WO2004080970A1 - Novel bicyclic aromatic compounds, the production and use thereof in the form of drugs - Google Patents

Abstract

The invention relates to novel aromatic bicycle compounds of formula (I), wherein Ar, X, Y and R1-R3 are such as specified in a claim 1. Said invention also relates to the tautomers, enantiomers, diasteriomers, mixtures, pro-drugs and salt thereof and to the production and use thereof in the form of drugs. The formula (I) compounds exhibit important pharmacological properties, in particular an antithrombotic effect and the inhibitory action of factor Xa.

Description

NEW AROMATIC BICYCLES, THEIR PRODUCTION AND THEIR USE, IN PARTICULAR AS INHIBITORS OF FACTOR XA

The present invention relates to new aromatic bicycles of the general formula

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

The compounds of the above general formula I, in which Ar is substituted by a cyano group, are valuable intermediates for the preparation of the other compounds of the general formula I, and the compounds of the above general formula I, which contain no cyano group, and their tautomers Their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases, have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa-inhibiting effect.

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

In the general formula above mean

X is a nitrogen atom or a methine group, Y is a methine group or a nitrogen atom which is optionally substituted by a d ₃ -alkyl or amino group,

Z is a nitrogen atom or a methine group,

R ^{1 is} an amino, C ₅ alkylamino, C ₃ - ₇ cycloalkylamino or phenyl C _1-3 alkylamino group, each on the amine nitrogen atom by a phenylcarbonyl or phenylsulfonyl group or by one in the alkyl part, optionally by a Carboxy group, an in vivo convertible group into a carboxy group, an amino, Cι-3-alkyl amino or di- (Cι _-3- alkyl) -amino group substituted Cι- ₃ alkyl or Cι-3-alkyl -carbonyl group can be substituted,

a di (Cι _-5 -alkyl) amino or N- (C3-7-cycloalkyl) -Cι _-5 -alkylamino group, the Cι-5-alkyl part with the exception of the 1-position each by a hydroxy, -Cι _{- 3} -alkoxy-, amino-, Cι- ₃ -alkylamino- or di- (Cι- ₃ -alkyl) -amino group can be substituted,

a 4- to 7-membered cycloalkyleneimmo group, a methylene group which is not directly adjacent to the imino group, by a hydroxy, d- ₃ -alkoxy-, amino-, Cι- ₃ -alkylamino- or di- (Cι- ₃ -alkyl) -amino group can be substituted,

a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group, where

the cycloalkyleneimino part by a C ₃ alkyl, amino C ₃ alkyl, C 1 ₃ alkyl amino C ₃ alkyl, di-CC ^ s-alkyl-amino-ds-alkyl -, Aminocarbonyl-, d- ₃ -alkylamino-carbonyl-, N- (C3-7-cycloalkyl) -Cι _-5 -alkylaminocarbonyl-, N- (phenyl-Cι _-3 - alkyl) -Cι _-5 -alkylaminocarbonyl - Or di- (-C ₃ alkyl) aminocarbonyl group may be substituted or

a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C _{3 -3} alkylamino or di (C _{3 -3} alkyl) amino group and / or a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkylene imino group can be replaced by a sulfur atom or by a sulfinyl or sulfonyl group or

a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimmo group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C _{2 -3} -alkanoyl) -, sulfinyl or sulfonyl group and / or

a -CH ₂ -CH ₂ - group in a 5- to 7-membered cycloalkyleneimmo group can be replaced by a -NH-CO- group,

one optionally by a C ₃ alkyl, amino C ₃ alkyl, C ₃ alkylamino C ₃ alkyl, di (C ₃ alkyl) amino C ₃ alkyl -, Aminocarbonyl-, d- ₃ -alkylamino-carbonyl-, N- (C _3- 7-cycloalkyl) -Cι-5-alkylaminocarbonyl-, N- (phenyl-Cι_.3-alkyl) -Cι _-5 - alkylaminocarbonyl- or di- (Cι _-3 -alkyl) -aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbbnyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group,

an aminosulfonyl or aminocarbonyl group which is optionally substituted by one or two d- ₃ -alkyl, phenyl-C _1-3 alkyl or C _3-7 cycloalkyl groups, where the substituents can be identical or different,

a straight-chain or branched d- ₅ -alkylcarbonyl group,

a C3-7 cycloalkyl carbonyl group, wherein

the methylene group in the 3- or 4-position in a C _5-7 cycloalkylcarbonyl group can be replaced by an -NH group in which

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

a phenylcarbonyl or heteroarylcarbonyl group or an optionally substituted by an amino, Cι _-3 alkylamino, di (Cι _-3 alkyl) arηino, hydroxy, phenyl or a 4- to 7-membered cycloalkyleneimino group, Cι- ₃ alkyl group, wherein

the phenyl substituents can be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, d- ₃ -alkyl or Cι- ₃ -alkoxy group,

R ^{2 is} a hydrogen, fluorine, chlorine or bromine atom,

a Cι. ₃ -alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or

a C ₂ - ₃ alkenyl, C _2-3 alkynyl, hydroxyl, C ₃ -3 alkoxy or trifluoromethoxy group,

R ^{3 is} a hydrogen atom,

a linear or branched d-β-alkyl group, which may be replaced by a hydroxy, Cι _-3- alkyloxy, carboxy, Cι- ₃ alkoxy-carbonyl, amino, d-3-alkylamino, di- (Cι - ₃ -alkyl) -amino-, d- ₃ -alkyl-carbonylamino-, -Cι- ₅ -alkoxy-carbonylamino- or phenyl-d- ₃ -alkoxy-carbbnylamino group is substituted,

a methyl or ethyl group, each

alkyloxy alkyloxy-carbonyl-d- _3, - by a phenyl or heteroaryl group which is optionally substituted in each case by a hydroxy, d- ₄ alkyloxy, benzyloxy, hydroxycarbonyl-Cι- ₃ alkoxy, C ₁ - ₃ Aminocarbonyl-d _-3 -alkyloxy-, C _-3 -alkyl- aminocarbonyl-d- ₃ -alkyloxy-, di- (d _-3 -alkyl) -aminocarbonyl-Cι. ₃ -alkyloxy-, carboxy-, Cι- ₃ alkyloxy-carbonyl group are substituted,

by a 1-H-pyridonyl or 1- (Cι _-3- alkyl) -pyridonyl group,

by a 4- to 7-membered cycloalkyleneimino group or by a 4- to 7-membered cycloalkyl group in which one or two methylene groups separated at least by a methylene group are each replaced by an oxygen or sulfur atom or by an -NH or -N (d _-3 -alkyl) group and in which, if the cycloalkyl group contains an -NH- or an -N (Cι- ₃ -AlkyI) - group, a methylene group adjacent to the nitrogen atom and, if the cycloalkyl group contains a total of two -NH- or -N (Cι _-3 -alkyl) - Contains groups, a methylene group adjacent to two nitrogen atoms can be replaced by a carbonyl group, are substituted, or

a phenyl or heteroaryl group, each through a hydroxy, C _-4 alkyloxy, benzyloxy, hydroxycarbonyl-d- _3- alkoxy, ds-alkyloxy-carbonyl-Ci-s-alkyloxy, aminocarbonyl-d-3 -alkyloxy-, d-3-alkylaminocarbonyl-Cι- ₃ -alkyloxy-, di- (C-ι-3-alkyl) - amihocarbonyl-Cι. ₃ -alkyloxy, carboxy, d- ₃ -alkyloxy-carbonyl group may be substituted, and

Ar is a phenyl group substituted by the radicals R ⁴ , R ⁵ and R ⁶ , where

R ^{4 is} a cyano group,

an optionally by one or two hydroxy, d _-3 alkyl, Cι _-8 alkyl carbonyl, d _-8 -alkoxy-carbonyl or benzoyl substituted amidino group,

an amino-C-3-alkyl-, d.3-alkylamino-Cι.3-alkyl- or di- (Cι- ₃ -alkyl) amino-

, d- ₃ alkyl group or

a group of the formula

in which R ^{7 is} a hydrogen atom or ad _-3 alkyl group and R ⁸ denotes ad _-3 -alkyl group,

R ^{5 is} a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, d _-3 - alkyl, hydroxy, hydroxy-Cι _-3 alkyl, d _-3 alkoxy, benzyloxy, C1.3 alkoxy-d. ₃ - alkyl, amino, Cι _-3 alkyl amino or di (Cι _-3 alkyl) amino group and

R ^{6 represents} a hydrogen, fluorine, chlorine or bromine atom or a d ₃ -alkyl group,

or a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group which is optionally substituted in the carbon structure by the groups R ⁴ and R ⁵ , where R ⁴ and R ⁵ are defined as mentioned above,

where, unless stated otherwise, the term "heteroaryl group" means a monocyclic group optionally substituted in the carbon skeleton by a C ₃ alkyl, carboxy d ₃ alkoxy carbonyl or C ₃ alkoxy carbonylamino group 5- or 6-membered heteroaryl group is to be understood, wherein

the 6-membered heteroaryl group has one, two or three nitrogen atoms and

the 5-membered heteroaryl group is an imino group optionally substituted by a C ₃ -C ₃ -alkyl or phenyl- ₃ -3-alkyl group, an oxygen or sulfur atom or

one optionally by a -C ₃ alkyl, amino -C. ₃ -alkyl-, Cι- ₃ -alkylamino- d- ₃ -alkyl-, di- (Cι.3-alkyl) -amino-Cι _-3 -alkyl- or phenyl-Cι _-3 -alkyl group substituted imino group or an oxygen- or sulfur atom and additionally a nitrogen atom or

contains an imino group optionally substituted by a C ₃ alkyl or phenyl d _-3 alkyl group and two or three nitrogen atoms, and a phenyl ring may also be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms

and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched,

and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms.

A group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a d-β-alkanol, a phenyl-d- _3- alkanol, a C ₃ -9- Cycloalkanol, where a C _δ -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 by an oxygen atom or by an imino group which is optionally substituted by a C ₃ alkyl, phenyl C ₃ alkyl, phenyl d ₃ alkoxycarbonyl or C _2-6 alkanoyl group and the cycloalkanol part is additionally replaced by one or two C 3 alkyl groups may be substituted, a C ₄ -7-cycloalkenol, a DS-s-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 originates from a carbon atom which is a double or triple bond carries a C ₃ .8-cycloalkyl-Cι _-3 alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which in the bicycloalkyl part additionally by one or two Cι. ₃ -alkyl groups can be substituted, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R _a -CO-0- (R _b CR _c ) -OH,

by doing R _a is a Cι _-8 alkyl, C alkyl _5- cycloalkyl, phenyl or phenyl-Cι _-3,

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

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

Those compounds of the general formula (I) which contain a group which can be split off in vivo, and those in which X, Y and Z and R ¹ to R ³ are defined as mentioned at the beginning and Ar is defined with the proviso that Ar is on the nitrogen atom by one or two hydroxy, d- _C3 alkyl, Cι- ₈ alkyl-carbonyl, Cι _-8 -alkoxy-carbonyl or benzoyl, or substituted amidino group by a group of formula II or a C Contains ₃ -alkyl- amino-d- ₃ -alkyl or di- (Cι _-3 -alkyl) amino-Cι _-3 -alkyl group, are prodrugs for those compounds of general formula (I) in which Ar is an amidino or contains aminoalkyl group.

Preferred compounds of the general formula I are those in which

X is a nitrogen atom or a methine group,

Y is a methine group which is optionally substituted by a d- ₃ -alkyl group,

Z is a nitrogen atom or a methine group,

R ^{1 is} an amino, ds-alkylamino or C ₃ - ₇ cycloalkylamino group, each on the amine nitrogen atom by a group in the alkyl part, optionally by a carboxy group, an in vivo convertible group to a carboxy group, an amino, d- _3- alkyl - amino- or di- (-C ₃ alkyl) amino group substituted d-3 alkyl or C _{3 -3} alkyl carbonyl group can be substituted,

a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group, where the Cycloalkyleniminoteil by a Cι- ₃ -alkyl-, amino-Cι _-3 -alkyl-, Cι _-3 -alkyl- amino-Cι _-3 -alkyl-, di- (C _1-3 -alkyl) -amino-Cι _{- 3} -alkyl-, aminocarbonyl-, d _-3 -alkylamino-carbonyl-, N- (C _3-7 -cycloalkyl) -Cι- ₅ -alkylaminocarbonyl- or di- (d _-3 -alkyl) -aminocarbonyIgruppe be substituted can or

a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C _{3 -3} alkylamino or di (C _{3 -3} alkyl) amino group and / or

a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by sulfinyl or sulfonyl group or

a methylene group in the 4-position of a 6- or 7-membered cycloalkylene imino group through an oxygen or sulfur atom or through an -NH-,

-N (C ₂ - ₃ alkanoyl) -, sulfinyl or sulfonyl group can be replaced and / or

a -CH2-CH2- group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO- group, 'an optionally by ad _-3 -alkyl-, amino-Cι- ₃ -alkyl-, C _1-3 -Alkylamino- -Cι _-3 -alkyl-, di- (Cι _-3 -alkyl) -amino-Cι _-3 -alkyl-, aminocarbonyl-, Cι _-3 -alkylamino- carbonyl-, N- (C _{3 7-} cycloalkyl) -C-5-alkylaminocarbonyl-, N- (phenyl-Cι-3-alkyl) -Cι-5-alkylaminocarbonyl or di- (d. ₃ -alkyl) -aminocarbonyl group substituted 2,5-dihydropyrrole- 1-yl-carbonyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group,

an optionally by one or two C _1-3 -alkyl, phenyl-C _1-3 alkyl- or C ₃ - ₇ - cycloalkyl substituted aminosulphonyl or aminocarbonyl, wherein the substituents may be identical or different,

a straight-chain or branched d _-5 -alkylcarbonyl group or

a C ₃ . _7- cycloalkyl-carbonyl group, R ^{2 is} a hydrogen, fluorine, chlorine or bromine atom,

a Cι- ₃ alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or

a C ₂ - ₃ alkenyl, C ₂ - ₃ alkynyl, hydroxy, C _{3 -3} alkoxy or trifluoromethoxy group,

R ^{3 is} a hydrogen atom,

a linear or branched Ci-e-alkyl group, which may be replaced by a

Hydroxy-, -C-- _3- alkyloxy-, carboxy-, d- ₃ -alkoxy-carbonyl-, amino-, d. ₃ -alkylamino-, di- (C _1-3 -alkyl) -amino-, d- ₃ -alkyl-carbonylamino-, -Cι _-5 -alkoxy-carbonylamino- or phenyl-Cι- ₃ -alkoxy-carbonylamino group is substituted, or

a methyl group that

by a phenyl or heteroaryl group, each optionally by a hydroxy, d- ₄ -alkyloxy, benzyloxy, hydroxycarbonyl-Cι.3-alkoxy-, C1-3- alkyloxy-carbonyl-Cι- alkyloxy, aminocarbonyl Cι. ₃ alkyloxy, Cι _-3 alkyl aminocarbonyl-Cι- ₃ alkyloxy, di- ₍₃ Cι- alkyl) aminocarbonyl-Cι- ₃ alkyloxy,

Carboxy, d- ₃ alkyloxy-carbonyl group are substituted, is substituted, and

Ar is a phenyl group substituted by the radicals R ⁴ , R ⁵ and R ⁶ , where

R ^{4 is} a cyano group,

one optionally by one or two hydroxy, d _-3 alkyl, C ₈ alkyl carbonyl, C ₁ . _8- alkoxy-carbonyl or benzoyl groups substituted amidino group,

an amino-C ₃ alkyl, C ₃ alkylamino C _-3 alkyl or di (d _-3 alkyl) amino d ₃ alkyl group or

a group of the formula

in which R ^{7 is} a hydrogen atom or a Cι.3 alkyl group and

R ^{8 is} a C _-3 alkyl group,

R ° is a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, C1. ₃ - alkyl, hydroxy, benzyloxy, amino or C _1-3 alkylamino group and

R ^{6 represents} a hydrogen, chlorine or bromine atom or a C ₃ alkyl group,

or a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group which is optionally substituted in the carbon structure by the groups R ⁴ and R ⁵ , where R ₄ and R _{5 are} as defined above,

where, unless stated otherwise, the expression "heteroaryl group" means a mono- optionally substituted in the carbon skeleton by a C ₃ -C ₃ -alkyl, carboxy, C ₃ -3 -alkoxy-carbonyl or C ₃ -alkoxy-carbonylamino group cyclic 5- or 6-membered heteroaryl group is to be understood, where

the 6-membered heteroaryl group has one, two or three nitrogen atoms and

the 5-membered heteroaryl group is an imino group optionally substituted by a C _-3 alkyl or phenyl C _{3 -3} alkyl group, an oxygen or

Sulfur atom or

one optionally by a -C 3 alkyl, amino -C. ₃ -alkyl-, C-ι-3-alkylamino- Cι- ₃ -alkyl-, di- (Cι _-3 -alkyl) -amino-Cι _-3 -alkyl- or phenyl-Cι _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally one

Nitrogen atom or contains an imino group optionally substituted by a d _-3 -alkyl or phenyl-Cι _-3 -alkyl group and two or three nitrogen atoms,

and in addition, a phenyl ring can be fused to the monocyclic heteroaryl groups mentioned above via two adjacent carbon atoms

and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched,

and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms,

their tautomers, their enantiomers, their diastereomers, their mixtures, their prodrugs and their salts.

