EP1414790A1 - Substituted n-acyl aniline derivatives, production and use thereof as medicaments - Google Patents

Abstract

The invention relates to novel substituted N-acyl aniline derivatives of general formula (I), where R1 to R5, A, X, Y and Z are as defined in claim 1, the tautomers, stereoisomers, mixtures, prodrugs, derivatives with a group, negatively-charged under physiological conditions, in place of a carboxy group and the salts thereof, in particular the physiologically-acceptable salts with inorganic or organic acids or bases with useful properties. Compounds of general formula (I), in which R2 does not represent an amidino group, are valuable intermediates for the production of amidino compounds of general formula (I), with useful pharmacological properties, in particular a thrombin-inhibiting effect.

Description

 Substituted N-acyl aniline derivatives, their preparation and their use as medicines

The present invention relates to new substituted N-acyl aniline derivatives of the general formula

their tautomers, their stereoisomers, their prodrugs, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable properties.

The compounds of the general formula I above, in which R ² contains no cyano group, have valuable pharmacological properties, in particular thrombin-inhibiting properties, and

the compounds of the above general formula I in which R ² contains a cyano group represent valuable intermediates for the preparation of the compounds of the general formula I in which R ^{2 represents} an optionally substituted amidino or aminomethyl group.

The present invention thus relates to the new compounds of the above general formula I and their preparation, the pharmaceutical compositions containing the pharmacologically active compounds and their use. In the general formula above means

A is a methylene group which is optionally substituted by a C _-3 alkyl group or

one possibly by a C- |. _3- alkyl group substituted straight-chain C ₂ - ₃ alkyl group, in which the methylene group linked to the aromatic or heteroaromatic can be replaced by an oxygen or sulfur atom or by an -NH group, the -NH group additionally by a Cι. ₃ -alkyl-, carboxy- C-ι- ₃ -alkyl- or Cι. ₃ -alkoxycarbonyl-Cι- ₃ alkyl group may be substituted,

R ^{1 is} a hydrogen atom or a C ¹ -C 3 -alkyl group which is optionally substituted by a carboxy group,

R ^{2 is} a cyano, aminomethyl or amidino group,

R ³ a Cι. ₅ -Alkyl- or carboxy-C- -alkyl group, each in the alkyl part by a C ₃ - ₇ cycloalkyl, phenyl, pyridyl, pyrrolidino, 2,5-dihydro-1 H-pyrrolino, piperidino or Hexamethyleneimino group can be substituted,

a carbonyl or sulfonyl group, each

by an optionally alkyl group by a Cι _-3 alkyl or carboxy-substituted Cι Cι- _{3 -5} alkyl, C _3-7 cycloalkyl or phenyl group,

by a by a Cι. ₅ alkyl, C _3-7 cycloalkyl, phenyl, phenyl-Cι. ₃ -alkyl-, pyridyl- or pyridyl-Cι _-3 -alkyl group substituted amino, Cι _-4 -alkylamino or carboxy-Cι- ₄ -alkylamino group or

is substituted by a pyrrolidino, 2,5-dihydro-1 H-pyrrolino, piperidino or hexamethyleneimino group which is optionally substituted by a C ₃ alkyl or carboxy C ₃ alkyl group, one in the alkyl part optionally by an amino, Cι. ₃ -Alkylamino- or di- (-Cι- ₃ -alkyl) -amino group substituted carboxy-C _1-3 -alkylcarbonylamino group, an amino, carboxy-Cι- ₃ -alkylaminocarbonylamino-, carboxy-Cι. ₃ -alkylamino- carbonyl-Cι _-3 -alkylcarbonylamino-, carboxy-C ^ s-alkylaminocarbonyl-C ^ -alkylamino- carbonylamino-, amino-Cι _-3 -alkylcarbonylamino-, Cι _-3 -alkylamino-Cι- ₃ -alkylcarbonyl- amino or di (-C ₃ alkyl) amino C ₃ alkylcarbonylamino group, each in the above-mentioned amino groups

ι the hydrogen atom of the amino group, which is linked to the phenyl ring, is replaced by a Cι _-6 alkyl, C ₃ - ₇ cycloalkyl, phenyl or pyridyl group, to the above-mentioned phenyl or pyridyl substituents each via two adjacent carbon atoms an n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring can be fused on or the above-mentioned aromatic substituents each additionally by a C-ι- ₃ alkyl, Cι_ ₃ alkyloxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups,

an amino, carboxy-C ₄ alkylamino, carboxy C ₃ alkylaminocarbonyl C ₃ alkyl alkyl, aminocarbonyl C ₃ alkylamino, Ci-s-alkylaminocarbonyl-Ci-s-alkylamino -, Di- (Cι- ₃ -alkyl) -aminocarbonyl-Cι- ₃ -alkylamino-, amino-C ₂ - ₃ -alkylamino-, C- -alkyl- amino-C ₂ - ₃ -alkylamino-, di- (Cι -4-alkyl) amino C2-3 alkylamino, pyrrolidinocarbonyl Cι. ₃ -alkylamino-, piperidinocarbonyl-C _1-3 -alkylamino-, hexahydroazepinocarbonyl- Cι- ₃ -alkylamino-, morpholinocarbonyl-C-ι- ₃ -alkylamino-, piperazinocarbonyl-Cι- ₃ -alkyl- amino- or N- (Cι_ _3- alkyl) -piperazinocarbonyl -CC-3-alkylamino group, each in the above-mentioned amino groups

the hydrogen atom of the amino group, which is linked to the phenyl ring, through a Cι _-5 alkylcarbonyl, C _1-5 alkylsulfonyl, C _3- cycloalkylcarbonyl, C _3- cycloalkylsulfonyl, benzoyl, phenylsulfonyl, phenyl -Cι- ₃ -alkylcarbonyl-, phenyl-Cι. ₃ -alkylsulfonyl or pyridinoyl group is replaced, to the above-mentioned phenyl or pyridyl substituents, each via two adjacent ones Carbon atoms an n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring can be fused or the above-mentioned aromatic substituents each additionally by a C ₃ alkyl, C ₃ alkyl oxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups,

a phenyl, pyridyl, imidazolyl or pyrazolyl group optionally substituted by one, two or three C ₃ alkyl groups, the alkyl substituents in each case being able to be the same or different and one of the alkyl substituents additionally being substituted by a carboxy, hydroxysulfonyl, aminosulfonyl, C _1-4 alkylamino sulfonyl, di (Cι- ₄ alkyl) aminosulfonyl or Cu alkylsulfonyl group can be substituted,

R ^{4 is} a fluorine, chlorine, bromine or iodine atom, a carboxy, C ₃ alkyl, carboxy C ₃ alkyl, trifluoromethyl or C ₃ alkoxy group or a hydrogen atom if

R ^{3 is} a C ₅ alkyl or carboxy ₄ alkyl group, each in the alkyl part by a C _3-7 cycloalkyl, phenyl, pyridyl, pyrrolidino, 2,5-dihydro-1 H-pyrrolino -, piperidino or hexamethyleneimino group is substituted,

represents an amino, carboxy-C _1-4 -alkylamino- or carboxy-Cι- ₃ -alkylaminocarbonyl- Cι- ₃ -alkylamino group, each in the above-mentioned amino groups

the hydrogen atom of the amino group, which is linked to the phenyl ring, by a Cι- ₅ alkylcarbonyl, Cι. ₅ -Alkylsulfonyl-, C3-7-cycloalkylcarbonyl, C _3-7 -cycloalkylsulfonyl-, benzoyl, phenylsulfonyl-, phenyl-C _1-3 -alkylcarbonyl-, phenyl-Cι- ₃ -alkylsulfonyl or pyridinoyl group is replaced the above-mentioned phenyl or pyridyl substituents can each be fused via two adjacent carbon atoms, an n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring, or the above-mentioned aromatic substituents each additionally by a C ₃ alkyl, C. ₃ -alkyloxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups,

R ^{5 is} a hydrogen, fluorine, chlorine, bromine or iodine atom, a C ₃ alkyl or trifluoromethyl group or

R ⁴ and R ⁵ together ^are a nC ₃ - ₄ alkylene group,

with the proviso that at least one of the radicals R ¹ , R ⁴ or R ^{5 is} not a hydrogen atom, and

X, Y and Z each denote nitrogen atoms or -CH groups with the proviso that at least one of the groups X, Y and Z represents a -CH group,

where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of the formula I defined above, unless stated otherwise, can be partially or completely replaced by fluorine atoms and

the carboxy groups mentioned in the definition of the above radicals can be 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, or

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

Such "prodrug groups" are described, for example, in WO 98/46576 and by NM Nielson et al. in International Journal of Pharmaceutics 39, 75-85 (1987). For example, the carboxy groups mentioned above in the definition of the radicals can be replaced by a tetrazolyl group or by a group which can be converted into a carboxy group in vivo, for example by a hydroxymethyl or formyl group, by a carboxy group esterified with an alcohol, in which the alcoholic part preferably contains one C- |. ₆ -alkanol, a phenyl-C _1-3 -alkanol, a C _3-9 -cycloalkanol, where a Cs-s-cycloalkanol can additionally be substituted by one or two Cι _-3- alkyl groups, a C ₅ . _8- Cycloalkanol, in which a methylene group in the 3- or 4-position through an oxygen atom or through an optionally by a -C ₃ alkyl, phenyl -C ₃ alkyl, phenyl-C- |. ₃ -alkoxycarbonyl or C ₂ - ₆ alkoxycarbonyl or C ₂ - ₆ alkanoyl group substituted imino group is replaced and the cycloalkanol moiety may additionally be substituted by one or two Cι- ₃ alkyl, C ₄ - ₇ -Cycloalkenol, a C _3-5 alkenol, a phenyl-C _3-5 alkenol, a C _3-5 -alkynol or phenyl-C _3-5 -alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom having a double - or triple bond, a C ₃ - ₈ cycloalkyl -C _{3 -3} alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which is additionally substituted in the bicycloalkyl part by one or two C _{3 -3} alkyl groups, a 1, 3-dihydro -oxo-1-isobenzfuranol or an alcohol of the formula

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

R _a is a Cι _-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl-C- |. ₃ -alkyl group,

R _{b is} a hydrogen atom, a Cι. ₃ alkyl, C _5-7 cycloalkyl or phenyl group and

R _{c represents} a hydrogen atom or a C _-3 alkyl group,

by a group negatively charged under physiological conditions such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C _1-6 alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino carbonyl, sulfonylamino carbonyl, Cι -, Benzylsulfonylaminocarbonyl- or Perfluor-Cι. _6- alkylsulfonylaminocarbonyl group and those of the imino or amino groups mentioned in the definition of the radicals can be substituted by a radical which can be split off in vivo, for example by a hydroxy- C _1-8 alkoxy, allyloxy, phenyloxy, benzyloxy, 3-methoxybenzyloxy, 4 -Methyl- benzyloxy or 4-chlorophenyl-Cι _-6 -alkyloxy group, by an acyl group such as the benzoyl or pyridinoyl group or a Cι-i ₆ alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or Hexanoyl group, through an allyloxycarbonyl group, through a Cι-i ₆ alkoxycarbonyl group such as the methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, tert.butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, nonylyloxycarbonyl, octyloxycarbonyl Decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, through a phenyl-C ₁₆ alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethyloxycarbonyl or phenylpropyloxycarbonyl group, through a C ι _-3 -alkylsulfonyl-C ₂ - ₄ alkoxycarbonyl-, Cι- ₃ -alkoxy-C _2-4 -alkoxy- C _2-4 -alkoxycarbonyl- or R _a CO-O- (R _b CR _c ) -O- CO group in which R _a to R _b are defined as mentioned above.

Furthermore, the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms, and the alkanoyl and unsaturated alkyl parts which contain more than 3 carbon atoms also include their branched isomers, such as, for example, the isopropyl, tert .Butyl, isobutyl group etc.

