HRP980082A2 - Disubstituted bicyclic heterocycles, their production and use as medicaments - Google Patents

Description

The subject of the proposed invention are new disubstituted bicyclic heterocycles of the general formula

Ra - A - Het - B - Ar - E (I)

their tautomers, their stereoisomers, their mixtures and their salts, especially 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 E represents the cyano group, represent valuable intermediates for the production of the remaining compounds of the general formula I, and the compounds of the above general formula I in which E represents the group RbNH-C(=NH), as well as their tautomers and their stereoisomers , have valuable pharmacological properties, especially thrombin inhibition and thrombin time prolongation.

The subject of the proposed patent application is therefore new compounds of the above general formula I as well as their production, drugs containing pharmacologically effective compounds and their use.

In the general formula I above

A represents a carbonyl or sulfonyl group connected to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno part of the residue Het, whereby the aforementioned parts may not contain any residue R1,

B represents an ethylene group in which one methylene group, which is connected to a Het residue or to an Ar residue, can be substituted with an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NR1-group, whereby

R1 represents a hydrogen atom or a C1-6-alkyl group,

E is cyano or the group RbNH-C(=NH)-, in which

Rb represents a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a residue that can be cleaved in vivo,

Ar represents a phenylene or naphthylene group, which can be substituted with a fluorine, chlorine or bromine atom or with a trifluoromethyl, C1-3-alkyl or

C1-3-Alkoxy group,

thienylene, thiazolylene, pyridylene, pyrimidylene, pyrazinylene or pyridazinylene group, which can be substituted in the carbon skeleton with a C1-3-alkyl group, if necessary,

Het represents the bicyclic heterocycle of the formula

[image]

where

X represents a nitrogen atom, i

Y represents an oxygen or sulfur atom or a nitrogen atom optionally substituted with one C1-6-alkyl or C3-7-cycloalkyl group, whereby additionally one or two non-angular methine groups in the phenyl part of the aforementioned bicyclic heterocycle can be substituted with one nitrogen atom, or

X represents a methine group optionally substituted with the residue R1, where R1 is defined as previously stated, and

Y represents a nitrogen atom optionally substituted with a C1-6-alkyl or C3-7-cycloalkyl group, or

Het represents a formula group

[image]

R1 is defined as previously stated,

Z is an oxygen or sulfur atom,

one of the residues D or G represents a nitrogen atom, and the other of the residues D or G represents a methine group, i

Ra represents a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted with a C1-3-alkyl group, whereby the C1-3-alkyl group can additionally be substituted with one carboxyl group or with one group which in vivo can translate into a carboxy group, or

R2NR3-group, in which

R2 represents a C1-4-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonyl, amino-carbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl group,

C2-4-alkyl group substituted with hydroxy, phenyl-

C1-3-Alkoxy, Carboxy, C1-3-Alkylamino, C1-3-Alkoxycarbonyl-C1-3-Alkylamino, N-(C1-3-Alkyl)-carboxy-C1-3-Alkylamino or N-(C1-3 -alkyl)-C1-3-Alkoxycarbonyl-C1-3-alkylamino group, whereby in the previously mentioned group the α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, or

piperidinyl group optionally substituted with C1-3-alkyl group I

R3 represents a hydrogen atom, a C1-6-alkyl group, a C3-7-cycloalkyl group, a C3-6-alkenyl or a C3-6-alkynyl group, which can be substituted with a C1-3-alkyl group if necessary, whereby the unsaturated part cannot be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with fluorine, chlorine or bromine, with a C1-3-alkyl or C1-3-alkoxy group, benzylic, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl , pyrimidinyl, pyrazolyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group, which can be substituted with a C1-3-alkyl group if necessary, or

R2 and R3, together with the nitrogen atom located between them, represent a five- to seven-membered cycloalkylenimine group optionally substituted with a carboxy or C1-4-alkoxycarbonyl group, on which one phenyl ring can additionally be condensed.

Compounds of the general formula I above, which contain one residue that can be cleaved in vivo, are thus so-called prodrugs, and compounds of the general formula I that contain two residues that can be cleaved in vivo, represent so-called double prodrugs.

A group that can be converted into a carboxy group in vivo means, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcohol part is preferably C1-6-alkanol, phenyl-C1-3-alkanol, C3-9-cycloalkanol, at where the C5-8-cycloalkanol can additionally be substituted with one or two C1-3-alkyl groups, C5-8-cycloalkanol, in which the methylene group in position 3 or 4 can be substituted with one oxygen atom or with an imino group by optionally substituted with a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanyl group, and the cycloalkanol part can additionally be substituted with one or two C1-3-alkyl groups, C4-7-cycloalkenol, C3-5-alkenol, phenyl-C3-5-alkenol, C3-5-alkynol or phenyl-C3-5-alkynol provided that no bond on the oxygen atom originates from a carbon atom bearing a double or triple bond, C3-8-cycloalkyl-C1-3-alkanol, bicycloalkanol with a total of 8 to 10 carbon atoms, k oji in the bicycloalkyl part can additionally be substituted with one or two C1-3-alkyl groups, 1,3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R4-CO-O-(R5CR6)-OH,

where

R4 represents a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,

R5 represents a hydrogen atom, C1-3-alkyl, C5-7-cycloalkyl or phenyl group and

R6 represents a hydrogen atom or a C1-3-alkyl group,

or

a residue that can be cleaved from an imino or amino group in vivo means, for example, a hydroxy group, an acyl group such as a benzoyl or pyridinoyl group, which can be substituted with a C1-3-alkyl group, e.g. benzoyl, p-ethyl -benzoyl, p-isopropyl-benzoyl or nicotinoyl group, or C1-16-alkanoyl group such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, allyloxycarbonyl group, C1-16-alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxy- carbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, phenyl-C1-6-alkoxycarbonyl group, as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, C1- 3-Alkylsulfonyl-C2-4-Alkoxycarbonyl, C1-3-Alkoxy-C 2-4-Alkoxy-C2-4-Alkoxycarbonyl or group

R 4 CO-O-(R 5 CR 6 )-O-CO-, wherein R 4 through R 6 are as defined above.

As a preferred residue of the prodrug for the carboxy group, a C1-6-Alkoxycarbonyl group such as a methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group or phenyl- C1-3-Alkoxycarbonyl group as benzoyloxycarbonyl group and for imino or amino group, C1-9-Alkoxycarbonyl group as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl , n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyl-oxylcarbonyl group, phenyl-C1-3-alkoxycarbonyl group as benzyloxycarbonyl group, phenylcarbonyl group, optionally substituted with C1-3-alkyl group, as benzoyl or 4-ethyl-benzoyl group, pyridinoyl group as nicotinoyl group, C1-3-alkylsulfonyl-n-C2-3-alkoxycarbons 1 or C1-3-Alkoxy-C2-3-Alkoxy-C2-4-Alkoxy-carbonyl group, such as 2-methylsulfonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl group.

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

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

A represents a carbonyl or sulfonyl group connected to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno part of the residue Het, whereby the aforementioned parts may not contain any residue R1,

B represents an ethylene group, in which one methylene group that is connected to a Het or Ar residue can be substituted with an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NR1-group, whereby

R1 represents a hydrogen atom or a C1-4-alkyl group,

E is a RbNH-C(=NH)- group, in which

Rb represents a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a residue that can be cleaved in vivo,

Ar represents a phenylene group optionally substituted with a fluorine, chlorine or bromine atom or with a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienylene, thiazolylene, pyridylene, pyrimidinylene, pyrazinylene or pyridazinylene group, each of which can optionally be substituted in the carbon skeleton with a C1-3-alkyl group,

Het represents the bicyclic heterocycle of the formula

[image]

X represents a nitrogen atom,

Y represents an oxygen or sulfur atom or a nitrogen atom optionally substituted with one C1-6-alkyl or C3-7-cycloalkyl group, whereby additionally one or two non-angular methine groups in the phenyl part of the aforementioned bicyclic heterocycle can be substituted with one nitrogen atom, or

X represents a methine group optionally substituted with the residue R1, where R1 is defined as previously stated, and

Y represents a nitrogen atom optionally substituted with a C1-6-alkyl or C3-7-cycloalkyl group, or

Het represents a formula group

[image]

R1 is defined as previously stated,

Z is an oxygen or sulfur atom,

one of the residues D or G represents a nitrogen atom, and the other of the residues D or G represents a methine group, i

Ra represents a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted with a C1-3-alkyl group, whereby the C1-3-alkyl group can additionally be substituted with one carboxyl group or with a group that can be convert to a carboxy group, or

R2NR3-group, in which

R2 represents a C1-4-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonyl, amino-carbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl group,

C2-4-alkyl group substituted with hydroxy, phenyl-

C1-3-Alkoxy, Carboxy, C1-3-Alkylamino, C1-3-Alkoxycarbonyl-C1-3-Alkylamino, N-(C1-3-Alkyl)-carboxy-C1-3-Alkylamino or N-(C1-3 -alkyl)-C1-3-Alkoxycarbonyl-C1-3-alkylamino group, whereby in the previously mentioned group the α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, or

a piperidinyl group optionally substituted with a C1-3-alkyl group and

R3 represents a hydrogen atom, a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted with a C1-3-alkyl group, a C3-6-alkenyl or alkynyl group, whereby the unsaturated part cannot be directly connected to a nitrogen atom groups R2NR3, phenyl group optionally substituted with fluorine, chlorine or bromine, with C1-3-alkyl or C1-3-alkoxy group, benzylic, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl , pyridazinyl, imidazolyl or piperidinyl group, each of which can be substituted with a C1-3-alkyl group if necessary or

R2 and R3, together with the nitrogen atom located between them, represent a five- to seven-membered cycloalkylenimine group, which can be substituted with a carboxy or C1-4-alkoxycarbonyl group, on which one phenyl ring can additionally be condensed,

especially those compounds in which

Het represents the previously mentioned benzimidazolylene, benzthiazolylene, benzoxazolylene, indolylene, quinazolinylene, quinoxazolinonylene, imidazo[4,5-b]pyridinylene, imidazo[1,2-a]pyridinylene, thiazolo[5,4-b]pyridinylene or thieno[ 2,3-d]imidazolylene group,

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

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

A represents a carbonyl or sulfonyl group connected to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno part of the residue Het, whereby the aforementioned parts may not contain any residue R1,

B represents an ethylene group, in which one methylene group, which is connected to the Ar residue, can be substituted with an oxygen or sulfur atom or

-NR1-group, whereby

R1 represents a hydrogen atom or a C1-4-alkyl group,

E is a RbNH-C(=NH)- group, in which

Rb represents a hydrogen atom, a hydroxy group, a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, wherein the ethoxyl part in position 2 of the aforementioned C1- 9-Alkoxycarbonyl groups can additionally be substituted with one C1-3-alkylsulfonyl or 2-(C1-3-Alkoxy)-ethyl group,

Ar represents a 1,4-phenylene or 2,5-thienyl group which, if necessary, can be substituted with a chlorine atom, with a methyl, ethyl or methoxy group,

Het represents 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene,

2,5-Benzthiazolylene, 1-(C1-3-alkyl)-2,5-indolylene,

1-(C1-3-alkyl)-2,5-imidazo[4,5-b]pyridinylene, 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene or 1- (C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group i

Ra represents the group R2NR3 in which

R2 represents a C1-4-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonyl-aminocarbonyl or 1H-tetrazol-5-yl group,

a C2-4-alkyl group substituted with hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-

C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino, or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, wherein in the previously mentioned α-carbon atom standing immediately next to the nitrogen atom cannot be substituted,

R3 represents a C3-7-cycloalkyl group, a propargyl group, whereby the unsaturated part cannot be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with fluorine or chlorine, with a methyl or methoxy group, a pyrazolyl, pyridazolyl or pyridinyl group, each of which may optionally be substituted with a methyl group or

R2 and R3, together with the nitrogen atom located between them, represent a five- to seven-membered cycloalkylenimine group optionally substituted with a carboxy or C1-4-alkoxycarbonyl group, on which one phenyl ring can additionally be condensed,

their tautomers, their stereoisomers and their salts.

A very special advantage is given to the compounds of the above general formula I, in which

A represents a carbonyl or sulfonyl group connected to the benzo, pyrido or thieno part of the Het residue, whereby the previously mentioned parts may not contain any R1 residue,

B represents an ethylene group, in which one methylene group, which is connected to the Ar residue, can be substituted with an oxygen or sulfur atom or with

-NR1-group, whereby

R1 represents a hydrogen atom or a methyl group,

E is a RbNH-C(=NH)- group, in which

Rb represents a hydrogen atom, a hydroxy group, a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxy-carbonyl, benzoyl, p-C1-3-alkyl-benzoyl or nicotinoyl group, whereby the ethoxyl part in position 2 of the aforementioned C1-9-alkoxycarbonyl group it can additionally be substituted with one C1-3-alkylsulfonyl or 2-(C1-3-alkoxy)-ethyl group,

Ar represents a 1,4-phenylene or 2,5-thienyl group, which, if necessary, can be substituted with a chlorine atom, with a methyl, ethyl or methoxy group,

Het represents 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4, 5-b]-pyridinylene, 3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and

Ra represents the group R2NR3 in which

R2 represents a C1-3-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,

C2-3-alkyl group substituted with hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-

C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino, or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, wherein in the previously mentioned group α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, i

R3 represents a propargyl group, whereby the unsaturated part cannot be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group or a pyridinyl group, which can be substituted with fluorine or chlorine, with a methyl or methoxy group, if necessary.

especially those in which

A represents a carbonyl group connected to the benzo or thieno part of the Het residue,

B represents an ethylene group, in which one methylene group, which is connected to the Ar residue, can be replaced by a -NR1-group, whereby

R1 represents a hydrogen atom or a methyl group,

E is a RbNH-C(=NH)- group, in which

Rb represents a hydrogen atom, a hydroxy group, a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxy-carbonyl, benzoyl, p-C1-3-alkyl-benzoyl or nicotinoyl group, whereby the ethoxyl part in position 2 of the aforementioned C1-9-alkoxycarbonyl group can additionally be substituted with one methylsulfonyl or 2-ethoxy-ethyl group,

Ar represents a 1,4-phenylene or 2,5-thienyl group, which can be substituted with a methoxy group if necessary,

Het represents 1-methyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and

Ra represents the group R2NR3 in which

R2 represents a C1-3-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,

C2-3-alkyl group substituted with hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-

C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino, or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, wherein in the previously mentioned group α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, i

R3 represents a phenyl or 2-pyridinyl group substituted with a fluorine atom,

their tautomers, their stereoisomers and their salts.