Those compounds of the general formula I in which

X is a nitrogen atom or a methine group,

Y is a methine group and

Z represents a nitrogen atom or a methine group,

R ^{1 is} an amino, d _-5 alkylamino or C _3-7 cycloalkylamino group, each of which on the amine nitrogen atom by a group in the alkyl part, optionally by a carboxy group, an in vivo convertible group to a carboxy group, an amino, Ci-s -Alkylamino- or di- (Cι-3-alkyl) -amino group substituted Cι- ₃ -AIkyI or d _-3 -alkyl- carbonyl group can be substituted, a 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein

the cycloalkyleneimino part by a C ₃ alkyl, amino C ₃ alkyl, C ₃ alkyl amino amino C ₃ alkyl, di (C ₃ alkyl) amino C 1. ₃ -alkyl-, aminocarbonyl-, C _1-3 -alkylamino-carbonyl- or di- (Cι. ₃ -alkyl) -aminocarbonylgruppe can be substituted or

a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, d- _3- alkylamino or di- (-C-- _3- alkyl) -amino group and / or

a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by sulfinyl or sulfonyl group or

a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C _2-3 -alkanoyl) -, sulfinyl or sulfonyl group and / or

a -CH ₂ -CH ₂ - group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO group,

an optionally by a C ₃ alkyl, amino C ₃ alkyl, C ₃ alkylamino C ₃ alkyl, di (C ₃ alkyl) amino C ₃ alkyl -, aminocarbonyl, Cι _-3 alkylamino carbonyl, N- (C ₃ - ₇ cycloalkyl) _-5 -Cι alkylaminocarbonyl, N- _(phenyl-3 Cι- alkyl) -Cι. ₅ - alkylaminocarbonyl or di (Cι _-3 alkyl) aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbonyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group,

an aminocarbonyl group optionally substituted by one or two C ₃ alkyl or C3-7 cycloalkyl groups, it being possible for the substituents to be the same or different,

a straight-chain or branched ds-alkylcarbonyl group or a C _3-7 cycloalkyl-carbonyl group,

R ^{2 is} a hydrogen, fluorine, chlorine or bromine atom,

ad ₃ -alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or

a Cι- ₃ alkoxy or trifluoromethoxy group,. - ^•

R ^{3 is} a hydrogen atom,

a linear or branched C ₆ alkyl group, which is optionally substituted by a hydroxy, C ₃ alkyloxy, carboxy or C ₃ alkoxy carbonyl group, or

a methyl group substituted by a phenyl group, and

Ar is a phenyl group substituted by the radicals R ⁴ and R ⁵ , where

R ^{4 is} a cyano group,

an amidino group which is optionally substituted by one or two hydroxyl, C 8 _-8- alkyl-carbonyl, Ci-β-alkoxy-carbonyl or benzoyl groups,

an amino-C ₃ alkyl group or

a group of the formula

in which R ^{7 is} a hydrogen atom or a Cι _-3 alkyl group and R ^{8 is} a C _-3 alkyl group,

and R ^{5 represents} a hydrogen atom or a hydroxy group,

or a thienylene group which is optionally substituted in the carbon structure by the group R ₄ , where R ₄ is defined as mentioned above,

where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched,

and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms,

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.

Those compounds of the general formula I in which

X, Y, Z, R ² , R ³ and Ar are as defined above and

R ^{1 is} a C _3- 7 cycloalkylamino group which is substituted on the amine nitrogen atom by a C ₃ -C ₃ -alkyl carbonyl group,

an azetidine-1 -ylcarbonyl group which is optionally substituted in position 3 by a dimethylamino group,

one optionally in position 2 by an aminomethyl or in position 3 by an amino, aminomethyl. Hydroxy- or benzyloxy group substituted pyrrolidin-1-yl-carbonyl or piperidinl -ylcarbonyl group, a 2,5-dihydropyrrol-1 -yl-carbonyl or thiazolidin-3-yl-carbonyl group or

is a di- (Cι _-3 -alkyl) -aminocarbonyl- or N-cyclohexyl-N- (Cι _-3 -alkyl) -amino- carbonyl group,

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.

The compounds having the absolute configuration shown in formula (Ia) are particularly preferred:

in which X, Y, Z, R ¹ , R ² , R ³ and Ar are defined as mentioned above,

their tautomers, their diastereomers, their mixtures and their salts.

For example, the following compounds of general formula I above are mentioned:

(1) 3 - {[7- (2,5-Dihydropyrrol-1 -yl-carbonyl) -quinazolin-4-yl] aminomethyl} -4-hydroxy-benzamidine - ^{. ,} - ^■ _

(2) 3-{2-Phenyl-1 -[7-(pyrrolidin-1 -yl-carbonyl)-chinolin-4-ylamino]-ethyl}-benzamidin

(2) 3- {2-Phenyl-1 - [7- (pyrrolidin-1 -yl-carbonyl) -quinolin-4-ylamino] ethyl} -benzamidine

(3) 4-Hydroxy-3 - {[7-methoxy-6- (pyrrolidin-1-yl-carbonyl) -isoquinolin-1-yylaminomethyl} benzamidine

(4) 4-Hydroxy-3- {2-phenyl-1- [7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-ylamino] -ethyl} -benzamidine

(5) 4-Hydroxy-3 - {[6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine

(6) 3- (3-Amidino-phenyl) -3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] amino} -propionic acid ethyl ester

(7) 3 - {[6- (N-Acetyl-N-cyclopentylamino) -7-methyl-isoquinolin-1-yl] aminomethyl} -4-hydroxy-benzamidine

(8) N-acetoxymethoxycarbonyl-4-hydroxy-3 - {[6-methyl-7- (pyrrolidin-1-ylcarbonyl) quinazolin-4-yl] aminomethyl} benzamidine

(9) 4-Hydroxy-3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} - benzamidine

as well as their tautomers and their salts. According to the invention, the compounds of the general formula I are obtained by processes known per se, for example by the following processes:

(a) For the preparation of a compound of the general formula (I) in which Ar, X, Y, Z and R ¹ to R ³ are defined as mentioned at the beginning:

Coupling a compound of the general formula

in der

in the

R ¹ , R ² , X, Y and Z are defined as mentioned above and L represents a leaving group such as a halogen atom, a sulfonyloxy or aryloxy group, for example a chlorine, bromine or iodine atom, a trifluoromethylsulfonyloxy, phenyloxy or p- Nitrophenyloxy group,

with a compound of the general formula

R ³

in which Ar and R ³ are defined as mentioned at the beginning and

and, if Ar is substituted by a cyano group, optionally subsequent conversion of the cyano compound thus obtained into one of the optionally substituted amidino or aminoalkyl compounds mentioned at the outset. The coupling reaction is advantageously carried out in a solvent such as toluene, dioxane, dimethoxyethane, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, preferably in the presence of a base such as sodium te / t-butylate, bis (trimethylsilyl) lithium amide, potassium carbonate, cesium carbonate, ethyldiisopropylamine (Hünig base ) or triethylamine at a temperature between 0 ° C and 200 ° C, preferably between 0 ° C and 150 ° C, optionally using a suitable catalyst, for example bis (tri-o-tolylphosphine) palladium (II) chloride , Tris (dibenzylidene acetone) dipalladium (0) / tris-o-tolylphosphine, tris (dibenzylidene acetone) - dipalladium (0) / tris (2-furyl) phosphine, tris (dibenzylidene acetone) dipalladium (0) / 2 , 2'- bis (diphenylphosphino) -1, 1 '-binaphthyl, tetrakis (triphenylphosphine) palladium (0), 1, 1'-bis (diphenylphosphino) ferrocene-palladium-dichloride or palladium-II-acetate / 1, 3-bis (triphenylphosphino) propane.

However, the coupling reaction can also be carried out without the addition of solvent in bulk by melting the compounds of the general formulas III and IV at temperatures between room temperature and 250 ° C., optionally in the presence of one of the bases mentioned above and / or optionally using one of the catalysts mentioned above, be performed.

The compounds of general formulas III and IV used as starting materials, some of which are known from the literature, are obtained by processes known from the literature. Furthermore, their preparation is described in the examples.

The preparation of a compound of the general formula (III) above, in which

R ¹ and R ² are defined as mentioned at the outset, Y represents a methine group, X and Z each represent a nitrogen atom and L represents a leaving group such as a halogen atom, for example a chlorine or bromine atom,

can be performed using the following procedure, for example: Cyclization of a compound of the general formula

in the

R ^{1 has} one of the meanings mentioned for R ¹ or represents an optionally protected carboxy group which can subsequently be converted into the radicals defined initially for R ¹ , R ² is defined as mentioned at the beginning and.

X ^{1 represents} a hydroxy or C ₄ alkoxy group or a halogen atom,

with formamide and subsequent reaction of the resulting compound of the general formula

in which R ¹ and R ² are defined as mentioned above, with a halogenating agent, for example with thionyl chloride, thionyl bromide or oxalyl chloride.

The cyclization is carried out, for example, in a high-boiling solvent such as chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or without further solvent in the presence of excess formamide at temperatures between 100 and 200 ° C., preferably between 130 and 170 ° C. The subsequent reaction with a halogenating agent, for example with thionyl chloride, thionyl bromide or oxalyl chloride, is advantageously carried out either without a solvent in the presence of dimethylformamide as a catalyst or by adding a solvent such as dimethylformamide, pyridine, 4- (Λ /, Λ / -dimethylamino ) -pyridine, benzene, carbon tetrachloride, 1, 2-dichloroethane or chloroform at temperatures between 20 and 120 ° C.

The preparation of a compound of the general formula (III) above, in which

R ¹ and R ² are defined as mentioned at the outset, X and Y each represent a methine group, Z a nitrogen atom and

L represents a leaving group such as a halogen atom, for example a chlorine or bromine atom,

can be performed using the following procedure, for example:

Implementation of a compound of the general formula

in the

R ¹ is defined as mentioned at the beginning or represents a bromine atom, R ² is defined as mentioned at the beginning and

X ^{2 represents} a hydroxy, d-β-alkoxycarbonyloxy or C ₄ alkoxy group or a halogen atom, with sodium azide, subsequent cyclization of the resulting compound to a. Compound of the general formula

in which R ¹ is defined as mentioned at the beginning or represents a bromine atom and R ² is defined as mentioned at the beginning,

and subsequent reaction with a halogenating agent, for example with thionyl chloride, thionyl bromide or oxalyl chloride.

If R ^{1 "is} a bromine atom, it can then be converted into the corresponding carboxylic acid by treatment with n-butyllithium and trapping the intermediate product with carbon dioxide.

The reaction with sodium azide is carried out, for example, in acetone in the presence of triethylamine and ethyl chloroformate at temperatures between 0 ° C. and room temperature.

The rearrangement cyclization sequence is carried out, for example, in a high-boiling solvent such as diphenyl ether, chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or without further solvent in the presence of tributylamine at temperatures between 100 and 250 ° C., preferably between 200 and 250 ° C, performed.

The subsequent reaction with a halogenating agent can be carried out, for example, as described above. The group R ¹ as defined above can also only after. Cyclization to the isoquinoline by substitution of a halogen atom and further modifications as described above are introduced (see Scheme 1):

Scheme 1: ^■

a) s. Synthesis of VII (for X = azide); b) s. Synthesis of VIII; c) conversion to 1-haloquinoline as described above; d) nBuLi, -70 ° C, THF, C0 ₂ ; e) R ₂ NH, N-methylmorpholine, TBTU, DMF, or by other amide coupling methods;

The synthesis of nitrogen-linked radicals R ¹ can also be carried out, for example, by palladium-catalyzed Buchwald couplings (JP Wolfe et. Al. Acc. Chem. Res. 1998, 31, 805 and JF Hartwig, Angew. Chem. Int. Ed. 1998 , 37, 2046) can be prepared according to the following scheme (Scheme 2):

Scheme 2:

f) (Ph ₃ P) Pd, Cs ₂ CO ₃ , CH ₃ CN; c) SOCI ₂ or SOBr ₂ or CI (CO). (CO) CI The preparation of a compound of the general formula (III) above, in which

R ¹ and R ² are defined as mentioned at the outset, X is a nitrogen atom Y and Z are each a methine group,

L represents a leaving group such as a halogen atom, for example a chlorine or bromine atom,

can be produced, for example, according to the following scheme 3: scheme 3:

a) conc. H ₂ S0 ₄ , 550 watt microwave; b) HNR ₂ , N-methylmorpholine, propanephosphonic anhydride

Methods for amide coupling are described, for example, in P.D. Bailey, I.D. Collier, K.M. Morgan in "Comprehensive Functional Group Interconversions", vol. 5, page 257ff., Pergamon 1995.

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

For example, the protective radical for a hydroxyl group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, te / t-butyl, trityl, benzyl or tetrahydropyranyl group,

as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert.- Butyl, benzyl or tetrahydropyranyl group and

as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, te / t-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the Amino group also includes the phthalyl group.

Further protecting groups and their splitting off are in T.W. Greene, P.G.M. Wuts, "Protecting Groups in Synthesis", Wiley, 1991.

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

However, a benzyl, methoxybenzyl or benzyloxycarbonyl residue is split 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 1 to 5 bar.

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

A methoxy group is advantageously eliminated in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C. A 2,4-dimethoxybenzyl residue is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A fe / t-butyl or ferf.-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 π-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

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

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 two asymmetric carbon atoms into their diastereomers on the basis of their physicochemical differences using methods known per se, for example by chromatography and / or fractional crystallization, if they are obtained in racemic form, they can then be separated into the enantiomers as mentioned above.

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 obtained in this way, 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-σ-tolytartaric 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 their pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose 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 formula I thus obtained, 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 compounds of the general formula I and their tautomers, their enantiomers, their diastereomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect which prolongs the aPTT time and on an inhibitory effect on related serine proteases such as, for. B. urokinase, factor VIIa, factor IX, factor XI and factor XII.

The compounds listed as examples were tested for their effect on the inhibition of factor Xa as follows:

Methodology:

Enzyme kinetic measurement with a chromogenic substrate. The amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of enzyme activity (relative to the solvent control) by the test substance is determined at different concentrations of test substance and from this the IC ₅ o calculated as the concentration which inhibits the factor Xa used by 50%.

Material: Tris (hydroxymethyl) aminomethane buffer (100 mmol) and sodium chloride (150 mmol), pH 8.0 plus 1 mg / ml Human Albumin Fraction V, protease free

Factor Xa (Calbiochem), specific activity: 217 lU / mg, final concentration: 7 lU / ml per reaction mixture

Substrate S 2765 (Chromogenix), final concentration: 0.3 mM / l (1 KM) per reaction mixture

Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μmol / l

Procedure: 10 μl of a 23.5-fold more concentrated starting solution of the test substance or solvent (control), 175 μl TRIS / HSA buffer and 25 μl factor Xa working solution of 65.8 U / L are incubated for 10 minutes at 37 ° C. After adding 25 μl of S 2765 working solution (2.82 mmol / L), the sample is measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds at 37 ° C.

