EP1360170A1 - Carboxylic amides, the production and use thereof as medicaments - Google Patents

Abstract

The invention relates to anti-thrombotic compounds of general formula (I), wherein R1 - R4, R8, R9 and Ar are defined as cited in claim 1, and for example, 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-chloro-4-(pyrrolidine-1-yl-carbonyl)-phenyl]-acetamide, tautomers thereof, stereoisomers, mixtures, pro-drugs and the salts thereof. The compounds of the above-mentioned general formula (I), wherein Ar represents a phenyl or napthyl group substituted by the radicals R5, R6 and R7 and R5 represents a cyano group, having valuable intermediate products for producing the corresponding compounds of general formula (I) wherein R5 represents, optionally, a amidino group substituted by one or two C1-3 alkyl groups. The compounds of the above-mentioned general formula (I) with the exception of compounds, wherein Ar represents a phenyl or naphthyl group substituted by the radicals R5, R6 and R7 and R5 represents a cyano group, have valuable pharmalogical properties, particularly anti-thrombotic properties and a factor Xa inhibiting property.

Description

 Carboxamides, their preparation and their use as medicines

The present invention relates to carboxamides of the general formula

their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives which, instead of a carboxy group, contain a group which is negatively charged under physiological conditions, and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable properties ,

The compounds of the above general formula I, in which Ar represents a phenyl or naphthyi group substituted by the radicals R ₅ , R _Θ and R ₇ and R _{5 represents} a cyano group, represent valuable intermediates for the preparation of the corresponding compounds of the general formula I, in which R _{5 is} an amidino group optionally substituted by one or two C ₃ alkyl groups. The compounds of the above general formula I with the exception of those compounds in which Ar represents a phenyl or naphthyi group substituted by the radicals R ₅ , Rβ and R ₇ and R _{5 represents} a cyano group, and also their tautomers, their stereoisomers, their mixtures, their prodrugs , their derivatives, which instead of a carboxy group contain a group which is negatively charged under physiological conditions, and their salts, in particular their physiologically tolerable salts with inorganic or organic salts, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa-inhibiting effect.

The present application thus relates to the new compounds of the general formula I above and the compounds

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide,

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide and

2- (5-carbamidoyl-2-hydroxy-phenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyI) phenylj-acetamide,

their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.

In the general formula above means

Ri a C ₃ . _7- Cycloalkyl-carbonyl group, wherein

the methylene group in the 3- or 4-position in a C ₅ . -Cycloalkyl-carbonyl group can be replaced by an -NH group in which

the hydrogen atom of the -NH group can be replaced by a C ₃ alkyl, C ₃ alkyl carbonyl, phenylcarbonyl or phenylsulfonyl group,

a terminal in the alkyl part, optionally by an amino, Cι. ₃ -alkylamino- or di- (C ₁ - ₃ -alkyl) -amino group substituted Cι- ₆ -alkylcarbonyl group, a group of the formula R _f R _g N- (CH ₂ ) m- (R _h ) N-CO-, in which

R _f , R _g and R independently of one another each represent a hydrogen atom or a C ₃ alkyl group and m is one of the numbers 2, 3, 4, 5 or 6,

a phenylcarbonyl, naphthylcarbonyl or heteroarylcarbonyl group,

a C 1 -C ₃ -alkyl group monosubstituted by a hydroxyl group or terminally disubstituted by a phenyl and a hydroxyl group, where

the phenyl substituent may be substituted by an amidino group which is optionally substituted by one or two C ₃ alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ₃ alkyl ₃ or C ₃ alkoxy group can

one by an amino -C ₃ alkyl, C ₃ alkylamino ~ C. ₃ -alkyl-, di- (Cι. ₃ -alkyl) - amino-Cι- ₃ -alkyl-, aminocarbonyl-, Cι- ₃ -alkylamino-carbonyl- or di- (Cι- ₃ -alkyl) - aminocarbonyl group substituted 4- up to 7-membered cycloalkyleneimino-carbonyl or cycloalkyleneimino-sulfonyl group,

a C ₃ - ₇ cycloalkylamino group which is substituted on the nitrogen atom by a C ₃ alkyl alkyl C ₃ alkyl or di (C ₃ alkyl) amino C ₃ alkyl group,

or also if R _{2 is} a trifluoromethyl group and / or R _{5 is} an amino-Cι- ₃ alkyl-,

C ^ s-alkylamino -C ₃ alkyl or di (C ₃ alkyl) amino -C. ₃ -alkyl group or / and R _{6 is} a carboxy-C ₃ alkoxy or C - [- ₄ alkoxy-carbonyl-C ₃ alkoxy group or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom assumes an unsubstituted 4- to 7-membered cycloalkyleneimino-carbonyl or cycloalkyleneimino-sulfonyl group, a C ₃ . _7- Cycloalkylamino- or

N- (Cι. ₃ alkyl) -C ₃ - ₇ -cycloalkylamino group, R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C 1-4 alkyl group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a hydroxy or C ₃ alkoxy group,

R _{3 is} a hydrogen atom or a Cι. ₃ -alkyl group,

R is a hydrogen atom or a C ₃ alkyl group which may be substituted by a carboxy group or a group which can be converted into a carboxy group in vivo,

Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , Rβ and R ₇ , where

R _{5 is} a cyano group, an amidino group which is optionally substituted by one or two C ₃ alkyl groups, an amino C ₃ alkyl ₃ , C ₃ alkylamino

C- ₃ alkyl or di (C ₃ alkyl) amino C ₃ alkyl group,

Rβ is a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C ₁ - ₃ - alkyl, hydroxy, hydroxy-Cι- ₃ -alkyl-, C-ι- ₃ -alkoxy-, cis-alkoxy- Ci-s-alkyl, carboxy, carboxy -CC. ₃ -alkyl-, carboxy-Cι- ₃ -alkoxy-, C-ι_ ₄ -alkoxy-carbonyl-

Cι_ ₃ -alkoxy-, PhenyI-Cι- ₃ -alkoxy-, amino, Cι- ₃ -alkylamino or di- (C-ι- ₃ -alkyl) amino group and

R represents a hydrogen, fluorine, chlorine or bromine atom or a C ₃ alkyl group,

or a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C 3 alkyl group,

R ₈ and R ₉ , which may be the same or different, each represent a hydrogen atom, one optionally substituted by a phenyl or heteroaryl group Cι- ₃ alkyl group or one optionally by one or two C-. ₃ -alkyl- or Cι- ₃ -alkyl-carbonyl-substituted amino group,

wherein under a heteroaryl group mentioned above, a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the

an imino group optionally substituted by a C-u-alkyl or Cι- alkyl carbonyl group, an oxygen or sulfur atom,

an imino group which is optionally substituted by a C ₄ alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom,

an imino group optionally substituted by a C ₄ alkyl group and two nitrogen atoms or

contains one oxygen or sulfur atom and two nitrogen atoms,

or a 6-membered heteroaryl group which contains one or two nitrogen atoms,

where a phenyl ring can be fused to the 5- or 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,

to understand

and wherein the unsubstituted or monosubstituted phenyl and naphthyl groups mentioned in the definition of the abovementioned radicals, or unsubstituted or monosubstituted phenyl and naphthyl parts contained in these radicals, and the heteroaryl groups mentioned on a carbon atom, optionally additionally in each case by a fluorine or chlorine or bromine atom, can be substituted by a trifluoromethyl, C ^ alkyl, C ^ alkoxy or Cι- ₃ alkoxy carbonyl group, unless otherwise stated. The mentioned in the definition of the aforementioned radicals carboxy groups may be replaced by an in-vivo into a carboxy group or by a viable ^as' physiological conditions, negatively charged group,

furthermore, the amino and imino groups mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo. Such groups are described, for example, in WO 98/46576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).

A group which can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C- |. ₆ -alkanol, a phenyl-C ₃ alkanol, a C ₃ .g-cycloalkanol, a Cs-s-cycloalkanol additionally by one or two Cι. ₃ -alkyl groups can be substituted, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an optionally by a C ₃ alkyl, phenyl ₃ C ₃ alkyl, phenyl-Cι- ₃ -alkoxycarbonyl or C ₂ - ₆ alkanoyl group substituted imino group is replaced and the cycloalkanol moiety ₃ alkyl groups may additionally be substituted by one or two Cι-, C. -Cycloalkenol, a C ₃ - ₅ -alkenol, a phenyl-C ₃ - ₅ -alkenol, a C ₃ . ₅ -alkinol or

Phenyl-C. _{3 5-} alkynol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C ₃ - ₈ cycloalkyl-C- |. _3- alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which can additionally be substituted in the bicycloalkyl part by one or two Cι- ₃ -Alky! Groups, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol formula

R _a -CO-O- (R _b CR _c ) -OH,

by doing

R _{a is} a ds-alkyl, Cs-r-cycloalkyl, phenyl or phenyl-Cι- ₃ alkyl group,

R _{b is} a hydrogen atom, a -C ₃ alkyl, C ₅ - ₇ cycloalkyl or phenyl group and R _{c represents} a hydrogen atom or a C ₃ alkyl group,

under a negatively charged under physiological conditions, such as a tetrazol-5-yl, Phenyicarbonylaminocarbonyl-, Trifluormethylcarbonylaminocarbonyl-, Cι- methylsulfonylamino ₆ alkylsulfonylamino, phenylsulfonylamino, Benzylsulfonylamino-, trifluoro, Cι- ₆ -Alkylsulfonylaminocarbonyl-, phenylsulfonylamino carbonyl, benzylsulfonylaminocarbonyl or perfluoro-Ci-β-alkylsulfonylamino-carbonyl group

and under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group such as one optionally by fluorine, chlorine, bromine or iodine atoms, by C 1-4 alkyl or C ₃ alkoxy groups disubstituted phenylcarbonyl group, where the substituents can be the same or different, a pyridinoyl group or a Cι.ι ₆ alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl group or allyloxycarbonyl group, a Cι. ₁₆ -alkoxycarbonyl or C-ι- ₁₆ alkylcarbonyloxy group, in which hydrogen atoms can be replaced in whole or in part by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.

Butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxy carbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyl , Isopropylcarbonyloxy, butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-Cι. _6- alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group in which the amino group is substituted by C 1 -C ₆ -alkyl or C ₃ . Cycloalkyl groups mono- or disubstituted and the substituents may be identical or different, represent a Cι- ₃ alkylsulfonyl-C _2-4 alkoxycarbonyl, Cι- ₃ alkoxy C ₂ - ₄ alkoxy-C ₂ - alkoxycarbonyl, R _a -CO-O- (R _b CR _c ) -O-CO-, de-alkyl-CO-NH- (R _d CR _e ) -O-CO- or d ^ alkyl-CO-0- (F ^ CReM ^ CRe) -0-CO group, in which R _a to R _c are defined as mentioned above,

R _d and R _e , which may be the same or different, represent hydrogen atoms or C ₃ alkyl groups,

to understand.