As particularly preferred compounds, the following can be mentioned, for example:

(a) 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide,

(b) 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-ethyl)-amide,

(c) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-

hydroxycarbonyl-ethyl)-amide,

(d) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-

hydroxycarbonyl-propyl)-amide,

(e) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxy-carbonylmethyl)-amide,

(f) 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl) -amide,

(g) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl)-amide,

(h) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl)-amide,

(i) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide,

(j) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl] -amide,

(k) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl] -amide,

(l) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)- amide,

(m) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)- amide,

(n) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide,

(o) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxy-carbonylethyl-N-methyl)-2- aminoethyl]-amide,

(p) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide,

(q) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide,

(r) 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide,

(s) 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl )-amide,

(t) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and

(u) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)- amide,

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

New compounds can be produced by methods known per se, for example by the following methods:

a) For the production of the compound of formula I, in which E represents the group RbNH-C(=NH), in which Rb represents a hydrogen atom, hydroxy or C1-3-alkyl group:

by chemical conversion as necessary in the reaction mixture of the resulting compound of the general formula

Ra - A - Het - B - Ar - C(=NH) - Z1 (II)

where

A, B, Ar, Het and Ra have the meaning stated in the introduction, a

Z1 represents an alkylthio or aralkylthio group such as a methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as a methylthio, ethylthio, n-propylthio or benzylthio group,

with amino of the general formula

H2N-R'b (III)

where

Rb' represents a hydrogen atom, a hydroxy or a C1-3-alkyl group.

The chemical conversion is expediently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane at temperatures between 0 and 150oC, preferably at temperatures between 20 and 120oC, with the compound of the general formula III or with the corresponding acid addition salt such as ammonium carbonate.

The compound of general formula II is obtained, for example, by chemical conversion of a compound of general formula I, in which E represents a cyano group, with a suitable alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid, or by conversion of the corresponding amide with trialkyloxonium salt, such as triethyloxonium tetrafluoroborate, in a solvent such as methylene chloride, tetrahydrofuran or dioxane, at temperatures between 0 and 50oC, preferably however at 20oC, or the corresponding nitrile with hydrogen sulphide, expediently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and then by alkylating the resulting thioamide with a suitable alkyl or aralkyl halide.

b) for the production of a compound of the general formula I, in which the group Ra-A and E are defined as introductory, provided that the group Ra-A contains a carboxy group and E is defined as introductory, or that the group Ra-A is defined as stated in the introduction, and E represents the group NH2-C(=NH), or that the group Ra-A contains a carboxy group, and E represents the group

NH2-C(=NH):

compound of the general formula

Ra' - A - Het - B - Ar - C - E' (IV)

in which they are

A, B, Ar and Het defined as introductory, a

the group Ra'-A and E' have the meanings stated in the introduction for the group Ra-A and E, provided that the group Ra'-A contains a group that can be converted into a carboxyl group by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, and E is defined as introductory, or E' contains a group that can be converted into the group NH2-C(=NH) by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, and the group Ra'-A has the meaning stated in the introduction for the group Ra- A, or the group Ra'-A contains a group which can be converted into a carboxyl group by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, and E' represents a group which can be converted into group NH2-C(=NH), is converted into a compound of the general formula I by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, in which the group Ra-A and E are defined as introductory, provided that the group Ra-A is defined as an introduction, so that the Ra-A group contains carb an oxy group, and E is defined as the introduction, or the group Ra-A has the meaning stated in the introduction, and E represents the group NH2-C(=NH), or the group Ra-A contains a carboxy group, and E represents the group NH2-C(= NH).

As a group that can be converted into a carboxyl group, for example a carboxyl group protected with a protective residue, such as its functional derivatives, e.g. its unsubstituted or substituted amide, ester, thioester, trimethylsilyl ester, orthoester or iminoester, which are purposefully converted by hydrolysis, comes into consideration to a carboxyl group, its ester with tertiary alcohols, e.g. tert.butyl ester, which is purposefully converted into a carboxyl group by treatment with acid or thermolysis, its esters with aralkanols, e.g. butyl ester, which is purposefully converted into a carboxyl group by hydrogenolysis.

Hydrolysis is carried out purposefully either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent as which is water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 120oC, eg at a temperature between room temperature and the boiling point of the reaction mixture.

If the group Ra'-A and/or E' in the compound of formula IV contains, for example, a tert.butyl- or tert.butyloxycarbonyl group, then it can also be cleaved by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120oC, e.g. at temperatures between 0 and 60oC , or also thermally if necessary in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid, preferably at the boiling point of the used solvents, eg at temperatures between 40 and 120oC.

If the group Ra'-A and/or E' in a compound of formula IV contains for example a benzyloxy- or benzyloxycarbonyl group, then this can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol , ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide, preferably at temperatures between 0 and 50oC, for example at room temperature, and under a hydrogen pressure of 1 to 5 bar.

c) For the production of a compound of the general formula I, in which the group Ra-A contains the ester group specified in the introduction to the definition of the group Ra-A:

by chemical conversion of the compound of the general formula

Ra'' - A - Het -B - Ar - E (V)

in which they are

B, E, Ar and Het defined as introductory, a

Ra''-A has the meaning stated in the introduction for the group Ra-A, provided that the group Ra''-A contains a carboxyl group or a group that can be converted into a corresponding ester group using alcohol,

with alcohol of the general formula

HO-R7 (VI)

where

R7 represents the initially mentioned alkyl part that can be cleaved in vivo into a carboxyl group, with the exception of the group R6-CO-O-(R5CR6), or with its formamida acetals,

or with a compound of the general formula

Z2-R8 (VII)

where

R8 represents the initially mentioned alkyl part that can be cleaved in vivo into a carboxyl group, with the exception of the group R6-CO-O-(R5CR6) and

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

The chemical conversion with an alcohol of the general formula VI is expediently carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, preferably however in an alcohol of the general formula VI, if necessary in the presence of an acid such as hydrochloric acid or in the presence of a water-extracting agent, eg in the presence of chloroformic acid isobutyl ester, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N,N '-dicyclohexylcarbodiimide, N'N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thiondiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/azodicarboxylic acid-diethyl ester if necessary in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine, expediently at temperatures between 0 and 150oC, preferably at temperatures between 0 and 80oC.

With a compound of general formula VII, the chemical conversion is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methyl-morpholine, which at the same time can also serve as a solvent, or if necessary in the presence of silver carbonate or silver oxide at temperatures between -30 and 100oC, preferably, however, at temperatures between -10 and 80oC.

d) For the production of a compound of the general formula I, in which Rb represents a residue that can be cleaved in vivo:

by chemical conversion of the compound of the general formula

Ra - A - Het - B - Ar - C(=NH) - NH2 (VIII)

in which they are

Ra, A, Het, B and Ar defined as introductory,

with a compound of the general formula

Z2-R5 (IX)

where

R5 represents a residue that can be cleaved in vivo, a

Z2 is a nucleophilic leaving group such as a halogen atom, eg a chlorine, bromine or iodine atom.

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

With a compound of the general formula IX, in which Z2 represents a nucleophilic leaving group, the chemical conversion is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide in the presence of a base such as sodium hydride, potassium carbonate, potassium tert .butylate or N-ethyl-diisopropylamine, at temperatures between 0 and 60oC.

e) For the production of compounds of the general formula I in which B represents an ethylene group in which one methylene group is replaced by one sulfinyl or sulfonyl group:

by oxidation of a compound of the general formula

Ra - A - Het - B' - Ar - E (X)

in which they are

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

Oxidation is preferably carried out in a solvent or in a mixture of solvents, e.g. in water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulfuric acid or in trifluoroacetic acid, and depending on the oxidizing agent used , is purposefully carried out at temperatures between -80 and 100oC.

For the production of the corresponding sulfinyl compound of the general formula I, the oxidation is expediently carried out with an equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 0 to 20oC or in acetone at 0 to 60oC, with a peracid such as is performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50oC or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80oC, with sodium periodate in aqueous methanol or ethanol at -15 to 25oC, with bromine in glacial acetic acid or aqueous acetic acid in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert.butyl hypochlorite in methanol at -80 to -30oC, with iodobenzodichloride in aqueous pyridine at 0 to 50oC, with nitric acid in glacial acetic acid at 0 to 20oC, with chromic acid in glacial acetic acid or in acetone at 0 to 20oC and with sulfuryl chloride in methylene chloride at -70oC, and the resulting thioether-chlorine complex is purposefully hydrolyzed with aqueous ethanol.

For the production of a sulfonyl compound of the general formula I, oxidation is carried out starting from the corresponding sulfinyl compound expediently with one or more equivalents of the oxidizing agent used or starting from the appropriate sulfenyl compound expediently with one or more equivalents of the oxidizing compound used, e.g. with hydrogen peroxide into glacial acetic acid/ in acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100oC or in acetone at 0 and 60oC, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60oC, with nitric acid in glacial acetic acid at 0 to 20oC, with chromic acid in glacial acetic acid, water/sulfuric acid or in acetone at 0 to 20oC. Thus, for example, during oxidation, starting from the corresponding sulfenyl compound, preferably in methylene chloride, by treatment with an appropriate amount of m-chloro-perbenzoic acid at temperatures between 20oC and the reflux temperature of the reaction mixture, a corresponding sulfonyl compound of the general formula I is obtained, which may contain an even insignificant amount of the corresponding sulfinyl compound.

f) For the production of a compound of the general formula I, in which E represents a cyano group, and B is an ethylene group in which one methylene group, which is connected to a Het residue or an Ar residue, with an oxygen or sulfur atom, is replaced by sulfinyl, sulfonyl , carbonyl or with -NR1 group:

by chemical conversion of the compound of the general formula

Ra - A - Het - U (XI)

with a compound of the general formula

V - Ar - CN (XII)

in which they are

Ra, A, Ar and Het defined as mentioned in the introduction, one of the residues U or V represents HO-, HS-, HOSO-, HOSO2- or the group HNR1, and the remaining of the residues represents the group Z3CH2, where R1 is defined as the introduction , and Z3 is a nucleophilic leaving group such as a halogen atom, eg a chlorine, bromine or iodine atom.

The chemical conversion is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethyl formamide if necessary in the presence of an inorganic or tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine, preferably at temperatures between 20oC and the boiling point of the solvent used, whereby a compound of the general formula XI or XII in which Z3 represents a halogen atom can also be produced in the reaction mixture.

g) For the production of the compound of the general formula I in which E represents the cyano group and Ra is the R2NR3 group:

by chemical conversion of the compound of the general formula

H - A - Het - B - Ar - CN (XIII)

in which they are

A, B, Het and Ar are defined as stated in the introduction, with an amine of the general formula

[image]

in which they are

R 2 and R 3 are defined as introductory, or with derivatives thereof capable of reaction.

The chemical conversion of the acid of the general formula XIII is carried out as necessary in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or in the corresponding amine of the general formula III if necessary in the presence of an agent which extracts water, e.g. in the presence of isobutyl ester of chloroformic acid, tetraethyl ester of orthocarbonic acid, trimethyl ester of orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N ,N'-dicyclohexylcarbodiimide/N-hydroxysulcinimide, N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and if necessary with the addition of a base such as pyridine, 4-di of methyl-aminopyridine, N-methyl-morpholine or triethylamine expediently at temperatures between 0 and 150oC, preferably at temperatures between 0 and 100oC.

The chemical conversion of a suitable reactive compound of formula XIII as its ester, imidazole or halide with an amine of the general formula XIV is preferably carried out in a suitable amine as a solvent if necessary in the presence of another solvent such as methylene chloride or an ether preferably in the presence of a tertiary organic base such as triethylamine, N -ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150oC, preferably at temperatures between 50 and 100oC.

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

by chemical conversion of the compound of the general formula

[image]

in which they are

Ra, A and Y defined as stated in the introduction, with the compound of the general formula

HO-CO-CH2CH2-Ar-E (XVI)

in which they are

Ar and E defined as stated in the introduction, or with their derivatives capable of reaction.

The chemical conversion is carried out expediently in a solvent or a mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, if necessary in the presence of a water-extracting agent, e.g. in the presence of isobutyl ester of chloroform acid, orthocarbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysulcinimide , N,N'-dicyclo-hexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1-benzotriazol- 1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate/1-hydroxybenzotriazole, N,N'-carbonyl diimidazole or triphenylphosphine/carbon tetrachloride, and if necessary with the addition of a base such as pyridine, 4-dimethyl-aminopyridine, N-methyl-morpholine or triethylamine purposefully at at temperatures between 0 and 150oC, preferably at temperatures between 0 and 100oC.

The chemical conversion of a suitable reactive compound of the formula XVI as its ester, imidazole or halide with an amine of the general formula XV is preferably carried out in a suitable solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N -methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150oC, preferably at temperatures between 50 and 100oC.

i) For the production of the quinoxalin-2-one compound of the general formula:

by chemical conversion of the compound of the general formula

[image]

in which they are

Ra, R1 and A are defined as stated in the introduction, with a compound of the general formula

HO-CO-COCH2-Ar-E (XVIII)

in which they are

Ar and E defined as stated in the introduction, or with its derivatives capable of reaction.

The chemical conversion is carried out expediently in a solvent or in a mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, ethanol or dioxane if necessary in the presence of a water-extracting agent, e.g. in the presence of isobutyl chloroformic acid ester, orthocarbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N -hydroxy sulcinimide, N,N'-dicyclo-hexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 2-( 1-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate/1-hydroxybenzo-triazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and if necessary with the addition of a base such as pyridine, 4- dimethyl-aminopyridine, N-methyl-morpholine or triethylamine purpose vito at temperatures between 0 and 150oC, preferably at temperatures between 0 and 100oC.