Evaluation: 1. Determination of the maximum increase (deltaOD / minutes) over 21 measuring points.

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

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

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

All the compounds tested had IC ₅ o-values less than 100 mol / L are.

The compounds prepared according to the invention are generally well tolerated.

Because of their pharmacological properties, the new compounds and their physiologically tolerable salts are suitable for prevention and

Treatment of venous and arterial thrombotic diseases, such as the prevention and treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT (C) A), as well as occlusion in peripheral arterial diseases, as well as prevention and treatment pulmonary embolism, disseminated intravascular coagulation, prophylaxis and treatment of coronary thrombosis. prophylaxis of stroke and prevention of occlusion of shunts. In addition, the compounds according to the invention are used for ahtithrombotic support in thrombolytic treatment, such as, for example, with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase

Prevention of long-term restenosis according to PT (C) A, for the prophylaxis and treatment of ischemic events in patients with all forms of coronary heart disease, for the prevention of metastasis and the growth of tumors and of inflammatory processes, for example in the treatment of pulmonary Fibrous, suitable for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue adhesions and / or scar tissue formation as well as for promoting wound healing processes. The new compounds and their physiologically tolerable salts can be used therapeutically in combination with acetylsalicylic acid, with platelet aggregation inhibitors such as fibrinogen receptor antagonists (eg abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogs, for example C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticiopidine), with P ₂ T receptor antagonists (e.g. Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (e.g. Terbogrel).

The dosage required to achieve a corresponding effect is expediently 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg for intravenous administration, and 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, each 1 to for oral administration 4 times a day.

For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate _3, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water / ethanol, water / - glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as

Incorporate hard fat or its suitable mixtures into conventional galenical preparations such as tablets, coated tablets, capsules, powders, suspensions or suppositories.

The following examples are intended to explain the invention in more detail, but without restricting its scope: The HPLC-MS data was generated on the following system: Waters ZMD, Alliance 2690 HPLC, Waters 2700 Autosampier, Waters 996 diode array detector

The mobile phase used was: A: water with 0.1% trifluoroacetic acid; B: acetonitrile with 0.1% trifluoroacetic acid The following gradient was used: time in min% A% B flow rate in ml / min

0.0 95 5 1.00

0.1 95 5 1, 00 5 5,, 11 2 2 9 988 1, 00

6.5 2 98 1.00

7.0 95 5 1.00

A column of Waters X-Terra ™ MS Cι ₈ 3.5μm, 4.6mm x 50mm (column temperature: constant at 25 ° C) was used as the stationary phase. The diode array detection was carried out in the wavelength range 210-500 nm

example 1

3- (f7- (2.5-Dihvdropyrrol-1-yl-carbonvh-quinazolin-4-vnaminomethyl) -4-hvdroxy-benzamidine-hydrochloride

50 mg (97 // mol) of 4-benzyloxy-3 - {[7- (2,5-dihydro-pyrrol-1-ylcarbonyl) -quinazolin-4-yl] aminomethyl} benzamidine hydrochloride [prepared by coupling 4 -Chlor- 7 (2,5-dihydropyrrolidin-1-yl-carbonyl) quinazoline (synthesis analogous to 8c) and 3-amino-methyl-4-benyloxy-benzonitrile (= Ex. 2d) analogous to example 8h and subsequent pinner reaction analogous to example 2h ] are dissolved in 5 ml of trifluoroacetic acid and 0.6 ml of thioanisole and stirred at 50 ° C for four days. The solvent is distilled off and the residue is dissolved in methanol. With the addition of ethereal hydrochloric acid a brown solid separates, which is dissolved twice in methanol and mixed with

Diethyl ether is precipitated.

Yield: 33.5 mg (81% of theory)

R _f value: 0.69 (silica gel; acetonitrile / chloroform / water / formic acid

75: 20: 10: 15)

C ₂ ιH2 ₀ N ₆ O ₂ x HCI (388.43 / 424.89)

Mass spectrum: (M + H) ⁺ = 389

Example 2

4-Hydroxy-3- (R7 (pyrrolidin-1-yl-carbonvπ-quinolin-4-vπaminomethyl) benzamidine

a ^. 2-Benzyloxy-5-bromobenzaldehvd 10.2 g (50 mmol) of 5-bromo-2-hydroxy-benzaldehyde are dissolved in 230 ml of N, N-dimethylformamide and, after addition of 6.9 g (50 mmol) of potassium carbonate, stirred for 15 minutes , Then 5.9 ml (50 mmol) of benzyl bromide are added dropwise and the mixture is stirred at room temperature for 5 hours. It is then poured onto ice water and extracted with dichloromethane. The combined organic extracts are dried and evaporated.

Yield: 12.7 g (87% of theory)

R _f value: 0.59 (silica gel; petroleum ether / ethyl acetate = 4: 1)

C ₁₄ HιιBr0 ₂ (291.14)

Mass spectrum: (M + H) ⁺ = 291/93 (bromine isotopes)

b ^ 4-Benzyloxy-3-formyl-benzonitrile

5.0 g (17.1 mmol) of 2-benzyloxy-5-bromo-benzaldehyde are dissolved in 115 ml of dimethylformamide and after the addition of 3.0 g (34.3 mmol) of copper (I) cyanide and 491 mg (0.42 mmol) of tetrakis-triphenylphosphine-palladium - (O) stirred at 145 ° C for 24 hours. After standing overnight, the solvent is distilled off, the residue in ethyl acetate suspended and aspirated. The filtrate is washed with 10% ammonia solution, the organic phase is separated off, dried and evaporated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (4: 1 and 7: 3). Yield: 2.4 g (59% of theory)

Massenspektrum: (M+H)⁺ = 238R _f value: 0.77 (silica gel; petroleum ether / ethyl acetate = 19: 1)

Mass spectrum: (M + H) ⁺ = 238

c. 4-benzyloxy-3-tert-butoxycarbonylaminomethyl-benzonitrile

15.0 g (63.2 mmol) of 4-benzyloxy-3-formyl-benzonitrile are dissolved in 300 ml of acetonitrile and after addition of 21.6 g (117 mmol) of tert-butyl carbamate, 29.7 ml (116 mmol) of triethylsilane and 9.4 ml (114 mmol) Trifluoroacetic acid stirred for 2 hours at room temperature. Diethyl ether is then added and the mixture is washed with sodium hydrogen carbonate solution. The combined organic extracts are dried and evaporated. Yield: 40.00 g (quantitative)

Massenspektrum: (M+H)⁺ = 339R _f value: 0.32 (silica gel; petroleum ether / ethyl acetate = 4: 1 + 0.5% ammonia solution)

Mass spectrum: (M + H) ⁺ = 339

d. 3-Aminomethyl-4-benzyloxy-benzonitrile

5.3 g (15.6 mmol) of 4-benzyloxy-3-tert-butoxycarbonylaminomethyl-benzonitrile are dissolved in 50 ml of 1,4-dioxane and, after adding 35 ml, conc. Hydrochloric acid stirred overnight at room temperature. It is then poured onto ice water, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with ethyl acetate / 1% ammonia. Yield: 2.0 g (54% of theory) Rf value: 0.10 (silica gel; petroleum ether / ethyl acetate = 1: 1 + 1% ammonia solution) C ₁₅ H ₁₄ N ₂ 0 (238.29) Mass spectrum: (M + H) ⁺ = 239

e. 4-chloro-quinoline-7-carboxylic acid 10.0 g (43.2 mmol) of 4-chloro-7-trifluoromethyl-quinoline are concentrated in 200 ml. Irradiated sulfuric acid for 2 hours at 550 watts in the microwave. The reaction solution is poured onto ice water and adjusted to pH 3-4 with sodium hydroxide solution. The precipitated product is filtered off, washed with water and dried. Yield: 8.9 g (99% of theory)

RrValue: 0.45 (silica gel; toluene / ethanol = 4: 1)

CιoH ₆ CIN0 ₂ (207.62)

Mass spectrum: (M + H) ⁺ = 208/10 (chlorine isotopes)

f. 4-Chloro-7- (pyrrolidin-1-ylcarbonvD-quinoline

5.2 g (25 mmol) of 4-chloro-quinoline-7-carboxylic acid and 2.1 ml (25 mmol) of pyrrolidine are suspended in 125 ml of ethyl acetate, 14.0 ml (128 mmol) of N-methylmorpholine are added and the mixture is then mixed with 29.2 ml (50.8 mmol ) Propanephosphonic anhydride added dropwise. After 40 hours, it is washed with 20 ml of sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with toluene / ethanol 95: 5. Yield: 4.7 g (72% of theory) Rr value: 0.18 (silica gel; toluene / ethanol = 9: 1)

Mass spectrum: (M + H) ⁺ = 261/63 (chlorine isotopes)

G_. 4-benzyloxy-3 - ([7- (pyrrolidin-1-ylcarbonyl) -quinolin-4-vπaminomethyll-benzonitrile

395 mg (1.51 mmol) of 4-chloro-7- (pyrrolidin-1-ylcarbonyl) -quinoline and 360 mg (1.51 mmol) of 3-aminomethyl-4-benzyloxy-benzonitrile are heated to 100 ° C for 16 hours.

The residue is cooled and chromatographed on silica gel, with toluene /

Ethanol 4: 1 is eluted.

Massenspektrum: (M+H)⁺ = 463Yield: 600 mg (86% of theory)

Mass spectrum: (M + H) ⁺ = 463

JL, 4-benzyloxy-3- (r7- (pyrrolidin-1-yl-carbonyl) -quinolin-4-vaminomethyl) -benzamidine hydrochloride 200 mg (0.43 mmol) of 4-benzyloxy-3 - {[7- (pyrrolidin-1-ylcarbonyl) -quinolin-4-yl] amino-methyl} -benzonitrile are dissolved in 5.5 ml of saturated ethanolic hydrochloric acid and stirred for 24 hours at room temperature , The solvent is distilled off, the residue is dissolved in 10 ml of absolute ethanol and 418 mg (4.36 mmol) of ammonium carbonate are added. After 16 hours, the mixture is filtered off, washed with ethanol, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica gel (gradient: dichloromethane / ethanol / concentrated ammonia solution 7: 3: 0.05 → methanol / concentrated ammonia solution 10: 1). Yield: 102 mg (46% of theory) C ₂₉ H ₂₉ N ₅ O ₂ x HCl (479.58 / 516.05) Mass spectrum: (M + H) ⁺ = 480

j. 4-Hvdroxyτ3 - ([7- (pyrrolidin-1-yl-carbonvπ-quinolin-4-yllaminomethyl) benzamidine hydrochloride 100 mg (0.194 mmol) 4-benzyloxy-3 - {[7- (pyrrolidin-1-yl- carbonyl) -quinolin-4-yl] aminomethylj-benzamidine hydrochloride are dissolved in 25 ml of methanol and, after the addition of 70 mg of palladium on activated carbon, hydrogenated at room temperature with hydrogen, then the catalyst is filtered off and the solution is evaporated purified by chromatography on silica gel (eluent: dichloromethane / methanol / concentrated ammonia solution 50: 50: 0.04). Yield: 53 mg (64% of theory).

RrValue: 0.21 (silica gel; dichloromethane / methanol = 1: 1 + 0.1% ammonia solution) C22H24N5O2 x HCI (389.47 / 427.92) mass spectrum: (M + H) ⁺ = 390 (MH) ^" = 388

Example 3

3- (r7- (Pyrrolidin-1 -yl-carbonyl) -quinoline-4-vnaminomethyl) -benzamidine

Hergestellt analog Beispiel 2h aus 3-{[7-(Pyrrolidin-1 -yl-carbonyl)-chinolin-4-yl]amino- methyl}-benzonitril und ethanolischer Salzsäure /Ammoniumcarbonat in Ethanol. Ausbeute: 34 % der Theorie R_f-Wert: 0.14 (Kieselgel; Dichlormethan / Methanol = 1 :1 + 0.1 % Ammoniaklösung)

Massenspektrum: (M+H)⁺ = 374

Prepared analogously to Example 2h from 3 - {[7- (pyrrolidin-1 -yl-carbonyl) -quinolin-4-yl] amino-methyl} -benzonitrile and ethanolic hydrochloric acid / ammonium carbonate in ethanol. Yield: 34% of theory R _f value: 0.14 (silica gel; dichloromethane / methanol = 1: 1 + 0.1% ammonia solution)

Mass spectrum: (M + H) ⁺ = 374

(MH) ^" = 372

Example 4

3- (2-phenyl-1-R7 (pyrrolidin-1-yl-carbonvπ-quinolin-4-ylamino1-ethyl) -benzamidine

εu 3-phenylmethylcarbonyl-benzonitrile

Massenspektrum: (M-H)^" = 22010.0 g (60.4 mmol) of 3-cyanobenzoyl chloride, 7.7 ml (64.7 mmol) of benzyl bromide and 2.0 g (2.85 mmol) of bis (triphenylphosphine) palladium (II) chloride are placed in 300 ml of tetrahydrofuran and, with ice cooling, 7.5 g ( 114.7 mmol) of zinc were added in portions. The mixture is then stirred under ice cooling for 30 minutes and at room temperature for 4 hours. The zinc is suctioned off and the solution is evaporated. The residue is chromatographed on silica gel, eluting with toluene / ethyl acetate 100: 1. Yield: 6.8 g (41% of theory) R _f value: 0.91 (silica gel; dichloromethane / methanol = 99: 1)

Mass spectrum: (MH) ^" = 220

tx 3- (1-amino-2-phenyl-ethyl) benzonitrile 6.8 g (24.6 mmol) of 3-phenylmethylcarbonyl-benzonitrile are dissolved in 160 ml of methanol and after addition of 19.3 g (245.9 mmol) of ammonium acetate, 1.6 g (24.6 mmol) of sodium cyanoborohydride and 15.8 g of molecular sieve for 4 hours at room temperature for 4 hours heated to reflux. After cooling, the mixture is poured onto water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol 95: 5. Yield: 2.2 g (40% of theory) Rr value: 0.10 (silica gel; toluene / acetone = 19: 1)

Mass spectrum: (M + H) ⁺ = 223

c. 3- (2-phenyl-1-r7- (pyrrolidin-1-yl-carbonvπ-quinolin-4-vnamino-ethyl) -benzonitrile Prepared analogously to Example 2g from 4-chloro-7- (pyrrolidin-1-ylcarbonyl) -quinoline and 3- (1-amino-2-phenyl-ethyl) benzonitrile at 100 ° C.

Yield: 85% of theory

RrValue: 0.43 (silica gel; toluene / ethanol = 4: 1)

Mass spectrum: (M + H) ⁺ = 447. ^• d. 3-f2-phenyl-1-f7- (pyrrolidin-1-yl-carbonvπ-quinolin-4-vnamino-ethyl-benzamidine Prepared analogously to Example 2h from 3- {2-phenyl-1- [7- (pyrrolidin-1-yl- carbonyl) -quinolin-4-yl] amino-ethyl} -benzonitrile and ethanolic hydrochloric acid / ammonium carbonate in ethanol. Yield: 58% of theory

RrValue: 0.30 (silica gel; dichloromethane / methanol = 1: 1 + 0.1% ammonia solution) C ₂₉ H ₂₉ N ₅ 0 (463.58) Mass spectrum: (M + H) ⁺ = 464

Example 5

3- (2-Methoxycarbonyl-1-r7- (pyrrolidin-1-yl-carbonvπ-quinolin-4-ylamino1-ethyl) benzamidine hydrochloride

Prepared analogously to Example 2h from 3- {2-methoxycarbonyl-1- [7- (pyrrolidin-1-ylcarbonyl) quinolin-4-ylamino] ethyl} benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.

