for the preparation of the compounds according to claims 1 to 9, characterized in that (a) in the preparation of a compound of formula I wherein R _c is cyano, the compound of formula II formed in the reaction mixture is cyclized by di: wherein R _a , R b, Ar A and B are as defined in the claims, Z 1 and Z ₂ , which may be the same or different, represent amino, hydroxy or mercapto groups optionally substituted by C 1-6 alkyl groups, or - 159 99 99 99 99 9 9 · 9 * 9 999 »99 999 99 99 99 99 99 99 Together and Z ₂ together represent an oxygen atom or a sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy group or an alkylenedithio group having 2 or 3 carbon atoms, or b) in the manufacture of a compound of formula I wherein R _a is a group R ₂ -CX'-C ₃ . _5- cycloalkylene, wherein R ₂ is as defined in claims 1 to 8 and X 'is one of the imino residues listed in claims 1 to 8 for X, reacts with a compound of formula IV wherein R b, R c, Ar, A and B are as defined in claims 1 to 8 and R _a 'represents a group R ₂ -CO-C 3-5 -cycloalkylene, wherein R ₂ is as defined in claims 1 to 8 8, with an amine of formula V H ₂ X '(V), wherein X' is one of the imino residues mentioned in claims 1 to 8 for X, or c) in the manufacture of a compound of formula I, wherein R _a is * 160 R ₂ -CX-C ₃ -5 -cycloalkylene, wherein R ₂ is as defined in claims 1 to 8 and X represents one of the alkylidene residues mentioned in claims 1 to 8 for X, reacts with a compound of formula IV A-B-Ar-R. (IV) wherein R b, R c, Ar, A and B are as defined in claims 1 to 8 and R _a 'represents a group R ₂ -CO-C ₃ . ₅ -cycloalkylene, wherein R ₂ is as defined in claims 1 to 8 with a phosphone of formula VI Z ₃ - HX (VI) where X is from the alkylidene residues mentioned in claims 1 to 8 for X Z ₃ is triphenylphosphono or di- (C 1-3 -alkoxy) -phosphono, or d) in the manufacture of a compound of formula I wherein R _c is an amidino group which may be substituted with one or two groups; -161 \ A C 1-3 -alkyl group, reacts a compound of formula VII, which in this case is formed in the reaction mixture, C (= NH) W ₄ (VII) wherein R _a , R _b , Ar, A, and B are as defined in claims 1 to 8 a Z4 represents an alkoxy, aralkyloxy, alkylthio or aralkylthio group, with an amine of the formula VIIIa H - R ₇ NR ₈ (VIII), where R ₇ and R 8, which may be the same or different, represent a hydrogen atom or a C 1-3 -alkyl group, or salts thereof, or e) in the manufacture of a compound of formula I wherein R _a is an imidazolidin-2,4-dion-5-yl group which may be substituted with one or two C 1-3 -alkyl groups, wherein the alkyl substituent may be simultaneously substituted with carboxy; or C1-3-alkoxycarbonyl, cyclizes a compound of formula IX, optionally formed in a reaction mixture, wherein Rb, Ar, A and B are as defined in claims 1 to 8, and R _a represents an aminocarbonylamino group which is substituted at the 3-position with a C _1-3 -alkoxycarbonyl-C _1-3 -alkyl group, or f) in the preparation of a compound of formula I wherein R _c is a hydroxyamidine group, a nitrile of formula X wherein R _a . R b, Ar, A and B are as defined in claims 1-8 with hydroxylamine or its salts, or g) in the manufacture of a compound of formula I, wherein R _a contains a carboxy group and R _c is defined as in claims 1 to 8 Or R _a is as defined in claims 1 to 8 and R _c is an amidino group optionally substituted by hydroxy or one or two C 1-3 -alkyl groups with a compound of formula XI wherein R _b , Ar, A and B are as defined in claims 1 to 8 a R _a '' and R _c 'as defined in claims 1 to 8 for R _a and R _c , wherein R a contains a carboxy-convertible group formed by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis and R _c is defined as set forth in claims 1 to 8 or R _c is a convertible group formed by hydrolysis, acid or base treatment, thermolysis, or hydrogenolysis of an amidino group optionally substituted by one or two C 1-8. ₃ alkyl groups and R _a is as defined in claims 1 to 8 converted by hydrolysis, acid or base treatment, thermolysis or hydrogenolysis to a compound of formula I wherein R _a contains a carboxy group and R e is as defined in of claims 1 to 8 or R a is as defined in claims 1 to 8 and R _c is an amidino group which is optionally substituted with hydroxy or one or two C _1-3 -alkyl groups, or - 164 - h) in the preparation of a compound of formula I wherein R _c is an amidino group which is substituted with one or two C 1-8 -alkoxycarbonyl groups or an in vivo leaving group, a compound of formula XIII (XII) wherein: Ra, Rb, Ar, A and B are as defined in claims 1 to 8 and R _o "represents aimidinoskupinu with a compound of formula XIII Z5-R9 (XIII), where R 8 is a C _1-8 -alkoxycarbonyl group or an acyl residue of one of the above in vivo cleavable residues, and Z 5 is a precursor leaving group, and the compound of formula I thus formed comprises a (R 3 NR 4) -C 1-3 alkyl group wherein at least one from the radicals R ₃ or R ₄ represents a hydrogen atom, it is converted by the corresponding isocyanate or carbamoyl halide into the corresponding urea compound of the formula I and / or - 165 sloučenina takto ♦ sloučenina sloučenina takto takto takto takto takto takto takto takto takto takto takto takto takto takto takto takto takto 4 takto takto takto takto takto takto 4 takto takto of formula I which contains an NH ₂ -C 3 -alkyl, is converted to the corresponding acrylic acid ester into the corresponding 2- (C 3 alkoxycarbonyl) ethyl compound of formula I and / or the resulting compound of formula I, which contains (R ₃ NR 4) -C 1-3 -alkyl, wherein R ₃ and R ₄ are hydrogen, is converted by the corresponding dihaloalkane to the corresponding compound of formula I, wherein R ₃ and R ₄ together with the nitrogen atom in the center represent 4- a 7-membered cycloalkyleneimino group and / or a compound of formula I, where R _c is an amidino group, is converted to a corresponding amidino compound substituted with one or two methyl groups by a haloacetic acid derivative followed by hydrolysis and decarboxylation and / or the compound of formula I, where R _c is hydroxyamino, is converted by catalytic hydrogenation to the corresponding amidine compound and / or the compound of formula I, wherein R _a contains a carboxy group, is converted by esterification to the corresponding ester and / or the protective residue which is used during the reaction to protect the reactive groups is cleaved and / or the compound of the formula I thus obtained is converted into its stereoisomer and / or 9 9 99 99 * 9 • 9 9 9 9 9 - 166 99 • 9 99 9 9 9 9 9 9 9 9 The compound of formula (I) thus obtained is converted into its salts, in particular to its physiologically acceptable salts with inorganic or organic acids or bases, which are used in pharmacy.