The chemical conversion is particularly preferably carried out with a suitable reactive compound of the general formula XVIII as its ester, imidazole or halide with an amine of the general formula XVII in a suitable solvent such as methylene chloride, ether, ethanol or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N- ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150oC, preferably at temperatures between 50 and 100oC.

j) For the conversion of the compound of the general formula I in which R2 represents a C1-4-alkyl group, which is substituted with one alkylsulfonylaminocarbonyl group:

by chemical conversion of the compound of the general formula

[image]

in which they are

R3, A, B, E and Het defined as stated in the introduction, a

R2 represents a C1-4-alkyl group, which is substituted with one carboxy group, or its reactive derivatives,

with one salt of a compound of the general formula

C1-3-alkyl-SO2-NH2 (XX)

The chemical conversion is preferably carried out with a suitable compound capable of reacting with the general formula IXX as its ester, imidazole or halide with one salt of the compound of the general formula XX, preferably with its alkali salt as with its sodium salt, in a solvent such as methylene chloride, ether, ethanol, tetrahydrofuran or dimethylformamide at temperatures between 0 and 150oC, preferably at temperatures between 50 and 100oC.

In the previously described chemical conversions, reactive groups such as hydroxy, carboxy, amino, alkylamino or imino groups can be protected during the conversion with the usual protective groups, which are removed again after the conversion.

As a protective residue for the hydroxy group, for example, a trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group can be considered, as a protective residue for a carboxy group, a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group can be considered , and an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group is considered as a protective residue for an amino, alkylamino or imino group, and a phthalyl group is additionally considered for the amino group .

If necessary, subsequent separation of the used protective residue is carried out, 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 alkaline bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100oC, preferably at temperatures between 10 and 50oC.

The removal of the benzyl, methoxybenzyl or benzyloxycarbonyl residue is, however, carried out, for example, hydrogenolytically, for example 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 with addition of acid as hydrochloric acid at temperatures between 0 and 50°C, preferably however at room temperature, and under a hydrogen pressure of 1 to 7 bar, preferably however under a pressure of 3 to 5 bar.

Removal of the methoxybenzyl group can also be carried out 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, preferably however at room temperature.

However, cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

Separation of the tert.butyl or butyloxycarbonyl residue is primarily carried out by treatment with an acid such as trifluoroacetic acid or with hydrochloric acid if necessary with the use of a solvent such as methylene chloride, dioxane or ether.

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

Cleavage of the allyloxycarbonyl residue is carried out by treatment with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(O) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess base such as morpholine or 1,3-dimedone at temperatures between 0 and 100oC, preferably at room temperature in under an inert gas atmosphere, or by treatment with a catalytic amount of tetrakis-(triphenylphosphine)-rhodium(I) chloride in a solvent such as anhydrous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70oC.

Compounds of the general formulas II to XX, which are partially known from the literature, can be obtained by methods known from the literature, and the rest regarding their production will be described in the examples.

Thus, for example, the compound of the general formula II can be obtained by chemical conversion of the corresponding nitrile, which in turn can be expediently obtained by processes f to h, with the corresponding thio- or alcohol in the presence of hydrogen chloride or hydrogen bromide.

Compounds of the general formulas IV, V, VIII, X and IXX, used as starting materials, can be purposefully obtained by the procedures according to the proposed invention.

The starting compound of the general formula XI, in which U represents a halogen-methyl group, is obtained by expedient connection in the praten of the corresponding ester, which is substituted in the o-position with a suitable halogen atom and a methoxy-acetamido group, in the corresponding bicyclic 2-alkoxy-methyl compound , then, if necessary, by hydrogenation and then, if necessary, amidation of the thus obtained carboxylic acid with a suitable amine, by converting the thus obtained alkoxy-methyl compound into a corresponding halogen-methyl compound, which can then be converted into the desired compound, if necessary, using a suitable compound. If here the ring closure is carried out with a suitable carbonic acid derivative, then the starting compound of the general formula XI is obtained in which U represents a hydroxy, mercapto or amino group.

The starting compound of the general formula XIII is obtained by closing the ring of the corresponding o-disubstituted ester, then by saponification of the thus obtained ester and then amidation of the thus obtained carboxylic acid with the corresponding amine.

Furthermore, the obtained substituted imidazo-pyridine can be converted into a corresponding hydroxymethyl compound by ring closure using a methyl group in position 5 via the appropriate N-oxide, which is converted by oxidation into the desired carboxylic acid of the general formula XIII.

Compounds of the general formulas III, VI, VII, IX and XII used as starting materials are obtained by known methods, for example by reduction of an aromatic ester that is substituted in the o-position with an amino group and a nitro group, if necessary, and then, if necessary, by ring closure as of the obtained o-diamino compound with the corresponding carboxylic acid.

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

Thus, for example, the obtained compounds of the general formula I, which appear as racemates, are separated by known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and the compounds of the general formula I with at least 2 asymmetric carbon atoms are separated on the basis of their physicochemical differences by known methods, e.g. chromatography and/or fractional crystallization, into their diastereomers, which, if they appear in racemic form, can then be separated into the above-mentioned enantiomers.

The separation of enantiomers is primarily carried out by separation on a column on chiral phases or by recrystallization from optically active solvents or by conversion with optically active substances that with racemic compounds form salts or derivatives such as esters or amides, especially with acids and their activated derivatives or alcohols, and the separation of diastereomeric a mixture of salts or derivatives obtained in such a way is carried out, for example, on the basis of different solubility, whereby free antipodes can be released from pure diastereomeric salts or derivatives by the action of a suitable agent. Especially useful optically active acids are, for example, D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolylvic acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols include (+)- or (-)-menthol, and optically active acyl residues include amides, such as (+)- or (-)-menthyloxycarbonyl.

Furthermore, the obtained compounds of formula I can be translated into their salts, especially for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of acids here include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

In addition, the new compounds of formula I obtained in this way, if they contain a carboxy group, can then, if desired, be converted into their salts with inorganic or organic bases, especially for pharmaceutical use into their physiologically tolerable salts. hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As mentioned in the introduction, the new compounds of the general formula I and their salts have valuable properties. Thus, the compounds of the general formula I in which E represents the cyano group represent valuable intermediates for the production of the remaining compounds of the general formula I, and the compounds of the general formula I, in which E represents the group RbNH-C(=NH), and their tautomers, stereoisomers, their physiological tolerable salts have valuable pharmacological properties, especially thrombin inhibitory action, thrombin time prolongation action and inhibitory action against related serine proteases such as trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI and factor XII, whereby several compounds, for example, the compound from example 16 has a slight inhibitory effect on platelet aggregation at the same time.

Dates

A = 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide,

B = 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonyl-propyl)-amide,

C = 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonyl-methyl)-amide,

D = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-methyl)-amide,

E = 1-methyl-2-[N-(2-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxy-carbonylmethyl)-amide,

F = 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]- amide, i

G = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl)-amide,

have been tested for their performance as follows:

Material: Plasma from human citrated blood,

Test-Thrombin (bovine), 30 U/ml, Behring Werke,

Marburg,

Diethylbarbiturate acetate buffer, ORWH 60/61,

Behring Werke, Merburg,

Biomatic B10 coagulometer, Sarstedt.

Implementation:

Determination of thrombin time was performed with a Biomatic B10 coagulometer from Sarstedt.

The test substance was placed in a test tube prescribed by the manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of diethylbarbiturate buffer (DBA buffer). The reaction mixture was incubated for one minute at 37oC. By adding 0.3 U of test thrombin to 0.1 ml of DBA buffer, the clotting reaction was started. Conditioned by the device, the time until the reaction mixture clots was measured by the addition of thrombin. Reaction mixtures to which 0.1 ml of DBA buffer was added served as a control.

By definition, the effective concentration of a substance, at which the thrombin time is doubled compared to the control, is determined via the effective dose curve.

The values found are shown in the following table:

[image]

For example, when applying compounds A, D, E and G up to a dose of 1 mg/kg i.v. no acute toxic side effects could be observed in the rat. Therefore, these compounds are well tolerated.

Based on their pharmacological properties, the new compounds and their physiologically tolerable salts are suitable for the suppression and treatment of venous and arterial thrombotic diseases, such as for the treatment of deep leg vein thrombosis, prevention of reocclusions after bypass operations or angioplasty (PT(C)A), as and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and for prevention of shunt or stent occlusions. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example after PT(C)A, to prevent metastases and growth of tumors that can coagulate and to prevent fibrin-dependent inflammatory processes.

The dosage required to achieve the appropriate effect in intravenous administration is expediently 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg, and in oral administration 0.1 to 50 mg/kg, preferably 0.3 to 30 mg /kg, in any case 1 to 4 times a day. In addition, the compounds of formula I produced according to the invention can, if necessary, be processed in combination with other active substances, together with one or more inert conventional carriers and/or diluents, such as, for example, corn starch, milk sugar, raw sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or substances containing fats, such as hard ointment or their suitable mixtures, in the usual galenic preparations as tablets, dragees, capsules, powder, suspensions or suppositories.

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

Previous notes

If not stated otherwise, Polygram-silica gel plates from the company E. Merck, Darmstadt, are always used for certain Rf values.

EKA mass spectra (cation electrospray mass spectra) are described for example in Chemie unserer Zeit 6, 308-316 (1991).

Example 1

3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

a) 6-methylamino-5-nitro-nicotinic acid-methyl ester

1.6 g (7.4 mmol) of 6-chloro-5-nitro-nicotinic acid methyl ester (see Bernie et al. in J. Chem. Soc. 1951, 2590) was stirred for 30 minutes at room temperature in 20 ml aqueous 40% solution of methylamine. Then the reaction mixture is diluted with ice water, the separated yellow precipitate is filtered off and dried.

Yield: 1.2 g (80% of theoretical),

Rf-value: 0.66 (silica gel; acetic ester/ethanol/glacial acetic acid = 90:5:5).

b) 5-amino-6-methylamino-nicotinic acid-methyl ester

To a solution of 3.1 g (15 mmol) of 6-methylamino-5-nitro-nicotinic acid-methyl ester in 100 ml of ethanol/dichloromethane (3:1) is added 1 g of palladium on charcoal (10% strength). and the resulting suspension is hydrated for 1.5 hours at room temperature under a hydrogen pressure of 5 bar. Then the catalyst is filtered off and the solvent is distilled off under vacuum. The resulting oily crude product is directly further chemically converted.

Yield: 2.4 g (92% of theoretical),

Rf-value: 0.44 (silica gel; acetic ester/ethanol/ammonia = 90:10:1).

c) 5-[2-(4-cyanophenyl)ethylcarbonylamino]-6-methylamino-nicotinic acid-methyl ester

A solution of 2.6 g (15 mmol) of 3-(4-cyanophenyl)-propionic acid in 25 ml of absolute tetrahydrofuran was mixed with 2.4 g (15 mmol) of N,N'-carbonyldiimidazole and stirred for 20 minutes at room temperature. . Then the imidazole is mixed with a solution of 2.3 g (13 mmol) of 5-amino-6-methylamino-nicotinic acid-methyl ester in 25 ml of dimethylformamide and heated for 3 hours at 100oC. The crude product obtained after removing the solvent in a vacuum is taken up in acetic ester, the organic phase is washed with water and after drying over sodium sulfate it is freed from the solvent again. The thus obtained residue is purified by vacuum chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol 19:1).

Yield: 2.1 g of beige solid (50% of theoretical),

Rf-value: 0.54 (silica gel; acetic ester/ethanol/ammonia = 90:10:1).

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

A solution of 2.0 g (5.9 mmol) of 5-[2-(4-cyanophenyl)-ethylcarbonylamino]-6-methylamino-nicotinic acid-methyl ester in 50 ml of glacial acetic acid is heated for 1 hour at 100oC. After removing the solvent, it is taken up in dichloromethane, washed with sodium hydrogen carbonate solution, dried with sodium sulfate and the solvent is distilled off again.

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

Rf-value: 0.50 (silica gel; acetic ester/ethanol/ammonia = 90:10:1).

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

A solution of 3.2 g (10 mmol) of 3-methyl-2-[2-(4-cyano-phenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-methyl ester in 150 ml of methanol it is mixed with a solution of 1.5 g of lithium hydroxide in 20 ml of water and stirred for 24 hours at room temperature, the alcohol is distilled off and the aqueous phase is washed with ethyl acetate. It is acidified with dilute hydrochloric acid and extracted several times with dichloromethane/methanol (9:1), the organic phase is dried with sodium sulfate and the solvent is distilled off.

Yield: 2.1 g of beige solid (70% of theoretical),

Rf-value: 0.38 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

f) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

A solution of 2.0 g (6.5 mmol) of 3-methyl-2-[2-(4-cyano-phenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid in 100 ml of dichloromethane was mixed with 20 ml of thionyl chloride and boiled for 2 hours under reflux. The liquid ingredients are distilled off and the crude product is taken up twice more in dichloromethane and the solvent is distilled off each time. The thus obtained crude acid chloride (2 g) is suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g (6.5 mmol) of N-(2-ethoxycarbonylethyl)aniline. Then, 0.73 g (7.2 mmol) of triethylamine was added dropwise over 5 minutes. It is stirred for 1 hour and then the solvent is distilled off in a vacuum, the residue is taken up in acetic ester, the organic phase is washed with water and dried with sodium sulfate. The solvent is distilled off and after vacuum chromatography (silica gel; dichloromethane to dichloromethane/ethanol = 49:1) the desired compound is isolated as a brownish oil.

Yield: 1.9 g (65% of theoretical),

Rf-value: 0.44 (silica gel; acetic ester/ethanol/ammonia = 90:10:1).

g) 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1.8 g (3.7 mmol) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2 -ethoxycarbonylethyl)-amide is first mixed for 16 hours at 0oC in 100 ml of ethanol saturated with hydrogen chloride and then once more at room temperature until the starting material can no longer be proven by thin-layer chromatography. Then the solvent is distilled off, the oily residue is taken up in 50 ml of absolute ethanol and mixed with 3.6 g (37 mmol) of ammonium carbonate. After 4 hours, the solvent is distilled off under vacuum, the resulting crude product is purified by vacuum chromatography (silica gel; gradient: dichloromethane/ethanol 19:1 to 4:1) and concentrated again.