Preferred compounds of general formula I are those in which

A is a methylene group or

a C ₂ - ₃ alkyl group, in which the methylene group linked to the aromatic or heteroaromatic can be replaced by an -NH group or by an oxygen atom, the -NH group additionally having a Cι. ₃ -alkyl-, carboxy-Cι _-3 -alkyl- or Cι- ₃ -alkoxycarbonyl-Cι _-3 -alkyl group may be substituted, R ^{1 is} a hydrogen atom or a C _1-3 alkyl group which is optionally substituted by a carboxy group,

R ² is a cyano or aminomethyl group or an optionally by a hydroxy, Cι _-8 -alkoxycarbonyl or benzoyl substituted amidino group,

R ^{3 is} a d- ₅ alkyl or carboxy-C ₄ alkyl group, each in the alkyl part by a C ₃ . _7- cycloalkyl, phenyl, pyridyl, pyrrolidino, 2,5-dihydro-1 H-pyrrolino, piperidino or hexamethyleneimino group,

a carbonyl or sulfonyl group, each

by an optionally alkyl group by a C-ι-3-alkyl or carboxy-substituted ₃ Cι- Cι- ₅ alkyl or C _3-7 cycloalkyl group,

by a substituted by a C _1-5 alkyl, C _3-7 cycloalkyl, phenyl, benzyl or pyridyl group amino, C-ι-4-alkylamino or carboxy- Cι_ ₄ alkylamino group or

is substituted by a pyrrolidino, 2,5-dihydro-1H-pyrrolino, piperidino or hexamethyleneimino group which is optionally substituted by a C 1 -C ₃ -alkyl or carboxy-C _{3 -3} -alkyl group,

a in the alkyl part optionally substituted by an amino group, carboxy-C ₃ alkylcarbonylamino group, an amino, carboxy-C ₃ -alkylaminocarbonyl-amino, carboxy-C _1-3 -alkylaminocarbonyl-C _{3 -3-} alkylcarbonylamino, carboxy Cι- ₃ -alkylaminocarbonyl-Cι _-3 -Alkylaminocarbonylamino- or amino-Cι. _3- alkylcarbonylamino group, each in the abovementioned amino groups

the hydrogen atom of the amino group, which is linked with the phenyl ring by Ci _ß alkyl, C ₃ _ ₇ cycloalkyl, phenyl or pyridyl group is substituted, the above-mentioned phenyl or pyridyl substituents in each case via two adjacent carbon atoms can be fused to a phenyl, pyridine or piperidine ring or the above-mentioned aromatic substituents are each additionally substituted by a C ₃ alkyl, C ₃ alkyloxy or trifluoromethyl group or by 2 to 4 methyl groups could be,

an amino, carboxy-Ci ^ alkylamino, carboxy-Cι. ₃ -alkylaminocarbonyl-Cι- ₃ -alkyl- amino-, aminocarbonyl-Cι- ₃ -alkylamino-, pyrrolidinocarbonyl-Cι- ₃ -alkylamino-, piperi- dinocarbonyl-Cι. ₃ -alkylamino- or morpholinocarbonyl-Cι _-3 -alkylamino group, each in the above-mentioned amino groups

the hydrogen atom of the amino group which is linked to the phenyl ring by a C-ι- ₅ alkylcarbonyl, Cι_ ₅ alkylsulfonyl, C ₃ . ₇ cycloalkylcarbonyl, C _3-7 -Cycloalkylsulfonyl-, benzoyl, phenylsulfonyl, phenyl-Cι- ₃ alkylcarbonyl or pyridinoyl group is substituted, the above-mentioned phenyl or pyridyl substituents in each case via two adjacent carbon atoms of a n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring can be fused or the above-mentioned aromatic substituents each additionally by a C _-3 alkyl, C _{3 -3} alkyloxy, trifluoromethyl or carboxy group or by 2 to 4 methyl groups can be substituted,

a phenyl, pyridyl, imidazolyl or pyrazolyl group optionally substituted by one, two or three C ₃ alkyl groups, the alkyl substituents in each case being able to be the same or different and one of the alkyl substituents additionally having a carboxy or hydroxysulfonyl group, an aminosulfonyl group, C ₄ alkylaminosulfonyl, di (C 4 alkyl) aminosulfonyl or CM alkylsulfonyl group may be substituted,

R ^{4 is} a chlorine or bromine atom, a carboxy, C-ι _-3 alkyl, carboxy Cι _-3 alkyl or trifluoromethyl group or a hydrogen atom, if R ³ a Cι. ₅ -alkyl or carboxy-C _-4 alkyl group, each of which is substituted in the alkyl part by a C _3-7 cycloalkyl, phenyl, pyridyl, pyrrolidino, piperidino or hexamethyleneimino group,

represents an amino, carboxy-C ₄ alkylamino or carboxy C _1-3 alkylaminocarbonyl C ₃ -alkylamino group, each in the above-mentioned amino groups

the hydrogen atom of the amino group which is linked to the phenyl ring by a Cι- ₅ alkylcarbonyl, Cι- ₅ alkylsulfonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkylsulfonyl, benzoyl, phenylsulfonyl, Phenyl-Cι- ₃ -alkylcarbonyl- or pyridinoyl group is replaced, an n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring may be fused to the above-mentioned phenyl or pyridyl substituents, in each case via two adjacent carbon atoms, or which may be aforementioned aromatic substi- tuenten each additionally by a C-ι _-3 alkyl, Cι- methyl group ₃ alkyloxy- or trifluoro- or may be substituted by 2 to 4 methyl groups,

R ^{5 is} a hydrogen, chlorine or bromine atom, a Cι- ₃ alkyl or trifluoromethyl group or

R ⁴ and R ⁵ together represent an nC _3-4 alkylene group,

with the proviso that at least one of the radicals R ¹ , R ⁴ or R ^{5 is} not a hydrogen atom and

X, Y and Z each denote nitrogen atoms or -CH groups with the proviso that at least one of the groups X, Y and Z represents a -CH group,

whose Cι _-3 alkyl and benzyl esters, their tautomers, their stereoisomers, their prodrugs, their mixtures and their salts, where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of formula I defined above, unless stated otherwise, can be partially or completely replaced by fluorine atoms and

where the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms, and the alkanoyl and unsaturated alkyl parts which contain more than 3 carbon atoms, also their branched isomers, for example the isopropyl, tert-butyl, , Include isobutyl group, etc.

Particularly preferred compounds of the present invention are the compounds of the general formula Ia

in the

A is a methylene group or

an ethylene group in which the methylene group linked to the aromatic can be replaced by an oxygen atom or by an -NH group, where the -NH group can additionally be substituted by a methyl, carboxymethyl or Cι_ ₃ alkoxycarbonylmethyl group,

R ^{1 is} a hydrogen atom, a methyl or ethyl group, R ² is a cyano or aminomethyl group or an optionally by a hydroxy, Cι _-8 alkyloxycarbonyl or benzoyl substituted amidino group,

R ³ is a group optionally substituted by a phenyl, pyridyl or piperidino straight or branched C-ι- ₅ alkyl group,

a carbonyl or sulfonyl group, each with a straight-chain or branched C _-5 alkyl, C _3-5 cycloalkyl, phenylamino, N- (C 4 alkyl) phenylamino, N, N-di (C _1-4 -alkyl) -amino-, N- (-Cι- ₄ -alkyl) -benzylamino-, N- (Cι-4-alkyl) -pyridylamino, pyrrolidino or methyl-pyrrolidino group is substituted,

an amino, methylamino, carboxymethylamino, Cι- ₃ alkoxycarbonylmethylamino or morpholinocarbonylmethylamino group, each on the amine nitrogen atom by an optionally substituted by one to four methyl groups, phenylsulfonyl group, by a trifluoromethyl, carboxy or C-ι_ _3rd -Alkoxy carbonyl group substituted phenylsulfonyl group, is substituted by a benzoyl, benzylsulfonyl, naphthylsulfonyl, quinolylsulfonyl or 1, 2,3,4-tetrahydroquinolylsulfonyl group, or

a straight or branched Cι_ ₅ -alkylamino or C _3-5 cycloalkylamino group, each of carbonyl on the amine nitrogen atom by a carboxy or C-ι- ₃ alkoxy or / and an amino group substituted C2- ₃ alkanoyl group, is substituted by a carboxymethylaminocarbonyl or Cι_ ₃ alkoxycarbonylmethylaminocarbonyl group, or

a pyrazol-1-yl group substituted by two straight-chain or branched C ₃ alkyl groups,

R ^{4 is} a chlorine or bromine atom, a methyl, trifluoromethyl, carboxymethyl or C ₃ alkoxycarbonylmethyl group or a hydrogen atom, if

R ^{1 is} an ethyl group or R ^{3 represents} a pyrrolidinocarbonyl group, a carboxymethylamino or C ₃ alkoxycarbonylmethylamino group, in each of which the amine nitrogen atom is substituted by a benzoyl group,

R ^{5 is} a hydrogen, chlorine or bromine atom or a methyl group or

R ⁴ and R ⁵ together represent an n-propylene group,

with the proviso that at least two of the radicals R ¹ , R ⁴ and R ^{5 are} not hydrogen atoms,

in particular those compounds of the general formula Ia in which

R ^{4 represents} a chlorine or bromine atom, a methyl or trifluoromethyl group,

where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of formula la defined above, unless otherwise stated, can be partially or completely replaced by fluorine atoms,

their tautomers, their stereoisomers, their prodrugs and their salts.

Very particularly preferred compounds of the general formula la above are those in which

A is an ethylene group in which the methylene group linked to the aromatic can be replaced by an -NH group,

R ^{1 is} a hydrogen atom, a methyl or ethyl group,

R ^{2 is} an amidino group, R ^{3 is} a C ₃ - ₅ alkyl group,

a carbonyl group through a straight-chain or branched Cι- ₅ alkyl, C ₃ . ₅ -Cyc! Oalkyl-, N, N-di- (Cι-4-alkyl) -amino-, N- (Cι ^ -alkyl) -benzylamino-,

N- (Cι- ₄ alkyl) pyridylamino, pyrrolidino or 2-methyl-pyrrolidino group is substituted,

a straight-chain or branched C ₅ alkylamino or C ₃ . ₅ -cycloalkylamino group, each of which is substituted on the amine nitrogen atom by a C _{2 -3} -alkoxycarbonyl or / and an amino group substituted by C ₂ - ₃ alkanoyl group, by a carboxymethylaminocarbonyl or C _{3 -3} -alkoxycarbonylmethylaminocarbonyl group on the amine nitrogen atom, or

a pyrazol-1-yl group substituted by two straight-chain or branched C _1-3 alkyl groups,

R ^{4 is} a chlorine or bromine atom, a methyl or trifluoromethyl group and

R represents a hydrogen, chlorine or bromine atom or a methyl group,

in particular those compounds of the general formula Ia in which

R ^{3 is} in position 4,

with the proviso that at least one of the radicals R ¹ or R ^{5 is} not a hydrogen atom,

where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of formula I defined above, unless stated otherwise, can be partially or completely replaced by fluorine atoms, their tautomers, their stereoisomers, their prodrugs and their salts.

Examples of the following particularly preferred compounds of the general formula I are mentioned:

(A) 4- {N- [2,5-dimethyl-4- (2-methyl-pyrrolidinocarbonyl) phenylaminocarbonylmethyl] aminoj-benzamidine,

(B) 4- [N- (2,5-dimethyl-4-isopropylcarbonylphenylaminocarbonylmethyl) amino] benzamidine and

(C) 4- {N- [2,5-Dimethyl-4- (N ^* -isopropyl-N ^, - (2-ethoxycarbonylethylcarbonyl) amino) - phenylaminocarbonylmethyl] amino} benzamidine

as well as 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) implementation of a compound of the general formula

in the

R ¹ and R ³ to R ⁵ are defined as mentioned at the outset,

with a carboxylic acid of the general formula

in the

A, X, Y, Z and R ₅ 2 are defined as mentioned above, or their reactive

Derivatives.

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

However, the reaction is preferably carried out using a carboxylic acid of the general formula III in the presence of a dehydrating or acid-activating compound, 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'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N.N'-carbonyldiimidazole, N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride, triphenylphosphine / azodicarbonyl ester, 1-benzodicarbonyl ester -yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or other amide coupling reagents, as described in Comprehensive Functional Group Transformations Vol. 5, pages 257 ff. (Pergamon, CJ Moody) and in the references cited therein, if appropriate in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine or with a corresponding end reactive derivative such as its anhydride, ester or halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone 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, is advantageously carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C.

b) To prepare a compound of general formula I, in which A is a optionally substituted by a straight-chain alkyl group Cι- ₃ C ₂ - ₃ alkyl group, in which associated with the aromatic or heteroaromatic methyl group by an oxygen atom or -NH group is replaced, the -NH-group in addition ι _carboxy-C-3 by a Cι_ alkyl or _-3 alkyl group may be substituted:

Implementation of a compound of the general formula

in the

R ¹ and R ³ to R ⁵ are defined as mentioned at the outset,

A 'optionally by a Cι. ₃ alkyl group substituted methylene or n-ethylene group and

Zi is a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or

Iodine atom, or a p-nitrophenyloxy group,

with a compound of the general formula

in the

X, Y, Z and R ² are defined as mentioned at the beginning and

B is an oxygen atom or one optionally by a C-ι. ₃ alkyl or carboxy

Cι_ ₃ alkyl group substituted -NH group means.

The reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C.

c) For the preparation of a compound of the general formula I in which R ^{2 represents} an amidino group:

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

in the

R ¹ , R ³ to R ⁵ , A, X, Y and Z are defined as mentioned at the outset and

Z _{2 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 the methylthio, ethylthio, n-propylthio or benzylthio group,

with ammonia or hydroxylamine and with their salts. 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 ammonia or one of its salts such as ammonium carbonate or ammonium acetate ,

A compound of general formula VI 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 formed Thioamids with a corresponding alkyl or aralkyl halide.

d) For the preparation of a compound of the general formula I in which R ^{2 represents} an amidino group substituted by a radical which can be split off in vivo:

Implementation of a compound of the general formula

in the

R ¹ , R ³ to R ⁵ , A, X, Y and Z are defined as mentioned at the outset, with a compound of the general formula

Z ₃ - R ⁶ , (VIII)

in the

R ^{6 is} the acyl residue of one of the residues which can be cleaved in vivo and

Z _{3 is} a nucleofugic leaving group such as a halogen atom, for example a chlorine, bromine or

Iodine atom, or a p-nitrophenyloxy group mean.