Yield: 2.5% of theory

RrValue: 0.21 (silica gel; dichloromethane / methanol = 1: 1 + 0.1% ammonia solution) C ₂₅ H ₂₇ N ₅ 0 ₃ x HCl (445.52 / 481.98) mass spectrum: (M + H) ⁺ = 446

(MH) ^" = 444

Example 6

3- (2-Hydroxycarbonyl-1-r7- (pyrrolidin-1-yl-carbonyl ^' ) -quinolin-4-ylamino1-ethyl} - benzamidine hydrochloride

35 mg (0.066 mmol) of 3- {2-methoxycarbonyl-1- [7- (pyrrolidin-1-yl-carbonyl) -quinolin-4-ylamino] -ethyl} -benzamidine hydrochloride are dissolved in 5 ml of 6 molar hydrochloric acid for 16 hours - The stirred at room temperature. The solvent is then distilled off with

Toluene added and evaporated.

Yield: 32 mg (96% of theory)

RrValue: 0.2 (silica gel; dichloromethane / methanol / ammonia = 8: 2: 0.01)

C24H25N5O3 X 2 HCI (431.49 / 504.42) mass spectrum: (M + H) ⁺ = 432 (MH) - = 430

Example 7

4-Hvdroxy-3- (r7-methoxy-6- (pyrrolidin-1-yl-carbonyl) -isochinoiin-1-yllaminomethyll-benzamidine-hydrochloride

a. (E) -3- (3-bromo-4-methoxy-phenv0-acrylic acid) 25.0 g (0.116 mol) of 3-bromoisaldehyde are dissolved in 120 ml of pyridine with gentle heating; then 15.6 g (0.150 mol) of malonic acid and 5.75 ml ( 0.058 mol) of piperidine was added, then the mixture was stirred for 2 hours at 100 ° C. (gas evolution) and overnight at room temperature, the solvent was distilled off, the residue was mixed with 500 ml of ice-water and adjusted to pH 4-5 with glacial acetic acid suction filtered, washed with water and dried Yield: 29.7 g (99% of theory) CιoH ₉ Br0 ₃ (257.09) mass spectrum: (MH) ⁺ = 255/57 (bromine isotopes)

bi (E) -3- (3-bromo-4-methoxy-phenvD-acrylic acid azide

14.9 g (58 mmol) (E) -3- (3-bromo-4-methoxy-phenyl) -acrylic acid are suspended in 285 ml acetone, mixed with 8.1 ml (58 mmol) triethylamine, at - 2 - + 2 ° C 8.4 ml (77 mmol) of ethyl chloroformate are added dropwise and the mixture is stirred at this temperature for 90 minutes. A solution of 5.6 g (87 mmol) of sodium azide in 15 ml of water is then added dropwise and the mixture is stirred for 1 hour without cooling. The reaction product is stirred into 800 ml of water and suction filtered. Yield: 15.6 g (86% of theory) CιoH ₈ BrN ₃ 0 ₂ (282.09) mass spectrum: (M) ⁺ = 281/83 (bromine isotopes) 6-bromo-7-methoxy-2-isoquinolin-1-on

A suspension of 15.5 g (55 mmol) of (E) -3- (3-bromo-4-methoxy-phenyl) acrylate in 50 is added to a solution of 13.1 ml (55 mmol) of tributylamine in 250 ml of diphenyl ether at 235 ° C ml of diphenyl ether were added and then kept at 235 ° C. for a further 2.5 hours. The mixture is then cooled to room temperature, stirred into 800 ml of n-hexane and the precipitate is filtered off with suction. The residue is boiled up in 400 ml of ethanol, cooled, suction filtered and washed with ethanol / ether and dried. Yield: 7.5 g (54% of theory) Cι ₀ H ₈ BrNO ₂ (254.08)

Mass spectrum: (M + H) ⁺ = 254/56 (bromine isotopes)

, 6-bromo-1-chloro-7-methoxy-isoquinoline

4.6 g (18 mmol) of 6-bromo-7-methoxy-2-isoquinolin-1-one are stirred in 20 ml of phosphorus oxychloride at 110 ° C. for 1.5 hours. The solvent is distilled off, the residue is mixed with ice / dichloromethane and adjusted to pH 8 with 10% sodium hydroxide solution. The organic phase is separated off, dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane. Yield: 2.6 g (53% of theory) Cι ₀ H ₇ BrCINO (272.53)

Mass spectrum: (M + H) ⁺ = 272/74/76 (bromine-chlorine isotope)

e _± 1-chloro-7-methoxy-isoquinoline-6-carboxylic acid

A solution of 2.3 g (8.4 mmol) of 6-bromo-1-chloro-7-methoxy-isoquinoline in 50 ml of tetrahydrofuran is added dropwise at - 70 ° C under a nitrogen atmosphere with 5.8 ml (9.3 mmol) of n-butyllithium (1.6 molar in tetrahydrofuran ) offset. Then dried carbon dioxide is introduced at -65-68 ° C for 40 minutes. Then the reaction is allowed to come to room temperature and ice water is added. Now with conc. Ammonia made alkaline and extracted with ethyl acetate. The aqueous phase is concentrated with. Acidified hydrochloric acid and extracted with ethyl acetate. The organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / (methanol / glacial acetic acid 19: 1) 0-5%. Yield: 950 mg (47% of theory) t 1 -Chlor-7-methoxy-6- (pyrrolidin-1-yl-carbonvO-isoquinoline

A solution of 0.94 g (4.0 mmol) of 1-chloro-7-methoxy-isoquinoline-6-carboxylic acid in

5 ml of N, N-dimethylformamide with 0.67 ml (6.0 mmol) of N-methylmorpholine and 0.42 ml (6.0 mmol) of pyrrolidine is mixed with 1.3 g (4.0 mmol) of 0- (benzotriazole) under a nitrogen atmosphere and stirring at room temperature. 1-yI) -N, N, N ', N'-tetramethyluronium tetrafluoroborate added. After 2.5 hours, the mixture is poured into ice water, the precipitate formed is filtered off and washed with a little cold water. Yield: 1.15 g (35% of theory). C15H1.5CIN2O2 (290.75)

Mass spectrum: (M + H) ⁺ = 291/93 (chlorine isotopes)

g ^ 7-Methoxy-1-phenoxy-6- (pyrrolidin-1 -yl-carbonvIVisoquinoline

Massenspektrum: (M+H)⁺ = 349A mixture of 0.34 g (1.17 mmol) of 1-chloro-7-methoxy-6- (pyrrolidin-1-yl-carbonyl) isoquinoline, 2.2 g (23.4 mmol) of phenol and 0.14 g (2.5 mmol) of powdered potassium hydroxide are added under a nitrogen atmosphere Stirred at 90 ° C for 22 hours. After cooling, ice water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with 1 molar sodium hydroxide solution, dried and evaporated. The residue is stirred with ether and suction filtered. Yield: 0.2 g (49% of theory)

Mass spectrum: (M + H) ⁺ = 349

H. 4-Benzyloxy-3- (r7-methoxy-6- (pyrrolidin-1-yl-carbonyl) -isoquinolin-1-vnamino-methvD-benzonitrile

170 mg (0.49 mmol) 7-methoxy-1-phenoxy-6- (pyrrolidin-1-yl-carbonyl) -isoquinoline and 607 mg (2.5 mmol) 3-aminomethyl-4-benzyloxy-benzonitrile are at 168 ° C for 8 hours heated. After cooling, the residue is chromatographed on silica gel, eluting with dichloromethane / methanol / ammonia 19: 1: 0.1 - 4: 1: 0.1.

Yield: 120 mg (50% of theory) C ₃ oH ₂₈ N ₄ 0 ₃ (492.58) mass spectrum: (M + H) ⁺ = 493 i. 4-Hvdroxy-3- (r7-methoxy-6- (pyrrolidin-1-yl-carbonvπ-isoquinolin-1-yllamino-methvD-benzamidine-hydrochloride

Prepared analogously to Example 2h from 4-benzyloxy-3 - {[7-methoxy-6- (pyrrolidin-1-yI-carbonyl) -isoquinolin-1-yl] amino-methyl} -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction analogous to Example 2i with palladium on activated carbon and hydrogen in methanol.

Yield: 52% of theory

RrValue: 0.63 (silica gel; dichloromethane / methanol = 3: 1 + 1% acetic acid)

C ₂ 3H ₂₅ N ₅ 0 ₃ x HCl (419.48 / 455.94) mass spectrum: (M + H) ⁺ = 420

(M + Cl) ^' = 454/56 (chloroisortopes)

Example 8

4-Hydroxy-3- (2-phenyl-1-r7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-ylamino-1-ethyl} - benzamidine hydrochloride

a. 4-oxo-3,4-di hvd ro-chi nazole in-7-carboxylic acid 25.0 g (0.13 mol) of aminoterephthalic acid are introduced into 55 ml (1.3 mol) of formamide and then stirred at 155 ° C. for 4.5 hours. The reaction mixture is cooled and stirred in ice water. The precipitate is filtered off and dried in a drying cabinet at 70 ° C. Yield: 22.6 g (86% of theory) C ₉ H ₆ N ₂ 0 ₃ (190.16)

Mass spectrum: (M + H) ⁺ = 191

(MH) ^' = 189

b. 4-Chloro-quinazoline-7-carboxylic acid chloride 1.10 g (5.8 mmol) of 4-oxo-3,4-dihydro-quinazoline-7-carboxylic acid are refluxed in 15 ml of thionyl chloride and 1 ml of dimethylformamide for 4 hours. Then the insoluble matter is filtered off and evaporated in vacuo. Yield: 1.3 g (quantitative)

Mass spectrum: (M) ⁺ = 226/28 (chlorine isotopes)

c. 4-Chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazoline

0.37 ml (4.4 mmol) of pyrrolidine are dissolved in 10 ml of dichloromethane, a suspension of 1.0 g (4.4 mmol) of 4-chloroquinazoline-7-carboxylic acid chloride in 35 ml of dichloromethane is added dropwise at −50 ° C. and the mixture is stirred for 5 minutes. Then 0.53 ml (5.2 mmol) of 10 molar sodium hydroxide solution are added dropwise at - 65 ° C. and the mixture is then stirred for 2 hours without cooling. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate = 1: 1.

Rr value: 0.35 (silica gel; ethyl acetate + 1% ammonia) yield: 0.44 g (38% of theory)

d. Methyl 2- (2-benzyloxy-5-cvano-phenvD-3-phenyl-propionate) 4.6 g (16.3 mmol) of 4-benzyloxy-3-methoxycarbonylmethyl-benzonitrile are dissolved in 10 ml of dimethyl sulfoxide, with 1.9 g (17 mmol) of potassium tert . Butylate is added and then 2.0 ml (16.8 mmol) of benzyl bromide are added dropwise. After 2 hours, the mixture is stirred with ice water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is triturated with diisopropyl ether and suction filtered. Yield: 3.7 g (61% of theory) R _f value: 0.43 (silica gel; petroleum ether / ethyl acetate = 4: 1)

e. 2- (2-Benzyloxy-5-cvano-phenvπ-3-phenyl-propionic acid 3.7 g (9.9 mmol) of methyl 2- (2-benzyloxy-5-cyano-phenyl) -3-phenyl-propionate are suspended in 40 ml of methanol and after the addition of 20 ml of 1 molar sodium hydroxide solution, the mixture is stirred for 1.5 hours at 60 ° C. The methanol is then distilled off, the residue is taken up in water and extracted with ether, the aqueous phase is brought to pH 6 with glacial acetic acid and the precipitated product is filtered off with suction. Yield: 3.3 g (93% of theory)

Melting point: 169-171 ° C

RrValue: 0.2 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 3)

f. 1- (2-benzyloxy-5-cvano-phenvD-N-tert-butoxycarbonyl-2-phenyl-ethylamine A suspension of 3.5 g (9.7 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -3- phenyl-propionic acid in 35 ml of tert-butanol is mixed with 1.4 ml (9.8 mmol) of triethylamine and 2.2 ml (9.8 mmol) of phosphoric acid di-phenyl ester azide at room temperature under a nitrogen atmosphere and heated to reflux for 2.5 hours, then cooled to room temperature, in portions with 0.88 g (7.8 mmol) potassium tert-butoxide is added and the mixture is stirred for an hour, then poured onto ice water, the precipitate is filtered off and chromatographed on silica gel, eluting with dichloromethane / methanol + 1% ammonia (0 - ^ 5%). 2.2 g (52% of theory) R _f value: 0.3 (silica gel; dichloromethane)

G. 1- (2-benzyloxy-5-cvano-phenylV2-phenyl-ethylamine

Prepared analogously to Example 2d from 1- (2-benzyloxy-5-cyano-phenyl) -N-tert-butoxycarbonyl-2-phenylethylamine and hydrochloric acid in dioxane. Yield: 77% of theory

RrValue: 0.5 (silica gel; petroleum ether / ethyl acetate / ammonia = 1: 1: 0.1)

H. 4-benzyloxy-3-f2-phenyl-1-r7- (pyrrolidin-1-yl-carbonylquinazolin-4-ylamino1- ethvD-benzonitrile A solution of 439 mg (1.3 mmol) 1- (2-benzyloxy-5-cyano- phenyl) -2-phenyl-ethyl-amine in 5 ml acetonitrile is added dropwise at room temperature with a solution of 350 mg (1.3 mmol) 4-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazoline in 5 ml acetonitrile and after adding 0.35 ml (2 mmol) of N, N-diisopröpyl-ethylamine, the mixture was stirred for 8 hours at 75 ° C. The solvent was distilled off and the residue was chromatographed on silica gel, using petroleum ether / ethyl acetate + 1% ammonia (1: 1 and 0: 1) is eluted.

Yield: 0.46 g (62% of theory) Rr value: 0.25 (silica gel; ethyl acetate + 1% ammonia) i. 4-Hvdroxy-3- (2-phenyl-1-r7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-ylaminol-ethyl) -benzamidine-hydrochloride Prepared analogously to Example 2h from 4-benzyloxy-3- {2 -phenyl-1- [7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-ylamino] -ethyl} -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction analogously to Example 2i with palladium on activated carbon and Hydrogen in methanol. Yield: 78% of theory (over 2 levels)

RrValue: 0.65 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 3) CssHseNeOg x HCl (480.56 / 517.03) Mass spectrum: (M + H) ⁺ = 481

Example 9

4-Hvdroxy-3 - ([6-methyl-7- (pyrrolidin-1-yl-carbonyl ^' ) -quinazolin-4-vaminomethyll-benzamidine-hydrochloride

Prepared analogously to Example 2i from 4-benzyloxy-3 - {[6-methyl-7- (pyrrolidin-1-ylcarbonyl) quinazolin-4-yl] aminomethyl} benzamidine hydrochloride, palladium on activated carbon and hydrogen in methanol.

Yield: 87% of theory

RrValue: 0.45 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 2)

C ₂₂ H ₂₄ N ₆ 0 ₂ x HCI (404.47 / 440.93)

Mass spectrum: (M + H) ⁺ = 405 - - ^. (MH) ^" = 403

Example 10

4-Hvdroxy-3- (r7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yl1aminomethyl) -benzamidine-hydrochloride

Prepared analogously to Example 2i from 4-benzyloxy-3 - {[7- (pyrrolidin-1-yl-carbonyl) -quinoline-4-yl] aminomethyl} -benzamidine hydrochloride, palladium on activated carbon and hydrogen in methanol.