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

Rf-value: 0.30 (silica gel; acetic ester/ethanol/ammonia = 90:5:5).

Example 2

3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide

A solution of 535 mg (1.0 mmol) of 3-methyl-2-[2-(4-amidino-phenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N- (2-Hydroxycarbonylethyl)-amide in 10 ml of ethanol was mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. It is then diluted with 10 ml of water, the alcohol is distilled off, the aqueous phase is washed with 20 ml of ethyl acetate and acidified with concentrated hydrochloric acid, whereby the desired compound is excreted as white crystals.

Utilization: 375 mg (74% of theoretical),

Rf-value: 0.23 (silica gel; acetic ester/ethanol/ammonia = 90:5:5).

C26H26N6O3 (470.54)

Mass spectrum: (M+H)+ = 471

Example 3

3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonyl-ethyl) )-amide hydrochloride

It was produced analogously to example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-(2-pyridyl)-N-(2 -methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium carbonate.

Utilization: 75% of the theoretical,

C26H27N7O3 (485.55)

Rf-value: 0.31 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

EKA-mass spectrum: (M+H)+ = 486

Example 4

3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide hydrochloride

It was produced analogously to example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic salt acid, ethanol and ammonium carbonate.

Utilization: 84% of the theoretical,

C27H28N6O3 (484.56)

Rf-value: 0.44 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 485

Example 5

3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-hydroxycarbonylmethyl-amide hydrochloride

It was produced analogously to example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide hydrochloride and sodium lye.

Utilization: 85% of the theoretical,

C25H24N6O3 (456.51)

Rf-value: 0.19 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 457

Example 6

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

It was produced analogously to example 1 from 2-[2-(4-cyano-phenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5 -b]pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate.

Utilization: 20% of the theoretical,

C27H26N6O3 (482.54)

Rf-value: 0.30 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

EKA-mass spectrum: (M+H)+ = 483

Example 7

2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-carboxy-2,3-dihydro-indol-1-yl-carbonyl)-imidazo[4,5-b]pyridine hydrochloride

It was produced analogously to example 2 from 2-[2-(4-amidino-phenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5 -b]pyridine hydrochloride i

sodium lye.

Utilization: 90% of the theoretical,

C26H24N6O3 (468.52)

Rf-value: 0.24 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 469

(M+Na)+ = 491

Example 8

1-methyl-2-[(4-amidinophenyl)oxymethyl]-imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)- amide

a) 2-amino-3-methylamino-6-methyl-pyridine

8.35 g (50 mmol) of 2-methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529 (1994) was dissolved in 300 ml of ethyl acetate and hydrogenated with 1.5 g of Raney nickel 3.5 hour at room temperature. The catalyst is then filtered off and the filtrate is concentrated. Crystallization of the residue from petroleum ether gives 5.75 g (84% of theory) of olive green crystals.

C7H11N3 (137.20)

Melting point: 112-113oC.

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

11.4 g (63 mmol) of 4-cyano-phenoxyacetic acid are dissolved in 200 ml of absolute tetrahydrofuran and mixed with 10.2 g (63 mmol) of N,N'-carbonyl-diimidazole at room temperature. After 15 minutes at 60°C, 5.70 g (41.5 mmol) of 2-amino-3-methylamino-6-methyl-pyridine are added. After 2 hours at 60oC, the solvent is distilled off, the crystalline residue is mixed with water, washed with water and dried. After crystallization from ethanol, 9.95 g (91% of theory) of white crystals are obtained.

C16H14N4O (278.32)

Mass spectrum: M+ = 278

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

2.62 g (10 mmol) of 1,5-dimethyl-2-[(4-cyanophenyl)-oxymethyl]-imidazo[4,5-b]pyridine are suspended in 125 ml of dichloromethane and mixed with 2.62 g ( 12.7 mmol) of m-chloro-perbenzoic acid, resulting in a clear solution. After 2 hours at room temperature, the solvent is distilled off and the resulting residue is mixed with sodium hydrogen carbonate solution. The obtained white crystalline product is sucked off after 30 minutes, washed with water and dried at 40oC.

Yield: 2.45 g (83% of theoretical),

C16H14N4O2 (294.30)

Mass spectrum: M+ = 294

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

2.40 g (8.2 mmol) of 1,5-dimethyl-2-[(4-cyanophenyl)-oxymethyl]-imidazo[4,5-b]pyridine-4-N-oxide is suspended in 75 ml of dichloromethane and is mixed with 2.4 ml of trifluoroacetic anhydride, resulting in a clear solution. After 16 hours at room temperature, the solvent is distilled off, the resulting viscous residue is taken up in 50 ml of dichloromethane and poured over with 50 ml of 2M sodium hydrogen carbonate solution. It is stirred vigorously for 3 hours and the resulting precipitate is suctioned off, washed with water and dried at 40oC.

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

C16H14N4O2 (294.30)

Melting point: 172oC.

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

3.65 g (12.5 mmol) of 1-methyl-2-[(4-cyanophenyl)-oxy-methyl]-5-hydroxymethyl-imidazo[4,5-b]pyridine are dissolved in 500 ml of dichloromethane and mixed with 15.0 g of manganese dioxide. After 96 hours at room temperature, it is filtered through silica gel and the solvent is distilled off. The resulting filtrate is concentrated, the crystalline precipitate is rubbed with ether, sucked off and dried.

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

C16H12N4O2 (292.30)

Melting point: 231-234oC.

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

1.25 g (4.3 mmol) of 1-methyl-2-[(4-cyanophenyl)-oxy-methyl]-imidazo[4,5-b]pyridine-5-carbaldehyde is dissolved in 10 ml of formic acid and at 0oC is mixed with 1.0 ml of hydrogen peroxide (33%). After 12 hours at 4oC, the resulting white precipitate is sucked off, washed with water and dried at 40oC.

Yield: 0.81 g (61% of theoretical),

C16H12N4O3 (308.7)

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

308 mg (1.0 mmol) of 1-methyl-2-[(4-cyanophenyl)oxy-methyl]-5-carboxy-imidazo[4,5-b]pyridine is suspended in 5 ml of dimethylformaldehyde and mixed with 303 mg (3.0 mmol) of N-methyl-morpholine and 321 mg (1.0 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2 mmol) of N-(2-pyridyl)-3-amino-propionic acid-methyl ester in 2 ml of dimethylformamide was added, resulting in a clear solution. After 12 hours at room temperature, the reaction solution is mixed into ice water. It is extracted three times with acetic ester and the combined organic extracts are washed with common salt solution, dried over sodium sulfate and evaporated. The resulting residue is chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1).

Yield: 165 mg of white powder (53% of theoretical),

C25H12N6O4 (407.50)

Melting point: 139-140oC.

h) 1-methyl-2-[(4-amidinophenyl)oxymethyl]-imidazo[4,5-b]-pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide

It was produced by converting 140 mg (0.3 mmol) g) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2- pyridyl)-N-(2-methoxycarbonyl-ethyl)-amide with ethanol saturated with hydrogen chloride and with ammonium carbonate/ethanol analogously to example 1g. The obtained product was purified by chromatography over silica gel with dichloromethane/ethanol (19:1 to 4:1).

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

C26H27N7O4 (501.57)

Mass spectrum: (M+H)+ = 502

Example 9

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

a) 4-fluoro-3-methoxyacetamido-benzoic acid-ethyl ester

A solution of 2.8 g (15.3 mmol) of 3-amino-4-fluoro-benzoic acid-ethyl ester (see L.S. Fosdick, A.F. Dodds in J. Amer. Chem. Soc. 65, 2305 (1943)) and 1 .56 ml (1.85 g = 17.0 mmol) of methoxyacetyl chloride in 50 ml of chlorobenzene was stirred for 1 hour at 50°C and then under reflux for 15 minutes. Then the solvent is distilled off in a vacuum and the resulting crude product is purified by vacuum chromatography (silica gel; dichloromethane/ethanol = 100:1). The initially oily secreted desired product solidifies in a few days.

Yield: 3.8 g (98% of theoretical),

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

b) 2-methoxymethyl-benzthiazole-5-carboxylic acid-ethyl ester

A mixture of 3.0 g (11.7 mmol) of 4-fluoro-3-methoxy-acetamido-benzoic acid and 2.1 g (5.2 mmol) of Lawesson's reagent is heated for 6 hours under reflux in 90 ml of toluene, again mixed with 1.0 g of Lawesson's reagent and heated for another 6 hours at 120oC. After replacing the solvent with xylene, it is heated for another 8 hours in a pressure vessel at 180oC. Then the solvent is distilled off in a vacuum, the crude product obtained is purified by vacuum chromatography (silica gel; acetic ester/petroleum ether = 5:95) and concentrated again.

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

Rf-value: 0.55 (silica gel; acetic ester/petroleum ether = 3:7)

c) 2-methoxymethyl-benzthiazole-5-carboxylic acid

A mixture of 2.1 g (8.36 mmol) of 2-methoxymethyl-benz-thiazole-5-carboxylic acid-ethyl ester and 16 ml of 2N sodium hydroxide solution in 60 ml of ethanol was stirred for 1 hour at room temperature. Then the alcohol is distilled off, the crude product is taken up in 20 ml of water, washed with 50 ml of diethyl ether and the aqueous phase is acidified with concentrated hydrochloric acid while cooling with ice. The beige-pink colored compound, which is then secreted, is sucked off, washed with water and dried.

Yield: 1.6 g (86% of theoretical),

Rf-value: 0.12 (silica gel; dichloromethane/ethanol = 29:1)

d) 2-methoxymethyl-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

A suspension of 1.6 g (7.2 mmol) of 2-methoxymethyl-benz-thiazole-5-carboxylic acid in 60 ml of dichloromethane was mixed with 1.6 ml (22 mmol) of thionyl chloride and refluxed for 1 hour. At, the solid dissolves after 20 minutes. The liquid ingredients are distilled off, and the crude product is taken up twice more in dichloromethane and the solvent is distilled off each time. The crude acid chloride thus obtained is taken up in 50 ml of tetrahydrofuran, added dropwise to a mixture of 1.4 g (7.2 mmol) of N-(2-ethoxycarbonylethyl)aniline and 3.0 ml (21 mmol) of triethylamine in 50 ml of tetrahydrofuran and stirred overnight at room temperature. The solvent is then distilled off in a vacuum, the residue is taken up in 30 ml of dichloromethane, the solution is washed with water and dried with sodium sulfate. The solvent is distilled off and after vacuum chromatography (silica gel; gradient: dichloromethane/ethanol 98.5:1.5: to 80:20) the desired compound is isolated as a brownish oil.

Yield: 2.05 g (72% of theoretical),

Rf-value: 0.40 (silica gel; acetic ester/petroleum ether = 1:1).

e) 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

A mixture of 2.5 g (5.14 mmol) of 2-methoxymethyl-benz-thiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide and 5.7 ml (5.7 mmol ) 1M solution of boron tribromide in dichloromethane is dissolved in a further 60 ml of dichloromethane and stirred for 16 hours at room temperature. It is then washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase is dried with sodium sulfate and the solvent is distilled off. The thus obtained 2-bromo-ethyl-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide (2.4 g) is taken up in 5.0 ml of N,N-diisopropyl-ethylamine and mixed with 0.64 g (5.4 mmol) of 4-amino-benzonitrile. It is heated for 1 hour at 130oC and then the solvent is distilled off in a vacuum, and the crude product obtained is purified by vacuum chromatography (silica gel; gradient: acetic ester/petroleum ether = 1:3 to 1:1), which after thickening the washing agent gives orange foam.

Yield: 1.1 g (44% of theoretical),

Rf-value: 0.35 (silica gel; acetic ester/petroleum ether = 7:3).

f) 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1.1 g (2.27 mmol) of 2-[N-(4-cyanophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide is mixed in 100 ml of ethanol saturated with hydrogen chloride for 5 hours first at 0oC and then at room temperature until nothing of the starting material can be demonstrated by thin-layer chromatography. Then the solvent is distilled off at a maximum bath temperature of 30oC, the oily residue is taken up in 100 ml of absolute ethanol and mixed with 1.6 g (22 mmol) of ammonium carbonate. After stirring for 18 hours at room temperature, the solvent is distilled off under vacuum and the crude product is purified by vacuum chromatography (silica gel; gradient: water/methanol = 19:1 to 4:1). By thickening the rinse agent, the desired compound is obtained as a white foam.

Yield: 0.77 g g (63% of theoretical),

Rf-value: 0.19 (silica gel; dichloromethane/ethanol = 3:7)

C27H27N5O3S (501.60)

Mass spectrum: (M+H)+ = 502

Example 10

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide

0.45 g (0.84 mmol) of 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was dissolved in 15 ml of ethanol. , mixed with 2 ml of 2N sodium hydroxide solution and stirred for 4 hours at room temperature. It is then acidified with 3 ml of 2N hydrochloric acid and the solvent is distilled off. The obtained crude product is taken up in 5 ml of dichloromethane/ethanol (2:1) and filtered from undissolved sodium chloride. After removing the solvent by distillation, the desired compound is obtained as a yellow foam.

Yield: 0.26 g (67% of theoretical),

Rf-value: 0.47 (silica gel; methanol/5% aqueous sodium chloride = 6:4)

C25H23N5O3S (473.55)

Mass spectrum: (M+H)+ = 474

Example 11

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide dihydrochloride

It was produced analogously to example 9 from 2-[N-(4-cyano-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanol hydrochloric acid, methanol and ammonium carbonate.

Utilization: 68% of the theoretical,

C25H24N6O3S (488.57)

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

EKA-mass spectrum: (M+H)+ = 489

Example 12

2-[2-(4-amidinophenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride

It was produced analogously to example 9 from 2-[2-(4-cyano-phenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 95% of the theoretical,

C26H25N5O3S (487.58)

Rf-value: 0.20 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid)

EKA-mass spectrum: (M+H)+ = 488

Example 13

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-

dihydrochloride

It was produced analogously to example 9 from 2-[N-(4-cyano-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utilization: 68% of the theoretical,

C25H24N6O3S (488.57)

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

EKA-mass spectrum: (M+H)+ = 489

Example 14

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide-

dihydrochloride

It was produced analogously to example 10 from 2-[N-(4-amidino-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide dihydrochloride and sodium alkalis.