The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an inorganic or a tertiary organic base such as sodium hydride, potassium carbonate, potassium tert-butylate or N-ethyl diisopropylamine at temperatures between 0 and the boiling point of the solvent used, preferably at temperatures between 0 and 60 ° C.

e) For the preparation of a compound of the general formula I in which at least one of the radicals A, R ¹ or R ³ contains a carboxy group:

Conversion of a compound of the general formula

in the

R ² , R ⁴ , R ⁵ , X, Y and Z are defined as mentioned at the beginning and

A ", R ¹ 'and R ³ ' have the meanings mentioned above for A, R ¹ and R ³ with the

Provided that at least one of the radicals A, R ¹ or R ³ passes through Contains hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a group which can be converted into a carboxy group,

by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of the general formula I in which at least one of the radicals A, R ¹ or R ³ contains a carboxy group.

A group which can be converted into a carboxy group is, for example, a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are expediently converted into a carboxyl group by means of hydrolysis,

their esters with tertiary alcohols, e.g. the tert-butyl ester, which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and

their esters with aralkanols, e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.

The 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 at temperatures between -10 and 120 ° C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

If a compound of formula IX contains, for example, the tert-butyl or tert-butyloxycarbonyly group, these can also be treated by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, Phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or also thermally optionally in an inert Solvents such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used, for example at temperatures between 40 and 120 ° C. be split off.

If a compound of formula IX contains, for example, the benzyloxy or benzyl ^" oxycarbonyl group, these can also preferably be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at temperatures between 0 and 50 ° C, for example at room temperature, and a hydrogen pressure of 1 to 5 bar.

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

For example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and comes as a protective radical for a carboxy group

as a protective radical for an amino or alkylamino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group.

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

However, 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.

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 ether.

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 removed 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 formulas II to IX used as starting materials, some of which are known from the literature, are obtained by processes known from the literature, and their preparation is also described in the examples.

For example, a compound of the general formula II is obtained by alkylation and / or acylation of a corresponding nitroaniline, the nitroaniline thus obtained then being reduced to a corresponding diamino compound and the diamine compound thus obtained, if necessary, by alkylation and / or acylation to the desired starting compound the general formula II is transferred. During these reactions, a reactive group such as an amino or imino group can optionally be protected by a customary protective radical which is subsequently split off again using customary methods.

A starting compound of the general formulas IV, VII and IX is advantageously obtained analogously to process a) of the present invention.

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 Allinger 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 suitable 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, the new compounds of the formula I obtained in this way, if they contain a carboxy group, 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. Suitable bases 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 their salts have valuable properties. Thus, the compounds of general formula I, in which R ^{2 represents} a cyano group, are valuable intermediates for the preparation of the other compounds of general formula I, and the compounds of general formula I, in which R ^{2 represents} one of the amidino groups mentioned at the outset, and Their tautomers, their stereoisomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on an action which influences thrombin or factor Xa, for example on an action which inhibits thrombin or factor Xa, on an action of the aPTT -Time extending effect and on an inhibitory effect on related serine proteases such. B. trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the connections

A = 4- {N- [2,5-dimethyl-4- (2-methyl-pyrrolidinocarbonyl) phenylaminocarbonylmethyl] aminoj-benzamidine,

B = 4- [N- (2,5-dimethyl-4-isopropylcarbonylphenylaminocarbonylmethyl) amino] benzamidine and

C = 4- {N- [2,5-Dimethyl-4- (N'-isopropyl-N '- (2-ethoxycarbonylethylcarbonyl) amino) phenylaminocarbonylmethyl] amino} benzamidine examined for their effect on the aPTT time extension as follows:

Material: -plasma, from human citrate blood,

-PTT reagent, Boehringer Mannheim (524298), calcium solution (0.025 mol / 1), Behring Werke, Marburg (ORH 056/57),

-Diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61), -Biomatic B10 coagulometer, Desaga, Wiesloch.

Execution:

The aPTT time was determined using a Biomatic B10 coagulometer from Desaga.

The test substance was placed in the test vessels prescribed by the manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of PTT reagent. The mixture was incubated at 37 ° C for three minutes. The coagulation reaction was started by adding 0.1 ml of calcium solution. Depending on the device, the calcium solution is measured and the time taken for the batch to clot is measured. Batches in which 0.1 ml of DBA buffer were added served as a control.

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

The following table contains the values found:

The compounds of general formula I prepared in accordance with the invention, in which R ² does not represent a cyano group, are well tolerated, since no toxic side effects could be observed in their pharmacological examination.

Due to their pharmacological properties, the new compounds and their physiologically tolerable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the treatment of deep vein thrombosis, the prevention of reocclusion 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 preventing long-term restenosis after 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 / adhesions and adhesions or scar tissue formation as well as to promote 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 (for example abciximab, eptifibatide, tirofiban), with inhibitors for ADP-induced aggregation (for example clopidogrel, ticlopidine), with P ₂ T- Receptor antagonists (eg Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (eg Terbogrel) can be used.

The dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration and 0.1 to 50 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day. For this purpose, the compounds of 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, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat suitable mixtures, work into common galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

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

example 1

4-fN (5-phenylsulfonylamino-2-methyl-phenyl) -aminocarbonylmethyl1-benzamidine

a. 5-phenylsulfonylamino-2-methyl-nitrobenzene

1.52 g (0.01 mol) of 4-methyl-3-nitro-aniline and 1.32 g (0.01 mol) of benzenesulfonic acid chloride are heated in 30 ml of pyridine on the steam bath for 1 hour. The solvent is distilled off and the residue is purified by chromatography (silica gel; dichloromethane / ethanol 99: 1). Yield: 2.9 g (100% of theory), R _f value: 0.29 (silica gel; dichloromethane / ethanol = 50: 1) b. 5-phenylsulfonylamino-2-methyl-aniline

2.9 g (0.01 mol) of 5-phenylsulfonylamino-2-methyl-nitrobenzene are dissolved in 100 ml

Dissolved methanol and after adding 0.5 g of 20% palladium on carbon

Room temperature hydrogenated with 5 bar hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated.

Yield: 1.7 g (65% of theory),

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

Melting point: 142-144 ° C.

c. 4-rN- (5-phenylsulfonylamino-2-methylphenyl) aminocarbonylmethvn-benzonitrile 240 mg (1.5 mmol) of N, N'-carbonyldiimidazole are added to a solution of 242 mg (1.5 mmol) of 4-cyanophenylacetic acid in 30 ml of tetrahydrofuran and stirred for 15 minutes. Then 393 mg (1.5 mmol) of 5-phenylsulfonylamino-2-methyl-aniline are added and the mixture is stirred for 48 hours. The solvent is distilled off and the residue is purified by chromatography (silica gel; dichloromethane / ethanol = 99: 1).

Yield: 0.53 g (87% of theory),

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 50: 1)

Melting point: 120-122 ° C.

d. 4-rN- (5-phenylsulfonylamino-2-methylphenyl) aminocarbonylmethvn-benzamidine 440 mg (1.09 mmol) 4- [N- (5-phenylsulfonylamino-3-methylphenyl) aminocarbonylmethylj-benzonitrile are in 35 ml of ethanol saturated with hydrogen chloride gas was stirred for 48 hours at room temperature. The solvent is removed in vacuo at a maximum bath temperature of 30 ° C and replaced with 35 ml of absolute ethanol. 1.05 g (11 mmol) of ammonium carbonate are added and the mixture is stirred for 48 hours. The solvent is then distilled off and the residue is purified by chromatography (silica gel; dichloromethane / ethanol = 9: 1).

Yield: 0.24 g (48% of theory),

R _f value: 0.27 (silica gel; dichloromethane / ethanol = 4: 1)

C ₂₂ H22N ₄ O ₃ S x HCI (422.52 / 458.98) Mass spectrum: (M + H) ⁺ = 423

(2M + H) ⁺ = 845

Example 2

4- [N- (4-phenylsulfonylamino-2-methyl-phenyl) -aminocarbonylmethvn-benzamidine

Prepared analogously to Example 1d from 4- [N- (4-phenylsulfonylamino-2-methylphenyl) aminocarbonylmethylj-benzonitrile, ethanol saturated with hydrogen chloride gas and

Ammonium carbonate.

Yield: 86% of theory,

C ₂₂ H ₂₂ N4O ₃ S x HCI (422.52 / 458.98)

Mass spectrum: (M + H) ⁺ = 423

Example 3

4-rN- (2,3-dimethyl-5-phenylsulfonylamino-phenyl) aminocarbonylmethvn-benzamidine Prepared analogously to Example 1d from 4- [N- (2,3-dimethyl-5-phenylsulfonylamino-phenyl) aminocarbonylmethyl] benzonitrile, with hydrogen chloride gas saturated ethanol and ammonium carbonate. Yield: 82% of theory,

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 4: 1) C ₂₃ H24N ₄ 0 ₃ S x HCl (436.54 / 473.01) mass spectrum: (M + H) ⁺ = 437

(2M + H) ⁺ = 873

Example 4

4- N- (2,6-dichloro-4-phenylsulfonylamino-phenvπ-aminocarbonylmethyl1-benzamidine) Prepared analogously to Example 1d from 4- [N- (2,6-dichloro-4-phenylsulfonylamino-phenyl) - a inocarbonylmethylj-benzonitrile, with Hydrogen chloride gas saturated ethanol and ammonium carbonate. Yield: 80% of theory, R _f value: 0.08 (silica gel; dichloromethane / ethanol = 4: 1) C ₂ ιH ₁₈ CI ₂ N ₄ θ ₃ S (477.39)

Mass spectrum: (M + H) ⁺ = 477/79/81 (chlorine isotopes)

(M + Na) ⁺ = 499/01/03

Example 5

4-fN- (2-ethyl-5-phenylsulfonylamino-phenyl) aminocarbonylmethvn-benzamidine Prepared analogously to Example 1d from 4- [N- (2-ethyl-5-phenylsulfonylamino-phenyl) aminocarbonylmethylj-benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 52% of theory,

R _f value: 0.32 (silica gel; dichloromethane / methanol = 5: 1) C ₂₃ H ₂₄ N ₄ θ ₃ S x HCl (436.53 / 472.99) mass spectrum: (M + H) ⁺ = 437

(2M + H) ⁺ = 873

Example 6

4- [N- (6-Phenylsulfonylamino-indan-4-yl) aminocarbonylmethyl1-benzamidine Prepared analogously to Example 1d from 4- [N- (6-phenylsulfonylamino-indan-4-yl) aminocarbonylmethylj-benzonitrile, with hydrogen chloride gas saturated ethanol and ammonium carbonate. Yield: 33% of theory, C ₂₄ H ₂₄ N ₄ O ₃ S x HCl (448.6 / 485.0) mass spectrum: (M + H) ⁺ = 449 Example 7

4- [N- (2.3-Dimethyl-4-phenylsulfonylaminophenyl) aminocarbonylmethvn-benzamidine Prepared analogously to Example 1d from 4- [N- (2,3-dimethyl-4-phenylsulfonylaminophenyl) aminocarbonylmethyl] benzonitrile, with Hydrogen chloride gas saturated ethanol and ammonium carbonate. Yield: 70% of theory, C ₂₃ H ₂₄ N ₄ O ₃ S x HCl (436.5 / 473.0) mass spectrum: (M + H) ⁺ = 437

Example 8

4-fN- (2,6-dimethyl-4-phenylsulfonylamino-phenyl) -aminocarbonylmethvn-benzamidine Prepared analogously to Example 1d from 4- [N- (2,6-dimethyl-4-phenylsulfonylamino-phenyl) -aminocarbonylmethyl] -benzonitrile, with hydrogen chloride gas saturated ethanol and ammonium carbonate. Yield: 71% of theory, C ₂₃ H ₂₄ N ₄ θ ₃ S x HCl (436.5 / 473.0) mass spectrum: (M + H) ⁺ = 437

(2M + H) ⁺ = 873

Example 9

4- [ ^' N- (2,6-Dimethyl-3-phenylsulfonylaminophenyl) aminocarbonylmethvn-benzamidine Prepared analogously to Example 1d from 4- [N- (2,6-dimethyl-3-phenylsulfonylaminophenyl) aminocarbonylmethyl] - benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 67% of theory, C ₂₃ H ₂₄ N ₄ θ ₃ S x HCl (436.5 / 473.0) mass spectrum: (M + H) ⁺ = 437 Example 10

4-fN-r2-methyl-5- (naphth-1-yl-sulfonylamino) -phenvn-aminocarbonylmethyl) -benzamidine

Prepared analogously to Example 1d from 4- {N- [2-methyl-5- (naphth-1-yl-sulfonylaminophenyl] aminocarbonylmethyl} benzonitrile, saturated with hydrogen chloride gas

Ethanol and ammonium carbonate.