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

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

Ri a C ₅ . _7- Cycloalkyl-carbonyl group in which the methylene group in the 3- or 4-position is replaced by an -NH group in which

the hydrogen atom through a C ₃ alkyl, C. _3- alkyl-carbonyl or phenyl-carbonyl group can be replaced,

a terminally substituted in the alkyl part optionally by a C ₃ alkylamino or di (C ₃ alkyl) amino group, d ₃ alkyl carbonyl group,

a group of the formula R _f R _g N- (CH ₂ ) m- (R _h ) N-CO- _> in the

Rf, R _g and R _h independently of one another each represent a hydrogen atom or a d- ₃ -alkyl group and m is one of the numbers 2, 3 or 4,

a phenylcarbonyl or heteroarylcarbonyl group,

wherein the heteroaryl portion is a 6-membered heteroaryl group containing one or two nitrogen atoms and attached to it via two adjacent carbon atoms Phenyl ring can be fused, wherein the bicyclic heteroaryl groups thus formed can be bound via the heteroaromatic or carbocyclic part, for example a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, Isoquinolinyl, quinoxalinyl or quinazolinyl group,

a C 1 -C ₃ -alkyl group monosubstituted by a hydroxyl group or terminally disubstituted by a phenyl and a hydroxyl group, where

the phenyl substituent can be substituted by an amidino group which may be substituted by one or two C ₃ alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ₃ alkyl or C ₃ alkoxy group,

one by an amino-C ₃ -alkyl-, ds-alkylamino-ds-alkyl-, di- (C ₃ -alkyl) -amino- C ₃ -alkyl, C ₄ -4 -alkoxy-carbonylamino-Cι -3-alkyl, aminocarbonyl, Cι. _3- alkylamino-carbonyl or di- (Cι_ ₃ -alkyl) -aminocarbonyl group substituted 4- to 7-membered cycloalkyleneimino-carbonyl group,

a Cs- _T cycloalkylamino group, which is attached to the nitrogen atom by a Cι- ₃ alkylamino

C ₃ alkyl or di (C ₃ alkyl) amino C ₃ alkyl group is substituted,

or also if R _{2 is} a trifluoromethyl group and / or R _{5 is} an amino-C ₃ alkyl or C ₃ -alkylamino-C ₃ -alkyl group or / and R _{6 is} a carboxy C ₃ -alkoxy or C 1 - -Alkoxy-carbonyl-Cι- ₃ -alkoxy group or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom, an unsubstituted 4- to 7-membered cycloalkyleneiminocarbonyl group, a C ₅ . _7- cycloalkyl-amino or N- (d- ₃ -alkyl) -C ₅ _ ₇ -cycloalkylamino group,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, ad- ₃ -alkyl, trifluoromethyl or d- ₃ -alkoxy group,

R3 is a hydrogen atom or ad ₃ -alkyl group, R is a hydrogen atom or a d-3-alkyl group,

Ar is a phenyl group substituted by the radicals R ₅ and R ₆ , where

R _{5 is} a cyano group, an amidino group optionally substituted by one or two d- ₃ -alkyl groups, an amino-Cι- _3- alkyl or d- ₃ -alkylamino-Ci- ₃ -alkyl group and

R _& a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C ₁ - ₃ -

Alkyl, hydroxy, C ₃ alkoxy, carboxy C 1. ₃ -alkoxy- or Cι- alkoxy-carbonyl-d- ₃ -alkoxy group, and

Rs and Rg, which may be the same or different, each have a hydrogen atom, an optionally substituted by a phenyl or pyridinyl group Cι- ₃ alkyl group or an optionally by one or two Cι- ₃ alkyl or Cι- ₃ alkyl - carbonyl-substituted amino group,

the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned radicals or unsubstituted or monosubstituted phenyl parts contained in these radicals and the heteroaryl groups mentioned on a carbon atom optionally additionally each by a fluorine, chlorine or bromine atom, by a trifluoromethyl , C ₃ alkyl, C _{1 3} alkoxy or C ₃ alkoxy carbonyl group may be substituted, unless stated otherwise,

and the connections

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide, 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide and

2- (5-carbamidoyl-2-hydroxy-phenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts,

but especially the connections in which

the radicals Ri to R, Rs and Rg are defined as mentioned above, but Ri is bonded in the 4-position to the phenyl radical contained in formula I and

Ar represents a phenyl group substituted by the radicals R ₅ and R ₆ , where

R ₅ is bonded in the 3-position if RQ represents a hydrogen atom, or is bonded in the 5-position if Rβ takes on a meaning other than that of the hydrogen atom, and an amidino group which is optionally substituted by one or two d- ₃ -alkyl groups , an amino-C ₃ alkyl or C ₃ alkyl-amino ₃ alkyl group and

Rδ is a hydrogen atom or a trifluoromethyl-, C1-3-, alkyl-, hydroxy-, Cι- ₃ -alkoxy-, carboxy-Cι- ₃ -alkoxy- or Cι- ₄ -alkoxy-carbonyl- Cι- ₃ bonded in the 2-position -alkoxy group means

as well as the connections

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide

and 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts.

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

R-ι is bound in the 4-position of the phenyl radical of formula I and

a C ₅ - -cycloalkyl-carbonyl group in which the methylene group in the 3- or 4-position is replaced by an -NH group,

a phenylcarbonyl or pyridylcarbonyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C ₃ -C ₃ -alkyl group,

a terminally disubstituted by a phenyl and a hydroxy group Cι- ₃ alkyl group, wherein

the phenyl substituent may be monosubstituted by a C ₃ alkyl or an amidino group or may be disubstituted by a C ₃ alkyl and an amidino group,

one by an amino-C ₃ alkyl, C ₃ alkylamino C ₃ alkyl ₃ , C ₄ alkoxy-carbonyI-amino- _3- alkyl, aminocarbonyl or C 1. _3- alkylamino-carbonyl group substituted 5- to 7-membered cycloalkyleneimino-carbonyl group,

or also, provided that R _{2 is} a trifluoromethyl group and / or R _{5 is} an amino C ₃ alkyl group or / and R _{6 is} a carboxy C ₃ alkoxy or C ₄ alkoxy-carbonyl C ₃ alkoxy - Group or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom, represents an unsubstituted 5- to 7-membered cycloalkyleneimino-carbonyl or cycloalkyleneimino-sulfonyl group and R _{2 is} a hydrogen atom or a substituent bonded in the 3-position of the phenyl radical, selected from fluorine, chlorine, bromine, C ₃ alkyl, C ₃ alkoxy and trifluoromethyl,

R ₃ and R ₄ each represent a hydrogen atom,

Ar is a phenyl group substituted by the radicals R ₅ and R ₆ , where

R ₅ is bonded in the 3-position when RQ represents a hydrogen atom, or is bonded in the 5-position when R $ has a meaning other than that of the hydrogen atom, and an amidino or amino-Cι- ₃ alkyl group and

R _{δ represents} a hydrogen atom or a bonded in the 2-position hydroxy, d- ₃ alkoxy, carboxy-C ₃ alkoxy or C ₄ -alkoxy-carbonyl-C ₃ alkoxy group, and

Rs and Rg, which may be the same or different, each have a hydrogen atom, an optionally substituted by a phenyl, 4- (Cι- ₃ alkoxycarbonyl) phenyl or pyridinyl group Cι- ₃ alkyl group or an optionally by one or two Cι_ ₃ alkyl or d- ₃ alkyl carbonyl groups substituted amino group,

as well as the connections

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide and

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts.

For example, the following preferred compounds are mentioned: (1) (L) -2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (2-aminocarbonylpyrrolidin-1-ylcarbonyl) phenyl] acetamide,

(2) 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- {3-methyl-4- [2- (tert.butoxycarbonylaminomethyl) piperidin-1-ylcarbonyl] phenyl} acetamide .

(3) 2- (5-aminomethyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

(4) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] isobutyramide,

(5) 2- (5-carbamimidoyl-2-ethoxycarbonylmethyloxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

(6) 2- (5-carbamimidoyl-2-carboxymethyloxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

(7) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (piperidin-3-yI-carbonyl) phenylj-acetamide,

(8) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- (3-methyl-4-benzoyl-phenyl) -acetamide,

(9) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (1-hydroxy-1-phenyI-methyl) phenyl] acetamide,

(10) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- {4- [1- (3-carbamimidoyl-phenyl) -1-hydroxy-methyl] -3-methyl-phenyl} -acetamide,

(11) 2- (3-carbamidoylphenyl) -N- [3-methyl-4- (pyridin-3-ylcarbonyl) phenyl] isobutyramide, (12) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1 -yl-carbonyl) phenylj-isobutyramide,

(13) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

(14) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -2-amino-acetamide,

(15) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -2- (acetylamino) -acetamide,

(16) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide,

(17) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenylj-propionamide,

(18) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide,

(19) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [4- (pyrrolidin-1-yl-carbonyl) -3-trifluoromethyl-phenylj-propionamide,

(20) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

(21) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-propionami,

(22) 2- (5-carbamidoyl-2-hydroxyphenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide, (23) 2- (3-carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3-phenyl-propionamide,

(24) 2- (3-carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3- (pyridin-4-yl) -propionamide and

(25) 2- (3-carbamimidoylphenyl) -N- [3-bromo-4- (pyrrolidin-1-ylcarbonyl) phenyl] -3- [4- (ethoxycarbonyl) phenyl] propionamide,

in which the amidino group can additionally be substituted by a C ₆ alkoxycarbonyl or phenylcarbonyl group, and their salts.

According to the invention, the compounds of general formula I are obtained by processes known per se, for example by the following processes:

a) For the preparation of a compound in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R, where Rβ and R ₇ are defined as mentioned at the outset and R _{5 represents} an amidino group:

Acylation of a compound of the general formula

in which R 1 to R ₄ are defined as mentioned at the outset, with a carboxylic acid of the general formula

in which R ₈ and R ₉ are defined as mentioned at the outset and Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R ₇ , where R _{5 is} a cyano group and R ₆ and R _{7 are} as defined at the outset, means, or with their reactive derivatives and subsequent conversion of the cyano compound thus obtained into an amidino compound.

The acylation is advantageously carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

However, the acylation can also be carried out with the free acid or an ester, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride , Phosphorus pentoxide, triethylamine, N, N'-dicyclohexylcarbodiimide, N.N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, O- (benzotriazol-1-yl) -N, N, N ', N ^, -tetramethyluronium tetrafluoroborate / N-methylmorpholine, propanephosphonic acid cyclo-anhydride / N-methylmorpholine, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C , but preferably at temperatures between -10 and 160 ° C.

The subsequent conversion of the cyano group into an amidino group is carried out as described in process b).

b) For the preparation of a compound of general formula I in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R ₇ , where

Rδ and R ₇ are defined as mentioned at the outset and R _{5 represents} an amidino group optionally substituted by one or two C ₃ alkyl groups: Reaction of a compound of the general formula optionally formed in the reaction mixture

in the

R 1 to R ₄ , R ₈ and Rg, as defined at the outset, Ar 'is a phenyl or naphthyl group substituted by the radicals R ₆ and R ₇ , where R _δ and R _{7 are} as defined at the outset, and

Z _{1 is} an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as that

Represents methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of the general formula

H - R ₁₀ NRn, (V)

in the

R ₁₀ and R ₁₁ , which may be the same or different, each have a hydrogen atom, a Cι- ₃ alkyl or optionally by one or two Cι- ₃ alkyl or d. _3- Alkyl-carbonyl groups substituted amino group, or with it

Salt.

The reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C., with an amine of the general formula V or with a corresponding acid addition salt such as ammonium carbonate or ammonium acetate. A compound of general formula IV is obtained, for example, by reacting an appropriate cyano compound with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting an appropriate amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding nitrile with hydrogen sulfide, advantageously in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.

c) For the preparation of a compound of the general formula I in which Ar denotes a phenyl or naphthyl group substituted by the radicals R ₅ , R _δ and R ₇ , where R _δ and R ₇ are defined as mentioned at the outset and R _{5 is} an aminomethyl , Cι. ₃ -alkyl-aminomethyl or di- (C. _3- alkyl) aminomethyl group:

Catalytic hydrogenation of a compound of the general formula

in the

Ar represents a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R ₇ , R ₁ to R ₄ and R ₆ to Rg are defined as mentioned at the outset and R _{5 represents} a cyano group, and optionally subsequent alkylation with a compound of the formula

in which R _{12 represents} a C ₃ alkyl group and Z _{2 represents} a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group.

The catalytic hydrogenation is carried out with hydrogen in the presence of a catalyst such as palladium / carbon, platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, or, for example, with Raney nickel, preferably in methanolic ammonia solution.

The optionally subsequent alkylation is advantageously carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide, dimethyl sulfate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, advantageously at temperatures between 0 and 150 ° C., preferably at temperatures between

0 and 100 ° C, carried out.

If, according to the invention, a compound of the general formula I is obtained which contains an amino or imino group, this can subsequently be converted into a corresponding acyl compound of the general formula I and / or with an appropriate acyl derivative

a compound of the general formula I which contains an esterified carboxy group, this can be converted into a corresponding carboxylic acid of the general formula I by hydrolysis and / or a compound of the general formula I which contains a carboxy group, this can then be converted into an appropriate ester by esterification.

The subsequent acylation is advantageously carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C. However, this can also be done with the free acid, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N.N'-dicyclohexylcarbodiimide /

1-Hydroxy-benzotriazole, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C., but preferably at temperatures between -10 and 160 ° C.