Yield: 83% of theory

RrValue: 0.73 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 3)

C2iH ₂₂ N ₆ θ2 x HCI (390.44 / 426.90)

Mass spectrum: (M + H) ⁺ = 391 (MH) ^" = 389

Example 11

3- (3-Amidino-phenvπ-3- (r6-chloro-7- (pyrrolidin-1-yl-carbonv -quinazolin-4-vnamino) - ethyl propionate acetate

a. 6-chloro-quinazolin-4-one-7-carboxylic acid hvdrochlorid

16.0 g (74.2 mmol) of 2-amino-5-chloroterephthalic acid are introduced into 40 ml (1.0 mol) of formamide and the mixture is heated to 155 ° C. for 6 hours with stirring. The mixture is then concentrated in vacuo and 100 ml of isopropanol are added at 40.degree. After 30 minutes, the precipitated crystal slurry is filtered off, washed with a mixture of ethyl acetate / diethyl ether 1: 1 and dried. 3.25 g of the resulting 11.85 g of the solid are then dissolved in 250 ml of distilled water and then mixed with 25 ml of 2N hydrochloric acid solution. The

Mixture is diluted with a further 200 ml of distilled water and added for 30 minutes Room temperature stirred. The precipitate is then filtered off, washed with a little distilled water and dried at 40.degree. Yield: 3.78 g (48%)

RrValue: 0.10 (silica gel; dichloromethane / ethanol / glacial acetic acid = 4: 1: 0.1) C ₉ H ₅ CIN ₂ 0 ₃ x HCl (224.60 / 261.07)

Mass spectrum: (M + H) ⁺ = 225/227 (chlorine isotopes)

b. 4.6-dichloro-7- (pyrrolidin-1-yl-quinazolin-carbonvh

Prepared using a synthesis sequence analogous to Examples 8b from 6-chloro-quinazolin-4-one, thionyl chloride and N, N-dimethylformamide and 8c from 4,6-dichloro-quinazoline-7-carboxylic acid chloride, pyrrolidine and 10N sodium hydroxide solution in dichloromethane.

Yield: 37% over 2 stages

RrValue: 0.45 (silica gel; dichloromethane)

Cι ₃ HnCI ₂ N ₃ 0 (296.16) mass spectrum: (M + H) ⁺ = 296/298/300 (chlorine isotopes)

c. 3 - ([6-Chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vnaminol-3- (3-cvano-phenvh-propionic acid ethyl ester

Massenspektrum: (M-H)⁺ = 476/478 (Chlorisotope)592 mg (2.00 mmol) 4,6-dichloro-7- (pyrrolidin-1-yl-carbonyl) -quinazoline are combined with 459 mg (2.00 mmol) 3-amino-3- (3-cyano-phenyl) - Ethyl propionate dissolved in 3 ml of N, N-dimethylformamide under a nitrogen atmosphere and 0.61 ml (2.20 mmol) of triethylamine added. The mixture is stirred for 3 hours at room temperature. It is then poured into ice water, the crystalline precipitate is filtered off, washed with a little distilled water and dried at 40.degree. The solid is treated with petroleum ether / diethyl ether 1: 1 and dried. Yield: 430 mg (45% of theory) Rr value: 0.60 (silica gel; dichloromethane / ethanol 9: 1)

Mass spectrum: (MH) ⁺ = 476/478 (chlorine isotopes)

d. 3- (3-Amidino-phenvπ-3- (r6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vn-aminol-propionic acid ethyl acetate) Prepared analogously to Example 2h from 3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] amino} -3- (3-cyano-phenyl) -propionic acid ethyl ester and hydrochloric acid / ammonium carbonate in ethanol. Yield: 25% of theory R _f value: 0.35 (silica gel; dichloromethane / ethanol / glacial acetic acid = 4: 1: 0.1) C ₂₅ H ₂₇ CIN ₆ 0 ₃ x C ₂ H ₄ 0 ₂ (494.98 / 555.03) mass spectrum: ( M + H) ⁺ = 495/97 (chlorine isotopes)

(MH) ^" = 493/95 (chlorine isotopes)

Example 12

3- (3-Amidino-phenvπ-3- (r6-chloro-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yllaminol-propionic acid) hydrochloride

Prepared analogously to Example 6 from 3- (3-amidino-phenyl) -3- [6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] amino-propionic acid ethyl acetate and 6 molar hydrochloric acid.

Yield: 74% of theory R _f value: 0.41 (reversed phase RP8; 5% sodium chloride solution / methanol = 3: 2) C ₂₃ H ₂₃ CIN ₆ 0 ₃ x HCl (466.92 / 503.39) Mass spectrum: (M + H) ⁺ = 467/69 (chlorine isotopes)

- (MH) ^" - = 465/67 (Chlαrisotope)...

Example 13

3- (3-Amidino-phenyl ^' ) -3 - ([7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yl1amino) propionic acid hydrochloride

130 mg (0.25 mmol) 3- (3-amidino-phenyl) -3 - {[7- (pyrrolidin-1-yl-carbonyl) -quinazoline-

Ethyl 4-yl] amino} -propionate are suspended in 2 ml of water and stirred with 0.65 ml of 1N sodium hydroxide solution for 4.5 h. The mixture is then adjusted to pH 3 with 1 N HCl, the solvent is distilled off, methanol is added and the mixture is filtered. Diethyl ether is added to the filtrate, the precipitate which has separated out is filtered off with suction and dried in a drying gun.

Yield: 77% of theory R _f value: 0.5 (reversed phase RP8; 5% sodium chloride solution / methanol = 2: 3)

C ₂₃ H ₂ 4N ₆ θ3 x HCI (432.48 / 468.95)

Mass spectrum: (M + H) ⁺ = 433

Example 14

3- (3-Amidino-phenyl) -3- (f7- (thiazolidin-3-yl-carbonyl) -quinazolin-4-yl1aminoV ethyl propionate hydrochloride

Prepared analogously to Example 2h from 3- (3-cyano-phenyl) -3 - {[7- (thiazolidin-3-yl-carbonyl) -quinazolin-4-yl] amineό} propionic acid ethyl ester and hydrochloric acid / ammonium carbonate in ethanol. Yield: 29% of theory Rr value: 0.17 (silica gel; dichloromethane / ethanol = 4: 1) C ₂₄ H ₂₆ N ₆ 0 ₃ S x HCl (478.57 / 551.49) Mass spectrum: (M + H) ⁺ = 479

(MH) ^" = 477

Example 15

3- (3-Amidino-phenyl) -3- (7- (thiazolidin-3-yl-carbonvπ-quinazolin-4-vnaminol-propionic acid) hydrochloride

Prepared analogously to Example 6 from 3- (3-amidino-phenyl) -3 - {[7- (thiazolidin-3-yl-carbonyl) -quinazoiin-4-yl] amino} -propionic acid ethyl ester and 6 molar hydrochloric acid.

Yield: 66% of theory

RrValue: 0.53 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 2: 3)

C ₂ 2H ₂₂ N ₆ 0 ₃ S x HCI (450.52 / 486.98) mass spectrum: (M + H) ⁺ = 451

(MH) ^" = 449

Example 16

3- (3-Amidino-phenvh-3- (r7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yllamino) propionic acid ethyl acetate acetate

Prepared analogously to Example 2h from 3- (3-cyano-phenyl) -3- [7- (pyrrolidin-1-yl-carbonyl) quinazolin-4-ylamino] propionic acid ethyl ester and hydrochloric acid / ammonium carbonate in Ethanol and subsequent chromatographic purification on silica gel, eluting with methylene chloride: (methanol / acetic acid 19/1) 9: 1. Yield: 76% of theory

RrValue: 0.43 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 2: 3) C ₂₅ H ₂₈ N ₆ 0 ₃ x C2H ₄ O2 (460.53 / 520.59) Mass spectrum: (M + H) ⁺ = 461

Examples 17 and 18

Rac-3- (r7- (3-benzyloxy-pyrrolidin-1-yl-carbonvπ-quinazolin-4-vnaminomethyl) -4- hydroxy-benzamidine acetate (17)

Rac-3- (r7- (3-hydroxy-pyrrolidin-1-yl-carbonyl) -quinazolin-4-vaminomethyl) -4-hydroxy-benzamidine acetate (18)

Prepared analogously to Example 2i from 3 - {[7- (3-benzyloxypyrrolidin-1-ylcarbonyl) quinazolin-4-yl] aminomethyl} -4-benzyloxybenzamidine dihydrochloride, palladium on activated carbon and hydrogen in methanol and subsequent chromatographic purification on silica gel, eluting with methylene chloride: (methanol / acetic acid 19/1) 9: 1> 6: 1. Yield 17: 51% of theory RrValue 17: 0.51 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 3) 17: C ₂₈ H ₂₈ N ₆ 0 ₃ x C ₂ H ₄ 0 ₂ (496.57 / 557.61) Mass spectrum: (M + H) ⁺ = 497

(MH) ^" = 495

Yield 18: 9% of theory

RrValue 18: 0.66 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 3) 18: C ₂ ιH ₂₂ N ₆ 0 ₃ (406.45) Mass spectrum: (M + H) ⁺ = 407 (MH) ^" = 405

Example 19

3- (f6- (N-Acetyl-N-cvclopentylamino) -7-methyl-isoquinoline-1-vaminomethyl) -4-hydroxy-benzamidine hydrochloride

a. (E) -3- (3-acetylamino-4-methyl-phenv0-acrylsäureazid

Prepared analogously to Example 7b from (E) -3- (3-acetylamino-4-methylphenyl) acrylic acid, ethyl chloroformate, sodium azide and triethylamine in acetone / water.

Yield: 80% of theory d ₂ Hι ₂ N ₄ 0 ₂ (244.25)

Mass spectrum: (M + H) ⁺ = 245 (MH) ^" = 243

b. N- (7-Methyl-1-oxo-1, 2-dihydro-isoquinoline-6-vπ-acetamide

Massenspektrum: (M+H)⁺ = 217Prepared analogously to Example 7c from (E) -3- (3-acetylamino-4-methylphenyl) acrylic acid azide and tributylamine in diphenyl ether. Yield: 26% of theory

Mass spectrum: (M + H) ⁺ = 217

(MH) ^" = 215

c. 6-amino-7-methyl-2H-isoquinolin-1-one

3.5 g (16.2 mmol) of N- (7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yl) acetamide are suspended in 20 ml of ethanol and after adding 4.8 ml of conc. Hydrochloric acid heated to reflux for 1 hour. The ethanol is distilled off, the residue is dissolved in water, with conc. The ammonia is adjusted to pH 10 and the precipitate which has precipitated is filtered off with suction.

Massenspektrum: (M+H)⁺ = 175Yield: 2.4 g (85% of theory)

Mass spectrum: (M + H) ⁺ = 175

d. 6-Cvclopentylamino-7-methyl-2H-isoquinolin-1-one

2.4 ml (27.6 mmol) of cyclopentanone and 2.4 g (13.8 mmol) of 6-amino-7-methyl-2H-isoquinolin-1-one are suspended in 25 ml of tetrahydrofuran and after the addition of 0.95 ml (16.6 mmol) of glacial acetic acid and 7.0 g (33.2 mmol) sodium triacetoxyborohydride heated to reflux for 4 hours. After standing overnight, the solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined organic phasers) are washed with sodium chloride, dried and evaporated. The crude product is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (3: 2 and 0: 1). Yield: 1.2 g (36% of theory) Cι ₅ Hι ₈ N ₂ 0 (242.32)

Mass spectrum: (M + Na) ⁺ = 265

e. N- (1-chloro-7-methyl-isoquinolin-6-vh-cvclopentylamin

Prepared analogously to Example 7d from 6-cyclopentylamino-7-methyl-2H-isoquinolin-1-one and phosphorus oxychloride. Yield: 85% of theory C ₁₅ Hι ₇ CIN ₂ (260.77) mass spectrum: (M + H) ⁺ = 261/63 (chlorine isotopes) f. N- (1-chloro-7-methyl-isoquinolin-6-yl) -N-cvclopentyl-acetamide

Massenspektrum: (M+H)⁺ = 303/05 (Chlorisotope)0.95 g (3.6 mmol) of N- (1-chloro-7-methyl-isoquinolin-6-yl) -cyclopentylamine are dissolved in 10 ml of tetrahydrofuran and after adding 3.2 g (65.6 mmol) of sodium hydride (50% solution in oil) Stirred at 40 ° C for 30 minutes. Then 7 ml (98.3 mmol) of acetyl chloride are added and the mixture is stirred at 70 ° C. for 2.5 hours. The solvent is then distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The crude product is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (7: 3 and 3: 2). Yield: 0.8 g (72% of theory)

Mass spectrum: (M + H) ⁺ = 303/05 (chlorine isotopes)

G. N-Cvclopentyl-N- (7-methyl-1-phenoxy-isoquinoline-6-vπ-acetamide Prepared analogously to Example 7g from N- (1-chloro-7-methyl-isoquinolin-6-yl) -N-cyclopentyl Acetamide and potassium hydroxide in phenol. Yield: 99% of theory C ₂₃ H ₂₄ N ₂ 0 ₂ (360.46) mass spectrum: (M + H) ⁺ = 361

Massenspektrum: (M+H)⁺ = 505H. 3 - ([6- (N-acetyl-cyclopentylamino) -7-methyl-isoquinoline-1-vaminomethylV4-benzyloxy-benzonitrile Prepared analogously to Example 7h from N-cyclopentyl-N- (7-methyl-1-phenoxy-isoquinoline-6 -yl) -acetamide and 3-aminomethyl-4-benzyloxy-benzonitrile Yield: 59% of theory

Mass spectrum: (M + H) ⁺ = 505

(MH) ^" = 503

i. 3 - ([6- (N-acetyl-cvclopentyl-amino) -7-methyl-isoquinoline-1-vaminomethyl) -4- hvdroxy-benzamidine-hydrochloride Prepared analogously to Example 2h from 4-benzyloxy-3 - {[6- ( N-acetyl-cyclopentylamino) -7-methyl-isoquinolin-1-yl] aminomethyl} benzonitrile and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction analogous to example 2i with palladium on activated carbon / hydrogen in methanol. Yield: 77% of theory over 2 stages

RrValue: 0.47 (Reversed Phase RP8; 5% sodium chloride solution / methanol = 1: 3) C25H29N5O2 X HCI (431.547468.00) Mass spectrum: (M + H) ⁺ = 432

(MH) ^" = 430

Example 20

N-Benzoyl-4-hydroxy-3- (r7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vπaminomethyl) benzamidine

Massenspektrum: (M+H)⁺ = 495853 mg (2.00 mmol) of 4-hydroxy-3 - {[7- (pyrrolidin-1-yl-carbohyl) -quinazolin-4-yl] amino-methyl} -benzamidine hydrochloride are suspended in 2.5 ml of N, N-dimethylformamide , 0.84 ml (6.0 mmol) of triethylamine were added and the mixture was stirred for 5 minutes. A solution of 486 mg (2.00 mmol) of 4-nitrophenylbenzoic acid in 7.5 ml of N, N-dimethylformamide is then added dropwise at 10 ° C. and the mixture is stirred at room temperature for 30 minutes. It is then poured onto ice water and extracted with dichloromethane. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with ethyl acetate / ethanol 9: 1 plus 7.5% ammonia (5-10%). Yield: 70 mg (7% of theory) R _f value: 0.45 (silica gel; ethyl acetate / ethanol = 9: 1 + a few drops of ammonia)

Mass spectrum: (M + H) ⁺ = 495

(MH) ^' = 493 Example 21

NN ^N -dibenzoyl-4-hvdroxy-3- (7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-vnamino-methyll-benzamidine-hvdrochloride

426 mg (1.00 mmol) of 4-hydroxy-3 - {[7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] amino-methylj-benzamidine hydrochloride are suspended in 10 ml of water and 15 ml of acetone. dated, mixed with 0.38 ml (3.3 mmol) of benzoyl chloride and stirred for 1 hour at room temperature. Then 0.54 g (4.0 mmol) of potassium carbonate are added and the mixture is stirred for 16 hours. The acetone is distilled off, the residue is triturated with water and suction filtered. The crude product is chromatographed on silica gel, eluting with ethyl acetate / ethanol 9: 1 plus 7.5% ammonia (2-20%). Yield: 90 mg (15% of theory)

Massenspektrum: (M+H)⁺ = 599Rr value: 0.59 (silica gel; ethyl acetate / ethanol = 9: 1 + a few drops of ammonia)