Yield: 29% of theory,

C ₂₆ H ₂ 4N4O ₃ S x HCI (472.66 / 509.03)

Mass spectrum: (M + H) ⁺ = 473

Example 11

4- {N-f2-Methyl-5- (3-methylphenylsulfonylamino) phenvn-aminocarbonylmethyl) benzamidine

Prepared analogously to Example 1d from 4- {N- [2-methyl-5- (3-methylphenylsulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 59% of theory, C ₂₃ H ₂₄ N ₄ O ₃ S x HCl (436.5 / 473.0) mass spectrum: (M + H) ⁺ = 437

Example 12

4-fN-r2-methyl-5- ( ^, 2-trifluoromethyl-phenylsulfonylamino) -phenvn-aminocarbonyl-methvD-benzamidine

Prepared analogously to Example 1d from 4- {N- [2-methyl-5- (2-fluoromethylphenylsulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 48% of theory, C ₂₃ H ₂ iF ₃ N ₄ O ₃ S x HCl (490.5 / 526.97) mass spectrum: (M + H) ⁺ = 491 Example 13

4- (N-r2-methyl-5- (2-ethoxycarbonylphenylsulfonylamino) phenyl1-aminocarbonylmethyll-benzamidine

Prepared analogously to Example 1d from 4- {N ~ [2-methyl-5- (2-ethoxycarbonylphenylsulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 34% of theory, C ₂₅ H ₂₆ N ₄ O ₅ S x HCl (494.55 / 531.04) mass spectrum: (M + H) ⁺ = 495

(2M + H) ⁺ = 989

Example 14

4- {N-r5- (N'-benzyl-N'-butyl-aminocarbonvπ-2-methyl-phenyl-aminocarbonylmethyl) benzamidine

Prepared analogously to Example 1d from 4- {N- [5- (N'-benzyl-N'-butylaminocarbonyl) -2-methylphenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 39% of theory, C ₂₈ H ₃₂ N ₄ θ2 x HCl (456.6 / 493.0) mass spectrum: (M + H) ⁺ = 457

Example 15

4-rN- (2,4-dimethyl-5-phenylsulfonylaminophenyl) aminocarbonylmethvn-benzamidine Prepared analogously to Example 1d from 4- [N- (2,4-dimethyl-5-phenylsulfonylaminophenyl) aminocarbonylmethyl] benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 85% of theory, C ₂₃ H ₂₄ N4θ ₅ S x HCl (436.54 / 473.01) mass spectrum: M ⁺ = 436 Example 16

4- {N-r2.4-Dimethyl-5- (naphth-1-yl-sulfonylamino) -phenyl1-aminocarbonylmethyl | - benzamidine

Prepared analogously to Example 1d from 4- {N- [2,4-dimethyl-5- (naphth-1-yl-sulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 79% of theory, C ₂₇ H ₂₆ N ₄ O ₅ S x HCl (486.60 / 523.07) mass spectrum: (M + H) ⁺ = 487

Example 17

4-RN (2,4-dimethyl-5-benzylsulfonylamino-phenyl) -aminocarbonylmethvn-benzamidine

Prepared analogously to Example 1d from 4- [N- (2,4-dimethyl-5-benzylsulfonylaminophenyl) aminocarbonylmethylj-benzonitrile, ethanol saturated with hydrogen chloride gas and

Ammonium carbonate.

Yield: 78% of theory,

C ₂₄ H ₂₆ N4O ₅ S x HCI (450.57 / 487.04)

Mass spectrum: M ⁺ = 450

Example 18

4-FN- ( ^' 2-ethoxycarbonylmethyl-5-phenylsulfonylaminophenyl) aminocarbonylmethvn-benzamidine

a. 2,4-diamino-phenylacetic acid tert.-butyl ester

Prepared analogously to Example 1b from 2,4-dinitro-phenylacetic acid tert-butyl ester,

10% palladium on carbon and hydrogen in methanol.

Yield: 94% of theory,

R _f value: 0.36 (silica gel; dichloromethane / methanol = 19: 1) b. 2-amino-4-phenylsulfonylamino-phenylacetic acid tert.-butyl ester

Prepared analogously to Example 1a from 2,4-diamino-phenylacetic acid tert-butyl ester and

Benzenesulfonic acid chloride in pyridine.

Yield: 30% of theory,

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

c. 4-rN- (2-ethoxycarbonylmethyl-5-phenylsulfonylamino-phenvπ-aminocarbonyl-methyll-benzamidine

Prepared analogously to Example 1c from 2-amino-4-phenylsulfonylamino-phenylacetic acid, tert-butyl ester, 4-cyanophenylacetic acid and N.N'-carbonyldiimidazole in tetrahydrofuran at 50 ° C., subsequent reaction analogously to Example 1d with ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 56% of theory, C ₂₅ H _{26 4} O ₅ S x HCl (494.56 / 531.03) mass spectrum: (M + H) ⁺ = 495

Example 19

4-rN- (2-trifluoromethyl-4-phenylsulfonylaminophenyl) aminocarbonylmethyll-benzamidine

Prepared analogously to Example 1d from 4- [N- (2-trifluoromethyl-4-phenylsulfonylaminophenyl) aminocarbonylmethyl] benzonitrile, saturated with hydrogen chloride gas

Ethanol and ammonium carbonate.

Yield: 46% of theory,

C ₂₂ Hi ₉ F ₃ N ₄ O ₃ S x HCI (476.48 / 512.94)

Mass spectrum: (M + H) ⁺ = 477 Example 20

4- (N-r2-Methyl-5- (2,3,5,6-tetramethyl-phenylsulfonylamino) -phenvn-aminocarbonyl-methvD-benzamidine

Prepared analogously to Example 1d from 4- {N- [2-methyl-5- (2,3,5,6-tetramethylphenylsulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate.

Yield: 79% of theory,

C ₂₆ H ₃₀ N ₄ O ₃ S x HCI (478.61 / 515.07)

R _f value: 0.18 (silica gel; dichloromethane / ethanol = 4: 1)

Mass spectrum: (M + H) ⁺ = 479

Example 21

4-fN- (2-Hvdroxycarbonylmethyl-5-phenylsulfonylamino-phenyl) -aminocarbonyl-methyll-benzam id in

A mixture of 0.53 g (0.001 mol) of 4- [N- (2-ethoxycarbonylmethyl-5-phenylsulfonylaminophenyl) aminocarbonylmethyl] benzamidine, 0.2 g (0.005 mol) of sodium hydroxide, 15 ml of water and 3 ml of ethanol becomes 2 Stirred for hours at room temperature. Then it is diluted with 10 ml of water and neutralized with 2 molar hydrochloric acid. The crystalline product is filtered off, dissolved in 10 ml of tetrahydrofuran and 3 ml of water, adjusted to pH 4 with 2 molar hydrochloric acid and evaporated. Yield: 0.31 g (62% of theory), C ₂₃ H ₂₂ N ₄ θ ₅ S x HCl (466.51 / 502.97) mass spectrum: (M + H) ⁺ = 467

(M + Na) ⁺ = 489 Example 22

4- {N- [5- (N '- (Ethoxycarbonylmethyl) -N' - (naphth-1-yl-sulfonyl) -amino) -2-methyl-phenvII-aminocarbonvirnethyD-benzamidine

a. 5- ^ N-Ethoxycarbonylmethyl-N- (naphth-1-yl-sulfonyl) -amino1-2-methyl-nitrobenzene To a solution of 6 g (0.017 mol) of 2-methyl-5- (naphthyl-1-yl-sulfonyl ) Amino-nitrobenzene in 120 ml of dimethyl sulfoxide is first added 2 g (0.018 mol) of potassium tert-butoxide and after 30 minutes 2.5 ml (0.023 mol) of ethyl bromoacetate and stirred for 12 hours. The reaction mixture is then diluted with ether, washed with 14% sodium chloride solution and dried. The solvent is distilled off and the residue is purified by chromatography (silica gel; dichloromethane / ethanol = 99: 1)

Yield: 6.7 g (92% of theory),

R _f value: 0.64 (silica gel; dichloromethane / ethanol = 50: 1)

b. 5-rN-ethoxycarbonylmethyl-N- (naphth-1-yl-ylsulfonvπ-aminol-2-methyl-aniline Prepared analogously to Example 1b from 5- [N-ethoxycarbonylmethyl-N- (naphth-1-yl-sulfonyl) amino] -2-methyl-nitrobenzene, 10% palladium on carbon and hydrogen in methanol.

Yield: 99% of the thoery,

R _f value: 0.46 (silica gel; dichloromethane / ethanol = 19: 1)

c. 4- (N-r5- (N '- (Ethoxycarbonylmethvπ-N' - (naphth-1-yl-sulfonyl) -amino) -2-methyl-phenvII-aminocarbonvirnethyD-benzamidine

Prepared analogously to Example 1c from 5- [N-ethoxycarbonylmethyl-N- (naphth-1-yl-sulfonyl) amino] -2-methyl-aniline, 4-cyanophenylacetic acid and N.N'-carbonyldiimidazole in tetrahydrofuran, subsequent reaction analogous to Example 1d with hydrogen chloride gas saturated ethanol and ammonium carbonate. Yield: 39% of theory, C ₃ oH ₃₀ N ₄ O ₅ S x HCl (558.7 / 595.1) mass spectrum: (M + H) ⁺ = 559 Example 23

4- {N-f5- (N '- (Morpholinocarbonylmethyl) -N' - (naphth-1-yl-sulfonyl) amino) -2-methylphenyl] aminocarbonylmethyl) benzamidine

Prepared analogously to Example 1d from 4- {N- [5- (N '- (Morpholinocarbonylmethyl) -N -

(naphth-1-yl-sulfonyl) amino) -2-methylphenyl] aminocarbonylmethyl} benzonitrile, with

Hydrogen chloride gas saturated ethanol and ammonium carbonate.

Yield: 13% of theory,

C ₃₂ H ₃₃ N ₅ θ ₅ S x HCI (599.7 / 636.18)

Mass spectrum: (M + H) ⁺ = 600

Example 24

4- (N-f5- (N'-Methyl-N '- (naphth-1-yl-sulfonyl) amino) -2-methyl-phenvn-aminocarbonyl-methvD-benzamidine

Prepared analogously to Example 1d from 4- {N- [5- (N'-methyl-N '- (naphth-1-yl-sulfonyl) amino) -2-methylphenyl] aminocarbonylmethyl} benzonitrile, saturated with hydrogen chloride gas Ethanol and ammonium carbonate.

Yield: 51% of theory,

C ₂₇ H ₂ 6N4O ₃ S x CH ₃ COOH (486.6 / 546.6)

Mass spectrum: (M + H) ⁺ = 487

Example 25

4-fN-r5- (N'-Hydroxycarbonylmethyl-N '- (naphth-1-yl-sulfonyl) -amino) -2-methyl-phenvinyl-aminocarbonvirnethylvbenzamidine

Prepared analogously to Example 21 from 4- {N- [5- (N'-ethoxycarbonylmethyl-N '- (naphth-1-ylsulfonyl) amino) -2-methylphenyl] aminocarbonylmethyl} benzamidine, sodium hydroxide solution in

Ethanol / water and subsequent treatment with hydrochloric acid.

Yield: 87% of theory,

C ₂ 8H26 ₄ O ₅ S x HCI (530.6 / 567.1)

Mass spectrum: (M + H) ⁺ = 531 Example 26

4- [N- (2-methyl-5-phenylaminosulfonyl-phenyl) -aminocarbonylmethvπ-benzamidine

Prepared analogously to Example 1d from 4- [N- (2-methyl-5-phenylaminosulfonylphenyl) - aminocarbonylmethylj-benzonitrile, ethanol saturated with hydrogen chloride gas and

Ammonium carbonate.

Yield: 17% of theory,

C ₂₂ H ₂₂ N ₄ O ₃ S x HCI (422.5 / 458.97)

Mass spectrum: (M + H) ⁺ = 423

Example 27

4- (N-r2-Methyl-4- (quinolin-8-yl-sulfonylamino) -phenvn-aminocarbonylmethyl) benzamidine

Prepared analogously to Example 1d from 4- {N- [2-methyl-4- (quinolin-8-yl-sulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate. Yield: 26% of theory, C ₂₅ H ₂₃ N ₅ θ ₃ S x HCl (473.6 / 510.1) mass spectrum: (M + H) ⁺ = 474

(2M + H) ⁺ = 947

Example 28

4-fN-r2-methyl-5- (1.2.3.4-tetrahvdroquinolin-8-yl-sulfonylamino) -phenyll-amino-carbonylmethyll-benzamidine

Prepared analogously to Example 1d from 4- {N- [2-methyl-5- (1, 2,3,4-tetrahydroquinolin-8-yl-sulfonylamino) phenyl] aminocarbonylmethyl} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate.

Yield: 43% of theory,

C ₂₅ H ₂₇ N ₅ O ₃ S x 2 HCI (477.6 / 550.52)

Mass spectrum: (M + H) ⁺ = 478 Example 29

4- {N- (4-Benzyl-phenyl) -N-ethyl-aminocarbonylmethyloxy) -benzamidine Prepared analogously to Example 1d from 4- {N- (4-benzyl-phenyl) -N-ethyl-aminocarbonyl-methyloxyj-benzonitrile, with Hydrogen chloride gas saturated ethanol and ammonium acetate.