Utilization: 90% of the theoretical,

C23H20N6O3S (460.52)

Rf-value:

EKA-mass spectrum: (M+H)+ = 461

(M+Na)+ = 483

(M+2Na)++ = 253

Example 15

2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 9e from 4-cyano-N-methyl-aniline and 2-methoxymethyl-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide.

Utilization: 57% of the theoretical,

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

b) 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

It was produced analogously to example 9 from 2-[N-(4-cyano-phenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 73% of the theoretical,

C28H29N5O3S (515.64)

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

EKA-mass spectrum: (M+H)+ = 516

Example 16

2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 10 from 2-[N-(4-amidino-phenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium lye.

Utilization: 96% of the theoretical,

C26H25N5O3S (487.58)

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

EKA-mass spectrum: (M+H)+ = 488

(M+2Na)++ = 266.5

Example 17

2-[(4-amidinophenyl)-thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 9 from 2-[(4-cyano-phenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 61% of the theoretical,

C27H26N4O3S2 (518.66)

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

EKA-mass spectrum: (M+H)+ = 519

Example 18

2-[(4-amidinophenyl)thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

It is produced analogously to example 10 from 2-[N-(4-amidino-phenyl)-thiomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkali.

Utilization: 95% of the theoretical,

C25H22N4O3S2 (490.61)

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

EKA-mass spectrum: (M+H)+ = 491

(M+Na)+ = 513

Example 19

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylmethyl)-amide-

hydrochloride

It is produced analogously to example 9 from 2-[N-(4-cyano-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylmethyl)-amide hydrochloride, ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utilization: 82% of the theoretical,

C26H25N5O3S (487.58)

Rf-value: 0.21 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid)

EKA-mass spectrum: (M+H)+ = 488

Example 20

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-

hydrochloride

It is produced analogously to example 10 from 2-[N-(4-amidino-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide hydrochloride and sodium alkali.

Utilization: 75% of the theoretical,

C24H21N5O3S (459.53)

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

EKA-mass spectrum: (M+H)+ = 460

(M+Na)+ = 482

Example 21

2-[2-(4-amidinophenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It is produced analogously to example 9 from 2-[2-(4-cyano-phenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 80% of the theoretical,

C28H28N4O3S (500.62)

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

EKA-mass spectrum: (M+H)+ = 501

Example 22

2-[2-(4-amidinophenyl)ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

It is produced analogously to example 10 from 2-[2-(4-amidino-phenyl)-ethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkali.

Utilization: 77% of the theoretical,

C26H24N4O3S (472.57)

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

EKA-mass spectrum: (M+H)+ = 473

(M+Na)+ = 495

(M+H+Na)++ = 259

Example 23

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-

hydrochloride

It was produced analogously to example 9 from 2-[N-(4-cyano-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide, ethanol hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 83% of the theoretical,

C24H29N5O3 (467.59)

Rf-value: 0.31 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid)

EKA-mass spectrum: (M+H)+ = 468

(2M+H)+ = 935

Example 24

2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-

hydrochloride

It was produced analogously to example 10 from 2-[N-(4-amidino-phenyl)-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium lye.

Utilization: 75% of the theoretical,

C22H25N5O3S (439.54)

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

EKA-mass spectrum: (M+H)+ = 440

(M+H+Na)++ = 231.6

Example 25

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 4-methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide

A solution of 24.7 g (0.115 mmol) of 4-methylamino-3-nitro-benzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxycarbonylethyl)-aniline in 300 ml of tetrahydrofuran with stirring at room temperature 13.1 g (0.13 mol) of triethylamine is added dropwise over 15 minutes. It is stirred for 2 hours and then the solvent is distilled off in the vacuum of a water pump and the residue is mixed with 700 ml of water while stirring. The mixture is extracted three times with 200 ml of dichloromethane, the organic extract is acidified with 200 ml of 2N hydrochloric acid, washed twice with 300 ml of water and dried over sodium sulfate. The solvent is distilled off and the thus obtained oily product is purified by column chromatography (1 kg of silica gel; eluant: petroleum ether/acetic ester = 2:1).

Yield: 35.0 g (82% of theoretical),

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

b) 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide

12.1 g (0.0326 mol) of 4-methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide is hydrogenated in 300 ml of ethanol and 150 ml of dichloromethane after the addition of approx. 4 g of palladium/charcoal (10%) at room temperature and under a hydrogen pressure of 5 bar. After that, the catalyst is filtered off and the filtrate is concentrated. The raw product thus obtained is further chemically converted without cleaning.

Yield: 10.6 g (95% of theoretical),

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

c) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benziimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide

6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N'-carbonyldiimidazole are heated in 300 ml of tetrahydrofuran for 30 minutes under reflux, then 10.6 g ( 0.032 mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and heated under reflux for another 5 hours. Then the solvent is distilled off, the residue is dissolved in 150 ml of glacial acetic acid and heated under reflux for one hour. Then the glacial acetic acid is distilled off in a vacuum, the residue is dissolved in approx. 300 ml of dichloromethane, the solution is washed twice with approx. 150 ml of water and then dried over sodium sulfate. The crude product obtained after evaporation of the solvent is purified by column chromatography (800 g silica gel; eluant: dichloromethane with 1-2% ethanol).

Yield: 8.5 g (57% of theoretical),

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

d) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

1.2 g (2.49 mmol) 1-methyl-2-[N-(4-cyanophenyl)-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide is mixed for 6 hours at room temperature in 100 ml of saturated ethanolic hydrochloric acid. It is then concentrated in vacuo to dryness, the residue is dissolved in 100 ml of ethanol, mixed with 2.5 g (26 mmol) of ammonium carbonate and stirred overnight at room temperature. The solvent is distilled off and the thus obtained crude product is purified by column chromatography (100 g silica gel; eluent: dichloromethane/ethanol = 4:1). Upon thickening the rinse agent, the desired compound is obtained as a white amorphous solid.

Yield: 1.10 g (83% of theoretical),

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

C28H30N6O3 x HCl (498.6)

EKA-mass spectrum: (M+H)+ = 499

(M+2H)++ = 250

(M+H+Na)++ = 261

Example 26

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-

amide

A mixture of 300 mg (0.56 mmol) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide -hydrochloride, 15 ml of ethanol, 4 ml of water and 120 mg (3.0 mmol) of sodium hydroxide are mixed for two hours at room temperature. It is then diluted with approx. 20 ml of water and make slightly acidic with glacial acetic acid. The product, which crystallizes in the process, is sucked off, washed with water and dried in a vacuum at 60oC.

Yield: 250 g (95% of theoretical),

C26H26N6O3 (470.5)

EKA-mass spectrum: (M+H)+ = 471

(M+H+Na)++ = 247

(M+2Na)++ = 258

Example 27

1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 4-methylamino-3-chloroacetamido-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide

A solution of 1.8 g (5.9 mmol) of 3-amino-4-methylamino-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide [prepared analogously to 3-amino-4- ethylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide], 1.1 g (6.8 g (6.8 mmol) of N,N'-carbonyldiimidazole and 0.65 g (6.9 mmol) of chloroacetic acid in 75 ml of tetrahydrofuran is stirred for 1 hour at room temperature.Then the solvent is distilled off in a vacuum, and the crude product is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 49:1).

Yield: 1.7 g (77% of theoretical) yellow oil,

Rf-value: 0.58 (silica gel; acetic ester/ethylanol/ammonia = 90:10:1)

b) 2-chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(ethoxycarbonylethyl)-amide

1.6 g (4.3 mmol) of 4-methylamino-3-chloroacetado-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide in 25 ml of acetic acid is heated for 30 minutes at 100°C. Then the solvent is distilled off, the crude product is taken up in 40 ml of methylene chloride/ethanol (9:1) and washed with 20 ml of saturated sodium hydrogen carbonate solution. The organic phase is dried with sodium sulfate and concentrated.

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

Rf-value: 0.63 (silica gel; acetic ester/ethanol/ammonia = 90:10:1)

c) 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonyl-

ethyl)-amide

A mixture of 1.5 g (4.1 mmol) of 2-chloromethyl-1-methyl-benz-imidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(ethoxy-carbonylethyl)-amide and 0 .65 g (4.8 mmol) of p-cyanothiophenol is heated in 10 ml of dimethylformamide and 10 ml of diisopropyl-ethylamine for 1 hour at 100oC. The solvent is distilled off under vacuum, the crude product is dissolved in ethyl acetate, washed with 30 ml of water and, after concentration, purified by vacuum chromatography (silica gel; methylene chloride/ethanol (49:1 to 19:1)).

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

Rf-value: 0.65 (silica gel; acetic ester/ethanol/ammonia = 90:10:1)

d) 1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

1.4 g (3.01 mmol) 1-methyl-2-[(4-cyanophenyl)-thio-methyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2- ethoxycarbonylethyl)-amide in 50 ml of ethanol saturated with hydrogen chloride is stirred first for 5 hours at 0oC and then at room temperature until nothing of the starting material can be demonstrated by thin-layer chromatography. Then the solvent is distilled off at a bath temperature of no more than 30oC, the oily residue is taken up in 40 ml of absolute ethanol and mixed with 2.8 g of ammonium carbonate. After 18 hours, the solvent is distilled off in a vacuum and the crude product is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 19:1 to 4:1).

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

Rf-value: 0.29 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

C22H25N6O3S (481.62)

EKA-mass spectrum: (M+H)+ = 482

Example 28

1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-hydroxycarbonylethyl)-amide hydrochloride

0.52 g (1.0 mmol) 1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)- amide hydrochloride is dissolved in 15 ml of ethanol, mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then 5 ml of water is added, the alcohol is distilled off and acidified with concentrated hydrochloric acid. The water is distilled off in a vacuum, and the crude product is taken up in 5 ml of ethanol and the undissolved sodium chloride is filtered off. The solvent is distilled off and the title compound is then isolated as a white solid.

Yield: 0.43 g (88% of theoretical),

Rf-value: 0.19 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

C23H27N5O3S (453.57)

EKA-mass spectrum: (M+H)+ = 454

(M+Na)+ = 476

Example 29

1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-methylpropyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-

of N-(2-methylpropyl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 83% of the theoretical,

C25H31N6O3S (495.65)

Rf-value: 0.30 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 496

Example 30

1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-ethoxycarbonylethyl)-amide-

hydrochloride

It was produced analogously to example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 90% of the theoretical,

C28H29N5O3S (515.64)

Rf-value: 0.24 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 516

(M+H+Na)++ = 269.7

Example 31

1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

It is produced analogously to example 28 from 1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkali.

Utilization: 76% of the theoretical,

C26H25N5O3S (487.58)

Rf-value: 0.31 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 488

(M+Na)+ = 510

Example 32

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methyl-piperidin-4-yl)-N-methyl-amide-

hydrochloride

a) 4-chloro-3-nitrobenzene-sulfonic acid-N-(1-methyl-piperidin-4-yl)-N-methyl-amide

To a solution of 2.2 ml (15 mmol) of 1-methyl-4-methylamino-piperidine in 60 ml of pyridine, add 3.8 g (15 mmol) of 4-chloro-3-nitrobenzene-sulfonic acid in portions and while cooling with ice. - chloride. After that, it is stirred for another two hours while cooling, then it is evaporated to dryness, the residue is mixed with approx. 50 ml of water and, with vigorous stirring, make it alkaline with concentrated ammonia. The secreted crude product is filtered off with suction and purified by column chromatography (250 g silica gel, eluant: dichloromethane with 1.5% ethanol).

Yield: 1.6 g (31% of theoretical),

C13H18ClN3O4S (347.8)

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

b) 4-methylamino-3-nitrobenzene-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide

1.6 g (4.6 mmol) of 4-chloro-3-nitrobenzene-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide was mixed with 30 ml of a 40% solution of methylamine and stirred in a closed flask for 4 hours at room temperature. It is then diluted with approx. 40 ml of water, the secreted product is sucked off, washed with water and dried.

Yield: 1.5 g (95% of theoretical),

C14H22N4O4S (343.4)

Rf-value: 0.45 (silica gel; dichloromethane/ethanol/ = 4:1)

c) 3-amino-4-methylamino-benzene-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide

1.5 g (4.4 mmol) of 4-methylamino-3-nitrobenzene-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide is dissolved in 100 ml of methanol and at room temperature hydrogenated catalytically (10% palladium on coal). Then the catalyst is filtered off and the filtrate is concentrated. The oily product thus obtained is further chemically converted without cleaning.

Yield: 1.4 g (100% of theoretical),

C14H24N4O2S (312.4)

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

d) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-

amide

532 mg (3.0 mmol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mmol) of 1,1'-carbonyldiimidazole are dissolved in 40 ml of tetrahydrofuran and heated for 15 minutes under reflux. Then 700 mg (2.24 mmol) of 3-amino-4-methylamino-benzene-sulfonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide was added and boiled for another eight hours. It is then evaporated and the thus obtained oily residue in 30 ml of glacial acetic acid is heated under reflux for one hour. Glacial acetic acid is distilled off, the residue is mixed with approx. 30 ml of water and with concentrated ammonia are made alkaline and the solution is extracted three times with approx. 20 ml of dichloromethane. The organic phase is dried and thickened. The product thus obtained is further chemically converted without cleaning.

Utilization: 400 mg (39% of the theoretical),

C23H27N5O3S (453.6)

Rf-value: 0.37 (silica gel; dichloromethane/ethanol/ = 4:1)

e) 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-

amide hydrochloride

It was produced analogously to example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-amide with

ethanolic hydrochloric acid and ammonium carbonate.

Utilization: 370 mg (83% of theoretical),

C23H30N6O3S (470.6)

EKA-mass spectrum: (M+H)+ = 471

(M+2H)++ = 236

Example 33

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-phenyl-amide hydrochloride

It is produced analogously to example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-phenyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 46% of the theoretical,

C23H23N5O3S (449.5)

EKA-mass spectrum: (M+H)+ = 450

(M+H+methanol)+ = 482

(M+2H)++ = 223

Example 34

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-amide hydrochloride

It was produced analogously to example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-amide, ethanolic salt acid, ethanol and ammonium carbonate.