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

The subsequent esterification is conveniently carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene or tetrahydrofuran Dioxane, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N. .N'-Dicyclohexyl-carbodiimide, N.N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyl-diimidazole or N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphinate such as a potassium carbonate / azodicarboxylic acid such as azodicarbonate , N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide , Dimethylformamide or acetone against optionally in the presence of a reaction accelerator such as sodium 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-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent at the same time, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.

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

For example, the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or. tetrahydropyranyl,

as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.

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

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar.

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

A methoxy group is advantageously removed in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.

However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole. A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or Ethe ^'s .

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

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

The compounds of general forms II to VI used as starting materials, some of which are known from the literature, are obtained by processes known from the literature, and their preparation is further described in the examples.

The chemistry of the compounds of the general formula II is described, for example, by Schröter in nitrogen compounds II, pages 341-730, Methods of Organic Chemistry (Houben-Weyl), 4th edition, Verlag Thieme, Stuttgart 1957. The preparation of carboxylic acid derivatives of the general formula III are described in Methods of Organic Chemistry (Houben-Weyl), Volume E5, Carboxylic Acids and Carboxylic Acid Derivatives, 4th Edition, Verlag Thieme, Stuttgart 1985.

Furthermore, the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers. For example, the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Aliinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Separate compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physicochemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, subsequently as mentioned above can be separated into the enantiomers.

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

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

Citric acid, tartaric acid or maleic acid. In addition, if the new compounds of formula I thus obtained contain a carboxy group, they can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts. Bases which can be used here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned at the beginning, the new compounds of the general formula I and the compounds 2- (5-carbamimidoyl-2-hydroxyphenyI) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) phenyl ] acetamide, 2- (5-carbamimidoyl-2-hydroxyphenyl) - N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenyl] acetamide, 2- (5-carbamimidoyl-2 - hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyI) -phenyI] -acetamide and_2- (5-carbamidoyl-2-hydroxy-phenyl) -N- [3-methoxy- 4- (pyrrolidin-1-yl-carbonyl) -phenyl] acetamide and its salts have valuable properties. Thus, the compounds of the general formula I in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R _δ and R ₇ and R _{5 is} a cyano group are valuable intermediates for the preparation of the corresponding compounds of the general formula I, in which R _{5 is} an amidino group optionally substituted by one or two C ₃ alkyl groups. The compounds of general formula I with the exception of those compounds in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R _δ and R ₇ and R _{5 is} a cyano group, and also their tautomers, their stereoisomers and their physiologically tolerable salts valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect prolonging the aPTT time and on an inhibitory effect on related serine proteases such as, for , B. trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the connections

(1) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1 -yl-carbonyl) -phenylj- isobutyramide hydrochloride, (2) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (piperidin-3-yl-carbonyl) phenylj-acetamide,

(3) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenylj-acetamide hydrochloride and

(4) 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride

examined for their effect on the inhibition of factor Xa as follows:

Methodology: Enzyme kinetic measurement with a chromogenic substrate. The amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (based on the solvent control) is determined at different test substance concentrations and the IC _{50 is} calculated from this as the concentration which inhibits the factor Xa used by 50%.

Material:

Tris (hydroxymethyl) aminomethane buffer (100 mmol) and sodium chloride (150 mmol), pH 8.0

Factor Xa (Röche), specific activity: 10 U / 0.5 ml, final concentration: 0.175 U / ml per reaction mixture

Chromozym X substrate (Röche), final concentration: 200 μmol / l per reaction mixture

Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μmol / l Procedure: 10 μl of a 23.5-fold more concentrated starting solution of the test substance or solvent (control), 175 μl tris (hydroxymethyl) aminomethane buffer and 25 μl factor Xa working solution of 1.65 U / ml are incubated at 37 ° C. for 10 minutes. After adding 25 μl Chromozym X working solution (1.88 μMol / l), the sample is measured in a photometer (SpectraMax 250) at 405 nm for 150 seconds at 37 ° C.

Evaluation:

1. Determination of the maximum increase (deltaOD / minutes) over 3 measuring points.

2. Determination of the% inhibition based on the solvent control.

3. Create a dose-response curve (% inhibition vs substance concentration).

4. Determination of the IC ₅ o by interpolating the X-value (substance concentration) of the dose response curve at Y = 50% inhibition.

The following table contains the values found:

The compounds produced according to the invention are well tolerated since no toxic side effects could be observed at therapeutic doses.

Because of their pharmacological properties, the new compounds are suitable, with the exception of those compounds in which Ar is one by the radicals R ₅ , R ₆ and R ₇ substituted phenyl or naphthyl group and R _{5 is} a cyano group, and their physiologically tolerable salts for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep vein thrombosis, the prevention of Reocclu - Sections after bypass surgery or angioplasty (PT (C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts. In addition, the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with Alteplase, Reteplase, Tenecteplase, Staphylokinase or Streptokinase, for the prevention of long-term restenosis according to PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients with unstable angina or non-transmural heart attack, to prevent metastasis and growth of coagulation-dependent tumors and fibrin-dependent inflammatory processes, e.g. in the treatment of pulmonary fibrosis for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue or adhesions and / Scar tissue formation and suitable for promoting wound healing processes. The new compounds and their physiologically tolerable salts can be used therapeutically in combination with inhibitors of platelet aggregation such as fibrinogen.

Receptor antagonists (eg abciximab, eptifibatide, tirofiban), with inhibitors of ADP-induced aggregation (eg clopidogrel, ticlopidine), with P ₂ T receptor antagonists (eg Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (eg become.

The dosage required to achieve a corresponding effect is expediently 3 to 30 mg / kg, preferably 1 to 10 mg / kg for intravenous administration, and 5 to 50 mg / kg, preferably 3 to 30 mg / kg, 1 to each for oral administration 4 times a day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water water/ Incorporate ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

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

Example 1 ^' .

(L) -2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (2-aminocarbonylpyrrolidin-1-ylcarbonyl) phenyl1-acetamide hydrochloride

a. 4-allyloxy-benzonitrile

100.1 g (0.84 mol) of 4-hydroxy-benzonitrile are dissolved in 600 ml of dimethylformamide and, after addition of 103.2 g (0.92 mol) of potassium tert-butoxide, stirred at 35 ° C. for 30 minutes. A solution of 79.6 ml (0.92 mol) of 3-bromopropene in 10 ml of dimethylformamide is then added dropwise. After 1 hour at 60 ° C., the reaction solution is poured onto ice water, 300 ml of 2 molar sodium hydroxide solution are added and the mixture is extracted with ethyl acetate. The organic extracts are dried and evaporated. Yield: 130.1 g (97% of theory),

R _f value: 0.25 (Kieselgei; petroleum ether / ethyl acetate = 8: 2)

b. 3-allyl-4-Hydroxy-benzonithl

47.8 g (0.3 mol) of 4-allyloxybenzonitrile are heated to 210 ° C. for 60 minutes under a nitrogen atmosphere. After cooling, the residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (9: 1 and 1: 1). Yield: 14.7 g (31% of theory), R _f value: 0.45 (silica gel; petroleum ether / ethyl acetate = 1: 1)

c. 3-allyl-4-benzyloxy-benzonitrile

14.6 g (0.09 mol) of 3-allyl-4-hydroxy-benzonitrile and 34.6 g (0.25 mol) of potassium carbonate are stirred in 200 ml of dimethylformamide for 15 minutes. After adding 12.1 ml (0.1 mol) of benzyl bromide, the reaction mixture is stirred for 2 hours at room temperature. The reaction solution is poured onto ice water and the crystalline product is suctioned off.

Yield: 19.9 g (87% of theory),

Rf value: 0.55 (silica gel; petroleum ether / ethyl acetate = 8: 2) d. (2-benzyloxy-5-cyano) phenylacetic acid

5.0 g (20 mmol) of 3-allyl-4-benzyloxy-benzonitrile are added in portions to a solution of 17.4 g (110 mmol) of potassium permanganate in 50 ml of water and 150 ml of glacial acetic acid, the temperature rising to 55 ° C. After 1 hour at 40 ° C, the reaction mixture is diluted with ethyl acetate and suction filtered through Celite. The organic phase is separated off and evaporated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (9: 1 and 1: 1). Yield: 2.2 g (40% of theory), R _f value: 0.2 (silica gel; petroleum ether / ethyl acetate = 1: 1)

e. 4-benzylamino-2-methyl-benzoic acid tert-butyl ester

21.5 g (77 mmol) of tert-butyl 4-bromo-2-methyl-benzoate and 10.2 g (93.2 mmol) of benzylamine are dissolved in 250 ml of toluene and, after adding 38 g (116.6 mmol) of cesium carbonate, 1.8 g (7.8 mmol) ) Palladium-II-acetate and 4.9 g (7.8 mmol) of 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl heated to 100 ° C for 23 hours under a nitrogen atmosphere. After cooling, the solution is filtered and evaporated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (95: 5). Yield: 16.7 g (72% of theory), R _f value: 0.3 (silica gel; petroleum ether / ethyl acetate = 9: 1)

f. 4-amino-2-methyl-benzoic acid tert-butyl ester

13.5 g (45 mmol) of tert-butyl 4-benzylamino-2-methyl-benzoate are dissolved in 250 ml of ethanol and, after addition of 5 g of palladium on activated carbon (10%), hydrogenated with hydrogen for 45 minutes at room temperature. The catalyst is then filtered off and evaporated. The residue is triturated with petroleum ether and suction filtered.

Yield: 9.2 g (97% of theory), Rf value: 0.4 (silica gel; petroleum ether / ethyl acetate = 7: 3)

G. 2- (5-cyano-2-benzyloxy-phenyl) -N- (3-methyl-4-tert-butoxycarbonyl-phenyl) acetamide 7.5 g (28 mmol) (2-benzyloxy-5-cyano) -phenylacetic acid are dissolved in 200 ml tetrahydrofuran and 20 ml dimethylformamide and after adding 9.5 g (29 mmol) 0- (benzotriazol-1-yl) -N, N , ^N, N ^I -tetramethyluroniumtetrafluorborat, 3.4 ml (30.6 mmol) of N-methylmorpholine and 6.1 g (29.5 mmol) of 4-amino-2-methyl -benzoic acid tert-butyl ester for 7 hours at 40 ° C stirring. The solvent is distilled off, the residue is dissolved in ethyl acetate and petroleum ether is added. The precipitated product is suctioned off and dried. Yield: 8.5 g (66% of theory), R _f value: 0.33 (silica gel; petroleum ether / ethyl acetate = 7: 3)

H. 2- (5-Cyano-2-benzyloxy-phenyl) -N- (3-methyl-4-carboxy-phenyl) -acetamide 4.4 g (9.6 mmol) of 2- (5-cyano-2-benzyloxy-phenyl) -N - (3-Methyl-4-tert.butoxycarbonylphenyl) acetamide are dissolved in 50 ml dichloromethane and mixed with 10 ml trifluoroacetic acid at 20 ° C. After 4 hours at room temperature, the solvent is distilled off, the residue is triturated with water and suction filtered. Yield: 3.8 g (97% of theory), R _f value: 0.3 (silica gel; petroleum ether / ethyl acetate / glacial acetic acid = 1: 1: 0.01)

i. (L) -2- (5-Cyano-2-benzyloxyphenyl) -N- [3-methyl-4- (2-aminocarbonylpyrrolidin-1-ylcarbonyl) phenyl] acetamide

1.3 g (3.2 mmol) of 2- (5-cyano-2-benzyloxy-phenyl) -N- (3-methyl-4-carboxy-phenyl) acetamide are dissolved in 55 ml of tetrahydrofuran and after the addition of 635 mg (3.9 mmol ) N.N'-carbonyldiimidazole stirred for 1 hour at 30 ° C. 720 mg (6.4 mmol) of L-prolinamide are then added at room temperature. After 18 hours, the solvent is distilled off and the residue is chromatographed on silica gel, eluting with ethyl acetate. Yield: 0.32 g (20% of theory), Rf value: 0.15 (silica gel; ethyl acetate + 1 drop of glacial acetic acid)

k. (L) -2- (5-Carbamimidoyl-2-benzyloxyphenyl) -N- [3-methyl-4- (2-aminocarbonylpyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride

300 mg (0.6 mmol) (L) -2- (5-cyano-2-benzyloxy-phenyl) -N- [3-methyl-4- (2-aminocarbonyl-pyrrolidin-1-yl-carbonyl) phenyl ] -acetamide become saturated in 15 ml dissolved ethanolic hydrochloric acid and stirred for 17 hours at room temperature. The solvent is distilled off, the residue is dissolved in 20 ml of absolute ethanol and 600 mg (6.2 mmol) of ammonium carbonate are added. After 22 hours, the mixture is evaporated to dryness. Ethanol is added to the residue, the insoluble inorganic salts are filtered off with suction, ether is added to the filtrate and the precipitated product is filtered off with suction. Yield: 0.18 g (54% of theory), R _f value: 0.5 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

I. (L) -2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (2-aminocarbonylpyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride

Manufactured analogously to example 1.f. from (L) -2- (5-carbamimidoyl-2-benzyloxy-phenyl) -N- [3-methyl-4- (2-aminocarbonyl-pyrrolidin-1-yl-carbonyl) phenyl] acetamide hydrochloride and palladium on activated carbonΛ / hydrogen in ethanol. Yield: 74% of theory,

R _f value: 0.73 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₂ H ₂₅ N ₅ O ₄ x HCl (423.48 / 459.94) mass spectrum: (M + H) ⁺ = 424

(M-H) - = 422

Example 2

2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- {3-methyl-4- [2- (tert-butoxycarbonylamino-methyl) -piperidin-1-yl-carbonyl] phenyl} acetamide hydrochloride

a. 2- (5-Cyano-2-benzyloxy-phenyl) -N- {3-methyl-4- [2- (tert-butyloxycarbonylamino-methyl) -piperidin-1-yl-carbonyl] phenyl} acetamide

Manufactured analogously to example 1.i. from 2- (5-cyano-2-benzyloxy-phenyl) -N- (3-methyl-4-carboxy-phenyl) -acetamide and 2- (tert-butyloxycarbonylaminomethyl) piperidine / O- (benzotriazol-1-yl ) -N, N, N \ N'-tetramethyluronium. Yield: 79% of theory, Rf value: 0.3 (Kieselgei; ethyl acetate / petroleum ether = 2: 3) b. 2- (5-N-Hydroxycarbamimidoyl-2-benzyloxy-phenyl) -N- {3-methyl-4- [2- (tert-butyloxycarbonylaminomethyl) piperidin-1-ylcarbonyl1-phenyl} acetamide

A solution of 0.73 g (1.22 mmol) of 2- (5-cyano-2-benzyloxy-phenyl) -N- {3-methyl-4- [2- (tert-butyloxycarbonylaminomethyl) piperidin-1-yl-carbonyl] - phenyl} -acetamide and 175 mg (2.5 mmol) of hydroxyiamine hydrochloride in 50 ml of methanol are mixed with a solution of 1.2 g (3.7 mmol) of cesium carbonate in 1.0 ml of water and heated under reflux for 18 hours. After cooling, the crude product is purified on silica gel, eluting with dichloromethane / ethanol (98: 2) plus 2% glacial acetic acid. The uniform fractions are combined and evaporated. Yield: 0.46 g (38% of theory),

R _f value: 0.46 (silica gel, dichloromethane / ethanol = 1: 1 + 1% glacial acetic acid)

c. 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- {3-methyl-4- [2- (tert.butyloxycarbonylaminomethyl) piperidin-1-ylcarbonyl] phenyl} acetamide Prepared analogously to Example 1.f. from 2- (5-N-hydroxycarbamimidoyl-2-benzyloxyphenyl) -N- {3-methyl-4- [2- (tert.butyloxycarbonylaminomethyl) piperidin-1-ylcarbonyl] phenyl} acetamide and palladium on activated carbon (20%) in glacial acetic acid.

Yield: 25% of theory

R _f value: 0.46 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) CssHsrNsOg x HCl (523.64 / 560.09) Mass spectrum: (M + H) ⁺ = 524

Example 3

2- (5-aminomethyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1 -ylcarbonyl) phenyl] acetamide

a. 2- (5-aminomethyl-2-benzyloxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl acetamide 300 mg (0.66 mmol) 2- (5-cyano-2 -benzyloxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1 -yl-carbonyl) -phenyl] -acetamide are dissolved in 30 ml of methanolic ammonia solution and after adding 300 mg of Raney nickel with hydrogen ( 5 atmospheres spheres) at room temperature. The catalyst is filtered off, the filtrate is evaporated.

Yield: 250 mg (79% of theory),

R _f value: 0.43 (silica gel; dichloromethane / ethanol = 8: 2 + ammonia)

b. 2- (5-aminomethyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide

Manufactured analogously to example 1.f. from 2- (5-aminomethyl-2-benzyloxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenylj-acetamide and hydrogen / palladium on activated carbon in methanol.

Yield: 54% of theory,

R _f value: 0.16 (silica gel; dichloromethane / ethanol = 8: 2)

C ₂ ιH ₂₅ N ₃ O ₃ (367.45)

Mass spectrum: (MH) ^" = 366

Example 4

2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] isobutyramide hydrochloride

a. 2- (3-cyano-phenyl) -2-methyl-propionic acid methyl ester

A solution of 2.5 g (15.4 mmol) of 3-cyanophenylacetic acid in 5 ml of dimethyl sulfoxide is added dropwise at 5 ° C. to a suspension of 1.9 g (48 mmol) of sodium hydride in 100 ml of dimethyl sulfoxide. After 10 minutes, 3 ml (47.7 mmol) of methyl iodide are added. After 1 hour at room temperature, the reaction solution is poured onto ice water, adjusted to pH 5 with glacial acetic acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The crude product is chromatographed on silica gel, eluting with dichloromethane. Yield: 2.4 g (77% of theory),

Rf value: 0.8 (silica gel; petroleum ether / ethyl acetate = 1: 1)

b. 2- (3-cyano-phenyl) -2-methyl-propionic acid 2.4 g (11.5 mmol) of methyl 2- (3-cyano-phenyl) -2-methyl-propionate are dissolved in 16 ml of tetrahydrofuran, a solution of 1 g (23.8 mmol) of lithium hydroxide in 20 ml of water is added and the mixture is stirred for 20 hours Room temperature stirred. The tetrahydrofuran is distilled off, the residue is adjusted to pH 4 with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.

Yield: 1.5 g (66% of theory), R _f value: 0.3 (silica gel; petroleum ether / ethyl acetate = 1: 1)

c. 2- (3-Cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -isobutyramide Prepared as in Example 1.g. from 2- (3-cyano-phenyl) -2-methyl-propionic acid, O- (benzotriazole-ly -NNN'.N'-tetramethyluronium tetrafluoroborate, N-methylmorpholine and 3-methyl-4- (pyrrolidin-1-yl-carbonyl ) -aniline in dimethylformamide, yield: 82% of theory, R _f value: 0.35 (silica gel; dichloromethane / ethanol = 19: 1)

d. 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] isobutyramide hydrochloride

Manufactured analogously to example 1.k. from 2- (3-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] isobutyramide and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 54% of theory,

R _f value: 0.35 (silica gel; dichloromethane / ethanol / glacial acetic acid = 8: 2: 0.2) C ₂₃ H ₂₈ N ₄ O ₂ x HCl (392.51 / 428.97) mass spectrum: (M + H) ⁺ = 393

Example 5

2- (5-carbamimidoyl-2-ethoxycarbonylmethyloxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl1-acetamide hydrochloride ^•

a. 2- (5-Cyano-2-ethoxycarbonylmethyloxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide 0.3 g (0.8 mmol) of 2- (5-cyano-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide are dissolved in 20 ml of acetone dissolved and after addition of 276 mg (2 mmol) of potassium carbonate stirred for 15 minutes at room temperature. Then 0.1 ml (0.9 mmol) of ethyl bromoacetate are added. After 1 hour at 40 ° C., the reaction solution is stirred in ice water and extracted with ethyl acetate. The combined organic extracts are dried, evaporated and crystallized with ether / petroleum ether. Yield: 0.22 g (59% of theory), R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1)

b. 2- (5-carbamimidoyl-2-ethoxycarbonylmethyloxy-phenyl) -N- [3-methyl-4- (pyrrolidin

1-yl-carbonyl) -phenyl] -acetamide hydrochlohd

Manufactured analogously to example 1.k. from 2- (5-cyano-2-ethoxycarbonylmethyloxy-phenyl) - N- [3-methyl-4- (pyrrolidin-1 -yl-carbonyl) phenyl] acetamide and hydrochloric acid / ammonium 5 carbonate in ethanol.

Yield: 73% of theory,

R _f value: 0.35 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

C ₂₅ H ₃ oN ₄ O ₅ x HCI (466.54 / 503.00)

Mass spectrum: (M + H) ⁺ = 467 0 (M + CIV = 501/03 (CI)

Example 6

2- (5-Carbamimidoyl-2-carboxymethyloxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride 5 0.12 g (0.24 mmol) 2- (5 Carbamimidoyl-2-ethoxycarbonylmethyloxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride are stirred in 10 ml of 6 molar hydrochloric acid for 16 hours at room temperature. The solvent is then distilled off, acetone and ether are added to the residue and the mixture is evaporated to dryness again. o Yield: 42 mg (37% of theory),

Rf value: 0.45 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₃ H26N ₄ O ₅ x HCl (438.49 / 474.95) Mass spectrum: (M + H) ⁺ = 439

(M-HV = 437

Example 7

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (piperidin-3-yl-carbonyl) phenylj-acetamide

a. 3-Methyl-4- (pyridin-3-yl-carbonyl) -aniline 14.9 g (111.6 mmol) aluminum chloride, 4.2 g (27.8 mmol) 3-methylacetanilide and 9.9 g (55.8 mmol) nicotinoyl chloride hydrochloride are 2 hours at 100 ° C stirred. The reaction mixture is stirred while hot in ice water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is stirred with 50 ml of 6 molar hydrochloric acid at 100 ° C. for 1.5 hours. It is then cooled, adjusted to pH 8 with ammonia and extracted with dichloromethane. The organic phase is evaporated and purified on silica gel, eluting with dichloromethane / methanol (1-4%). Yield: 1.4 g (24% of theory), R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1)

b. 2- (5-Cyano-2-benzyloxyphenyl) -N- [3-methyl-4- (pyridin-3-ylcarbonyl) phenyl] acetamide

Manufactured analogously to example 1.g. from 3-methyl-4- (pyridin-3-yl-carbonyl) aniline, (2-benzyloxy-5-cyanophenyl) acetic acid, O- (benzotriazol-1-yl) -N, N, N ', N ^, -tetra-methyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 56% of theory, Rf value: 0.8 (silica gel; ethyl acetate / ethanol = 9: 1)

c. 2- (5-CarbamimidoyI-2-benzyloxy-phenyI) -N- [3-methyl-4- (pyridin-3-yl-carbonyI) phenyl-acetamide

Manufactured analogously to example 1.k. from 2- (5-cyano-2-benzyloxy-phenyl) -N- [3-methyl-4- (pyridin-3-yl-carbonyl) phenyl] acetamide and hydrochloric acid / ammonium carbonate in ethanol. Yield: 44% of theory,

R _f value: 0.2 (silica gel; dichloromethane / ethanol / glacial acetic acid = 8: 2: 0.2)

d. 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (piperidin-3-ylcarbonyl) phenyl] acetamide

0.32 g (0.6 mmol) of 2- (5-carbamimidoyl-2-benzyloxy-phenyl) -N- [3-methyl-4- (pyridin-3-yl-carbonyl) -phenyl] -acetamide are dissolved in 75 ml of methanol, with 0.5 ml conc.

Ammonia adjusted to pH 8 and after adding 0.15 g palladium on activated carbon

(10%) hydrogenated with hydrogen for 70 minutes at room temperature. The catalyst is then filtered off and evaporated. The residue is mixed with ethyl acetate / ether /

Petroleum ether (1: 1: 1) stirred and the crystalline product suction filtered.