Yield: 33% of theory, C ₂₄ H ₂₅ N ₃ O ₂ x Hl (387.48 / 515.40) mass spectrum: (M + H) ⁺ = 388

Example 30

4- {2- (N-r4- (N'-Ethoxycarbonylmethyl-N '- (naphth-1-yl-sulfonvπ-amino) -phenyll-N-ethyl-aminocarbonvDethylj-benzamidine

a. 4- (naphth-1-yl-sulfonylamino) nitrobenzene

10 g (0.042 mol) of naphthalene-4-sulfonic acid chloride are added to a solution of 5.8 g (0.042 mol) of 4-nitrobenzene in 20 ml of pyridine while cooling in an ice bath and the mixture is heated to a bath temperature of 100 ° C. within 20 minutes. After a further 20 minutes, the mixture is cooled to 50 ° C., 8 ml of 6 molar sodium hydroxide solution are added, and the mixture is then stirred at 60 ° C. for 20 minutes. The solvent is distilled off, the residue is stirred into 150 ml of water and the product is filtered off with suction. Yield: 11.2 g (81% of theory), melting point: 210-215 ° C.

b. 4-fN-ethoxycarbonylmethyl-N-fnaphth-1-yl-sulfonyl) -amino1-nitrobenzene

3.9 g (39 mmol) of potassium tert-butoxide are added to a solution of 11.1 g (33.8 mmol) of 4- (naphthalene-1-sulfonylamino) nitrobenzene in 100 ml of dimethylformamide at 0 ° C and 7 g (42 mmol) ethyl bromoacetate. The mixture is then stirred for 1.5 hours at 0 ° C and 12 hours at room temperature. Then it is diluted with ethyl acetate and washed with water. The organic see phase is dried and evaporated. The residue is purified by chromatography (silica gel; methylene chloride). Yield: 14 g (100% of theory), R _f value: 0.43 (silica gel; dichloromethane)

c. 4-rN-ethoxycarbonylmethyl-N- (naphth-1-yl-sulfonyl) -aminoj-aniline

Prepared analogously to Example 1b from 4- [N-ethoxycarbonylmethyl-N- (naphth-1-yl-sulfonyl) -amino] -nitrobenzene, 10% palladium on carbon and hydrogen in

Ethanol.

Yield: 82% of theory,

Melting point: 98-103 ° C

C ₂ oH ₂ oN ₂ O ₄ S (384.45)

Mass spectrum: M ⁺ = 384

d. N-r4- (N'-ethoxycarbonylmethyl-N '- (naphth-1-yl-sulfonvπ-amino) -phenyll-ethylamine To a solution of 3.2 g (84 mmol) of 4- [N-ethoxycarbonylmethyl-N- (naphth- 1-yl-sulfonyl) -amino] -aniline in 100 ml of methanol, 0.48 ml (84 mmol) of acetaldehyde and 0.48 ml of glacial acetic acid are added at 0 ° C. and 0.53 g (84 mmol) of sodium cyanoborohydride are then added in portions, and the reaction is then allowed to proceed come to room temperature and stir for a further 5 hours. The solvent is distilled off, the residue is taken up in ethyl acetate and washed with water. The combined organic extracts are dried and evaporated. Yield: 3.3 g (95% of theory),

R _f value: 0.36 (silica gel; dichloromethane / ethyl acetate = 19: 1)

e. 4- (2- (N-r4- (N'-Ethoxycarbonylmethyl-N '- (naphth-1-yl-sulfonyl) amino) -phenvn-N-ethyl-aminocarbonyl) ethyl) -benzonitrile

0.96 ml (86 mmol) of N-methylmorpholine and 1 ml (79 mmol) of isobutyl chloroformate are added to a solution of 1.3 g (72 mmol) of 4-cyanophenylpropionic acid in 70 ml of tetrahydrofuran at -40 ° C and the mixture is stirred for 1 hour. Then 3.4 g (82 mmol) of N- [4- (N'-ethoxycarbonylmethyl-N'- (naphth-1-y! -Sulfonyl) -amino) -phenyl] -ethylamine are added at 0 ° C. and the reaction is allowed to - warm up to room temperature overnight. Then it is diluted with ethyl acetate and washed with water. The combined organic extracts are dried and evaporated. The residue is purified by chromatography (silica gel; dichloromethane / ethyl acetate = 19: 1). Yield: 1.3 g (32% of theory).

f. 4- (2- (N-r4- (N'-Ethoxycarbonylmethyl-N '- (naphth-1-yl-sulfonyl) -amino) -phenvn-N-ethvI-aminocarbonvIlethvD-benzamidine

In a solution of 1.25 g (2.2 mmol) of 4- {2- {N- [4- (N'-ethoxycarbonylmethyl-N'- (naphth-1-yl-sulfonyl) amino) phenyl] -N-ethyl- aminocarbonyl} ethyl} -benzonitrile and 0.66 g (7 mmol) of triethylamine in 30 ml of pyridine is introduced for 20 minutes at 0 ° C. hydrogen sulfide and stirred for 20 minutes. The solvent is then distilled off, the residue is taken up in dichloromethane and washed with water. The organic phase is dried and evaporated. The residue is taken up in 40 ml of acetone and 3.1 g (0.022 mol) of methyl iodide are added. After 48 hours, the mixture is evaporated, the crude product is taken up in 50 ml of ethanol, 0.9 g (0.012 mol) of ammonium acetate are added and the mixture is stirred at room temperature for 20 hours. After evaporation of the solvent, the residue is purified by chromatography (silica gel; dichloromethane / ethanol = 9: 1). Yield: 0.5 g (31% of theory), melting point: 75-79 ° CC ₃₂ H ₃₄ N ₄ θ ₅ S x Hl (586.71 / 714.62) mass spectrum: (M + H) ⁺ = 587

Example 31

4- (2- (N-r4- (N'-Hydroxycarbonylmethyl-N'-maphth-1-yl-sulfonyl) -aminoVphenyll-N-ethyl-aminocarbonyltethyll-benzamidine

Prepared analogously to Example 21 from 4- {2- {N- [4- (N'-ethoxycarbonylmethyl-N '- (naphth-1-yl-sulfonyl) amino) phenyl] -N-ethyl-aminocarbonyl} ethyl} - benzamidine, sodium hydroxide solution in

Ethanol and subsequent treatment with hydrochloric acid.

Yield: 50% of theory, Melting point: 191-195 ° CC ₃ oH ₃ oN ₄ θ ₅ S x HCl (558.66 / 595.12) Mass spectrum: (M + H) ⁺ = 559

(M + Na) ⁺ = 581

Example 32

4-fN-r2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropyl-amino) -phenyl-aminocarbonyl-methyl-benzamidine

Prepared analogously to Example 1d from 4- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenyl] aminocarbonylmethyl} benzonitrile, with

Hydrogen chloride gas saturated ethanol and ammonium acetate.

Yield: 64% of theory,

C2 ₅ H33N5O4 x HCI (467.57 / 504.03)

Mass spectrum: (M + H) ⁺ = 468

(M + Cl) - = 502/04 (chlorine isotopes)

Example 33

4- {2- {N-f2.5-Dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropyl-amino) -phenvII-aminocarbonyllethyl-benzamidine

Prepared analogously to Example 1d from 4- {2- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenyl] aminocarbonyl} ethyl} benzonitrile, with

Hydrogen chloride gas saturated ethanol and ammonium acetate. Yield: 73% of theory, C ₂₆ H35N5O4 x HCl (481.59 / 518.06) mass spectrum: (M + H) ⁺ = 482

(M-HV = 480 Example 34

4- {N-r4-Phenylsulfonylamino-phenvn-N-ethyl-aminocarbonylmethylaminoV benzamidine

Prepared analogously to Example 1d from 4- {N- [4-phenylsulfonylaminophenyl] -N-ethylaminocarbonylmethylamino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium carbonate.

Yield: 54% of theory,

C ₂₃ H ₂₅ N ₅ O ₃ S x HCI (451.55 / 488.01)

Mass spectrum: (M + H) ⁺ = 452

Example 35

4- (N-rN'-ethyl-N '- (4-piperidinomethylphenyl) aminocarbonylmethvn-N-ethoxycarbonylmethylamino) benzamidine

a. N-ethyl aniline-4-piperidinomethyl-

10 ml of formaldehyde (37% in water) are added dropwise to 8.5 g (0.1 mol) of piperidine while cooling with ice and then 12.1 g (0.1 mol) of N-ethyl-aniline and then 3 g (0.05 mol) of glacial acetic acid are added dropwise at 15 ° C. Then 40 ml of ethanol are added and the mixture is heated under reflux for 18 hours. The ethanol is distilled off, the residue is taken up in dichloromethane and washed with dilute sodium hydroxide solution. The organic phase is dried and purified by chromatography (silica gel; ethyl acetate). Yield: 6.4 g (30% of theory), R _f value: 0.35 (silica gel; ethyl acetate / ethanol / ammonia = 9: 1: 0.1)

b. 4-fN-rN'-ethyl-N '- (4-piperidinomethyl-phenvπ-aminocarbonylmethyll-N-ethoxycarbonylmethyl-aminol-benzamidine

Prepared analogously to Example 30e from N-ethyl-4-piperidino-methyl-aniline, 4- (N-

Hydroxycarbonylmethyl-N-methoxycarbonyl) -amino-benzonitrile, N-methyl-morpholine and isobutyl chloroformate in tetrahydrofuran. Yield: 58% of theory,

R _f value: 0.74 (silica gel; dichloromethane / ethyl acetate = 9: 1)

c. 4- (N-rN'-ethyl-N '- (4-piperidinomethyl-phenyl) -aminocarbonylmethvn-N-ethoxy-carbonylmethyl-aminol-benzamidine

Prepared analogously to Example 1d from 4- {N- [ethyl- (4-piperidino-methyl-phenyl) -amino-carbonylmethyl] -methoxycarbonylmethyl} -amino-benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate.

Yield: 52% of theory,

C27H ₃ 7N5O ₃ x 2 HCI (479.63 / 552.55)

Mass spectrum: (M + H) ⁺ = 480

Example 36

4- (N-rN'-ethyl-N '- (3-benzyl-phenyl) -aminocarbonylmethvn-N-ethoxycarbonylmethylaminoT-benzamidine

Prepared analogously to Example 1d from 4- {N- [N'-ethyl-N '- (3-benzylphenyl) aminocarbonylmethyl] -N-ethoxycarbonylmethylamino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate.

Yield: 47% of theory,

C _2S H32N4O ₃ x HCI (472.59 / 509.05)

Mass spectrum: (M + H) ⁺ = 473

Example 37

4-fN-rN'-ethyl-N '- (4-fpyridin-3-yl-methvπ-phenvπ-aminocarbonylmethyll-N-ethoxycarbonylmethyl-aminol-benzamidine

Prepared analogously to Example 1d from 4- {N- [N'-ethyl-N '- (4- (pyridin-3-ylmethyl) phenyl) aminocarbonylmethyl] -N-ethoxycarbonylmethylamino} benzonitrile, saturated with hydrogen chloride gas Ethanol and ammonium acetate. Yield: 51% of theory, C ₂₇ H3iN ₅ O ₃ x HCl (473.54 / 510.04) Mass spectrum: (M + H) ⁺ = 474

Example 38

4- (N-r4- (3,5-Diethyl-pyrazol-1-yl ^' ) -3-methyl-phenylaminocarbonylmethvnamino) benzamidine

a. 4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-iodobenzene

A mixture of 0.7 g (5.07 mmol) of heptane-3,5-dione, 1.4 g (5.06 mmol) of 4-hydrazino-3-methyl-iodobenzene and 0.7 ml (5.1 mmol) of triethylamine are stirred in 40 ml of methanol for 3 hours at room temperature , The solvent is distilled off, the residue is taken up in 100 ml of ether, washed with 50 ml of 1N hydrochloric acid, dried and evaporated. The crude product is purified by chromatography (silica gel; dichloromethane / ethanol = 99: 1 to 97: 3). Yield: 1.1 g (64% of theory), Cι ₄ H ₁₇ IN ₂ (340.21)

Mass spectrum: (M + H) ⁺ = 341

(2M + H) ⁺ = 681

b. 4- (3,5-diethyl-pyrazol-1-vD-3-methyl-N-benzyl-aniline

A mixture of 1.1 g (3.2 mmol) of 4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-iodobenzene, 0.5 ml (4.57 mmol) of benzylamine, 44 mg (0.19 mmol) of palladium (II) acetate, 120 mg (0.19 mmol) of 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl and 0.6 g (6.4 mmol) of sodium tert-butoxide are stirred in 50 ml of dioxane at 100 ° C. for 2 hours , The solvent is then distilled off and the residue is purified by chromatography (silica gel; dichloromethane / ethanol = 49: 1). Yield: 0.7 g (68% of theory), C ₂₁ H ₂₅ N ₃ (319.45) mass spectrum: (M + H) ⁺ = 320

(M-H) - = 318

(2M + Na) ⁺ = 661 c. 4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-aniline