Mass spectrum: (M + H) ⁺ = 599

Example 22

N-Hvdroxy-4-hvdroxy-3- (r6-methyl-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-vnamino-methvD-benzamidine

a. N-Hvdroxy-4-benzyloxy-3-( 6-methyl-7-(pyrrolidin-1-yl-carbonyl)-chinazolin-4- yllaminomethyl^' -benzamidin

a. N-Hydroxy-4-benzyloxy-3- (6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4- yllaminomethyl ^{'-benzamidine}

0.300 g (0.628 mmol) of 4-benzyloxy-3 - {[6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzonitrile are dissolved in 15 ml of methanol and successively 0.125 g (1.52 mmol) sodium acetate in 0.25 ml water and 0.106 g (1.52 mmol) hydroxylamine hydrochloride in 0.25 ml water and heated to boiling. After 2 hours, 0.2 g of sodium acetate and 0.18 g of hydroxylamine hydrochloride are again added and the mixture is heated to boiling for a further 3 hours. The solvent is distilled off and the residue is purified by chromatography on silica gel twice (1st column: methylene chloride: (methanol / ammonia 19/1) 100: 0 → 70:30; 2nd column: methylene chloride / methanol 98: 2 → 94 : 6). Yield: 50 mg (16% of theory) Rr value: 0.55 (silica gel; methylene chloride / methanol = 9: 1) C ₂₉ H ₃ or ₆ 0 ₃ (510.60) mass spectrum: (M + H) ⁺ = 511

(MH) ^' = 509

(M + HCOO) - = 555

b. N-Hvdroxy-4-hvdroxy-3- (f6-methyl-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yllaminomethvD-benzamidine

Prepared analogously to Example 2i from N-hydroxy-4-benzyloxy-3 - {[6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine, palladium on activated carbon and hydrogen in methanol. Yield: 97% of theory R _f value: 0.45 (silica gel; methylene chloride / methanol = 9: 1) C ₂₂ H ₂₄ N ₆ 0 ₃ (420.48) mass spectrum: (M + H) ⁺ = 421

(MH) ^" = 419

Example 23

N-acetoxymethoxycarbonyl-4-hydroxy-3- (r6-methyl-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-vaminomethyll-benzamidine

a. N-acetoxymethoxycarbonyl-4-benzyloxy-3- (f6-methyl-7- (pyrrolidin-1-yl-carbonvh-quinazolin-4-vaminomethyll-benzamidine) 0.495 g (1.00 mmol) 4-benzyloxy-3 - {[6-methyl -7- (pyrrolidin-1 -yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine are suspended in 25 ml of methylene chloride, with 0.42 ml (3.0 mmol) of triethylamine and 0.306 g (1.20 mmol) of 4-acetoxymethoxycarbonyloxy-nitrobenzene The reaction mixture is concentrated to about 3 ml and purified by chromatography with silica gel (methylene chloride / methanol 19: 1).

Yield: 300 mg (49% of theory)

Rr value: 0.69 (silica gel; ethyl acetate / ethanol = 9: 1 + a few drops of ammonia)

Mass spectrum: (M + H) ⁺ = 611 (M + HCOO) ^" = 655

b. N-acetoxymethoxycarbonyl-4-hydroxy-3- (r6-methyl-7- (pyrrolidin-1-yl-carbonyl) quinazolin-4-vaminomethyl} benzamidine

Prepared analogously to Example 2i from N-acetoxymethoxycarbonyl-4-benzyloxy-3 - {[6- methyl-7- (pyrrolidin-1 -yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine, palladium on activated carbon and hydrogen in methanol. Yield: 30% of theory

Massenspektrum: (M+H)⁺ = 521R _f value: 0.65 (silica gel; ethyl acetate / ethanol = 9: 1 + a few drops of ammonia)

Mass spectrum: (M + H) ⁺ = 521

Example 24 N- (n-Hexyloxycarbonvπ-4-hvdroxy-3- {r7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yl1-aminomethyll-benzamidine

0.390 g (1.00 mmol) of 4-hydroxy-3 - {[7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine are suspended in 15 ml of methylene chloride, with 0.289 g (1.08 mmol) 4-n-hexyloxycarbonyloxy-nitrobenzene and 0.70 ml (5.0 mmol) triethylamine were added and the mixture was heated to boiling for 2.5 h. The reaction mixture is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. After chromatographic purification, the title compound is obtained (silica gel, ethyl acetate / methanol 100: 0 → 80:20). Yield: 20 mg. (4% of theory) Rr value: 0.63 (silica gel; ethyl acetate / ethanol = 9: 1)

Mass spectrum: (M + H) ⁺ = 519

Example 25

3 - {[7- (N-Ethyl-N-methylaminocarbonyl) -quinazoline-4-vaminomethyl) -4-hydroxy-benzamidine hydrochloride

Prepared analogously to Example 2i from 4-benzyloxy-3 - {[7- (thiazolidin-3-yl-carbonyI) -quinazolin-4-yl] aminomethyl} -benzamidine dihydrochloride, palladium on activated carbon and hydrogen in methanol and subsequent chromatographic purification. Yield: 17% of theory

R _f value: 0.50 (reversed phase RP8; 5% sodium chloride solution / methanol = 4: 6)

C ₂ oH ₂₂ N ₆ θ2 x 2 HCI (378.44 / 451.36)

Mass spectrum: (M + H) ⁺ = 379

Example 26

4-Hvdroxy-3- (r7- (thiazolidin-3-yl-carbonvπ-quinazolin-4-yl1aminomethyl) benzamidine dihydrochloride

0.210 g (0.367 mmol) 4-benzyloxy-3 - {[7- (thiazolidin-3-yl-carbonyl) -quinazolin-4-yJ] - aminomethylj-benzamidine-dihydrochloride and 0.435 g (2.94 mmol) pentamethylbenzene are added in 5 ml Trifluoroacetic acid heated at 60 ° C for 18 h and after adding 80 mg of pentamethylbenzene for 3 h at 70 ° C. It is then concentrated and purified on a silica gel column (methylene chloride / methanol 90:10 -> 80:20).

Yield: 91% of theory Rr value: 0.55 (reversed phase RP8; 5% sodium chloride solution / methanol = 4: 6) C ₂ oH ₂ oN ₆ 0 ₂ S x 2 HCl (408.49 / 481.41) mass spectrum: (M + H) ⁺ = 409

(M + H) - = 407

Example 27

4-Benzyloxy-3- (r2-methyl-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-vnaminomethyll-benzamidine-hydrochloride

Prepared analogously to Example 2h from 4-benzyloxy-3 - {[2-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzonitrile and hydrochloric acid / ammonium carbonate in

Ethanol.

Yield: 25% of theory

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

C ₂₉ H _{3 on 6} θ2 x HCI (494.60 / 531.06)

Mass spectrum: (M + H) ⁺ = 495

Example 28

4-Hvdroxy-3- (r2-methyl-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-vπaminomethyll-benzamidine-hydrochloride

Prepared analogously to Example 2i from 4-benzyloxy-3 - {[2-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} benzamidine hydrochloride, palladium on activated carbon and hydrogen in methanol. Yield: 96% of theory

R _f value: 0.57 (reversed phase RP8; 5% sodium chloride solution / methanol = 4: 6) C ₂₂ H ₂₄ N ₆ θ ₂ x HCl (404.48 / 440.94) mass spectrum: (M + H) ⁺ = 405

(MH) ^" = 403 Example 29

4-Hydroxy-3- (6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yllaminomethyl) benzamidine acetate

a. 2-amino-5-chloro-terephthalate

104 g (0.50 mol) dimethyl aminoterephthalate are dissolved in 750 ml methylene chloride and 77 ml (0.96 mol) sulfuryl chloride are added at 0 ° C. The mixture is then heated to boiling for 1 hour, 200 ml of diethyl ether are added, and the precipitate which has separated out is filtered off. Yield: 23% of theory

RrValue: 0.45 (silica gel; petroleum ether / ethyl acetate = 6: 4)

Mass spectrum: (M + H) ⁺ = 244/246 (chlorine isotopes)

b. 4- Hvd roxy-3- (r6-chloro-7- (pyrrole idi n- 1 -yl-carbonvP-chi nazol i n-4-yllami nomethyl) - benzamidine acetate The title compound is obtained from 2-amino-5- chloro-terephthalic acid dimethyl ester after saponification with sodium hydroxide solution analogous to example 13 and the synthesis sequence analogous to example: 8a, 8b, 8c, 8h, 2h and final debenzylation with palladium / carbon in methanol analogous to example 2i and chromatographic purification (silica gel: methylene chloride / Ethanol 9: 1-7: 3 + 1% glacial acetic acid) Yield: 13% of theory (last stage)

RrValue: 0.65 (silica gel; methylene chloride / ethanol 7: 3 + 1% glacial acetic acid) C21H21CIN6O2 x C2H4O2 (424.90 / 484.95) mass spectrum: (M + H) ⁺ = 425/427 (chlorine isotopes)

(MH) ^" = 423/425 (chlorine isotopes) Example 30

5-lf6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vaminomethyll-thiophene-2-amidine hydrochloride

Prepared analogously to Example 2h from 5 - {[6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazoline-4-yl] aminomethyl} -thiophene-2-nitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 56% of theory

C ₂ oH ₂₂ N ₆ OSx HCI (394.50 / 430.96) mass spectrum: (M + H) ⁺ = 395

(M + Cl) ^" = 429/431 (chlorine isotopes)

(MH) ^" = 393

Example 31

4-Hvdroxy-3-f2-phenyl-1-r7- (pyrrolidin-1-yl-carbonvπ-quinolin-4-ylamino1-ethyl) -benzamidine-hydrochloride

Prepared analogously to Example 2i from 4-benzyloxy-3- {2-phenyl-1- [7- (pyrrolidin-1-ylcarbonyl) quinolin-4-ylamino] ethyl} benzamidine hydrochloride, palladium on activated carbon and hydrogen in methanol. Yield: 75% of theory RrValue: 0.69 (silica gel; acetonitrile / chloroform / water / formic acid

75: 20: 10: 15)

C ₂₉ H ₂₉ N ₅ O ₂ X HCI (479.58 / 516.05)

Mass spectrum: (M + H) ⁺ = 480

Example 32

N-Benzoyl-4-hydroxy-3- (r6-methyl-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yllaminomethyll-benzamidine

a. N-benzoyl-4-benzyloxy-3- (f6-methyl-7- (pyrrolidin-1-yl-carbonv0-quinazolin-4-yllaminomethyll-benzamidine

Prepared analogously to Example 20 from 4-benzyloxy-3 - {[6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine, 4-nitrophenyl-benzoate and

Triethylamine in N, N-dimethylformamide.

Yield: 7.1%

RrValue: 0.45 (silica gel; ethyl acetate / ethanol 9: 1 + 0.5% ammonia solution)

b. N-benzoyl-4-hydroxy-3- (r6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-ylaminol-methyll-benzamidine

Prepared analogously to Example 2i from N-benzoyl-4-benzyloxy-3 - {[6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine, palladium on activated carbon and hydrogen in methanol. Yield: 34% of theory

RrValue: 0.36 (silica gel; ethyl acetate / ethanol 9: 1 + 0.5% ammonia solution) C ₂₉ H ₂₈ N ₆ 0 ₃ (508.56) Mass spectrum: (M + H) ⁺ = 509

Example 33

N-Benzoyl-3- (r6-chloro-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-yllaminomethyl) -4-hydroxy-benzamidine

Prepared analogously to Example 24 from 4-benzyloxy-3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine, 4-nitrophenyl-benzoate and triethylamine in Dichloromethane and subsequent reaction analogous to Example 2i with palladium on activated carbon / hydrogen in methanol. Yield: 26% of theory over 2 steps Rr value: 0.71 (silica gel; dichloromethane / ethanol 9: 1)

Mass spectrum: (M + H) ⁺ = 529/531 (chlorine isotopes)

Example 34

3-fr6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vaminomethyll-N- (n-hexyloxycarbonvD-4-hydroxy-benzamidine

a. 4-Benzyloxy-3-{[6-chlor-7-(pyrrolidin-1-yl-carbonyl)-chinazolin-4-vnaminomethyl)-

a. 4-benzyloxy-3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vnaminomethyl) -

N- (n-hexyloxycarbonyl) benzamidine Prepared analogously to Example 24 from 4-benzyloxy-3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} benzamidine , 0- (n-Hexyl) -0 '- (p-nitrophenyl) carbonate and triethylamine in dichloromethane. Yield: 67%

RrValue: 0.75 (silica gel; dichloromethane / ethanol 9: 1) mass spectrum: (M + H) ⁺ = 643/645 (chlorine isotopes)

C ₃₅ H ₃₉ CIN ₆ 0 ₄ (643.19).

Massenspektrum: (M+H)⁺ = 553/555 (Chlorisotope)b. 3- (f6-Chloro-7- (pyrrolidin-1-yl-carbonvπ-quinazolin-4-vnaminomethyl) -N- (n-hexyloxycarbonvD-4-hvdroxy-benzamidine Prepared analogously to Example 2i from 4-benzyloxy-3 - {[ 6-chloro-7- (pyrrolidin-1-yl-carbonyl) quinazolin-4-yl] aminomethyl} -N- (n-hexyloxycarbonyl) -benzamidine, palladium on activated carbon and hydrogen in methanol. Yield: 51% of theory Rr value : 0.70 (silica gel; ethyl acetate / ethanol 9: 1)

Mass spectrum: (M + H) ⁺ = 553/555 (chlorine isotopes)

Example 35

2-Amidino-5- (r7- (2.5-dihvdropyrrol-1-yl-carbonyl) -quinazolin-4-vaminomethyll-thiophene-hydrochloride

Prepared analogously to Example 2h from 2-cyano-5 - {[7- (2,5-dihydropyrrol-1-ylcarbonyl) quinazolin-4-yl] aminomethyl} thiophene and hydrogen chloride / ammonium carbonate in ethanol. Yield: 38% of theory RrValue: 0.1 (silica gel; ethyl acetate / ethanol 8: 2) Cι ₉ Hι ₈ N ₆ OS ^* HCI (414.92 / 378.46) Mass spectrum: (M + H) ⁺ = 379

Example 36

3- (r7- (2.5-Dihvdropyrrol-1-yl-carbonvπ-quinazolin-4-vnaminomethyl) benzamidine hydrochloride

Prepared analogously to Example 2h from 3 - {[7- (2,5-dihydropyrrol-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzonitrile and hydrogen chloride / ammonium carbonate in ethanol. Yield: 91% of theory

RrValue: 0.07 (silica gel; dichloromethane / ethanol 8: 2) C ₂ ιH ₂₀ N ₆ O ^* HCl (408.89 / 372.43) Mass spectrum: (M + H) ⁺ = 373

Example 37

3-f [7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-vnaminomethyll-benzamidine hvdrochlorid

150 mg (0.37 mmol) of 3 - {[7- (2,5-dihydropyrrol-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl} -benzamidine hydrochloride are dissolved in 5.0 ml of methanol, with 15 mg Platinum dioxide added and hydrogenated for 2.5 hours at 3 bar under a hydrogen atmosphere. After filtration, the solvent is removed in vacuo, the residue in ethanol taken up and filtered through silica gel. The filtrate is freed from the solvent in vacuo.

Yield: 50 mg of yellow crystals (33% of theory)

RrValue: 0.21 (Reversed Phase RP8; 5% sodium chloride solution / methanol 3: 2) C ₂ ιH ₂₂ N ₆ 0 * HCl (374.45 / 410.91). Mass spectrum: (M + H) ⁺ = 375

Example 38

4-Hydroxy-3- (2-phenyl-1-r7- (pyrrolidin-1-yl-carbonyl) -quinolin-4-ylamino1-ethyl-benzylamine

Prepared analogously to Example 2i from 4-benzyloxy-3- {2-phenyl-1- [7- (pyrrolidin-1-ylcarbonyl) quinolin-4-ylamino] ethyl} benzonitrile, palladium on activated carbon and

Hydrogen in methanol.