Yield: 0.13 g (55% of theory),

R _f value: 0.7 (reversed phase RP 8; 5% sodium chloride solution / methanol = 1: 1)

C ₂₂ H _2δ N ₄ O ₃ (394.47) mass spectrum: (M + H) ⁺ = 395

(M-H) - = 393

The following compounds are prepared analogously to Example 7:

(1) 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- (3-methyl-4-benzoyl-phenyl) -acetamide hydrochloride

Yield: 12% of theory,

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 7: 3 + 1% glacial acetic acid) C ₂₃ H ₂ ιN ₃ O ₃ x HCl (387.44 / 423.90) mass spectrum: (M + H) ⁺ = 388

(M-H) - = 386

(2) 2- (5-carbamimidoyl-2-hydroxyphenyI) -N- [3-methyl-4- (1-hydroxy-1-phenylmethyphenyl acetamide hydrochloride Yield: 23% of theory,

Rf value: 0.35 (silica gel; dichloromethane / ethanol = 7: 3 + 1% glacial acetic acid) C23H ₂₃ N ₃ O ₃ x HCl (389.46 / 425.92) mass spectrum: (M + H) ⁺ = 390 (MH) ^" = 388

(3) 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- {4- [1 - (3-carbamimidoyI-phenyl) -1-hydroxy-methyl] -3-methyl-phenyl} -acetamide dihydrochloride

5 Yield: 37% of theory,

R _f value: 0.25 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₄ H ₂₅ N ₅ O ₃ x 2 HCl (431.50 / 504.42) mass spectrum: (M + H) ⁺ = 432

o (4) 2- (3-carbamidoylphenyl) -N- [3-methyl-4- (pyridin-3-ylcarbonyl) ph amide hydrochloride

Yield: 48% of theory,

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 8: 2 + 1% glacial acetic acid) C ₂ H ₂₄ N ₄ O ₂ x HCl (400.48 / 436.94) 5 mass spectrum: (M + H) ⁺ = 401

(M + Cl) - = 435/37 (CI)

Example 8

0 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenylj-isobutyramide hydrochloride

a. 3- (1, 1-dimethyl-allyl) -4-hydroxy-benzonitrile

25 g (0.13 mol) of 4- (3-methyl-but-2-enyloxy) benzonitrile are heated under reflux in 250 ml of dimethyl 5-formamide for 90 hours. The solvent is distilled off and the

Residue taken up in ethyl acetate / water. The organic phase is dried and evaporated. The residue is dissolved in toluene and extracted with 2 molar sodium hydroxide solution. The aqueous phase is filtered through activated carbon and acidified with glacial acetic acid. The precipitate formed is suction filtered and dried. o Yield: 1.8 g (7% of theory),

Rf value: 0.53 (silica gel; petroleum ether / ethyl acetate = 7: 3)

b. 4-benzyloxy-3- (1, 1-dimethyl-allyl) benzonitrile Manufactured analogously to example 1.c. from 3- (1, 1-dimethyl-allyl) -4-hydroxy-benzonitrile,

Benzyl bromide and potassium carbonate in dimethylformamide.

Yield: 93% of theory,

R _f value: 0.70 (silica gel; petroleum ether / ethyl acetate = 7: 3)

c. 2- (2-benzyloxy-5-cyano-phenyl) -2-methyl-propionic acid

2.2 g (7.9 mmol) of 4-benzyloxy-3- (1,1-dimethyl-allyl) benzonitrile are dissolved in 60 ml of acetonitrile and, after adding a solution of 11.9 g (55.6 mmol) of sodium metaperiodate and 50 mg (0.24 mmol ) Ruthenium (II!) - chloride in 80 ml of water stirred at 45 ° C for 4.5 hours. Then it is diluted with ethyl acetate, the organic

Phase is separated off and evaporated. The residue is dissolved in dichloromethane and extracted with 1 molar sodium hydroxide solution. The aqueous phase is filtered through activated carbon, the filtrate is poured onto 400 ml of 6 molar hydrochloric acid and 200 g of ice. The precipitate is filtered off and dried. Yield: 0.95 g (41% of theory),

R _f value: 0.22 (silica gel; petroleum ether / ethyl acetate / glacial acetic acid = 7: 3: 0.1)

d. 2- (2-benzyloxy-5-cyano-phenyl) -2-methyl-propionic acid

510 mg (1.73 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -2-methyl-propionic acid are dissolved in 10 ml of dichloromethane and after adding 0.38 ml (5.21 mmol) of thionyl chloride and 0.1 ml of dimethylformamide for 2.5 hours heated to 50 ° C. The reaction mixture is then evaporated and reacted further without purification. Yield: 530 mg (98% of theory).

e. 2- (2-Benzyloxy-5-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1 -yl-carbonyl) phenyl] isobutyramide

A solution of 390 mg (1.9 mmol) of 3-methyl-4- (pyrrolidin-1-yl-carbonyl) aniline in 50 ml of tetrahydrofuran is mixed with 0.7 ml (5.18 mmol) of triethylamine. A solution of 530 mg (1.69 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -2-methyl-propionic acid chloride in 20 ml of tetrahydrofuran is then added dropwise. After 14

The solvent is evaporated for hours at room temperature and the residue is purified on silica gel, eluting with ethyl acetate / petroleum ether (4: 1). Yield: 410 mg (50% of theory), RrValue: 0.38 (silica gel; ethyl acetate)

f. 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] isobutyramide hydrochloride Prepared as in Example 1.k. from 2- (2-benzyioxy-5-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] isobutyramide and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction as in Example 1.1 , with hydrogen / palladium on activated carbon in methanol. Yield: 77% of theory, Rr value: 0.5 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₃ H ₂₈ N ₄ O ₃ x HCl (408.50 / 444.96) mass spectrum: (M + H ) ⁺ = 409

(MH) ^' = 407

Example 9

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride

a. 3-chloro-4- (pyrrolidin-1 -ylcarbonyl) nitrobenzene

Manufactured analogously to example 1.g. from 2-chloro-4-nitrobenzoic acid, O- (benzotriazol-1-yl) -N, N, N'-N'-tetramethyluronium fluoroborate, N-ethyl-diisopropylamine and pyrrolidine in tetrahydrofuran / water 9: 1 , Yield: 72% of theory, Rf value: 0.65 (silica gel; dichloromethane / ethanol = 95: 5)

b. 3-chloro-4- (pyrrolidin-1 -yl-carbonyl) aniline

Manufactured analogously to example 1.f. from 3-chloro-4- (pyrrolidin-1-yl-carbonyl) nitrophenol and hydrogen / palladium on activated carbon in methanol / dichloromethane (1: 1). Yield: 100% of theory,

RrValue: 0.42 (silica gel; dichloromethane / ethanol = 95: 5) c. 2- (2-Benzyloxy-5-cyano-phenyl) -N-r3-chloro-4- (pyrrolidin-1-yl-carbonyl) -phenyl1-acetamide

Manufactured analogously to example 8.e. from 3-chloro-4- (pyrrolidin-1-yl-carbonyl) aniline, (2-benzyloxy-5-cyanophenyl) acetic acid chloride and triethylamine in tetrahydrofuran. Yield: 64% of theory,

RrValue: 0.75 (silica gel; dichloromethane / ethanol = 95: 5)

d. 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide hydrochloride Prepared analogously to Example 1.k. from 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction as in Example 1.1 , with hydrogen / palladium on activated carbon in methanol. Yield: 50% of theory, R _f value: 0.5 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₀ H ₂ ιClN ₄ O ₃ x HCl (400.87 / 437.33) Mass spectrum: ( M + H) ⁺ = 401

(MH) ^" = 399

(M + CIV = 435/37 (CI)

Example 10

2- (3-Carbamimidoylphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -2-aminoacetamide dihydrochloride

a. 5- (3-bromophenyl) -imidazolidin-2,4-dione

A mixture of 68.0 g (0.58 mol) of 3-bromobenzaldehyde, 43.0 g (0.66 mol) of potassium cyanide and 259 g (2.7 mol) of ammonium carbonate are suspended in 1 liter of water and 1 liter of ethanol and stirred at 60 ° C. for 1 hour. It is then cooled and concentrated with 665 ml. Hydrochloric acid carefully adjusted to pH 4. The resulting suspension is cooled to 5 ° C, suction filtered, washed with water and dried. Yield: 100.6 g (68% of theory), Rr value: 0.5 (silica gel; dichloromethane / ethanol = 9.5: 0.5) b. Amino (3-bromophenyl) -acetic acid

^• 100 g (0:39 mole) of 5- (3-bromophenyl) -imidazolidin-2,4-dione are suspended in 170 ml of water and added dropwise over 25 minutes with 295 ml (5.4 mol) of conc. Added sulfuric acid, the temperature rising to 85 ° C. The reaction mixture is then heated to 150 ° C. for 6.5 h. After cooling, 10 g of activated carbon are added and suction filtered. The solution is poured onto ice water, with about 650 ml of conc. Ammonia adjusted to pH 6.5 and the precipitate formed is suction filtered. Yield: 83.6 g (93% of theory),

RrValue: 0.6 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

c. Amino (3-bromophenyl) -essiqsäureethylester-hvdrochlorid

Prepared analogously to Example 6 from amino (3-bromophenyl) acetic acid and 6 molar hydrochloric acid in ethanol.

Yield: 95% of theory,

RrValue: 0.45 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

d. (3-bromophenyl) tert-butoxycarbonylamino-acetic acid 12.1 g (41 mmol) of amino- (3-bromophenyl) -acetic acid hydrochloride are dissolved in 90.4 ml (90.4 mmol) of 1 molar sodium hydroxide solution. After adding a solution of 9.0 g (41 mmol) of di-tert-butyl dicarbonate in 100 ml of tetrahydrofuran, the reaction mixture is stirred at room temperature for 18 hours. The mixture is then extracted with ether. The aqueous phase is adjusted to pH 1 with 1 molar hydrochloric acid and extracted with ether. The combined organic extracts are dried and evaporated.

Yield: 12.0 g (89% of theory),

RrValue: 0.15 (silica gel; dichloromethane / ethanol = 95: 5)

e. (3-bromophenyl) acetic acid benzyl ester -tert.butoxycarbonylamino-

Manufactured analogously to example 1.c. from (3-bromophenyl) -tert.butoxycarbonylamino-acetic acid, benzyl bromide and potassium carbonate in dimethylformamide. Yield: 85% of theory RrValue: 0.24 (silica gel; petroleum ether / ethyl acetate = 9: 1)

f. tert-Butoxycarbonylamino- (3-cyanophenyl) -acetic acid benzyl ester 11.4 g (27 mmol) (3-bromophenyl) -tert.butoxycarbonylamino-acetic acid benzyl ester are dissolved in 100 ml dimethylformamide and after adding 4.8 g (53.6 mmol) copper (I) -cyanide and 0.7 g (0.6 mmol) of tetrakis-triphenylphosphine-palladium- (O) stirred at 145 ° C for 8 hours. The warm suspension is suctioned off and the mother liquor is distributed in sodium chloride solution / ethyl acetate. The aqueous phase is extracted three times with ethyl acetate, the combined organic extracts are washed with 0 sodium hydroxide solution, dried, evaporated and chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (15-25%). Yield: 3.7 g (37% of theory), Rr value: 0.25 (silica gel; dichloromethane / ethanol = 4: 1)

5 g. tert-butoxycarbonylamino- (3-cyanophenyl) acetic acid

Manufactured analogously to example 1.f. from tert-butoxycarbonylamino- (3-cyanophenyl) acetic acid benzyl ester and palladium on activated carbon / hydrogen in methanol. Yield: 100% of theory, Rr value: 0.2 (silica gel; dichloromethane / ethanol = 95: 5) 0 h. 2- (3-Cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -2- (tert.butoxycarbonylamino) acetamide

0.7 g (2.5 mmol) of tert-butoxycarbonylamino- (3-cyanophenyl) acetic acid, 0.5 g (2.5 mmol) of 3-methyl-4- (pyrrolidin-1-yl-carbonyl) aniline and 1.7 ml (15.2 mmol) of N -Methyl- 5 morpholine are dissolved in 30 ml dichloromethane and at - 10 ° C with 3.0 ml (5 mmol)