0.7 g (2.2 mmol) of 4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-N-benzyl-aniline are dissolved in 40 ml of methanol and, after addition of 0.5 g of palladium hydroxide on carbon, for 4 hours at room temperature hydrogenated with 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated. Yield: 0.2 g (48% of theory), Cι ₄ H ₁₉ N ₃ (229.33)

Mass spectrum: (M + H) ⁺ = 230

(M + Na) ⁺ = 252

d. N-r4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-phenyllaminocarbonylmethylbromid

0.2 g (1 mmol) of 4- (3,5-diethyl-pyrazole-1) are added to a solution of 0.1 ml (1 mmol) of bromoacetyl chloride and 0.2 g (1.5 mmol) of potassium carbonate in 15 ml of dioxane and 15 ml of water at 0 ° C -yl) -3-methyl-aniline added dropwise. After 10 minutes, the solvent is distilled off, the residue is taken up in 200 ml of ethyl acetate and 50 ml of water, the organic phase is separated off, dried and evaporated. Yield: 0.4 g (100% of theory).

e. 4- {N-r4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-phenylaminocarbonylmethyllaminol-benzonitrile

A mixture of 0.3 g (0.86 mmol) of N- [4- (3,5-diethyl-pyrazol-1-yl) -3-methylphenyl] aminocarbonylmethyl bromide and 0.2 g (1.28 mmol) of 4-cyanoaniline is dissolved in 15 ml N-ethyl-diisopropylamine stirred at 100 ° C for 3 hours. The reaction mixture is then concentrated and purified by chromatography. Yield: 40 mg (12% of theory), C ₂₃ H ₂₃ N ₅ O (387.49) mass spectrum: (MH) ^" = 386 f. 4- {N-r4- (3,5-diethyl-pyrazol-1-yl) -3-methyl-phenylaminocarbonylmethyllamino) benzamidine

Prepared analogously to Example 1d from 4- {N- [4- (3,5-diethyl-pyrazol-1-yl) -3-methylphenylaminocarbonylmethyl] amino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate. Yield: 79% of theory, C ₂₃ H ₂ sN ₆ O x HCl (404.43 / 440.98) mass spectrum: (M + H) ⁺ = 405

Example 39

4- {N-r3-Methyl-4- (pyrrolidinocarbonvπ-phenylaminocarbonylmethvnamino} - benzamidine

Prepared analogously to Example 1d from 4- {N- [3-methyl-4- (pyrrolidinocarbonyl) phenylaminocarbonylmethyl] amino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate. Yield: 59% of theory, C ₂ ιH ₂₅ N ₅ θ2 x HCl (379.47 / 415.93) mass spectrum: (M + H) ⁺ = 380

Example 40

4 N-rN'-methyl-3-methyl-4-pyrrolidinocarbonyl) phenylaminocarbonylmethvnamino) benzamidine

Prepared analogously to Example 1d from 4- {N- [N'-methyl-3-methyl-4- (pyrrolidinocarbonyl) phenylaminocarbonylmethyl] amino} -benzonitrile, saturated with hydrogen chloride gas

Ethanol and ammonium acetate.

Yield: 59% of theory,

C ₂₂ H ₂ 7N5O2 x HCI (393.49 / 429.95)

Mass spectrum: (M + H) ⁺ = 394

(M-H + HCI) ^" = 428/30 (chlorine isotopes) Example 41

4- (N-Methyl-N-r4- (N'-methyl-N '- (pyridin-2-yl) aminocarbonyl) -3-methyl-phenylamino-carbon-methylethyl-amino-T-benzamidine

Prepared analogously to Example 1d from 4- {N-methyl-N- [4- (N'-methyl-N '- (pyridin-2-yl) - aminocarbonyl) -3-methyl-phenylaminocarbonylmethyl] amino} -benzonitrile, with hydrogen chloride gas saturated ethanol and ammonium acetate. Yield: 21% of theory, C ₂₄ H ₂₆ N ₆ O ₂ x HCl (430.51 / 466.98) mass spectrum: (M + H) ⁺ = 431

Example 42

4- {N-r2.5-Dimethyl-4- (2-methyl-pyrrolidinocarbonyl) phenyl aminocarbonylmethyl] aminol benzamidine

Prepared analogously to Example 1d from 4- {N- [2,5-dimethyl-4- (2-methyl-pyrrolidinocarbonyl) phenylaminocarbonylmethyl] amino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate.

Yield: 100% of theory,

C ₂₃ H ₂₉ N ₅ θ ₂ x HCI (407.52 / 443.98)

Mass spectrum: (M-H + HCI) ^" = 442/44 (chlorine isotopes)

Example 43

4- (N-r2,5-Dimethyl-4- (N'-methyl-N'-phenylaminocarbonyl) phenylaminocarbonylmethyl] amino) benzamidine

Prepared analogously to Example 1d from 4- {N- [2,5-dimethyl-4- (N'-methyl-N'-phenylaminocarbonyl) phenylaminocarbonylmethyl] amino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate. Yield: 36% of theory, C ₂₅ H ₂₇ N ₅ O ₂ x HCl (429.53 / 465.99) mass spectrum: (M + H) ⁺ = 430 Example 44

4-fN- (2,5-dimethyl-4-isopropylcarbonyl-phenylaminocarbonylmethyl) amino1-benzamidine

Prepared analogously to Example 1d from 4- [N- (2,5-dimethyl-4-isopropylcarbonyl-phenylaminocarbonylmethyl) amino] benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate. Yield: 30% of theory, C21H2 ₆ N4O2 x HCl (366.47 / 402.93) mass spectrum: (M + H) ⁺ = 367

Example 45

4- {N-f2,5-Dimethyl-4-isobutyl-phenylaminocarbonylmethyll-amino} -benzamidine When converting 2,5-dimethyl-4-isopropylcarbonyl-N-benzyl-aniline to 2,5-dimethyl-4-isopropylcarbonyl -aniline analogous to Example 38c, 2,5-dimethyl-4-isobutyl-aniline is also obtained as an inseparable by-product. The mixture was converted into the corresponding amide using 4-cyanophenylaminoacetic acid and N, N'-carbonyldiimidazole in tetrahydrofuran and then analogously to Example 1d to give a mixture of 4- {N- [2,5-dimethyl-4-isopropylcarbonylphenyl - aminocarbonylmethyl] amino} -benzamidine and 4- {N- [2,5-dimethyl-4-isobutylphenyl] - aminocarbonylmethylaminoj-benzamidine, which is purified by HPLC (Inertsil ODS2, 250 mm x 10 mm, 5 μm, 0.1% KH ₂ PO ₄ / methanol, retention time of the title compound: 21.25 minutes). C ₂ iH ₂₈ N ₄ O x HCl (352.48 / 388.49) mass spectrum: (M + H) ⁺ = 353

Example 46

4- (N-r2.5-Dimethyl-4- (N'-isopropyl-N '- (2-ethoxycarbonylethylcarbonyl) -aminoV phenvIaminocarbonvImethyllaminoT-benzamidine of the formula

a. 2.5-dimethyl-4-isopropylamino-benzyloxycarbonyl-aniline

To a solution of 2.1 g (7.7 mmol) of 4-amino-2,5-dimethyl-benzyloxycarbonyl-aniline and 0.6 ml (8.5 mmol) of acetone in 30 ml of tetrahydrofuran are 0.7 ml (11.6 mmol)

Glacial acetic acid and 0.1 g (1 mmol) of p-toluenesulfonic acid were added and the mixture was stirred for 30 minutes.

Then 2.3 g (10.1 mmol) of sodium triacetoxyborohydride are added and 3

Stirred for days. Then it is diluted with water, made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is purified by chromatography (silica gel; petroleum ether / ethyl acetate = 85:15 to 75:25).

Yield: 2.1 g (87% of theory),

R _f value: 0.35 (silica gel; petroleum ether / ethyl acetate = 9: 1)

C ₁₉ H ₂₄ N ₂ O ₂ (312.42)

Mass spectrum: (MH) ^" = 311

b. 2,5-dimethyl-4-rN- (2-ethoxycarbonylethylcarbonyl) -N-isopropyl-aminol-N-benzyl-oxycarbonyl-aniline

A mixture of 0.9 ml (6.1 mmol) of succinic acid monoethyl ester monochloride, 2.1 g (6.7 mmol) of 2,5-dimethyl-4-isopropylamino-benzyloxycarbonyl-aniline, 3.2 ml (18.3 mmol) of Hünig base and 74.7 mg (0.6 mmol) of 2-dimethylamino -pyridine are in 50 ml

Tetrahydrofuran stirred for 5 hours. Then the solvent distilled off and the residue purified by chromatography (silica gel; dichloromethane / ethanol = 98: 2). Yield: 1.9 g (70% of theory), R _f value: 0.18 (silica gel; petroleum ether / ethyl acetate = 3: 1)

c. 2.5-Dimethyl-4-fN- (2-ethoxycarbonylpropionyl) -N-isopropyl-aminol-aniline Prepared analogously to Example 1b from 2,5-dimethyl-4- [N- (2-ethoxycarbonylethylcarbonyl) -N-isopropyl-amino ] -N-benzyloxycarbonyl-aniline, 10% palladium on carbon and hydrogen in methanol.

Yield: 100% of theory,

R _f value: 0.23 (silica gel; dichloromethane / ethanol = 95: 5)

Cι ₇ H ₂₆ N ₂ O ₃ (306.41)

Mass spectrum: (M + Na) ⁺ = 329

d. 4- (N-r2.5-Dimethyl-4- (N'-isopropyl-N '- (2-ethoxycarbonylethylcarbonyl) amino) - phenylaminocarbonvImethvIlaminoVbenzonitril

A mixture of 1.3 g (4.3 mmol) of 2,5-dimethyl-4- [N- (2-ethoxycarbonylpropionyl) -N-isopropylamino-aniline, 1.0 g (5.5 mmol) of N- (4-cyano-phenyl) -glycine, 1.8 g (5.5 mmol) of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate and 0.8 ml (5.5 mmol) of triethylamine are stirred in 35 ml of dimethylformamide for 4 hours. The reaction mixture is poured onto water and extracted with ethyl acetate. The combined organic extracts are evaporated and then purified by chromatography (silica gel; dichloromethane / ethanol = 97: 3). Yield: 1.7 g (88% of theory), R _f value: 0.23 (silica gel; dichloromethane / ethanol = 95: 5) Mass spectrum: (M + H) ⁺ = 465

(M + Na) ⁺ = 487 e. 4- {N- [2,5-Dimethyl-4- (N'-isopropyl-N '- (2-ethoxycarbonylethylcarbonyl) amino) - phenylaminocarbonvImethvIlaminoVbenzamidin

Prepared analogously to Example 1d from 4- {N- [2,5-dimethyl-4- (N'-isopropyl-N '- (2-ethoxycarbonylethylcarbonyl) amino) phenylaminocarbonylmethyl] amino} benzonitrile, with

Hydrogen chloride gas saturated ethanol and ammonium acetate.

Yield: 79% of theory,

C ₂₆ H ₃₅ N ₅ θ ₄ x HCI (481.59 / 518.06)

Mass spectrum: (M + H) ⁺ = 482

Example 47

4- {N- [2,5-Dimethyl-4- (N '- (2-hydroxycarbonylethylcarbonyl-N'-isopropylamino) phenylaminocarbonylmethylamino) benzamidine

0.3 g (0.6 mmol) of 4- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylethylcarbonyl-N'-isopropylamino) phenyl] aminocarbonylmethylamino} benzamidine are 6 molar in 35 ml

Hydrochloric acid stirred for 7 hours. It is then evaporated, the residue in

Acetone taken up and evaporated again.

Yield: 0.3 g (88% of theory),

C ₂₄ H ₃ ιN ₅ O ₄ x HCI (453.55 / 490.01)

Mass spectrum: (M + H) ⁺ = 454

(M-H) - = 452

(M-H + HCI) ^" = 488/90 (chlorine isotopes)

Example 48

4-fN-f2.5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) - phenvπ-aminocarbonylmethylamino-benzamidine

Prepared analogously to Example 1d from 4- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenyl] aminocarbonylmethylamino} benzonitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate.

Yield: 42% of theory,

C2 ₅ H3 ₄ N ₆ O ₄ x HCI (482.59 / 519.06) Mass spectrum: (M + H) ⁺ = 483

(MH) ^' = 481

(M-H + HCI) ^" = 517/519 (chlorine isotopes)

Example 49

4- (N-r2.5-Dimethyl-4- (N'-hydroxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenylaminocarbonylnethylaminol-benzamidine

Prepared analogously to Example 21 from 4- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenyl] aminocarbonylmethylamino} benzamidine and sodium hydroxide in ethanol / water and subsequent treatment with Hydrochloric acid.