Yield: 91% of theory

Massenspektrum: (M+H)⁺ = 467RrValue: 0.42 (silica gel; dichloromethane / methanol 8: 2 + 0.1% ammonia solution)

Mass spectrum: (M + H) ⁺ = 467

Example 39

3 - ([7- (3-amino-piperidin-1-yl-carbonyl) -quinazolin-4-yl1aminomethyl) benzamidine

Hergestellt analog Beispiel 8h aus 4-Chlor-7-(3-tert.-butoxycarbonylamino-piperidin- 1-yl-carbonyl)-chinazolin, 3-Aminomethyl-benzamidin und N,N-Diisopropylethylamin in Dimethylformamid bei Raumtemperatur. Anschließend wird zur Boc-Abspaltung nach Entfernen des Lösungsmittels im Vakuum der Rückstand mit einer Mischung aus Dichlormethan / Trifluoressigsäure / destilliertem Wasser 30:63:7 über 2 Tage behandelt. Flüchtige Bestandteile werden danach im Vakuum entfernt. HPLC-MS Ergebnisse: Retentionszeit: 2.31 min

Prepared analogously to Example 8h from 4-chloro-7- (3-tert-butoxycarbonylamino-piperidin-1-yl-carbonyl) -quinazoline, 3-aminomethyl-benzamidine and N, N-diisopropylethylamine in dimethylformamide at room temperature. Subsequently, to remove Boc, after removing the solvent in vacuo, the residue is treated with a mixture of dichloromethane / trifluoroacetic acid / distilled water 30: 63: 7 for 2 days. Volatile components are then removed in vacuo. HPLC-MS results: retention time: 2.31 min

Mass spectrum: (M + H) ⁺ = 404

Example 40

3- (r7- (2-Aminomethyl-piperidin-1-yl-carbonvπ-quinazolin-4-vnaminomethyl) benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (2-tert-butoxycarbonylaminomethyl-piperidin-1-yl-carbonyl) -quinazoline, 3-aminomethyl-benzamidine and diisopropylethyl-amine in dimethylformamide at room temperature and subsequent Boc elimination with trifluoroacetic acid analogous to example 39.

HPLC-MS results:

Retention time: 2.46 min C ₂₃ H ₂₇ N ₇ 0 (417.51)

Mass spectrum: (M + H) ⁺ = 418

Example 41

3-lf7- (azetidin-1-yl-carbonvπ-quinazolin-4-yl1aminomethyl) benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (azetidin-1-yl-carbonyl) -quinazoline, 3-

Aminomethyl-benzamidine and diisopropylethylamine in dimethylformamide

Room temperature.

HPLC-MS results:

Retention time: 2.52 min

C ₂ oH ₂ oN ₆ 0 (360.42)

Mass spectrum: (M + H) ⁺ = 361

Example 42

3 - ([7- (3-Aminomethylpiperidin-1-yl-carbonvh-quinazolin-4-yllaminomethyll-benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (3-tert-butoxycarbonylaminomethyl-piperidin-1-yl-carbqnyl) -quinazoline, 3-aminomethyl-benzamidine and diisopropylethylamine in dimethylformamide at room temperature and subsequent Boc elimination with trifluoroacetic acid analogously to Example 39. HPLC-MS results: retention time: 2.41 min C ₂₃ H ₂₇ N ₇ 0 (417.51) mass spectrum: (M + H) ⁺ = 418

Example 43 3- {l ^' 7- (2,5-Dihvdropyrrol-1-yl-carbonyl) -quinazolin-4-yllaminomethyl} benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (2,5-dihydropyrrol-1-yl-carbonyl) quinazoline, 3-aminomethylbenzamidine and diisopropylethylamm in dimethylformamide at room temperature. HPLC-MS results: retention time: 2.64 min C ₂ ιH ₂ oN ₆ 0 (372.43) mass spectrum: (M + H) ⁺ = 373

Example 44

3- (R7 (piperidin-1-yl-carbonvπ-quinazolin-4-vnaminomethyl) benzamidine

Massenspektrum: (M+H)⁺ = 389Prepared analogously to Example 8h from 4-chloro-7- (piperidin-1-yl-carbonyl) -quinazoline, 3-aminomethyl-benzamidine and diisopropylethylamine in dimethylformamide at room temperature. HPLC-MS results: retention time: 2.77 min

Mass spectrum: (M + H) ⁺ = 389

Example 45

3 - ((7-diethylaminocarbonyl-quinazolin-4-v0aminomethyl) benzamidine

Prepared analogously to Example 8h from 4-chloro-7-diethylaminocarbonyl-quinazoline, 3-

Aminomethyl-benzamidine and diisopropylethylamine in dimethylformamide

Room temperature.

HPLC-MS results:

Retention time: 2.70 min

C ₂ ιH ₂₄ N ₆ 0 (376.46)

Mass spectrum: (M + H) ⁺ = 377

Example 46

3 - ([7- (3-Dimethylaminoazetidin-1-yl-carbonvπ-quinazolin-4-vnaminomethyl} - benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (3-dimethylaminoazetidin-1-yl-carbonyl) quinazoline, 3-aminomethylbenzamidine and diisopropylethylamine in dimethylformamide at room temperature. HPLC-MS results: retention time: 2.32 min C ₂₂ H ₂₅ N ₇ 0 (403.49) mass spectrum: (M + H) ⁺ = 404

Example 47 3- {r7- (N-Cvclohexyl-N-methyl-aminocarbonvπ-quinazolin-4-vnaminomethyl) benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (N-cyclohexyl-N-methylaminocarbonyl) quinazoline, 3-aminomethylbenzamidine and diisopropylethylamine in dimethylformamide at room temperature. HPLC-MS results: retention time: 3.15 min C ₂₄ H ₂₈ N ₆ 0 (416.53)

Mass spectrum: (M + H) ⁺ = 417

Example 48

3 - ([7- (N-benzyl-N-methyl-aminocarbonvπ-quinazolin-4-yllaminomethyl} -benzamidine

Massenspektrum: (M+H)⁺ = 425Prepared analogously to Example 8h from 4-chloro-7- (N-benzyl-N-methylamihocarbonyl) quinazoline, 3-aminomethylbenzamidine and diisopropylethylamine in dimethylformamide at room temperature. HPLC-MS results: retention time: 3.11 min

Mass spectrum: (M + H) ⁺ = 425

Example 49 3- (r7- (3-Amino-pyrrolidin-1-yl-carbonyl) -quinazoline-4-vaminomethyl> -benzamidine

Prepared analogously to Example 8h from 4-chloro-7- (3-tert-butoxycarbonylamino-pyrrolidin-1-yl-carbonyl) -quinazoline, 3-aminomethyl-benzamidine and diisopropylethylamine in

Dimethylformamide at room temperature and subsequent cleavage with

Trifluoroacetic acid analogous to Example 39.

HPLC-MS results:

Retention time: 2.31 min C ₂ ιH ₂₃ N ₇ 0 (389.46)

Mass spectrum: (M + H) ⁺ = 390

Example 50

3 - ([7- (Pyrrolidin-1-yl-carbonyl) -6-chloro-quinazolin-4-yllaminomethyll-4-hydroxy-benzylamine

a. 3- {f7- (Pyrrolidin-1-yl-carbonvh-6-chloro-quinazolin-4-vnaminomethyl) -4-benzyloxy-benzylamine

496 mg (1.00 mmol) 3 - {[7- (2,5-dihydropyrrol-1-yl-carbonyl) -6-chloro-quinazolin-4-yl] - aminomethyl} -4-benzyloxy-benzonitrile are made more methanolic in 75 ml Ammonia solution mixed with 500 mg Raney nickel and treated with hydrogen at 5 atm pressure for 7.5 hours. It is then filtered and the solvent is removed in vacuo. The residue is treated with 20 ml of dichloromethane / diethyl ether 1: 1 and the crystalline solid is filtered off. Yield: 210 mg (42% of theory) Rr value: 0.15 (silica gel; dichloromethane / ethanol 9: 1 + 1% acetic acid)

C ₂₈ H ₂₈ CIN ₅ 0 ₂ (502.02)

Mass spectrum: (M + H) ⁺ = 502/504 (chlorine isotopes)

b. 3- (f7- (Pyrrolidin-1-yl-carbonvπ-6-chloro-quinazolin-4-vnaminomethyl) -4-hydroxy-benzylamine hydrochloride 75 mg (0.15 mmol) 3 - {[7- (pyrrol-1-yl -carbonyI) -6-chloro-quinazolin-4-yl] aminomethyl} - 4-benzyloxy-benzylamine are mixed with 180 mg of pentamethylbenzene in 3 ml of trifluoroacetic acid and heated to 60 ° C. under a nitrogen atmosphere for 6 hours The mixture was stirred at room temperature for 16 hours, volatiles were removed in vacuo, 50 ml of ice water were added to the residue, the resulting precipitate was filtered off and the filtrate was concentrated in vacuo, the residue was taken up twice in toluene and once in diethyl ether and in each case concentrated in vacuo the remaining residue is dissolved in 2 ml of absolute ethanol and treated with ethereal hydrochloric acid, the resulting precipitate is filtered off, treated with 30 ml of a solvent mixture of petroleum ether / diethyl ether / ethyl acetate 1: 10: 1 and the crystalline solid is filtered off mg (36% of theory) Rr value: 0.15 (reversed phase RP8; 5% sodium chloride solution / methanol 3: 2) C ₂ ιH ₂₂ CIN ₅ 0 ₂ x HCl (448.36 / 411.89)

Mass spectrum: (M + H) ⁺ = 412/414 (chlorine isotopes)

The following examples describe the preparation of pharmaceutical use forms which contain any compound of the general formula (I) as active ingredient:

Example I

Dry ampoule with 75 mg 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 II

Dry ampoule with 35 mα 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 III

Tablet with 50 mα 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 mα

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 facets on both sides and partial notch on one side. Tablet diameter: 9 mm.

Example IV

Tablet with 350 mα active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) Polyvinylpyrrolidone 30.0 mg

(5) Magnesium stearate 4.0 mα

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 facets on both sides and partial notch on one side. Tablet diameter: 12 mm.

Example V

Capsules with 50 mα active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg (3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate 2.0 mg

160.0 mg

production:

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

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

Example VI

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 mα

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 VII

Suppositories with 100 mg of active ingredient 1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

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

2000.0 mg

production:

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

Claims

claims 1. Compounds of the general formula

R ² (I), in the X is a nitrogen atom or a methine group, Y is a methine group or a nitrogen atom which is optionally substituted by a C ₃ alkyl or amino group, Z is a nitrogen atom or a methine group, R ¹ is an amino, Cι _-5 alkylamino, C _3- cycloalkylamino, or phenyl-Cι _-3 alkyl amino group, each on the amine nitrogen atom by a phenylcarbonyl or phenylsulphonyl group or by a in the alkyl moiety is optionally substituted by a carboxy group, an in vivo convertible group into a carboxy group, an amino, Cι- ₃ alkylamino or di- (Cι _-3 alkyl) amino group substituted Cι _-3 alkyl or Cι- ₃ alkyl carbonyl group can be substituted . a di- (Cι _-5 -alkyl) amino or N- (C _3- cycloalkyl) -Cι- ₅ alkylamino group, the d- ₅ alkyl part with the exception of the 1 position each by a hydroxy, Cι- 3-alkoxy, amino, Cι _-3 alkylamino or di (Cι _-3 alkyl) amino group may be substituted, a 4- to 7-membered cycloalkyleneimino group, a methylene group, which is not directly adjacent to the imino group, by a hydroxy-, d _-3 -alkoxy-, amino-, d- ₃ -alkylamino- or di- (Cι _{- 3} -alkyl) -amino group can be substituted, a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group, where the cycloalkyleneimino part by a C ₃ alkyl, amino C ₃ alkyl, C ₃ alkyl amino C ₃ alkyl, DKd-s-alkyamino-Ci-s-alkyl, Aminocarbonyl-, d- ₃ -alkyl-amino-carbonyl-, N- (C _{3. 7} -cycloalkyl) -Cι- ₅ -alkylaminocarbonyl-, N- (phenyl-Cι _-3 - alkyl) -Cι _-5 -alkylaminocarbonyl- or di- (-C _-3 alkyl) aminocarbonyl group may be substituted or a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C _{3 -3} alkylamino or di (C _{3 -3} alkyl) amino group and / or a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by a sulfinyl or sulfonyl group or a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C _2-3 -alkanoyl) -, sulfinyl or sulfonyl group and / or a -CH ₂ -CH ₂ - group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO group, an optionally by a C ₃ alkyl, amino C ₃ alkyl, C ₃ alkylamino C ₃ alkyl, di (C _{3 3} alkyl) amino C ₃ alkyl -, Aminocarbonyl-, Cι _-3 -alkylamino- carbonyl-, N- (C _3-7 -cycloalkyl) -d _-5 -alkylaminocarbonyl-, N- (phenyl-Cι- ₃ -alkyl) -Cι _-5 - alkyl aminocarbonyl - or di- (Cι- ₃ -alkyl) -aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbonyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group, an aminosulfonyl or aminocarbonyl group optionally substituted by one or two C ₃ alkyl, phenyl C 3 alkyl or C _3-7 cycloalkyl groups, where the substituents can be the same or different, a straight-chain or branched d _-5 -alkylcarbonyl group, a C _3-7 cycloalkyl carbonyl group, wherein the methylene group in the 3- or 4-position in a C _5- 7-cycloalkyl-carbonyl group can be replaced by an -NH group in which the hydrogen atom of the -NH group can be replaced by a C ₃ alkyl, C ₃ alkyl carbonyl, phenylcarbonyl or phenylsulfonyl group, a phenylcarbonyl or heteroarylcarbonyl group or an optionally substituted by an amino, Cι _-3 alkylamino, di (d _-3 alkyl) amino, hydroxy, phenyl or a 4- to 7-membered cycloalkyleneimino group, Cι- ₃ alkyl group, wherein the phenyl substituents can be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _{3 -3} alkyl or C _{3 -3} alkoxy group, R ^{2 is} a hydrogen, fluorine, chlorine or bromine atom, a Cι _-3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or a C _2-3 alkenyl, C _2-3 alkynyl, hydroxy, d- ₃ alkoxy or trifluoromethoxy group, R ^{3 is} a hydrogen atom, a linear or branched d _-6 alkyl group, which may be replaced by a hydroxy, d _-3 alkyloxy, carboxy, C 3 alkoxy carbonyl, amino, C _{3 -3} alkylamino, di (C 1 _-3 alkyl) amino, C ₃ alkyl carbonylamino, C ₅ alkoxy carbonyl amino or phenyl d ₃ alkoxy carbonylamino group is substituted, a methyl or ethyl group, each by a phenyl or heteroaryl group, each optionally by a hydroxy, C ₄ alkyloxy, benzyloxy, hydroxycarbonyl C ₃ alkoxy, C 1. ₃ - alkyloxy-carbonyl-Cι _-3 -alkyloxy-, aminocarbonyl-Cι _-3 -alkyloxy-, Cι- ₃ -alkyl- aminocarbonyl-C - ₃ -alkyloxy-, di- (Cι. ₃ -alkyl) -aminocarbonyl-Cι_ , ₃ -alkyloxy-, carboxy-, d- ₃ -alkyloxy-carbonyl groups are substituted, by a 1 -H-pyridonyl or 1 - (Cι- ₃ alkyl) pyridonyl group, by a 4- to 7-membered cycloalkyleneimino group or by a 4- to 7-membered cycloalkyl group in which one or two methylene groups separated from one another at least by a methylene group each by an oxygen or sulfur atom or by an —NH— or -N (Cι- ₃ alkyl) - group are replaced and in which, if the cycloalkyl group contains an -NH or a -N (Cι- ₃ alkyl) group, a methylene group adjacent to the nitrogen atom and, if the cycloalkyl group as a whole contains two -NH- or -N (Cι- ₃ alkyl) - groups, a methylene group adjacent to two nitrogen atoms can be replaced by a carbonyl group, are substituted, or a phenyl or heteroaryl group, each with a hydroxy, Cι- ₄ alkyloxy, benzyloxy, hydroxycarbonyl-Cι _-3 -alkoxy-, Cι _-3 -Alkyloxy-carbonyl-Cι_. ₃ -alkyloxy-, aminocarbonyl-d- ₃ -alkyloxy-, Cι- ₃ -alkylaminocarbonyl-Cι _-3 -alkyloxy-, di- (Cι _-3 -alkyl) - aminocarbonyl-d- ₃ -alkyloxy-, carboxy-, Cι _-3- Alkyloxy-carbonylgruppe can be substituted, and Ar is a phenyl group substituted by the radicals R ⁴ , R ⁵ and R ⁶ , where R ^{4 is} a cyano group, an optionally by one or two hydroxy, Cι- ₃ alkyl, group Cι _-8 alkyl carbonyl, Cι _-8 -alkoxy-carbonyl or benzoyl substituted amidino, an amino Cι. ₃ -alkyl-, Cι- ₃ -alkylamino-Cι _-3 -alkyl- or di- (Cι _-3 -alkyl) amino- Cι- ₃ -alkyl group or a group of the formula