Propanephosphonic acid cyclo-anhydride added. The reaction mixture is stirred for 1 h at -10 ° C and 48 hours at room temperature. The solvent is distilled off, the residue is taken up in ethyl acetate, washed with sodium hydroxide solution and water. The organic phases are dried and evaporated. o yield: 0.8 g (64% of theory),

RrValue: 0.3 (silica gel; dichloromethane / ethanol = 95: 5) Mass spectrum: (M + H) ⁺ = 463

(MH) ^" = 461

i. 2- (3-carbamimidoylphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -2-amino-acetamide dihydrochloride

Manufactured analogously to example 1.k. from 2- (3-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -2- (tert-butoxycarbonylamino) -acetamide and hydrochloric acid / ammonium carbonate in ethanol. Yield: 100% of theory, R _f value: 0.2 (silica gel; dichloromethane / ethanol = 4: 1 + 5% ammonia) C21H25N ₅ O2 x 2 HCl (379.46 / 452.39) mass spectrum: (M + H) ⁺ = 380

The following connection is established analogously to Example 10:

(1) 2- (3-carbamimidoylphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -2-

(Acetylamino) -acetamide hvdrochlorid

Yield: 96% of theory,

RrValue: 0.59 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₃ H2 ₇ N ₅ O ₃ x HCl (421, 5 / 457.95)

Mass spectrum: (M + H) ⁺ = 422

(MH) ^" = 420

Example 11

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenyl-acetamide hydrochloride

a. 4-Acetylamino-2-methyl-benzenesulfonic acid chloride 5.0 g (33.5 mmol) of 3-methyl-phenylacetamide are added in portions to 11.1 ml (167 mmol) of chlorosulfonic acid at room temperature. The reaction mixture is heated to 60 ° C. for 2 hours, cooled, poured onto ice water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. Yield: 7.0 g (85% of theory),

RrValue: 0.2 (silica gel; dichloromethane / ethanol = 9: 1)

b. N- [3-Methyl-4- (pyrrolidin-1 -yl-sulfonyl) -phenyl1-acetamide 7.0 g (28.4 mmol) of 4-acetylamino-2-methyl-benzenesulfonic acid chloride are dissolved in 70 ml of water and 60 ml of 0.5 molar sodium hydroxide solution suspended and mixed at 0 ° C with a solution of 2.5 ml (29.8 mmol) of pyrrolidine in 60 ml of acetone. After 12 hours at room temperature, the resulting solution is acidified with 2 molar hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.

Yield: 7.2 g (89% of theory),

RrValue: 0.55 (silica gel; dichloromethane / ethanol = 9: 1)

c. 3-Methyl-4- (pyrrolidin-1-yl-sulfonyl) -aniline 7.2 g (25.3 mmol) of N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) -phenyl] -acetamide are dissolved in 10 ml Dissolved ethanol and stirred after adding 70 ml of 6 molar hydrochloric acid at 40 ° C for 11 hours. The mixture is then extracted several times with dichloromethane, the combined organic extracts are washed with sodium bicarbonate solution, dried and evaporated. Yield: 3.8 g (63% of theory),

RrValue: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)

d. 2- (2-Benzyloxy-5-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenyl) acetamide Prepared analogously to Example 8.e. from 3-methyl-4- (pyrrolidin-1-yl-sulfonyl) aniline, 2-benzyloxy-5-cyano-phenylacetic acid chloride and triethylamine in tetrahydrofuran. Yield: 81% of theory, Rr value: 0.79 (silica gel; dichloromethane / ethanol = 9: 1)

e. 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide hydrochloride

Manufactured analogously to example 1.k. from 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenyl) acetamide and hydrochloric acid / ammonium carbonate in Ethanol and subsequent reaction with hydrogen / palladium on activated carbon in methanol as in Example 1.1. Yield: 56% of theory,

RrValue: 0.57 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂₀ H ₂₄ N ₄ O ₄ S x HCl (416.50 / 452.97) Mass spectrum: (M + H) ⁺ = 417

(M) ^" = 415

(M + Cl) - = 451/53 (CI)

Example 12

2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyrj-propionamide hydrochloride

a. (2-benzyloxy-5-cyano-phenyl) -acetic acid methyl ester

Manufactured analogously to example 8.d. from 2-benzyloxy-5-cyano-phenylacetic acid and thionyl chloride in dichloromethane and subsequent reaction with methanol. Yield: 85% of theory, Rr value: 0.7 (silica gel; ethyl acetate / petroleum ether = 1: 1)

b. 2- (2-benzyloxy-5-cyano-phenyl) -propionic acid methyl ester

Manufactured analogously to example 4.a. from 2-benzyloxy-5-cyano-phenylacetic acid methyl ester, sodium hydride and methyl iodide in tetrahydrofuran. Yield: 78% of theory, R _f value: 0.53 (silica gel; dichloromethane / ethyl acetate = 7: 3)

c. 2- (2-benzyloxy-5-cyano-phenyl) -propionic acid

Manufactured analogously to example 4.b. from 2- (2-benzyloxy-5-cyano-phenyl) propionic acid methyl ester and sodium hydroxide solution in methanol. Yield: 93% of theory,

RrValue: 0.22 (silica gel; petroleum ether / ethyl acetate / glacial acetic acid = 7: 3: 0.1)

d. 2- (2-benzyloxy-5-cyano-phenyl) propionic acid chloride Manufactured analogously to example 8.d. from 2- (2-benzyloxy-5-cyano-phenyl) propionic acid and thionyl chloride in dichloromethane. Yield: 96% of theory

e. 2- (2-Benzyloxy-5-cyano-phenyl) -N- [3-methyl-4 - (- pyrrolidin-1 -yl-carbonyl) phenyl] propionamide

Manufactured analogously to example 8.e. from 3-methyl-4- (pyrrolidin-1-yl-carbonyl) aniline, 2- (2-benzyloxy-5-cyano-phenyl) propionic acid chloride and triethylamine in tetrahydrofuran. Yield: 97% of theory,

RrValue: 0.4 (silica gel; ethyl acetate)

f. 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenylj-propionamide hydrochloride Prepared analogously to Example 1.k. from 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] propionamide and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction with hydrogen / Palladium on activated carbon in methanol as in Example 1.1. Yield: 62% of theory, R _f value: 0.45 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

C ₂ 2H ₂ 6N ₄ O ₃ x HCl (394.48 / 430.95) mass spectrum: (M + H) ⁺ = 395

(MH) ^" = 393

Example 13

2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) ρhenyl] acetamide hydrochloride

a. 3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -nitrobenzene

Manufactured analogously to example 1.g. from 4-Nϊtrc 2-trifluoromethyl-benzoic acid, pyrrolidine, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 69% of theory,

RrValue: 0.6 (silica gel; dichloromethane / ethanol = 9: 1)

b. 3-Trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -aniline 1.4 g (4 mmol) of 3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -nitrobenzene are dissolved in 25 ml of ethyl acetate and 25 ml of methanol and after addition of 0.5 g palladium on activated carbon (10%) hydrogenated with hydrogen for 45 minutes at room temperature. The catalyst is filtered off and the solution is evaporated. The crude product is recrystallized from ethyl acetate. Yield: 0.6 g (60% of theory),

RrValue: 0.45 (silica gel; dichloromethane / ethanol = 9: 1)

c. 2- (2-Benzyloxy-5-cyano-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyI) - phenylj-acetamide Prepared as in Example 1.g. from 3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) aniline, 2-benzyloxy-5-cyano-phenylacetic acid, O- (benzotriazol-1-yI) -N, N, N ', N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 32% of theory, Rr value: 0.5 (silica gel; dichloromethane / ethanol = 9: 1)

d. 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride

Manufactured analogously to example 1.k. from 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1 -yl-carbonyl) -phenyl] -acetamide and hydrochloric acid / ammonium carbonate in ethanol and subsequent Reaction with hydrogen / palladium

Activated carbon in methanol as in Example 1.1.

Yield: 35% of theory,

RrValue: 0.25 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

C2iH ₂ ιF ₃ N ₄ θ ₃ x HCl (434.42 / 470.89) mass spectrum: (M + H) ⁺ = 435

(MH) ^" = 433

The following connection is made as in Example 13: (1) 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [4- (pyrrolidin-1-yl-carbonyl) -3-trifluoromethyl-phenyl] -propionamide hydrochloride

Yield: 50% of theory,

RrValue: 0.24 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3)

C ₂₂ H ₂₃ F ₃ N ₄ O ₃ x HCI (448.45 / 484.92)

Mass spectrum: (M + H) ⁺ = 449

(M + H) - = 447

(M + Cl) - = 483/85 (CI)

Example 14

2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide hyd rochloride

a. 3-bromo-4- (pyrrolidin-1-yl-carbonyl) -nitrobenzene

Manufactured analogously to example 1.g. from 2-bromo-4-nitro-benzoic acid, pyrrolidine, O- (benzotriazol-1-yl) -N, N, N \ N: etramethyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 77% of theory,

RrValue: 0.25 (silica gel; petroleum ether / ethyl acetate = 1: 1)

b. 3-bromo-4- (pyrrolidin-1-ylcarbonyl) aniline

Manufactured analogously to example 13.b. from 3-bromo-4- (pyrrolidin-1-yl-carbonyl) nitrobenzene and hydrogen / palladium on activated carbon in ethyl acetate. Yield: 28% of theory, Rr value: 0.33 (silica gel; ethyl acetate / petroleum ether = 9: 1 + 1 drop of ammonia)

c. 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenyl] acetamide

Manufactured analogously to example 1.g. from 3-bromo-4- (pyrrolidin-1-yl-carbonyl) aniline, 2-benzyloxy-5-cyano-phenylacetic acid, O- (benzotriazol-1-yI) -N, N, N ', N'-tetramethyl uronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 53% of theory, Rr value: 0.4 (silica gel; ethyl acetate)

d. 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenyl-acetamide hydrochloride

Manufactured analogously to example 1.k. from 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction with hydrogen / Palladium on activated carbon in methanol as in Example 1.1. Yield: 46% of theory,

RrValue: 0.5 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂ oH ₂ iBrN ₄ O ₃ x HCl (445.32 / 481.79) Mass spectrum: (M + H) ⁺ = 445/47 ( Br)

The following connection is made as in Example 14:

(1) 2- (5-Carbamimidoyl-2-hydroxyphenyl) -N- [3-bromo-4- (pyrrolidin-1-ylcarbonyl) phenylj-propionamide hydrochloride

Yield: 20% of theory, R _f value: 0.4 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂ ιH ₂ 3BrN ₄ O ₃ x HCl (459.35 / 495.81) Mass spectrum: ( M + H) ⁺ = 459/61 (Br)

Example 15

2- (5-Carbamidoyl-2-hydroxyphenyl) -N- [3-methoxy-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide hydrochloride

a. 3-methoxy-4- (pyrrolidin-1 -yl-carbonyl) -nitrobenzene Prepared analogously to Example 1.g. from 2-methoxy-4-nitro-benzoic acid, pyrrolidine, O- (benzotriazol-1-yl) -N, N, N \ N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 70% of theory, RrValue: 0.45 (silica gel; dichloromethane / ethanol = 19: 1)

b. 3-Methpxy-4- (pyrrolidin-1 -yl-carbonyl) aniline

Manufactured analogously to example 13.b. from 3-methoxy-4- (pyrrolidin-1-yl-carbonyl) nitrobenzene and hydrogen / palladium on activated carbon in methanol. Yield: 75% of theory, Rr value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1)

c. 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenyl] acetamide

Manufactured analogously to example 1.g. from 3-methoxy-4- (pyrrolidin-1-yl-carbonyl) -aniIin, 2-benzyloxy-5-cyano-phenylacetic acid, O- (benzotriazol-1-yl) -N, N, ^N, N'-tetramethyl uronium tetrafluoroborate and N-methylmorpholine in dimethylformamide. Yield: 22% of theory, R _f value: 0.45 (silica gel; dichloromethane / ethanol = 19: 1)

d. 2- (5-Carbamidoyl-2-hydroxyphenyl) -N- [3-methoxy-4- (pyrrolidin-1-ylcarbonyl) phenylj-acetamide hydrochloride

Manufactured analogously to example 1.k. from 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenyl] acetamide and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction with hydrogen / Palladium on activated carbon in methanol as in Example 1.1. Yield: 22% of theory,

RrValue: 0.25 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 2: 3) C ₂ ιH ₂₄ N ₄ O ₄ x HCl (396.45 / 432.92)

Mass spectrum: (M + H) ⁺ = 397

(MH) ^" = 395

(M + Cl) - = 431/33 (CI) Example 16

2- (3-Carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide hydrochloride

a. 2- (3-Cyano-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide

A solution of 0.4 g (1.0 mmol) of 2- (3-cyano-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -acetamide in 4 ml of dimethyl sulfoxide is porous at room temperature - 0.2 g (2.0 mmol) of potassium tert-butoxide were added and stirred for 15 minutes. After adding 0.1 ml of 1.0 mmol) of benzyl bromide, the reaction mixture is stirred for a further 2 hours at room temperature and mixed with ice water. The precipitate formed is filtered off, dried and purified on silica gel, eluting with petroleum ether / ethyl acetate (1/0 to 0/1). The uniform fractions are combined and evaporated.