Yield: 48% of theory, C ₂₃ H3oN ₆ θ4 (454.53) mass spectrum: (MH) ^" = 453

(M + H) ⁺ = 455

(M + Na) ⁺ = 477

Example 50

4- (N-r2,5-Dimethyl-4- (N '- (3-amino-3-ethoxycarbonyl-propionyl) -N'-isopropyl-amino) -phenyl-aminocarbonyl-methylamino-benzamidine

Prepared analogously to Example 1d from 4- {N- [2,5-dimethyl-4- (N '- (3-amino-3-ethoxycarbonylpropionyl) -N'-isopropylamino) phenyl] aminocarbonylmethylamino} -benzo-nitrile, ethanol saturated with hydrogen chloride gas and ammonium acetate.

Yield: 17% of theory,

C ₂₆ H ₃ 6N ₆ θ4 x 2 HCI (496.62 / 569.54)

Mass spectrum: (M + H) ⁺ = 497 Example 51

4-fN-r2.5-dimethyl-4- (N '- (3-amino-3-hydroxycarbonyl-propionvπ-N'-isopropyl-aminoV phenyll-aminocarbonylmethylaminol-benzamidine

Prepared analogously to Example 21 from 4- {N- [2,5-dimethyl-4- (N '- (3-amino-3-ethoxycarbonylpropionyl) -N'-isopropylamino) phenyl] aminocarbonylmethylamino} -benz- amidine and sodium hydroxide in methanol / water and subsequent treatment with hydrochloric acid.

Yield: 25% of theory,

C ₂₄ H ₃₂ N ₆ θ ₄ x 2 HCI (468.56 / 541.48)

Mass spectrum: (M + H) ⁺ = 469

Example 52

4- (N-f2.5-Dimethyl-4- (N'-hydroxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenylaminocarbonylmethyll-benzamidine

Prepared analogously to Example 47 from 4- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenyl] aminocarbonylmethyl} benzamidine and 6N hydrochloric acid.

Yield: 95% of theory, C _20S H ₂₉ N5O4X HCI (439.52 / 475.98) mass spectrum: (M + H) ⁺ = 440

(MH) ^' = 438

Example 53

4- (2- {N-f2,5-Dimethyl-4- (N'-hydroxycarbonylmethylaminocarbonyl-N'-isopropylamino) -phenvπ-aminocarbonyl) ethyl) -benzamidine

Prepared analogously to Example 47 from 4- {2- {N- [2,5-dimethyl-4- (N'-ethoxycarbonylmethylaminocarbonyl-N'-isopropylamino) phenyl] aminocarbonyl} ethyl} benzamidine and 6N

Hydrochloric acid.

Yield: 91 of theory, C ₂₄ H ₃₁ N ₅ θ4X HCI (453.55 / 490.01) mass spectrum: (M + H) ⁺ = 454

(M-H) - = 452

Example 54

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 55

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 56

Tablet with 50 mg of active ingredient

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 57

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) polyvinyl pyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg

600.0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (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 58

Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Dried corn starch 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 trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine. Example 59

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) Corn starch dried 46.0 mg

(3) Milk sugar powdered 30.0 mg

(4) Magnesium stearate 4.0 mq

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 in a size 0 hard gelatin capsule on a capsule filling machine.