Utilization: 57% of the theoretical,

C28H31N5O5S (549.7)

EKA-mass spectrum: (M+H)+ = 550

Example 35

1-methyl-2-[(3-amidinophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-pyrrolidide hydrochloride

It is produced analogously to example 32 from 1-methyl-2-[(3-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulfonic acid-pyrrolidide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 71% of the theoretical,

C20H23N5O3S (413.5)

EKA-mass spectrum: (M+H)+ = 414

Example 36

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-methoxycarbonyl-propyl)-amide-

dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxycarbonyl-propyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.

Utilization: 83.5% of the theoretical,

Rf-value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)

C29H31N5O3 (497.6)

EKA-mass spectrum: (M+H)+ = 498

(M+H+Na)++ = 260.7

Example 37

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonyl-propyl)-amide-

hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-methoxycarbonyl-propyl)-amide dihydrochloride and sodium alkalis.

Utilization: 92% of the theoretical,

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

C28H29N5O3 (483.6)

EKA-mass spectrum: (M+H)+ = 484

(M+Na)+ = 506

(M+H+Na)++ = 253.7

Example 38

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonyl-propyl)-amide dihydrochloride

a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tertbutyloxy-

carbonyl-propyl)-amide

It was produced analogously to example 25c from N-(4-cyano-phenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(3-tert.butyl-oxycarbonylpropyl)-amide.

Utilization: 65% of the theoretical,

Rf-value: 0.17 (silica gel; dichloromethane/ethanol = 19:1)

b) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonyl-

propyl)-amide dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tertbutyloxycarbonyl-propyl)-amide and ethanol hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 68% of the theoretical,

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

C29H32N6O3 (512.6)

EKA-mass spectrum: (M+H)+ = 513

(M+H+Na)++ = 268

Example 39

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonyl-propyl)-amide hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonyl-propyl)-amide dihydrochloride and sodium lye.

Utilization: 73.5% of the theoretical,

C27H28N6O3 (484.6)

EKA-mass spectrum: (M+H)+ = 485

(M+2H)++ = 243

(M+H+Na)++ = 254

Example 40

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide-

hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 73% of the theoretical,

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

C28H29N5O3 (483.6)

EKA-mass spectrum: (M+H)+ = 484

(M+H+Na)++ = 253.7

Example 41

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonyl-methyl)-amide-

hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide hydrochloride and

sodium lye.

Utilization: 97% of the theoretical,

C26H25N5O3 (455.5)

EKA-mass spectrum: (M+H)+ = 456

(M+Na)+ = 478

(M+2Na)++ = 250.6

Example 42

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 76% of the theoretical,

Rf-value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)

C27H27N5O4 (485.6)

EKA-mass spectrum: (M+H)+ = 486

(M+H+Na)++ = 254.7

Example 43

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonyl-methyl)-amide hydrochloride

It is produced analogously to example 26 from 1-methyl-2-[(4-amidinophenyl)oscimethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide hydrochloride and sodium alkali.

Utilization: 58% of the theoretical,

C25H23N5O4 (457.5)

EKA-mass spectrum: (M+H)+ = 458

(M+Na)+ = 480

(M+2Na)++ = 251.6

Example 44

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide and ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utilization: 74% of the theoretical,

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

C27H28N6O3 (484.6)

EKA-mass spectrum: (M+H)+ = 485

(M+H+Na)++ = 254

Example 45

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonyl-methyl)-

amide hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide hydrochloride and sodium alkalis.

Utilization: 84% of the theoretical,

C25H24N6O3 (456.5)

EKA-mass spectrum: (M+H)+ = 457

(M+Na)+ = 479

(M+2Na)++ = 251

Example 46

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(ethoxycarbonyl-ethyl)-

amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonyl-ethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 14% of the theoretical,

C26H27N7O4 (501.6)

EKA-mass spectrum: (M+H)+ = 502

Example 47

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide and ethanolic salt acid, ethanol and ammonium carbonate.

Utilization: 44% of the theoretical,

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

C26H26N6O4 (486.5)

EKA-mass spectrum: (M+H)+ = 487

(M+2H)++ = 244

(M+H+Na)++ = 255

Example 48

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonyl-methyl)-

amide hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide dihydrochloride and sodium lye.

Utilization: 85% of the theoretical,

C24H22N6O4 (458.5)

EKA-mass spectrum: (M+H)+ = 459

(M+Na)+ = 481

(M+2Na)++ = 252

Example 49

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide dihydrochloride

a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-

methyl)-amide

It was produced analogously to example 25c from N-(4-cyano-phenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide.

Utilization: 24% of the theoretical,

Rf-value: 0.56 (silica gel; dichloromethane/ethanol = 4:1)

b) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-

methyl)-amide dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 70% of the theoretical,

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

C26H27N7O3 (485.6)

EKA-mass spectrum: (M+H)+ = 486

(M+2H)++ = 243.7

(M+H-Na)++ = 254.6

Example 50

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonyl-methyl)-amide hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide -dihydrochloride and sodium lye.

Utilization: 91% of the theoretical,

C24H23N7O3 (457.5)

EKA-mass spectrum: (M+H)+ = 458

(M+Na)+ = 480

(M+2Na)++ = 251.7

Example 51

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide-

dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 90% of the theoretical,

Rf-value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)

C27H28N6O3 (484.6)

EKA-mass spectrum: (M+H)+ = 485

(M+2H)++ = 243

(M+H+Na)++ = 254

Example 52

1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonyl-methyl)-amide hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-methyl)-amide- dihydrochloride and sodium lye.

Utilization: 89% of the theoretical,

C25H24N6O3 (456.5)

EKA-mass spectrum: (M+H)+ = 457

(M+Na)+ = 479

Example 53

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide and

methanolic hydrochloric acid, methanol and ammonium carbonate.

Utilization: 87% of the theoretical,

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

C27H28N6O3 (484.6)

EKA-mass spectrum: (M+H)+ = 485

(M+2H)++ = 243

(M+H+Na)++ = 254

Example 54

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide-

hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 79.5% of the theoretical,

C28H29N5O4 (499.6)

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

EKA-mass spectrum: (M+H)+ = 500

(M+H+Na)++ = 261.7

Example 55

1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride and sodium alkali .

Utilization: 82% of the theoretical,

C26H25N5O4 (471.5)

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

EKA-mass spectrum: (M+H)+ = 472

(M+H+Na)++ = 247.6

(M+Na)+ = 494

(M+2Na)++ = 258.6

Example 56

1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-ethyl)-amide hydrochloride

a) 1-methyl-2-[2-(2-cyanothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-

ethyl)-amide

It was produced analogously to example 25c from 3-(2-cyano-thiophen-5-yl)propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxy-carbonyl- ethyl)-amide.

Utilization: 18% of the theoretical,

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

b) 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-

ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(2-cyanothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonyl-ethyl) )-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 53% of the theoretical,

C26H28N6O3S (504.6)

Rf-value: 0.22 (silica gel; dichloromethane/ethanol = 5:1)

EKA-mass spectrum: (M+H)+ = 505

(M+H+Na)++ = 264

Example 57

1-methyl-2-[2-(4-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl) -ethyl)-amide dihydrochloride and sodium lye.

Utilization: 98% of the theoretical,

C24H24N6O3S (476.6)

EKA-mass spectrum: (M+H)+ = 477

(M+Na)+ = 499

(M+2H)++ = 239

Example 58

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-

ethyl)-amide

It was produced analogously to example 25c from N-(4-cyano-phenyl)glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxy-carbonyl-ethyl)-amide.

Utilization: 61% of the theoretical,

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

b) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-

ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 71% of the theoretical,

C27H29N7O3 (499.6)

Rf-value: 0.28 (silica gel; dichloromethane/ethanol = 5:1)

EKA-mass spectrum: (M+H)+ = 500

(M+H+Na)++ = 261.8

(M+2H)++ = 250.8

Example 59

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl) -amide hydrochloride and sodium alkali.

Utilization: 91% of the theoretical,

C25H25N7O3 (471.5)

EKA-mass spectrum: (M+H)+ = 472

(M+H+Na)++ = 247.6

(M+2H)++ = 236.7

(M+2Na)++ = 258.6

Example 60

1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

a) 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-

ethyl)-amide

It was produced analogously to example 149a from 3-(4-cyano-phenyl)propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxy-carbonyl-ethyl)-amide .

Utilization: 22% of the theoretical,

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

b) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-

ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)- amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 85% of the theoretical,

C28H30N6O3 (498.6)

Rf-value: 0.30 (silica gel; dichloromethane/ethanol = 5:1)

EKA-mass spectrum: (M+H)+ = 499

(M+H+Na)++ = 261

Example 61

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)- amide hydrochloride and sodium lye.

Utilization: 97% of the theoretical,

C26H26N6O3 (470.5)

EKA-mass spectrum: (M+H)+ = 471

(M+H+Na)++ = 247

(M+Na)+ = 493

Example 62

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonyl-methyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 86% of the theoretical,

C29H31N5O3 (497.6)

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

EKA-mass spectrum: (M+H)+ = 498

(M+2H)++ = 249.8

Example 63

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-ethyl)-amide-

hydrochloride

is derived analogously to example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-propyl)-amide hydrochloride and

sodium lye.

Utilization: 71% of the theoretical,

C27H27N5O3 (469.6)

EKA-mass spectrum: (M+H)+ = 470

(M+H+Na)++ = 246.6

(M+Na)+ = 492

(M+2H)++ = 235.6

Example 64

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonyl-methyl)-amide dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonyl-methyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate.

Utilization: 73% of the theoretical,

C25H25N7O3 (471.5)

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

EKA-mass spectrum: (M+H)+ = 472

(M+H+Na)++ = 247.8

Example 65

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonyl-propyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonyl-ethyl)-amide and

methanolic hydrochloric acid, methanol and ammonium carbonate.

Utilization: 78% of the theoretical,

C26H27N7O3 (485.6)

Rf-value: 0.31 (silica gel; dichloromethane/methanol = 5:1)

EKA-mass spectrum: (M+H)+ = 486

(M+H+Na)++ = 254.8

Example 66

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide

hydrochloride

a) 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-

amide

It was produced analogously to example 25c from 3-(4-cyano-phenyl)propionic acid and 3-amino-4-methylamino-benzoic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]- amide.

Utilization: 67% of the theoretical,

IR-mass spectrum (KBr): characteristic bands at 3439.5 cm-1 (N-H); 2235.5 cm-1 (C≡N); 1631.6 cm-1 (C=O)

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

amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl) ethyl]amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 82% of the theoretical,

C27H27N9O (493.6)

EKA-mass spectrum: (M+H)+ = 494

(M+Na)+ = 516

(M+2H)++ = 258.7

Example 67

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

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl) )ethyl]-amide and

ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 29% of the theoretical,

C26H26N10O (494.6)

EKA-mass spectrum: (M+H)+ = 495

Example 68

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-n-

hexyloxycarbonyl-ethyl)-amide-hydrochloride

In approx. 0.60 g (1.1 mmol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-( 2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)-amide-hydrochloride and stirred for 19 hours at room temperature. The hexanol is then distilled off under vacuum, the residue is mixed with 5 ml of 1N ammonia solution and evaporated again. The crude product thus obtained is purified by column chromatography (silica gel, dichloromethane/methanol = 5:1).

Utilization: 53% of the theoretical,

C31H37N7O3 (555.7)

Rf-value: 0.36 (silica gel; dichloromethane/methanol = 5:1)

EKA-mass spectrum: (M+H)+ = 556

Example 69

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy-carbonylethyl) -amide hydrochloride

a) 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxycarbonylethyl)-amide

It was produced analogously to example 25c from N-(4-cyano-phenyl)-N-methyl-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide .

Utilization: 71% of the theoretical,

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

b) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benz-imidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxy-carbonylethyl)-amide-hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 77% of the theoretical,

C28H31N7O3 (513.6)

EKA-mass spectrum: (M+H)+ = 514

(M+H+Na)++ = 268.7

Example 70

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

hydroxycarbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- of ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 66% of the theoretical,

C26H27N7O3 (485.6)

EKA-mass spectrum: (M+H)+ = 486

(M+Na)+ = 508

(M+2Na)++ = 265.6

Example 71

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 65% of the theoretical,

C28H35N5O3 (489.6)

EKA-mass spectrum: (M+H)+ = 490

Example 72

1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkali .

Utilization: 89% of the theoretical,

C26H31N5O3 (461.6)

EKA-mass spectrum: (M+H)+ = 462

(M+H+Na)++ = 242.6

(M+Na)+ = 484

(M+2H)++ = 231.6

Example 73

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utilization: 60% of the theoretical,

C27H34N6O3 (490.6)

EKA-mass spectrum: (M+H)+ = 491

Example 74

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkalis.

Utilization: 45% of the theoretical,

C25H30N3O4 (462.6)

EKA-mass spectrum: (M+H)+ = 463

(M+H+Na)++ = 243

(M+Na)+ = 485

(M+2H)++ = 254

Example 75

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benz-imidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxy-

carbonylmethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 54% of the theoretical,

C27H29N7O3 (499.6)

EKA-mass spectrum: (M+H)+ = 500

(M+2H)++ = 250.7

Example 76

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxy-carbonylmethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl) -amide hydrochloride and sodium alkali.

Utilization: 68% of the theoretical,

C25H25N7O3 (471.5)

EKA-mass spectrum: (M+H)+ = 472

(M+Na)+ = 494

(M+2Na)++ = 258.6

Example 77

1-Methyl-2-[2-(4-amidinophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 91% of the theoretical,

C28H30N6O3 (498.6)

Rf-value: 0.19 (silica gel; dichloromethane/methanol = 4:1)

EKA-mass spectrum: (M+H)+ = 499

Example 78

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide dihydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 86% of the theoretical,

C27H29N7O3 (499.6)

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

EKA-mass spectrum: (M+H)+ = 500

Example 79

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -dihydrochloride and sodium lye.