Yield: 0.1 g (22% of theory)

RrValue: 0.46 (silica gel; ethyl acetate + 1% ammonia)

b. 2- (3-Carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide hydrochloride

Manufactured analogously to example 1.k. from 2- (3-cyano-phenyl) -N- [3-bromo-4- (pyrrolidin-1-ylcarbonyl) phenyl-3-phenyl-propionamide and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 81% of theory, R _f value: 0.36 (reversed phase RP 8; 5% sodium chloride solution / methanol = 1: 2) C27H ₂₇ BrN ₄ θ2 x HCl (519.36 / 555.91) Mass spectrum: (M + H ) ⁺ = 519/21 (Br)

(MH) ^' = 517/19 (Br)

The following is prepared as in Example 16:

(1) 2- (3-Carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenylj- 3- (pyridin-4-yl) -propionamide hydrochloride Yield: 95% of theory,

RrValue: 0.48 (Reversed Phase RP 8; 5% sodium chloride solution / methanol = 1: 2) C ₂₆ H ₂₆ BrN ₅ θ ₂ x HCl (520.36 / 556.89) Mass spectrum: (M + H) ⁺ = 520/22 ( Br) (M + Cl) ^" = 554/56/58 (CI, Br)

(2) 2- (3-carbamimidoylphenyl) -N- [3-bromo-4- (pyrrolidin-1-ylcarbonyl) phenyl] -

3-f4 (ethoxycarbonyl) phenyl] propionamide hydrochloride

Yield: 93% of theory, R _f value: 0.3 (silica gel; methylene chloride / methanol = 4: 1 + 1% ammonia) C ₃₀ H ₃ ιBrN ₄ O ₄ x HCl (591.51 / 627.97) mass spectrum: (M + H) ⁺ = 591/93 (Br)

(M + Cl) ^" = 625/27 (CI.Br)

Example 17

Dry ampoule with 75 mg of active ingredient per 10 ml

Composition:

Active ingredient 75.0 mg

Mannitol 50.0 mg

Water for injections ad 10.0 ml

production:

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

Example 18

Dry ampoule with 35 mg of active ingredient per 2 ml Composition:

Active ingredient. 35.0 mg

Mannitol 100.0 mg

Water for injections ad 2.0 ml

production:

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

Example 19

Tablet with 50 mg of active ingredient F

Composition:

(1) Active ingredient 50.0 mg

(2) milk sugar 98.0 mg

(3) corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg 215.0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm. Example 20

Tablet with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg

(5) Magnesium stearate 4.0 mg

600.0 mg

Preparation: (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.

Example 21

Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg

(3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate 2.0 mg 160.0 mg production:

(1) is triturated with (3). This rubbing becomes more intense with the mixture of (2) and (4). Mixture added.

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

Example 22

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg (2) Dried corn starch 46.0 mg

(3) Milk sugar powdered 30.0 mg

(4) Magnesium stearate 4.0 mg

430.0 mg

production:

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

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

Example 23

Suppositories with 100 mg of active ingredient 1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

Polyethylene glycol (M.G. 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg

2000.0 mg

production:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. The milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Claims

claims

1. Carboxamides of the general formula

in the Ri a C ₃ . _7- Cycloalkyl-carbonyl group, wherein

the methylene group in the 3- or 4-position in a C ₅ . _7- Cycloalkyl-carbonyl group can be replaced by an -NH group in which

the hydrogen atom of the -NH group can be replaced by a Cι- ₃ alkyl, d- ₃ alkyl carbonyl, phenylcarbonyl or phenylsulfonyl group,

a terminally substituted in the alkyl part optionally by an amino, Cι- ₃ alkylamino or di- (Cι- ₃ alkyl) amino group Cι- ₆ alkylcarbonyl group,

a group of the formula R _f R _g N- (CH ₂ ) _m - (R _h ) N-CO-, in which

R _f , R _g and R _h independently of one another each represent a hydrogen atom or a d- ₃ -alkyl group and m is one of the numbers 2, 3, 4, 5 or 6,

a phenylcarbonyl, naphthylcarbonyl or heteroarylcarbonyl group,

a C 1 -C ₃ -alkyl group monosubstituted by a hydroxyl group or terminally disubstituted by a phenyl and a hydroxyl group, where the phenyl substituent can be substituted by an amidino group optionally substituted by one or two d- ₃ alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ₃ alkyl or d ₃ alkoxy group,

one by an amino-C-3-alkyl-, C-ι-3-alkylamino-Cι-3-alkyl, di- (C _{1, 3} -alkyl) - amino-C-ι- ₃ -alkyl, aminocarbonyl -, D_3 ~ alkylamino-carbonyl or di- (. ₁ C ₃ alkyl) - aminocarbonyl group substituted 4- to 7-membered Cycloalkylenimino-carbonyl or Cycloalkylenimino-sulfonyl group,

a C ₃ - ₇ cycloalkylamino group, which on the nitrogen atom by a Cι- ₃ -alkyl-amino-Cι- ₃ -AIkyl- or di- (Cι. ₃ alkyl) amino-C ₁ . ₃ -alkyl group is substituted,

or also, provided that R _{2 is} a trifluoromethyl group and / or R _{5 is} an amino-Cι- ₃ -alkyl-, d- ₃ -AIkylamino-Cι- ₃ -alkyl- or di- (Cι-3-alkyl) amino-Cι- _3rd -AIkylgruppe or / and R _{6 is} a carboxy -CC. ₃ -alkoxy- or Cι- ₄ -alkoxy-carbonyl-Cι- ₃ -alkoxygruppe or / and at least one of the radicals Rs or Rg has a different meaning than that of the hydrogen atom, an unsubstituted 4- to 7-membered cycloalkyleneimino-carbonyl or Cycloalkyleniminosulfonyl group, a C ₃ . _7- Cycloalkylamino- or N- (Cι- ₃ alkyl) -C ₃ . cycloalkylamino,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C ₃ alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a hydroxy or C ₃ alkoxy group,

R _{3 is} a hydrogen atom or a C ₃ alkyl group,

R is a hydrogen atom or a C ₃ alkyl group which may be substituted by a carboxy group or a group which can be converted into a carboxy group in vivo,

Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R ₇ , where R _{5 is} a cyano group, an amidino group optionally substituted by one or two C ₃ alkyl groups, an amino C ₃ alkyl, C ₃ alkyl alkyl C ₃ alkyl or di (C 1. ₃ -alkyl) amino -CC. ₃ -alkyl group,

R _{6 is} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C ₁ - ₃ - alkyl, hydroxy, hydroxy-Cι- ₃ -alkyl, Cι- ₃ alkoxy, Cι- ₃ alkoxy -Cι- ₃ -alkyl-, carboxy-, carboxy-Cι- ₃ -alkyl-, carboxy-Cι- ₃ -alkoxy-, Cι- ₄ -alkoxy-carbonyl- Cι- ₃ -alkoxy-, phenyl-Cι- ₃ - alkoxy, amino, C 3 alkylamino or di (C ₃ alkyl) amino group and

R _{7 represents} a hydrogen, fluorine, chlorine or bromine atom or a d ₃ -alkyl group,

or an optionally in the carbon skeleton by a Cι. _3- alkyl group substituted thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,

R ₈ and Rg, which may be the same or different, each represent a hydrogen atom, one optionally substituted by a phenyl or heteroaryl group

C ₃ alkyl group or an amino group optionally substituted by one or two d ₃ alkyl or C ₃ alkyl carbony groups,

wherein under a heteroaryl group mentioned above, a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the

an imino group optionally substituted by a C ₄ alkyl or C ₄ alkyl carbonyl group, an oxygen or sulfur atom,

an imino group which is optionally substituted by a C- _M alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom, an imino group optionally substituted by a C 4 alkyl group and two nitrogen atoms or

contains one oxygen or sulfur atom and two nitrogen atoms,

or a 6-membered heteroaryl group which contains one or two nitrogen atoms,

to understand

where a phenyl ring can be fused to the 5- or 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,

and wherein the unsubstituted or monosubstituted phenyl and naphthyl groups mentioned in the definition of the abovementioned radicals or unsubstituted or monosubstituted phenyl and naphthyl parts contained in these radicals, and the heteroaryl groups mentioned on a carbon atom, optionally additionally in each case by a fluorine, chlorine or or bromine atom, can be substituted by a trifluoromethyl, d- ₃ alkyl, C ₃ alkoxy or C ₃ alkoxy carbonyl group, unless stated otherwise,

the carboxy groups mentioned in the definition of the abovementioned radicals are replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions and

the amino and imino groups mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo,

as well as the connections

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) -phenylj-acetamide, 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide,

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-bromo-4- (pyrroiidin-1-yl-carbonyl) phenylj-acetamide and

2- (5-carbamidoyl-2-hydroxy-phenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts.

2. Carboxamides of the general formula I according to claim 1, in which

Ri a C ₅ . _7- Cycloalkyl-carbonyl group in which the methylene group in the 3- or 4-position is replaced by an -NH group in which

the hydrogen atom can be replaced by a C ₃ alkyl, C ₃ alkyl carbonyl or phenyl carbonyl group,

one in the alkyl part terminal optionally by a Cι. ₃ -alkylamino- or di- (Cι- ₃ -alkyl) -amino group substituted Cι- ₃ -alkyl-carbonyl group,

5 a group of the formula R _f R _g N- (CH ₂ ) _m - (R _h ) N-CO-, in which

Rf, R _g and R _h independently of one another each represent a hydrogen atom or a d-3-alkyl group and m is one of the numbers 2, 3 or 4, 0 is a phenylcarbonyl or heteroarylcarbonyl group, wherein the heteroaryl part is a 6-membered heteroaryl group which contains one or two nitrogen atoms and to which a phenyl ring can be fused via two adjacent carbon atoms, the bicyclic heteroaryl groups thus formed being bonded via the heteroaromatic or carbocyclic part, for example a 2- Pyridyl, 3-pyridyl, 4-pyridyl,

Pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl or quinazolinyl group,

a C 1 -C ₃ -alkyl group monosubstituted by a hydroxyl group or terminally disubstituted by a phenyl and a hydroxyl group, where

the phenyl substituent may be substituted by an amidino group optionally substituted by one or two C ₃ alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ₃ alkyl or d ₃ alkoxy group,

one by an amino-Cι. ₃ -alkyl-, Cι- ₃ alkylamino-d. ₃ -alkyI-, di- (Cι- ₃ -alkyl) -amino- d- ₃ -AIkyl-, Cι- ₄ -alkoxy-carbonyI-amino-Cι- ₃ -alkyl-, aminocarbonyl-, Cι- ₃ -alkylamino- carbonyl or di- (C. ₃ -alkyl) -aminocarbonyl group substituted 4- to 7-membered cycloalkyleneimino-carbonyl group,

a C ₅ .- -Cycloalkylaminogrup.pe _7, the C-ι_ at the nitrogen atom by a ₃ alkylamino d- ~ ₃ alkyl or di- (Cι- ₃ alkyl) _amino-d-3 alkyl group is substituted,

or also if R _{2 is} a trifluoromethyl group and / or R _{5 is} an amino-Cι. ₃ alkyl or C ₃ alkylamino d ₃ alkyl group or / and R _δ βine carboxy C ₃ alkoxy or C ₁ alkoxy carbonyl C ₃ alkoxy group or / and at least one of the Radicals R ₈ or Rg have a different meaning than that of the hydrogen atom, an unsubstituted 4- to 7-membered cycloalkyleneimino-carbonyl group a C ₅ _ ₇ -cycloalkylamino- or N- (C ₁ - ₃ ^ AIkyI) -C ₅ - ₇ -cycloalkylamino group,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C ₃ alkyl ~, trifluoromethyl or C ₃ alkoxy group, R _{3 is} a hydrogen atom or a C ₃ alkyl group,