Example 60

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

2,000.0 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. Substituted N-acyl aniline derivatives of the general formula in the A is a methylene group which is optionally substituted by a C _-3 alkyl group or a straight-chain C _2-3 alkyl group optionally substituted by a C 1 -C ₃ -alkyl group, in which the methylene group linked to the aromatic or heteroaromatic can be replaced by an oxygen or sulfur atom or by an -NH group, where the -NH group additionally by a C _1-3 alkyl, carboxy Cι _-3 alkyl or Cι- ₃ alkoxycarbonyl Cι. ₃ -alkyl group can be substituted, R ^{1 is} a hydrogen atom or a C ¹ -C 3 -alkyl group which is optionally substituted by a carboxy group, R ^{2 is} a cyano, aminomethyl or amidino group, R ^{3 is} a C ₅ alkyl or carboxy ₄ alkyl group, each in the alkyl part by a C ₃ - ₇ cycloalkyl, phenyl, pyridyl, pyrrolidino, 2,5-dihydro-1 H pyrrolino, piperidino or hexamethyleneimino group can be substituted, a carbonyl or sulfonyl group, each by a possibly by a Cι. ₃ -Alkyl- or carboxy-Cι _-3 alkyl group substituted Cι _-5 alkyl-, C ₃ . _7- cycloalkyl or phenyl group, by a by a Cι _-5 alkyl, C _3-7 cycloalkyl, phenyl, phenyl-Cι. ₃ -alkyl-, pyridyl- or pyridyl-Cι _-3 -alkyl group substituted amino, C- _M -alkylamino or carboxy-Cι _-4 -alkylamino group or by a possibly by a Cι. ₃ -alkyl- or carboxy-Cι _-3 -alkyl group substituted pyrrolidino, 2,5-dihydro-1 H-pyrrolino, piperidino or hexamethyleneimino group is substituted, a in the alkyl part optionally substituted by an amino, C _1-3 -alkylamino or di- (C-ι- ₃ -alkyl) -amino group, carboxy-Cι- ₃ -alkylcarbonylamino group, an amino, carboxy-Cι- ₃ -alkylaminocarbonylamino -, Carboxy-Cι- ₃ -alkylamino- carbonyl-Cι- ₃ -alkylcarbonylamino-, carboxy-Cι- ₃ -alkylaminocarbonyl-Cι- ₃ -alkylamino- carbonylamino-, amino-C-ι- ₃ -alkylcarbonylamino-, Cι _-3 -Alkylamino-Cι _-3 -alkylcarbonyl- amino- or di- (Cι _-3 -alkyl) -amino-Cι- ₃ -alkylcarbonylamino group, each in the above-mentioned amino groups the hydrogen atom of the amino group linked to the phenyl ring is replaced by a Ci-β-alkyl, C _3-7 cycloalkyl, phenyl or pyridyl group, to the above-mentioned phenyl or pyridyl substituents each via two adjacent carbon atoms n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring may be fused or the above-mentioned aromatic substituents each additionally by a C 1 -C ₃ -alkyl, C ₃ -C ₃ -alkyloxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups, an amino, carboxy-Cι _-4 -alkyIamino-, carboxy Cι_ ₃ alkylaminocarbonyl ₃ Cι_ alkyl amino, aminocarbonyl-Cι _-3 alkylamino, alkylaminocarbonyl Cι_ _{3-Cι -3} alkylamino, di - (Cι _-3 -alkyl) -aminocarbonyl-Cι _-3 -alkylamino-, amino-C _2-3 -alkylamino-, Cι _-4 -alkyl- amino-C _2-3 -alkylamino-, di- (Cι. ₄ -alkyl) -amino-C ₂ - ₃ -alkylamino-, pyrrolidinocarbonyl- Cι _-3 -alkylamino-, piperidinocarbonyl-C _1-3 -alkylamino-, hexahydroazepinocarbonyl- Cι- ₃ -alkylamino-, morpholinocarbonyl-Cι. ₃ -alkylamino-, piperazinocarbonyl-Cι_ ₃ -alkyl- amino- or N- (Cι- ₃ alkyl) -piperazinocarbonyl-Cι- ₃ -alkylamino group, each in the above-mentioned amino groups the hydrogen atom of the amino group, which is linked to the phenyl ring, by a Ci-s-alkylcarbonyl, Cι _-5 alkylsulfonyl, C ₃ . ₇ cycloalkylcarbonyl, C _3-7 -Cycloalkylsulfonyl-, benzoyl, phenylsulfonyl, phenyl-Cι- ₃ alkylcarbonyl, phenyl-Cι alkylsulfonyl _-3 or pyridinoyl group is substituted, the above-mentioned phenyl or pyridyl substituents in each case an n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring can be fused onto two adjacent carbon atoms or the aromatic substituents mentioned above can each additionally be substituted by a C _{3 -3} -alkyl, C- |. ₃ -alkyloxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups, one optionally by one, two or three Cι. _3- alkyl groups substituted phenyl, pyridyl, imidazolyl or pyrazolyl group, where the alkyl substituents may be the same or different and one of the alkyl substituents additionally by a carboxy, hydroxysulfonyl, aminosulfonyl, C 1-4 alkylaminosulfonyl , Di- (-C ₄ alkyl) -aminosulfonyl or C- _M alkylsulfonyl group may be substituted, R ^{4 is} a fluorine, chlorine, bromine or iodine atom, a carboxy, Cι. ₃ -Alkyl-, carboxy- C-ι- ₃ -alkyl, trifluoromethyl or Cι_ ₃ alkoxy group or a hydrogen atom, if R ^{3 is} a C ₅ alkyl or carboxy C ₄ alkyl group, each in the alkyl part by a C3-7 cycloalkyl, phenyl, pyridyl, pyrrolidino, 2,5-dihydro-1 H-pyrrolino , Piperidino or hexamethyleneimino group is substituted, represents an amino, carboxy-C ₄ alkylamino or carboxy-C ₃ -alkylaminocarbonyl C ₃ -alkylamino group, each in the above-mentioned amino groups the hydrogen atom of the amino group which is linked to the phenyl ring by a C-ι _-5 alkylcarbonyl, Cι_ ₅ alkylsifonyl, C _3-7 cycloalkylcarbonyl, C _3-7 cycloalkylsulfonyl, benzoyl, phenylsulfonyl , Phenyl-Cι- ₃ -alkylcarbonyl-, phenyl-Cι- ₃ -alkylsulfonyl- or pyridinoyl group is replaced, to the above-mentioned phenyl or pyridyl substituents, each via two adjacent carbon atoms, an n-propylene or n-butylene bridge, a phenyl, Pyridine or piperidine ring can be fused or the above-mentioned aromatic substituents each additionally by a C 1 -C ₃ alkyl, C 1. ₃ -alkyloxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups, R ^{5 is} a hydrogen, fluorine, chlorine, bromine or iodine atom, a C ₃ alkyl or trifluoromethyl group or R ⁴ and R ⁵ together form an nC ₃ . ₄ alkylene group, with the proviso that at least one of the radicals R ¹ , R ⁴ or R ^{5 is} not a hydrogen atom, and X, Y and Z each denote nitrogen atoms or -CH groups with the proviso that at least one of the groups X, Y and Z represents a -CH group, where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of the formula I defined above, unless stated otherwise, can be partially or completely replaced by fluorine atoms, and which also include their branched isomers in the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms, and the alkanoyl and unsaturated alkyl parts which contain more than 3 carbon atoms, the carboxy groups mentioned in the definition of the above radicals may be 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, or the amino or imino groups mentioned in the definition of the above radicals can be substituted by a radical which can be split off in vivo, their prodrugs, their tautomers, their stereoisomers, their mixtures and their salts. 2. Substituted N-acyl-aniline derivatives of the general formula I according to claim 1, in which A is a methylene group or a C _2-3 alkyl group in which the methylene group linked to the aromatic or heteroaromatic can be replaced by an -NH group or by an oxygen atom, the -NH group additionally being replaced by a C _{3 -3} -alkyl, carboxy- Cι _-3 alkyl or Cι _-3 alkoxycarbonyl-Cι- ₃ alkyl group may be substituted, R ^{1 is} a hydrogen atom or a C _1-3 alkyl group which is optionally substituted by a carboxy group, R ^{2 is} a cyano or aminomethyl group or an amidino group which is optionally substituted by a hydroxy, Ci-a-alkoxycarbonyl or benzoyl group, R ^{3 is} a C _-5 alkyl or carboxy-C ^ alkyl group, each in the alkyl part by a C _3- cycloalkyl, phenyl, pyridyl, pyrrolidino, 2,5-dihydro-1 H-pyrrolino , Piperidino or hexamethyleneimino group can be substituted, a carbonyl or sulfonyl group, each by an optionally alkyl group by a Cι_ ₃ alkyl or carboxy-substituted ₃ Cι- Cι- ₅ alkyl or C _3-7 cycloalkyl group, by a C 1 -C ₅ -alkyl, C ₃ -C 7 -cycloalkyl, phenyl, benzyl or pyridyl group substituted amino, C- -alkylamino or carboxy-C ₄ -C ₄ -alkyl amino group or is substituted by a pyrrolidino, 2,5-dihydro-1H-pyrrolino, piperidino or hexamethyleneimino group which is optionally substituted by a C ₃ alkyl or carboxy C ₃ alkyl group, a in the alkyl part optionally substituted by an amino group, carboxy-C ₃ alkylcarbonylamino group, an amino, carboxy-C ₃ -alkylaminocarbonyl-amino, carboxy-C _{3 -3-} alkylaminocarbonyl-C ₃ -alkylcarbonylamino, carboxy-C ₃ -alkylaminocarbonyl-Cι _-3 -alkylaminocarbonylamino- or amino-Cι- ₃ -alkylcarbonylamino group, each in the above-mentioned amino groups the hydrogen atom of the amino group which is linked to the phenyl ring, by a C _1-6 alkyl, C ₃ - is replaced ₇ cycloalkyl, phenyl or pyridyl group, the above-mentioned phenyl or pyridyl substituents in each case via two adjacent carbon atoms a phenyl, pyridine or piperidine ring can be fused on or the above-mentioned aromatic substituents each additionally by a Cι. _3- alkyl, C 1-4 alkyloxy or trifluoromethyl group or can be substituted by 2 to 4 methyl groups, an amino, carboxy -C _-4 alkylamino, carboxy Cι- ₃ alkylaminocarbonyl -Cι. ₃ -alkyl- amino-, aminocarbonyl-Cι- ₃ -alkylamino-, pyrrolidinocarbonyl-Cι- ₃ -alkylamino-, piperidino-carbonyl-C- |. ₃ -alkylaιτιino- or morpholinocarbonyl-Cι. ₃ -alkylamino group, each in the above-mentioned amino groups the hydrogen atom of the amino group, which is linked to the phenyl ring, by a Cι. ₅ -alkylcarbonyl-, Cι- ₅ -alkylsulfonyl-, C _3-7 -cycloalkylcarbonyl-, C ₃ . _7- Cycloalkylsulfonyl-, benzoyl, phenylsulfonyl, phenyl-Cι- ₃ -alkylcarbonyl- or pyridinoyl group is replaced, on the above-mentioned phenyl or pyridyl substituents, each via two adjacent carbon atoms, an n-propylene or n-butylene bridge, a phenyl , Pyridine or piperidine ring can be fused or the above-mentioned aromatic substituents each additionally by a Cι. ₃ -alkyl, Cι- ₃ -alkyloxy, trifluoromethyl or carboxy group or can be substituted by 2 to 4 methyl groups, a phenyl, pyridyl, imidazolyl or pyrazolyl group optionally substituted by one, two or three Ci- _3- alkyl groups, where the alkyl substituents can be the same or different and one of the alkyl substituents can additionally be substituted by a carboxy or hydroxysulfonyl group, an aminosulfonyl, C ₄ alkylaminosulfonyl, di (C 4 alkyl) aminosulfonyl or C _M alkylsulfonyl group may be substituted, R ^{4 is} a chlorine or bromine atom, a carboxy, C ^ alkyl, carboxy-Cι _-3 alkyl or trifluoromethyl group or a hydrogen atom, if R ^{3 is} a C _-5 alkyl or carboxy-C ^ alkyl group, which is substituted in the alkyl part by a C _3-7 cycloalkyl, phenyl, pyridyl, pyrrolidino, piperidino or hexamethyleneimino group, represents an amino, carboxy-C _1-4 -alkylamino or carboxy-C _1-3 -alkylaminocarbonyl- Cι_3-alkylamino group, each in the above-mentioned amino groups the hydrogen atom of the amino group, which is linked to the phenyl ring, by a C _-5 alkylcarbonyl, C _-5 alkyl sulfonyl, C ₃ . ₇ cycloalkylcarbonyl, C _3-7 -Cycloalkylsulfonyl-, benzoyl, phenylsulfonyl, phenyl-Cι _-3 alkylcarbonyl or pyridinoyl group is substituted, the above-mentioned phenyl or pyridyl substituents in each case via two adjacent carbon atoms of a n-propylene or n-butylene bridge, a phenyl, pyridine or piperidine ring can be fused or the above-mentioned aromatic substituents each additionally by a C ₃ alkyl, C ₁ -C. ₃ -alkyloxy or trifluoromethyl group or can be substituted by 2 to 4 methyl groups, R ^{5 is} a hydrogen, chlorine or bromine atom, a C _-3 alkyl or trifluoromethyl group or R ⁴ and R ⁵ together represent an nC _3-4 alkylene group, with the proviso that at least one of the radicals R ¹ , R ⁴ or R ^{5 is} not a hydrogen atom and X, Y and Z each denote nitrogen atoms or -CH groups with the proviso that at least one of the groups X, Y and Z represents a -CH group, where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of the formula I defined above, unless stated otherwise, can be partially or completely replaced by fluorine atoms and which also include their branched isomers in the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms, and the alkanoyl and unsaturated alkyl parts which contain more than 3 carbon atoms, whose Cι _-3 alkyl and benzyl esters, their tautomers, their stereoisomers, their prodrugs, their mixtures and their salts, 3. Substituted N-acyl aniline derivatives of the general formula in the A is a methylene group or an ethylene group in which the methylene group linked to the aromatic can be replaced by an oxygen atom or by an -NH group, the -NH group being additionally substituted by a methyl, carboxymethyl or C _{-3 -3} alkoxycarbonylmethyl group . R ^{1 is} a hydrogen atom, a methyl or ethyl group, R ^{2 is} a cyano or aminomethyl group or, optionally, by a hydroxy, C- |. _8- alkyloxycarbonyl or benzoyl group substituted amidino group, R ^{3 is} a straight-chain or branched C ₅ alkyl group optionally substituted by a phenyl, pyridyl or piperidino group, a carbonyl or sulfonyl group, each represented by a straight-chain or branched C _1-5 alkyl, C _3-5 cycloalkyl, phenylamino, N- (C _1- alkyl) phenylamino, N, N-Di - (C 1-4 -alkyl) -amino-, N- (Cι- ₄ -alkyl) -benzylamino-, N- (Cι_ ₄ -alkyl) -pyridylamino, pyrrolidino or methyl-pyrrolidino group is substituted, an amino, methylamino, carboxymethylamino, Cι. ₃ -alkoxycarbonylmethylamino or morpholinocarbonylmethylamino group, each on the amine nitrogen atom by an optionally substituted by one to four methyl groups, phenylsulfonyl group, by a trifluoromethyl, carboxy or Cι. ₃ -alkoxycarbonyl group substituted phenylsulfonyl group, substituted by a benzoyl, benzylsulfonyl, naphthylsulfonyl, quinolylsulfonyl or 1,2,3,4-tetrahydroquinolylsulfonyl group, or a straight-chain or branched Cι-5-alkylamino or C ₃ . ₅ -cycloalkylamino group, each on the amine nitrogen atom by a carboxy or Cι. ₃ -alkoxycarbonyl or / and an amino group substituted C ₂ - ₃ alkanoyl group, is substituted by a carboxymethylaminocarbonyl or Cι.3-alkoxycarbonylmethylaminocarbonyl group, or a pyrazol-1-yl group substituted by two straight-chain or branched C 3 alkyl groups, R ^{4 is} a chlorine or bromine atom, a methyl, trifluoromethyl, carboxymethyl or C-ι- ₃ alkoxycarbonylmethyl group or a hydrogen atom, if R ^{1 is} an ethyl group or R ^{3 represents} a pyrrolidinocarbonyl group, a carboxymethylamino or C 3 alkoxycarbonylmethylamino group, in each of which the amine nitrogen atom is substituted by a benzoyl group, R ^{5 is} a hydrogen, chlorine or bromine atom or a methyl group or R ⁴ and R ⁵ together represent an n-propylene group, with the proviso that at least two of the radicals R ¹ , R ⁴ and R ^{5 are} not hydrogen atoms, where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of formula la defined above, unless otherwise stated, can be partially or completely replaced by fluorine atoms, their prodrugs, their tautomers, their stereoisomers and their salts. 4. Substituted N-acyl-aniline derivatives of the general formula Ia according to Claim 3, in which R ^{4 represents} a chlorine or bromine atom, a methyl or trifluoromethyl group, their prodrugs, their tautomers, their stereoisomers and their salts. 5. Substituted N-acyl-aniline derivatives of the general formula Ia according to Claim 3, in which A is an ethylene group in which the methylene group linked to the aromatic can be replaced by an -NH group, R ^{1 is} a hydrogen atom, a methyl or ethyl group, R ^{2 is} an amidino group, R ^{3 is} a C ₃ - ₅ alkyl group, a carbonyl group through a straight-chain or branched Cι _-5 alkyl, C ₃ - ₅ cycloalkyl, N, N-di (C- |. ₄ alkyl) amino, N- (Cι. ₄ - alkyl) -benzylamino-, N- (-C ₄ alkyl) pyridylamino, pyrrolidino or 2-methyl-pyrrolidino group is substituted, a linear or branched Cι _-5 alkylamino or C _3-5 cycloalkylamino group, each of carbonyl on the amine nitrogen atom by a carboxy or a Cι- ₃ alkoxy or / and an amino substituted C ₂ - ₃ alkanoyl group, is substituted by a carboxymethylaminocarbonyl or -CC 3-alkoxycarbonylmethylaminocarbonyl group, or one by two straight-chain or branched C-ι. _3- alkyl groups substituted pyrazol-1-yl group, R ^{4 is} a chlorine or bromine atom, a methyl or trifluoromethyl group and R ^{5 represents} a hydrogen, chlorine or bromine atom or a methyl group, with the proviso that at least one of the radicals R ¹ or R ^{5 is} not a hydrogen atom, where the hydrogen atoms in the methyl and methoxy groups mentioned in the definition of the abovementioned radicals or in the methyl parts contained in the groups of the formula I defined above, unless stated otherwise, can be partially or completely replaced by fluorine atoms, their tautomers, their stereoisomers, their prodrugs and their salts. 6. Substituted N-acyl-aniline derivatives of the general formula Ia according to Claim 5, in which R ^{3 is} in position 4, their prodrugs, their tautomers, their stereoisomers and their salts. 7. The following substituted N-acyl-aniline derivatives of the general formula I according to Claim 1: (a) 4- {N- [2,5-dimethyl-4- (2-methyl-pyrrolidinocarbonyl) phenylaminocarbonylmethyl] aminoj-benzamidine, (b) 4- [N- (2,5-Dimethyl-4-isopropylcarbonyl-phenylaminocarbonylmethyl) amino] -benzamidine and (c) 4- {N- [2,5-Dimethyl-4- (N'-isopropyl-N '- (2-ethoxycarbonylethylcarbonyl) amino) phenylaminocarbonylmethyl] amino} benzamidine as well as their salts. 8. Physiologically acceptable salts of the compounds according to claims 1 to 7, in which R ^{2 represents} one of the amidino groups mentioned in claims 1 to 7. 9. Medicament containing a compound according to at least one of claims 1 to 7, in which R ^{2 represents} one of the amidino groups mentioned in claims 1 to 7, or a salt according to claim 8, optionally together with one or more inert carriers and / or diluents. 10. Use of a compound according to at least one of claims 1 to 7, in which R ^{2 represents} one of the amidino groups mentioned in claims 1 to 7, or a salt according to claim 8 for the manufacture of a medicament with an action which prolongs the thrombin time, an antithrombin action and an inhibitory effect on related serine proteases. 11. A process for the manufacture of a medicament according to claim 9, characterized in that a compound according to at least one of claims 1 to 7, in which R ^{2 represents} one of the amidino groups mentioned in claims 1 to 7, or a salt according to claim 8 is incorporated into one or more inert carriers and / or diluents. 12. A process for the preparation of the compounds according to claims 1 to 8, characterized in that a) a compound of the general formula in the R ¹ and R ³ to R ^{5 are defined} as mentioned in claims 1 to 7, with a carboxylic acid of the general formula in the A, X, Y, Z and R ^{2 are defined} as mentioned in claims 1 to 7, or their reactive derivatives are reacted or b) for the preparation of a compound of general formula I, in which A is a straight-chain C _2-3 alkyl group optionally substituted by a C ₃ alkyl group, in which the methylene group linked to the aromatic or heteroaromatic compound is represented by an oxygen atom or -NH -Group is replaced, wherein the -NH group can additionally be substituted by a -C ₃ alkyl or carboxy -C ₃ alkyl group, a compound of the general formula in the R ¹ and R ³ to R ^{5 are defined} as mentioned in claims 1 to 7, A 'is a methylene or n-ethylene group which is optionally substituted by a C ₃ alkyl group and Zi is a nucleofugic leaving group, with a compound of the general formula in the X, Y, Z and R ^{2 are} as defined in claims 1 to 7 and B is an oxygen atom or an optionally by a C ₃ alkyl or carboxy Cι. ₃ alkyl group substituted -NH group means, is reacted or c) for the preparation of a compound of the general formula I in which R ^{2 represents} an amidino group, a compound of the general formula optionally formed in the reaction mixture in the R ¹ , R ³ to R ⁵ , A, X, Y and Z are as defined in claims 1 to 7 and Z ₂ represents an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with ammonia or hydroxylamine and with their salts, or d) for the preparation of a compound of general formula I, in which R ^{2 represents} an amidino group substituted by a residue which can be split off in vivo, a compound of general formula in the R ¹ , R ³ to R ⁵ , A, X, Y and Z are as defined in claims 1 to 7, with a compound of the general formula Z ₃ - R ⁶ , (VIII) in the R ^{6 is} the acyl radical of one of the in vivo mentioned in claims 1 to 7 Leftovers and Z _{3 represents} a nucleofugic leaving group, is implemented or e) for the preparation of a compound of the general formula I in which at least one of the radicals A, R ¹ or R ³ contains a carboxy group, a compound of the general formula in the R ² , R ⁴ , .R ⁵ , X, Y and Z are as defined in claims 1 to 7 and A ", R ¹ 'and R ³ ' are those for A, R ¹ and R ³ in claims 1 to Have the meanings mentioned with the proviso that at least one of the radicals A, R ¹ or R ³ contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I in which at least one of the radicals A, R ¹ or R ³ contains a carboxy group and if necessary, a protective residue used during the reactions to protect reactive groups is then split off and / or if desired, 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.