Utilization: 85% of the theoretical,

C25H25N7O3 (471.5)

EKA-mass spectrum: (M+H)+ = 472

(M+2H)++ = 236.6

(M+2Na)++ = 258.6

Example 80

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2- ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 64% of the theoretical,

C28H31N7O3 (513.6)

EKA-mass spectrum: (M+H)+ = 514

Example 81

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxy-carbonyl- ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2- of ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 70% of the theoretical,

C26H27N7O3 (485.6)

EKA-mass spectrum: (M+H)+ = 486

(M+Na)+ = 508

(M+2Na)++ = 265.6

Example 82

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

a) 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benz-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide

was prepared analogously to example 25c from N-(4-cyano-phenyl)-N-methyl-glycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide.

Utilization: 71% of the theoretical,

Rf-value: 0.38 (silica gel; dichloromethane/methanol = 19:1)

b) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benz-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide , ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 74% of the theoretical,

C29H32N6O3 (512.6)

EKA-mass spectrum: (M+H)+ = 513

(M+H+Na)++ = 268

(M+2H)++ = 257

Example 83

1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-

hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and sodium lye.

Utilization: 80% of the theoretical,

C27H28N6O3 (484.6)

EKA-mass spectrum: (M+H)+ = 485

(M+H+Na)++ = 254

(M+Na)+ = 507

(M+2Na)+ = 265

Example 84

1-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-ethyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and

ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 85% of the theoretical,

C28H31N7O3 (513.6)

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

EKA-mass spectrum: (M+H)+ = 514

(M+H+Na)++ = 268.6

(M+2H)++ = 257.7

Example 85

1-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and sodium lye.

Utilization: 49% of the theoretical,

C26H27N7O3 (485.6)

EKA-mass spectrum: (M+H)+ = 486

(M+H+Na)++ = 254.6

(M+2H)++ = 243.6

(M+2Na)+ = 265.7

Example 86

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 88% of the theoretical,

C28H29FN6O3 (516.6)

Rf-value: 0.08 (silica gel; dichloromethane/methanol = 4:1)

EKA-mass spectrum: (M+H)+ = 517

(M+H+Na)++ = 270

(M+2H)++ = 259

Example 87

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and sodium lye.

Utilization: 45% of the theoretical,

C26H25FN6O3 (488.5)

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

EKA-mass spectrum: (M+H)+ = 489

(M+H+Na)++ = 267

(M+2H)++ = 256

Example 88

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 79% of the theoretical,

C29H32N6O3 (512.6)

Rf-value: 0.10 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 513

(M+H+Na)++ = 268

Example 89

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-

hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and sodium lye.

Utilization: 62% of the theoretical,

C27H28N6O3 (484.6)

EKA-mass spectrum: (M+H)+ = 485

(M+H+Na)++ = 254

(M+Na)+ = 507

(M+2Na)++ = 265

Example 90

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

1.1 g (2.06 mmol) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide -hydrochloride is dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, then 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of chloroformic acid-n-hexyl ester are added and stirred for 2 hours at room temperature. The solvent is then distilled off, the residue is mixed with approx. 50 ml of saturated table salt solution and the solution thus obtained is extracted three times with 20 ml of dichloromethane each. The extracts are dried over sodium sulfate and concentrated. The crude product thus obtained is purified by column chromatography (100 g silica gel; dichloromethane + 5% ethanol).

Utilization: 78% of the theoretical,

C35H42N6O5 (626.8)

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

EKA-mass spectrum: (M+H)+ = 627

(M+H+Na)++ = 325

(M+2H)++ = 314

Example 91

1-methyl-2-[N-[4-(N-methoxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-

ethoxy-carbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroform acid-methyl ester.

Utilization: 41% of the theoretical,

C30H32N6O5 (556.6)

Rf-value: 0.85 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 557

(M+H+Na)++ = 290

(M+Na)+ = 579

Example 92

1-methyl-2-[N-[4-(N-ethoxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-

methoxy-carbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroform acid-ethyl ester.

Utilization: 62% of the theoretical,

C30H32N6O5 (556.6)

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

EKA-mass spectrum: (M+H)+ = 557

(M+H+Na)++ = 290

(M+2H)+ = 279

Example 93

1-methyl-2-[N-[4-(N-cyclohexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroform acid-cyclohexyl ester.

Utilization: 25% of the theoretical,

C34H38N6O5 (610.7)

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

EKA-mass spectrum: (M+H)+ = 611

(M+2H)+ = 306

Example 94

1-methyl-2-[N-[4-[N-[2-(methylsulfonyl)ethyloxycarbonyl]-amidino]phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2- ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and chloroform acid-2-(methylsulfonyl)-ethyl ester.

Utilization: 66% of the theoretical,

C32H36N6O7S (648.8)

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

EKA-mass spectrum: (M+H)+ = 649

(M+H+Na)++ = 336

(M+2H)+ = 325

Example 95

1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroform acid-n-octyl ester.

Utilization: 41% of the theoretical,

C36H44N6O5 (640.8)

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

EKA-mass spectrum: (M+H)+ = 641

(M+Na)+ = 663

Example 96

1-methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonylethyl)-amide

1.44 g (3.0 mmol) 1-methyl-2-[N-(4-cyanophenyl)-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide, 0.625 g (9.0 mmol) of hydroxylamine hydrochloride and 0.425 g (4.0 mmol) of sodium carbonate are dissolved in 80 ml of ethanol and heated under reflux for 7 hours. Then another 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate are added, boiled for another 5 hours and then concentrated in a vacuum. The residue is dissolved in approx. 30 ml of dichloromethane, the resulting solution is washed with 20 ml of water, the organic phase is dried and concentrated. The crude product thus obtained is purified by column chromatography (200 g of silica gel, dichloromethane + 4% ethanol).

Utilization: 39% of the theoretical,

C28H30N6O4 (514.6)

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

EKA-mass spectrum: (M+H)+ = 515

(M+Na)+ = 537

(2M+H)+ = 1029

(2M+Na)+ = 1051

Example 97

1-methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-heptyl ester.

Utilization: 43% of the theoretical,

C35H42N6O5 (626.8)

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

EKA-mass spectrum: (M+H)+ = 627

(M+H+Na)++ = 325

(M+Na)+ = 649

Example 98

1-methyl-2-[N-[4-(N-benzoylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy-carbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and benzoyl chloride.

Utilization: 88% of the theoretical,

C34H32N6O4 (588.7)

Rf-value: 0.37 (silica gel; dichloromethane/ethanol = 19:1)

1H-NMR spectrum (D6-DMSO): 2.61 (t, 2H); 3.54 (s, 3H); 3.76 (s, 3H); 4.10 (t, 2H); 4.61 (d, 2H); 6.83 (d, 2H); 7.05 to 7.55 (m, 12H); 8.03 (d, 2H); 8.25 (dd, 2H); 8.98 (s, 1H); 10.48 (s, 1H).

Example 99

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 54% of the theoretical,

C34H40N6O5 (612.7)

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

EKA-mass spectrum: (M+H)+ = 613

Example 100

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide

It is produced analogously to example 90 from 1-methyl-2-[N-(4-amidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 31% of the theoretical,

C36H44N6O5 (640.8)

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

EKA-mass spectrum: (M+H)+ = 641

(M+H+Na)++ = 332

(M+Na)+ = 663

Example 101

1-methyl-2-[N-[4-(N-ethoxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-ethyl ester.

Utilization: 72% of the theoretical,

C29H31N7O5 (557.6)

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

EKA-mass spectrum: (M+H)+ = 558

(M+H+Na)++ = 290.8

(M+Na)+ = 580

Example 102

1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)- amide

It is produced analogously to example 90 from 1-methyl-2-[N-(4-amidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl) -amide-hydrochloride and chloroformic acid-n-octyl ester.

Utilization: 57% of the theoretical,

C35H43N7O5 (641.8)

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

EKA-mass spectrum: (M+H)+ = 642

(M+H+Na)++ = 332.8

(M+Na)+ = 664

Example 103

1-methyl-2-[N-[4-(N-n-methoxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-methyl ester.

Utilization: 48% of the theoretical,

C29H31N7O5 (557.6)

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

EKA-mass spectrum: (M+H)+ = 558

(M+H+Na)++ = 290.7

(M+Na)+ = 580

Example 104

1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)- amide

0.7 g (1.1 mmol) 1-methyl-2-[N-[4-(N-n-octyloxy-carbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl )-N-(2-methoxycarbonylethyl)-amide in a mixture of 0.12 g (3.0 mmol) of sodium hydroxide, 5 ml of water and 10 ml of methanol was stirred for 1 hour at room temperature. It is then diluted with 20 ml of water and adjusted to pH 6 with glacial acetic acid. Then approx. 5 ml of diethyl ether and stir vigorously for one hour. The product, which is secreted in the process, is sucked off, washed with a little water, then washed with diethyl ether and dried.

Utilization: 80% of the theoretical,

C34H41N7O5 (627.8)

EKA-mass spectrum: (M+H)+ = 628

(M+H+Na)++ = 325.7

(M+Na)+ = 650

(M+2Na)++ = 337.7

Example 105

1-methyl-2-[N-[4-[N-(2-methylsulfonyl-ethyloxycarbonyl)-amidino]-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N -(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-2-(methylsulfonyl)-ethyl ester.

Utilization: 65% of the theoretical,

C31H35N7O7S (649.7)

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

EKA-mass spectrum: (M+H)+ = 650

(M+H+Na)++ = 336.6

(M+Na)+ = 672

(M+2Na)++ = 347.6

Example 106

1-methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)- amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-butyl ester.

Utilization: 30% of the theoretical,

C31H35N7O5 (585.7)

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

EKA-mass spectrum: (M+H)+ = 586

(M+H+Na)++ = 304.7

(M+2H)++ = 293.7

Example 107

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)- amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 51% of the theoretical,

C33H39N7O5 (613.7)

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

EKA-mass spectrum: (M+H)+ = 614

(M+H+Na)++ = 318.7

(M+2H)++ = 307.6

Example 108

1-methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)- amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-heptyl ester.

Utilization: 21% of the theoretical,

C34H41N7O5 (627.8)

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

EKA-mass spectrum: (M+H)+ = 628

(M+H+Na)++ = 325.7

(M+2H)++ = 314.7

Example 109

1-methyl-2-[N-[4-(N-n-pentyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-pentyl ester.

Utilization: 66% of the theoretical,

C32H37N7O5 (599.7)

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

EKA-mass spectrum: (M+H)+ = 600

(M+H+Na)++ = 311.7

(M+Na)+ = 622

Example 110

1-methyl-2-[N-[4-(N-n-nonyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)- amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-nonyl ester.

Utilization: 60% of the theoretical,

C36H45N7O5 (655.8)

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

EKA-mass spectrum: (M+H)+ = 656

(M+H+Na)++ = 339.8

(M+Na)+ = 678

Example 111

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

methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and benzoyl chloride.

Utilization: 62% of the theoretical,

C33H31N7O4 (589.7)

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

EKA-mass spectrum: (M+H)+ = 590

(M+Na)+ = 612

Example 112

1-methyl-2-[N-[4-(N-nicotinoylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

methoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide -hydrochloride and chloride of nicotinic acid.

Utilization: 40% of the theoretical,

C32H30N8O4 (590.7)

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

EKA-mass spectrum: (M+H)+ = 591

(M+H+Na)++ = 307

(M+Na)++ = 613

Example 113

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 51% of the theoretical,

C34H41N7O5 (627.8)

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

EKA-mass spectrum: (M+H)+ = 628

(M+H+Na)++ = 325.7

(M+2H)++ = 314.7

Example 114

1-methyl-2-[N-[4-(N-octyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)- amide

is derived analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-octyl ester.

Utilization: 57% of the theoretical,

C36H45N7O5 (655.8)

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

EKA-mass spectrum: (M+H)+ = 656

(M+H+Na)++ = 339.7

(M+2H)++ = 328.7

Example 115

1-methyl-2-[N-[4-[N-(2-methylsulfonyl-ethyloxycarbonyl)-amidino]-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N -ethoxycarbonylmethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide hydrochloride and chloroform acid-2-(methylsulfonyl)-ethyl ester.

Utilization: 72% of the theoretical,

C30H33N7O5S (635.7)

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

EKA-mass spectrum: (M+H)+ = 636

(M+H+Na)++ = 329.8

Example 116

1-methyl-2-[N-[4-(N-cyclohexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-

pyridyl)-N-methoxycarbonylmethyl-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide hydrochloride and chloroform acid-cyclohexyl ester.

Utilization: 40% of the theoretical,

C32H35N7O5 (597.7)

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

EKA-mass spectrum: (M+H)+ = 598

(M+Na)+ = 620

Example 117

1-methyl-2-[N-[4-(N-methoxycarbonylamidino)-phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide hydrochloride and chloroform acid-methyl ester.

Utilization: 62% of the theoretical,

C28H29N7O5 (543.6)

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

EKA-mass spectrum: (M+H)+ = 544

(M+H+Na)++ = 283.8

(M+Na)+ = 566

Example 118

1-methyl-2-[N-[4-(N-ethoxycarbonylamidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-

methoxycarbonylmethyl-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide hydrochloride and chloroform acid-ethyl ester.

Utilization: 42% of the theoretical,

C28H29N7O5 (543.6)

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

EKA-mass spectrum: (M+H)+ = 544

Example 119

1-methyl-2-[N-[4-(N-octyloxycarbonyl-amidino)-phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2- ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-octyl ester.

Utilization: 35% of the theoretical,

C36H45N7O5 (655.8)

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

EKA-mass spectrum: (M+H)+ = 656

(M+2H)++ = 328.7

Example 120

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 58% of the theoretical,

C35H43N7O5 (641.2)

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

EKA-mass spectrum: (M+H)+ = 642

(M+H+Na)++ = 332.7

Example 121

1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-octyl ester.

Utilization: 36% of the theoretical,

C37H47N7O5 (669.8)

EKA-mass spectrum: (M+H)+ = 670

(M+H+Na)++ = 346.8

(M+2H)++ = 335.6

Example 122

1-methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)-phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-butyl ester.

Utilization: 34% of the theoretical,

C33H39N7O5 (613.7)

EKA-mass spectrum: (M+H)+ = 614

(M+H+Na)++ = 318.7

(M+Na)+ = 636

Example 123

1-methyl-2-[N-[4-(N-benzoylamidino)phenyl]-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) )-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide hydrochloride and benzoyl chloride.