in which R ^{7 is} a hydrogen atom or a Cι _-3 alkyl group and R ^{8 is} a C _-3 alkyl group, R ^{5 is} a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, d _-3 - alkyl, hydroxy, hydroxy-Cι- ₃ -alkyl, Cι _-3 -A! Koxy-, benzyloxy-, Cι _-3 -alkoxy-Cι _-3 - alkyl, amino, Cι _-3 -alkylamino or di (Cι _-3 -alkyl) amino group and R ^{6 represents} a hydrogen, fluorine, chlorine or bromine atom or a C _{3 -3} alkyl group, or a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group which is optionally substituted in the carbon structure by the groups R ⁴ and R ⁵ , where R ⁴ and R ^{5 are} as defined above, where, unless stated otherwise, the expression "heteroaryl group" means one in the carbon skeleton, optionally by ad _-3 -alkyl-, carboxy-, Cι _-3 -alkoxy-carbonyl or Cι _-3 -alkoxy-carbonylamino group substituted monocyclic 5- or 6-membered heteroaryl group is to be understood, wherein the 6-membered heteroaryl group has one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a C _-3 alkyl or phenyl C ₃ alkyl group, an oxygen or sulfur atom or one optionally by a d- ₃ -alkyl-, amino-Cι _-3 -alkyl-, -Cι _-3 -alkylamino- Cι _-3 -alkyl-, di- (Cι- ₃ -alkyl) -amino-d _-3 -alkyl- or phenyl-Cι- ₃ -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or one optionally substituted by a C ₃ alkyl or phenyl C ₃ alkyl group , tuated imino group and two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, a phenyl ring _. can be condensed and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring, where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched, and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures, their prodrugs and their salts. 2. Compounds of general formula I according to claim 1, in which X is a nitrogen atom or a methine group, Y is a methine group optionally substituted by a d _-3 alkyl group, Z is a nitrogen atom or a methine group, R ^{1 is} an amino, ds-alkylamino or C ₃ - ₇ cycloalkylamino group, which in each case on the amine nitrogen atom by a group in the alkyl part, optionally by a carboxy group, an in vivo convertible to a carboxy group, an amino, ds-alkylamino or Di- (C ₃ alkyl) amino group substituted C ₃ alkyl or C ₃ alkyl carbonyl group may be substituted, a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group, where the cycloalkyleneimino part by a C ₃ alkyl, amino C ₁ s alkyl, C ₃ alkyl amino C ₃ alkyl ₃ , di (C ₃ alkyl) amino C 1. ₃ -alkyl-, aminocarbonyl-, Cι _-3 -alkylamino-carbonyl-, N- (C ₃ - ₇ cycloalkyl) -Cι- ₅ -alkylaminocarbonyl- or di- (Cι _-3 - alkyl) -aminqcarbonylgruppe be substituted can or a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C ₃ alkyl alkyl or di (C ₃ alkyl) amino group and / or a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by sulfinyl or sulfonyl group or a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C _2-3 -alkanoyl) -, sulfinyl or sulfonyl group and / or a -CH ₂ -CH ₂ - group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO group, an optionally by a C ₃ alkyl, amino C ₃ alkyl, C ₃ alkylamino C ₃ alkyl ₃ , di (C ₃ alkyl) amino C ₃ alkyl -, Aminocarbonyl-, Cι- ₃ -alkylamino- carbonyl-, N- (C ₃ - ₇ cycloalkyl) -Cι- ₅ -alkylaminocarbonyl-, N- (phenyl-Cι- ₃ -alkyl) -Cι- ₅ - alkylaminocarbonyl- or di- (-C ₃ -alkyl) -aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbonyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group ,. an aminosulfonyl or aminocarbonyl group which is optionally substituted by one or two C ₃ alkyl, phenyl C ₃ alkyl or C ₃ - ₇ cycloalkyl groups, it being possible for the substituents to be identical or different, a straight-chain or branched C-5-alkylcarbonyl group or a C _3-7 cycloalkyl-carbonyl group, R ^{2 is} a hydrogen, fluorine, chlorine or bromine atom, a Cι- ₃ alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or a C _2-3 alkenyl, C ₂ - ₃ alkynyl, hydroxyl, C 3 alkoxy or trifluoromethoxy group, R ^{3 is} a hydrogen atom, a linear or branched Cι- ₆ alkyl group, optionally by a hydroxy, Cι- ₃ alkyloxy, carboxy, Cι- ₃ alkoxycarbonyl, amino, Cι. ₃ -alkylamino-, di- (Cι _-3 -alkyl) -amino-, Cι- ₃ -alkylcarbonylamino-, d. ₅ -alkoxy-carbonylamino- or phenyl-Cι- ₃ -alkoxy-carbonylamino group is substituted, or a methyl group that by a phenyl or heteroaryl group, each optionally by a hydroxy, Cι- ₄ alkyloxy, benzyloxy, hydroxycarbonyl-d _-3 -alkoxy-, Cι _-3 - alkyloxy-carbonyl-Cι. ₃ ~ alkyloxy-, aminocarbonyl-d- ₃ -alkyloxy-, d _-3 -alkyl- aminocarbonyl-Cι- ₃ -alkyloxy-, di- (Cι _-3 -alkyl) -aminocarbonyl-Cι _-3 -alkyloxy-, carboxy- , Cι- ₃ alkyloxy-carbonyl group are substituted, is substituted, and Ar is a phenyl group substituted by the radicals R ⁴ , R ⁵ and R ⁶ , where R ^{4 is} a cyano group, an optionally by one or two hydroxy, Cι _-3 alkyl, Cι group _-8 alkyl carbonyl, Cι _-8 -alkoxy-carbonyl or benzoyl substituted amidino, an amino -C ₃ alkyl, C ₃ alkylamino C ₃ alkyl ₃ or di (C ₃ alkyl) amino Cι- ₃ -alkyl group or a group of the formula

in which R ^{7 is} a hydrogen atom or a Cι _-3 alkyl group and R ^{8 is} a C _-3 alkyl group, R ^{5 is} a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, Cι _-3 - alkyl, hydroxy, benzyloxy, amino or Cι _-3 alkylamino group and R ^{6 represents} a hydrogen, chlorine or bromine atom or a d-3-alkyl group, or a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group which is optionally substituted in the carbon structure by the groups R ⁴ and R ⁵ , where R ₄ and R _{5 are} as defined above, where, unless stated otherwise, the expression “heteroaryl group” denotes a mono- optionally substituted in the carbon skeleton by a C ₃ -C ₃ -alkyl, carboxy, C ₃ -3 alkoxy-carbonyl or d ₃ -alkoxy carbonylamino group Cyclic 5- or 6-membered heteroaryl group is to be understood, wherein the 6-membered heteroaryl group has one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a C ₃ -C ₃ -alkyl or phenyl- ₃ -3-alkyl group, an oxygen or sulfur atom or an optionally by ad _-3 -alkyl-, amino-Cι _-3 -alkyl-, -Cι _-3 -alkylamino- Cι- ₃ -alkyl-, di- (Cι. ₃ -alkyl) -amino-Cι _-3 -alkyl - Or phenyl-C _-3 alkyl group substituted imino group or an oxygen or sulfur atom and in addition a nitrogen atom or a possibly by a Cι. _3- alkyl or phenyl-d _-3- alkyl group substituted imino group and two or three nitrogen atoms, and, in addition, a phenyl ring may be fused to the monocyclic heteroaryl groups mentioned above via two adjacent carbon atoms and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring, where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched, and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures, their prodrugs and their salts. 3. Compounds of general formula I according to claim 2, in which X is a nitrogen atom or a methine group, Y is a methine group and Z represents a nitrogen atom or a methine group, R ^{1 is} an amino, d _-5 -alkylamino or C ₃ - ₇ cycloalkylamino group, each of which on the amine nitrogen atom through a group in the alkyl part, optionally through a carboxy group, an in vivo convertible group into a carboxy group, an amino, ds-alkylamino - or di- (C ₃ alkyl) amino group substituted C ₃ alkyl or C ₃ alkyl carbonyl group may be substituted, a 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein the Cycloalkyleniminoteil by a Cι- ₃ -alkyl-, amino-Cι- ₃ -alkyl-, Cι- ₃ -alkyl- amino-Cι- ₃ -alkyl-, di- (Cι- ₃ -AIkyl) -amino-Cι- _3rd alkyl, aminocarbonyl, C ₃ alkyl alkyl carbonyl or di (C ₃ alkyl) aminocarbonyl group may be substituted or a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C _{3 -3} alkyl amino or di (C _{3 -3} alkyl) amino group and / or a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by sulfinyl or sulfonyl group or a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C _{2 -3} -alkanoyl) -, sulfinyl or sulfonyl group and / or a -CH ₂ -CH ₂ - group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO group, one optionally by a C ₃ alkyl, amino C 3 alkyl, C ₃ alkylamino C ₃ alkyl ₃ , di (C ₃ alkyl) amino C ₃ alkyl -, Aminocarbonyl, Cι. ₃ -alkylamino-carbonyl-, N- (C ₃ - ₇ -cycloalkyl) -Cι- ₅ -alkylaminocarbonyl-, N- (phenyl-Cι- ₃ -alkyl) -Cι- ₅ - alkylaminocarbonyl- or di- (Cι- _3rd alkyl) aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbonyl or 1,2,5,6-tetrahydropyridin1-yl-carbonyl group, an aminocarbonyl group optionally substituted by one or two C ₃ alkyl or C _{3 to 7} cycloalkyl groups, it being possible for the substituents to be the same or different, a straight-chain or branched C ₅ alkylcarbonyl group or a C ₃ -7-cycloalkyl-carbonyl group, R ^{2 is} a hydrogen, fluorine, chlorine or bromine atom, a Cι- ₃ alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or a Ci-s-alkoxy or trifluoromethoxy group, R ^{3 is} a hydrogen atom, a linear or branched Ci-β-alkyl group, which is optionally substituted by a hydroxy, Cι- ₃ alkyloxy, carboxy or Cι- ₃ alkoxycarbonyl group, or a methyl group substituted by a phenyl group, and Ar is a phenyl group substituted by the radicals R ⁴ and R ⁵ , where R ^{4 is} a cyano group, an amidino group which is optionally substituted by one or two hydroxyl, d _-8- alkylcarbonyl, C1-8-alkoxycarbonyl or benzoyl groups, an amino -CC _-3 alkyl group or a group of the formula

in which R ^{7 is} a hydrogen atom or a Cι _-3 alkyl group and R ^{8 is} a C _-3 alkyl group, and R ^{5 represents} a hydrogen atom or a hydroxy group, or a thienylene group which is optionally substituted in the carbon structure by the group R ₄ , where R ₄ is defined as mentioned above, where the alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched, and the hydrogen atoms of the methyl or ethyl groups contained in the definitions can be replaced in whole or in part by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts. 4. Compounds of general formula I according to claim 3, in which X, Y, Z, R ² , R ³ and Ar are as defined in claim 3 and R ^{1 is} a C _{3 to 7} cycloalkylamino group which is substituted on the amine nitrogen atom by a C ₃ alkyl carbonyl group, an azetidine-1 -ylcarbonyl group which is optionally substituted in position 3 by a dimethylamino group, a pyrrolidine-1-yl-carbonyl or piperidinyl-carbonyl group which is optionally substituted in position 2 by an aminomethyl or in position 3 by an amino, aminomethyl, hydroxy or benzyloxy group, a 2,5-dihydropyrrol-1-yl-carbonyl or thiazolidin-3-yl-carbonyl group or represents a di- (Cι- ₃ -alkyl) -aminocarbonyl- or N-cyclohexyl-N- (Cι- ₃ -alkyl) -amino- carbonyl group, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts. 5. Compounds of the general formula

R2 (la), in which X, Y, Z, R, R, R and Ar are defined as mentioned in claim 3 or 4, their tautomers, their diastereomers, their mixtures and their salts. 6. The following compounds of general formula I according to claim 1: (1) 3 - {[7- (2,5-Dihydropyrrol-1 -yl-carbonyl) -quinazolin-4-yl] aminomethyl} -4-hydroxy-benzamidine

(2) 3- {2-Phenyl-1 - [7- (pyrrolidin-1 -yl-carbonyl) -quinolin-4-ylamino] ethyl} benzamidine

(3) 4-Hydroxy-3 - {[7-methoxy-6- (pyrrolidin-1-yl-carbonyl) -isoquinolin-1-yylaminomethyl} benzamidine

(4) 4-Hydroxy-3- {2-phenyl-1 - [7- (pyrrolidin-1-yI-carbonyl) -quinazolin-4-ylamino] -ethyl} - benzamidine

(5) 4-Hydroxy-3 - {[6-methyl-7- (pyrrolidin-1-yI-carbonyl) -quinazolin-4-yl] aminomethyl} - benzamidine

(6) 3- (3-Amidino-phenyl) -3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] amino} -propionic acid ethyl ester

(7) 3 - {[6- (N-Acetyl-N-cyclopentylamino) -7-methyl-isoquinolin-1-yl] aminomethyl} -4-hydroxy-benzamidine

(8) N-Acetoxymethoxycarbonyl-4-hydroxy-3 - {[6-methyl-7- (pyrrolidin-1 -yl-carbonyl) quinazolin-4-yl] aminorrϊethyl} benzamidine

(9) 4-Hydroxy-3 - {[6-chloro-7- (pyrrolidin-1-yl-carbonyI) -quinazolin-4-yl] aminomethyl} - benzamidine

as well as their tautomers and their salts. 7. Physiologically acceptable salts of the compounds according to claims 1 to 6, in which R ^{4 is} not a cyano group. 8. Medicament containing a compound according to at least one of claims 1 to 6, in which R ⁴ does not represent a cyano group, or a salt according to claim 7 in addition to optionally one or more inert carriers and / or diluents. 9. Use of a compound according to at least one of claims 1 to 6, in which R ^{4 is} not a cyano group, or a salt according to claim 7 for the manufacture of a medicament with an inhibitory effect on factor Xa and / or an inhibitory effect on related serine proteases. 10. The method for producing a medicament according to claim 9, characterized in that a compound according to at least one chemical route one of claims 1 to 6, in which R ^{4 is} not a cyano group, or a salt according to claim 7 is incorporated into one or more inert carriers and / or diluents. 11. A process for the preparation of the compounds of formula I according to claims 1 to 7, characterized in that a compound of the general formula

in the R ¹ , R ² , X, Y and Z are defined as mentioned in claims 1 to 7 and L represents a leaving group such as a halogen atom, a sulfonyloxy or aryloxy group, with a connection of the general formula R ³

in which Ar and R ^{3 are defined} as mentioned in claims 1 to 7, is implemented and, if Ar is substituted by a cyano group, the cyano compound thus obtained is then optionally converted into one of the optionally substituted amidino or aminoalkyl compounds mentioned in claims 1 to 7 and if desired, a protective residue used during the reactions to protect reactive groups is then split off and / or a compound of the general formula I thus obtained is separated into its stereoisomers and / or a compound of the general formula I obtained in this way is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.