R is a hydrogen atom or a C ₃ alkyl group,

Ar is a phenyl group substituted by the radicals R ₅ and R ₆ , where

R _{5 is} a cyano group, an amidino group optionally substituted by one or two C ₃ alkyl groups, an amino C ₃ alkyl or C ₃ alkyl amino C ₃ alkyl group and

R _{6 is} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C ₁ - ₃ - alkyl, hydroxy, C ₃ alkoxy, carboxy C ₃ alkoxy or ₄ alkoxy represents carbon ₃ -C ₃ alkoxy group, and

Rs and Rg, which may be the same or different, each have a hydrogen atom, an optionally substituted by a phenyl or pyridinyl group Cι- ₃ -AlkyI- or one optionally by one or two Cι- ₃ alkyl or d- ₃ alkyl - carbonyl-substituted amino group,

the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned radicals or unsubstituted or monosubstituted phenyl parts contained in these radicals and the heteroaryl groups mentioned on a carbon atom optionally additionally in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl , Cι_ ₃ -alkyl-,

C ₃ alkoxy or C ₃ alkoxy carbonyl group may be substituted, unless stated otherwise,

and the connections

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) -phenylj-acetamide, 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide,

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide and

2- (5-carbamidoyl-2-hydroxy-phenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts.

3. carboxamides of the general formula I according to one of claims 1 or 2, in which

the radicals R 1 to R ₄ , Rs and Rg are as defined in claim 1 or 2, but R 1 is bonded in the 4 position to the phenyl radical contained in formula I and

Ar represents a phenyl group substituted by the radicals R ₅ and R _δ , where

R ₅ is bonded in the 3-position when R _{δ represents} a hydrogen atom, or in

5-position is bound when R _{δ takes on} a different meaning than that of the hydrogen atom, and an amidino group which is optionally substituted by one or two C ₃ alkyl groups, an amino C ₃ alkyl or C 3 alkylamino -Cι-3-alkyl group and

Rδ is a hydrogen atom or a trifluoromethyl-, C ₁ - ₃ - alkyl-, hydroxy-, Cι- ₃ -alkoxy-, carboxy-Cι- ₃ -alkoxy- or d- ₄ -alkoxy-carbonyl- C - bonded in the 2-position - 3-alkoxy group means

as well as the connections

2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) -phenylj-acetamide and 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts.

4. carboxamides of the general formula I according to claim 1, in which

Ri is bound in the 4-position of the phenyl radical of the formula I and

a C ₅ . _7- cycloalkyl-carbonyl group in which the methylene group in the 3- or 4-position is replaced by an -NH group,

a phenylcarbonyl or pyridylcarbonyl group optionally substituted by a fluorine, chlorine or bromine atom or by a 5 -CC ₃ -alkyl group,

a terminally disubstituted by a phenyl and a hydroxy group Cι- ₃ alkyl group, wherein

o the phenyl substituent may be monosubstituted by a C ₃ alkyl or an amidino group or may be disubstituted by a C ₃ alkyl and an amidino group,

one by an amino-C ₃ alkyl, C. ₃ -Alkylamino-Cι. ₃ -alkyl-, -C-4-alkoxy-carbonyl- 5 amino-Cι- ₃ -alkyl-, aminocarbonyl or Cι- ₃ -alkylamino-carbonyl group substituted 5- to 7-membered cycloalkyleneimino-carbonyl group,

or also if R _{2 is} a trifluoromethyl group and / or R _{5 is} an amino -CC. ₃ -alkyl group or / and R _{6 is} a carboxy -CC. ₃ -alkoxy- or Cι- ₄ -alkoxy-carbonyl-Cι-3-alkoxy- o group or / and at least one of the radicals R ₈ or Rg has a different meaning than that of the hydrogen atom, an unsubstituted 5- to 7-membered cyclo - Alkylenimino-carbonyl or cycloalkylenimino-sulfonyl group and R _{2 is} a hydrogen atom or a substituent bonded in the 3-position of the phenyl radical selected from fluorine, chlorine, bromine, d- ₃ -alkyl, Cι- ₃ -alkoxy and trifluoromethyl,

R ₃ and R ₄ each represent a hydrogen atom,

Ar is a phenyl group substituted by the radicals R5 and R _B , where

R ₅ is bound in the 3-position when R _{6 represents} a hydrogen atom, or is bound in the 5-position when R _{δ takes on} a meaning other than that of the hydrogen atom, and an amidino or amino-Cι- ₃ alkyl group and

R _{6 is} a hydrogen atom or a bonded in the 2-position hydroxy, C ₃ ~ alkoxy, carboxy C ₃ alkoxy or C ₄ alkoxy carbonyl -C. _{3 represents} alkoxy group, and

Rs and Rg, which may be the same or different, each have a hydrogen atom, an optionally substituted by a phenyl, 4- (Cι- ₃ -alkoxycarbonyl) phenyl or pyridinyl group Cι- ₃ alkyl group or an optionally by one or two C ₃ alkyl or C ₃ alkyl carbonyl groups substituted amino group,

as well as the connections

2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide and

2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

their stereoisomers and their salts.

5. The following compounds of general formula I according to claim 1: (1) (L) -2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (2-aminocarbonyI-pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

(2) 2- (5-Carbamimidoyl-2-hydroxy-phenyl) -N- {3-methyl-4- [2- (tert-butoxycarbonyl-5 aminomethyl) -piperidin-1-yl-carbonyl] -phenyl} - acetamide,

(3) 2- (5-aminomethyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

l o (4) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidine-1-yl-carbonyl) -phenyl] isobutyramide,

(5) 2- (5-carbamimidoyl-2-ethoxycarbonylmethyloxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

15

(6) 2- (5-carbamimidoyl-2-carboxymethyloxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

(7) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (piperidin-3-yl-carbonyl) - 20 phenylj-acetamide,

(8) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- (3-methyl-4-benzoyl-phenyl) -acetamide,

(9) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-methyl-4- (1-hydroxy-1-phenyl-25-methyl) -phenyl] -acetamide,

(10) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- {4- [1- (3-carbamimidoyl-phenyl) -1-hydroxy-methyl] -3-methyl-phenyl} -acetamide,

30 (11) 2- (3-carbamidoylphenyl) -N- [3-methyl-4- (pyridin-3-ylcarbonyl) phenylj isobutyramide, (12) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1 -yl-carbonyl) phenylj-isobutyramide,

(13) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-chloro-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

(14) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -2-amino-acetamide,

(15) 2- (3-carbamimidoyl-phenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -2- (acetylamino) -acetamide,

(16) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-yl-sulfonyl) phenylj-acetamide,

(17) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-methyl-4- (pyrrolidin-1-ylcarbonyl) phenylj-propionamide,

(18) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] acetamide,

(19) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [4- (pyrrolidin-1-yl-carbonyl) -3- trifluoromethyl-phenyl-propionamide,

(20) 2- (5-carbamimidoyl-2-hydroxyphenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide,

(21) 2- (5-carbamimidoyl-2-hydroxy-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) phenyl-propionamide,

(22) 2- (5-carbamidoyl-2-hydroxyphenyl) -N- [3-methoxy-4- (pyrrolidin-1-yl-carbonyl) phenylj-acetamide, (23) 2- (3-carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3-phenyl-propionamide,

(24) 2- (3-carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3- (pyridin-4-yl) -propionamide and

(25) 2- (3-carbamimidoyl-phenyl) -N- [3-bromo-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3- [4- (ethoxycarbonyl) -phenyrj-propionamide,

in which the amidino group can additionally be substituted by a C - ₆ alkoxycarbonyl or phenylcarbonyl, and their salts.

6. Physiologically acceptable salts of the compounds according to claims 1 to 5 with the exception of those compounds in which Ar represents a phenyl or naphthyl group substituted by the radicals Rs, R _δ and R ₇ and R _{5 represents} a cyano group.

7. Medicament containing a compound according to at least one of claims 1 to 5 with the exception of those compounds in which Ar represents a phenyl or naphthyl group substituted by the radicals R ₅ , R _δ and R and R _{5 represents} a cyano group, or a salt according to Claim 6 in addition to optionally one or more inert carriers and / or diluents.

8. Use of a compound according to at least one of claims 1 to 5 with the exception of those compounds in which Ar represents a phenyl or naphthyl group substituted by the radicals R5, R _δ and R ₇ and R _{5 represents} a cyano group, or a salt according to claim 6 for the manufacture of a medicament with an antithrombotic effect.

9. A process for the preparation of a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 5 is formed by a non-chemical route, with the exception of those compounds in which Ar is a phenyl substituted by the radicals R ₅ , R ₆ and R ₇ - or naphthyl group and R ₅ represents a cyano group, or a salt according to claim 6 is incorporated into one or more inert carriers and / or diluents.

10. A process for the preparation of the compounds according to claims 1 to 6, characterized in that

a) for the preparation of a compound in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R ₇ , R ₆ and R _{7 being} as defined in claims 1 to 5 and R _{5 being} an amidino group, means

a compound of the general formula

R _*

in which R to R are as defined in claims 1 to 5, with a carboxylic acid of the general formula

in which Rs and Rg are as defined in claims 1 to 5 and Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R ₇ , where R _{5 is} a

Represents cyano group and R ₆ and R are as defined in claims 1 to 5, or acylated with their reactive derivatives and the cyano compound thus obtained is subsequently converted into an amidino compound or

b) for the preparation of a compound of the general formula I in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , Rδ and R ₇ , where R ₆ and R are as defined in claims 1 to 5 and R _{5 represents} an amidino group optionally substituted by one or two C ₃ alkyl groups,

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

in the

Ri to R ₄ , R _S and Rg as defined in claims 1 to 5, Ar 'one by the

Rβ and R ₇ radicals substituted phenyl or naphthyl group, wherein Rβ and R _{7 are} as defined in claims 1 to 5, and

Z represents an alkoxy, aralkoxy, alkylthio or aralkylthio group, with an amine of the general formula

H - RioNRn, (V)

in the

Rio and Rn, which can be the same or different, each represent a hydrogen atom, a C ₃ alkyl or an amino group optionally substituted by one or two C ₃ alkyl or C ₃ alkyl carbonyl groups, or with its salts is implemented or

c) for the preparation of a compound of the general formula I in which Ar is a phenyl or naphthyl group substituted by the radicals R ₅ , R ₆ and R, R ₆ and R _{7 being} as defined in claims 1 to 5 and R ₅ represents an aminomethyl, C 3 alkylaminomethyl or di (C ₃ alkyl) aminomethyl group,

a compound of the general formula in the

Ar represents a phenyl or naphthyl group substituted by the radicals R5, δ and R ₇ , R to R and R _δ to Rg are as defined in claims 1 to 5 and R _{5 represents} a cyano group, catalytically hydrogenated and optionally subsequently with a compound of the formula

R ₁₂ - Z ₂ (VI),

in which R ₁ 2 represents a C ₃ alkyl group and Z _{2 represents} a leaving group, is alkylated and

if desired, a compound of the general formula I thus obtained which contains an amino or imino group is subsequently converted into a corresponding acyl compound of the general formula I by means of a corresponding acyl derivative and / or

a compound of the general formula I thus obtained, which contains an esterified carboxy group, is converted into a corresponding carboxylic acid of the general formula I by hydrolysis and / or

a compound of the general formula I thus obtained, which contains a carboxy group, is converted into an appropriate ester by esterification and / or

a protective residue used during the reactions to protect reactive groups is split off and / or

a compound of the general formula I thus obtained is separated into its stereoisomers and / or a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.