Utilization: 63% of the theoretical,

C35H35N7O4 (617.7)

EKA-mass spectrum: (M+H)+ = 618

(M+H+Na)++ = 320.7

(M+Na)+ = 640

Example 124

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

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

8.4 g (40 mmol) of 3-(4-chlorobenzoyl)-propionic acid are dissolved in 300 ml of tetrahydrofuran and 5.8 g (120 mmol) of sodium hydride (50-60% suspension in paraffin oil) are added in portions. . Then, with stirring, it is heated for 1.5 hours at reflux, then 8.9 ml (60 mmol) of 1,5-diiopentane are added dropwise and boiled for another three hours. When it cools down, the solution is mixed with 200 ml of ice water, then tetrahydrofuran is distilled off in a vacuum, the resulting aqueous solution is acidified with 2n hydrochloric acid and extracted three times with 150 ml of dichloromethane each. The organic phase is dried and concentrated, the thus obtained crude product is purified by column chromatography (500 g silica gel; eluent: dichloromethane with 1-2% ethanol).

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

C15H17ClO3 (280.8)

Rf-value: 0.56 (silica gel; dichloromethane/ethanol = 19:1)

b) 4-chloro-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone

7.0 g (25 mmoles) of 4-chlorophenyl-(1-hydroxycarbonyl-methyl-cyclohex-1-yl)-ketone are introduced in portions with stirring at -5 to -10°C in 80 ml of fuming nitric acid. Then it is stirred for another 10 minutes, then the solution is mixed in 200 ml of ice water, the excreted product is washed with water and dried.

Yield: 7.8 g (96% of theoretical),

C15H16ClNO5 (325.8)

Rf-value: 0.41 (silica gel; petroleum ether/acetic ester = 4:6)

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

7.8 g (23.9 mmol) of 4-chloro-3-nitrophenyl-(1-hydroxy-carbonylmethyl-cyclohex-1-yl)-ketone in 100 ml of a 40% aqueous solution of methylamine was stirred for 14 hours at room temperature , then dilute with approx. 150 ml of water and slightly acidify with glacial acetic acid. The excreted product is sucked off, washed with water and dried.

Yield: 7.1 g (93% of theoretical),

C16H20N2O5 (320.4)

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

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

4.9 g (15 mmol) of 4-methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-cyclohex-1-yl)-ketone are dissolved in 100 ml of tetrahydrofuran, 2.4 g (15 mmol) of 1,1' are added -carbonyl-diimidazole and heated for 15 minutes under reflux. Then the solvent is evaporated, 30 ml of methanol is added and it is boiled for three hours with stirring. Methanol is distilled off and then the thus obtained crude product is purified by column chromatography (250 g silica gel, eluent: dichloromethane with 1 to 5% ethanol).

Yield: 2.4 g (48% of theoretical),

C17H22N2O5 (334.4)

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

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

2.4 g (7.2 mmol) of 4-methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone in 100 ml of methanol is catalytically hydrogenated at room temperature and under a hydrogen pressure of 5 bar (10 % palladium on coal). The raw product thus obtained is further chemically converted without cleaning.

Yield: 2.1 g (96% of theoretical),

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

f) 3-(4-cyanophenyloxyacetylamino)-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone

620 mg (3.5 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of 1,1'-carbonyldiimidazole in 50 ml of tetrahydrofuran are heated for 15 minutes under reflux. Then 1.0 g (3.28 mmol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone was added and boiled for another 4 hours. The solvent is then evaporated and the thus obtained crude product is purified by column chromatography (150 g silica gel; eluent: dichloromethane with 0 to 2% ethanol).

Yield: 1.4 g (93% of theoretical),

C26H29N3O5 (463.5)

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

g) 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone

1.4 g (3.02 mmol) of 3-(4-cyanophenyloxyacetylamino)-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone in 50 ml of glacial acetic acid is heated under reflux for one hour. Then the glacial acetic acid is distilled, the residue is mixed with 20 ml of water and made alkaline with concentrated ammonia. This solution is extracted three times with dichloromethane, the organic extracts are dried and concentrated. The thus obtained crude product is purified by column chromatography (100 g silica gel; eluent: dichloromethane with 0 to 2% ethanol).

Yield: 700 g (52% of theoretical),

C26H27N3O5 (445.5)

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

hydrochloride

It was produced analogously to example 25d from 700 mg (1.57 mmol) of 1-methyl-2-(4-cyanophenyloxymethyl)-benzimidazol-5-yl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone with

ethanolic hydrochloric acid and ammonium carbonate.

Utilization: 390 mg (50% of theoretical),

C27H32N4O4 (476.6)

EKA-mass spectrum: (M+H)+ = 477

1H-NMR spectrum (d 6 -DMSO): 1.10 (t, 3H); 1.0-2.15 (m, 10H); 3.36 (s, 3H); 3.90 (s, 2H); 3.94 (q, 2H); 5.60 (s, 2H);

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

Example 125

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

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-tert.butyl-ketone, ethanolic hydrochloric acid and ammonium carbonate.

Utilization: 59% of the theoretical,

C21H25N5O (363.5)

EKA-mass spectrum: (M+H)+ = 364

Example 126

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

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-(1-methyl-cyclopent-ketone), ethanolic hydrochloric acid and ammonium carbonate.

Utilization: 63.5% of the theoretical,

C23H27N5O (389.5)

EKA-mass spectrum: (M+H)+ = 390

Example 127

2-[(4-amidinophenyl)sulfinylmethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

A solution of 0.15 g (0.27 mmol) of 2-[(4-amidinophenyl)-thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride in 10 ml of acetic acid is mixed with 0.09 ml (approx. 0.81 mmol) of a 30% hydrogen peroxide solution and stirred at room temperature. After 4 days, add another 0.81 ml of hydrogen peroxide solution and mix for another two days. The product obtained after removing the solvent in a vacuum is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 10:1 to 4:1).

Utilization: 58% of the theoretical,

C27H26N4O4S2 (534.66)

Rf-value: 0.24 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid)

EKA-mass spectrum: (M+H)+ = 535

Example 128

1-methyl-2-[(4-amidinophenyl)sulfonylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

A solution of 0.40 g (0.70 mmol) of 1-methyl-2-[(4-amidino-phenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2 -ethoxycarbonylethyl)-amide hydrochloride in 10 ml of formic acid is mixed with 2 ml of a 30% hydrogen peroxide solution and stirred for 16 hours at room temperature. The solvent is then distilled off in vacuo to give the desired product as a beige solid (contaminated with a little 1-methyl-2-[(4-amidinophenyl)sulfinylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n -propyl)-N-(2-ethoxycarbonyl-ethyl)-amide-hydrochloride).

Utilization: 95% of the theoretical,

C25H31N6O5S (513.62)

Rf-value: 0.50 (silica gel; acetic ester/ethanol/1N hydrochloric acid = 50:45:5)

EKA-mass spectrum: (M+H)+ = 514

Example 129

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-thiazolo[5,4-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonyl-ethyl)-amide-hydrochloride

a) 5-amino-6-chloro-nicotinic acid-methyl ester

a solution of 1.08 g (5.00 mmol) of 6-chloro-5-nitro-nicotinic acid-methyl ester (see A.H. Berrie, G.T. Newbold, F.S. Spring in J. Chem. Soc., 2590, 1951) in 25 ml of absolute ethanol is successively mixed with 0.53 ml (29 mmol) of water, 3.2 g (57 mmol) of iron powder and 0.030 ml of concentrated hydrochloric acid and heated for one hour at boiling point. Then an equal amount of water, iron powder and hydrochloric acid is added once more and heated for 30 minutes at boiling point. That which is secreted during cooling is filtered off, washed with ethanol and the solvent is distilled off in a vacuum.

Yield: 0.75 g (81% of theory) yellow-green solid,

Rf-value: 0.31 (silica gel; acetic ester/petroleum ether = 1:4)

C7H7ClN2O2 (186.60)

YEF-mass spectrum: M+ = 186 and 188 (chlorine isotopes)

b) 6-chloro-5-methoxyacetamido-nicotinic acid-methyl ester

A solution of 0.75 g (4.02 mmol) of 5-amino-6-chloro-nicotinic acid-methyl ester and 0.43 g = 0.35 ml (4.5 mmol) of methoxyacetyl chloride in 20 ml of chlorobenzene is mixed once hour at 110oC. The crude product obtained after removing the solvent in vacuo is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 100:1), concentrated again in vacuo and then digested with petroleum ether.

Yield: 0.55 g (53% of theoretical) light yellow amorphous solid,

Rf-value: 0.33 (silica gel; acetic ester/petroleum ether = 1:4).

c) 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-methyl ester

A mixture of 0.53 g (2.05 mmol) of 6-chloro-5-methoxy-acetamido-nicotinic acid-methyl ester and 0.42 g (1.0 mmol) of Lawesson's reagent in 25 ml of xylene is heated under reflux for 16 hours . The crude product, obtained after removing the solvent in vacuo, is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 100:1) and concentrated again in vacuo.

Yield: 0.33 g (67% of theoretical) yellow amorphous solid,

Rf-value: 0.52 (silica gel; acetic ester/petroleum ether = 1:4).

d) 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid

A mixture of 1.1 g (4.62 mmol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid methyl ester and 9.2 ml of 2N sodium hydroxide solution in 50 ml of ethanol is stirred for one hour at room temperature. Then 9.2 ml of 2N hydrochloric acid is added, the alcohol is distilled off and diluted with 20 ml of water. The aqueous phase is acidified with concentrated hydrochloric acid, after which the secreted beige precipitate is filtered off, and then washed with water and dried.

Yield: 1.03 g (100% of theoretical),

Rf-value: 0.10 (silica gel; acetic ester/petroleum ether = 3:7).

e) 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

A suspension of 1.03 g (4.62 mmol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid in 40 ml of methylene chloride was mixed with 1.6 g = 1.0 ml ( 13.5 mmol) of thionyl chloride and refluxed for 90 minutes, during which the solid gradually dissolved. The liquid component is distilled off and the crude product is taken up twice more in methylene chloride and concentrated again. The thus obtained crude acid chloride (1.2 g) is taken up in 40 ml of tetrahydrofuran, added dropwise to a mixture of 0.94 g (4.86 mmol) of N-(2-ethoxycarbonylethyl)aniline and 2.1 ml (13 .8 mmol) of triethylamine in 30 ml of tetrahydrofuran and stirred for 2 hours at room temperature. It is then diluted with 200 ml of acetic ester, washed with 100 ml of a 14% table salt solution and the organic phase is dried with sodium sulfate. The crude product obtained after removing the solvent in a vacuum is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 100:1).

Yield: 1.57 g (87% of theory) of yellow oil,

Rf-value: 0.55 (silica gel; methylene chloride/ethanol = 19:1).

f) 2-[N-(4-cyanophenyl)-aminomethyl]-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide

A mixture of 1.54 g (3.85 mmol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mmol) of a 1 molar solution of boron tribromide in methylene chloride is dissolved in a further 30 ml of methylene chloride and stirred for 5 hours at room temperature. It is then washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase is dried with sodium sulfate and the solvent is distilled off. The crude product (1.9 g) is taken up in 15.0 ml of N,N-diisopropylethylamine, mixed with 0.50 g (4.2 mmol) of 4-aminobenzonitrile and heated at reflux for one hour. Then the solvent is distilled off in a vacuum, the crude product is taken up in 100 ml of methylene chloride, the organic phase is washed with 100 ml of water and dried with sodium sulfate. The crude product, obtained by removing the solvent in vacuo, is purified by vacuum chromatography (silica gel; acetic ester/petroleum ether = 35:65 to 1:1) and concentrated again in vacuo.

Yield: 45 g (24% of theoretical) yellow amorphous solid,

Rf-value: 0.34 (silica gel; acetic ester/petroleum ether = 1:1).

g) 2-[N-(4-amidinophenyl)aminomethyl]-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

0.39 g (0.803 mmol) 2-[N-(4-cyanophenyl)aminomethyl]-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)- the amide is first mixed in 40 ml of ethanol saturated with hydrogen chloride for 5 hours at 0oC and then at room temperature until the starting material can no longer be proven by thin-layer chromatography. Then the solvent is distilled off at a bath temperature of no more than 30oC, the oily residue is taken up in 40 ml of absolute ethanol and mixed with 0.5 g of ammonium carbonate. After 18 hours, the solvent was removed in vacuo and the obtained crude product was purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1).

Recovery: 78% of the theoretical yellow foam,

C26H26N6O3S(502.60)

Rf-value: 0.19 (silica gel; methylene chloride/ethanol = 4:1).

EKA-mass spectrum: (M+H)+ = 503

Example 130

1-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-

hydrochloride

a) 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

A solution of 6.5 g (19 mmol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.5 g (22.8 mmol) of N,N'- of thiocarbonyldiimidazole is dissolved in a nitrogen atmosphere in 100 ml of tetrahydrofuran, heated for 4 hours at 90oC and left to stand for 16 hours at room temperature. The crude product obtained after removing the solvent in a vacuum is purified by vacuum chromatography (silica gel; petroleum ether/acetic ester = 100:0 to 65:35).

Yield: 6.8 g (93% of theory) beige colored crystalline solid,

Rf-value: 0.55 (silica gel; acetic ester).

b) 1-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

A solution of 1.30 g (3.4 mmol) of 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide, 0.52 g ( 3.74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) of 4-bromo-methylbenzonitrile are dissolved in 40 ml of absolute ethanol, stirred for 4 hours at 60°C and 16 hours at room temperature. Then the solvent is distilled off in a vacuum, the crude product is taken up in 30 ml of methylene chloride, washed with 40 ml of water and dried with sodium sulfate. After filtration and removal of the solvent by distillation, the desired compound is isolated as a beige-white solid.

Yield: 1.8 g (100% of theoretical),

Rf-value: 0.64 (silica gel; acetic ester).

c) 1-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

1.5 g (3.0 mmol) of 1-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide in 80 ml of ethanol saturated with hydrogen chloride is mixed first for 6.5 hours at 0oC, and then at room temperature until thin-layer chromatography can no longer prove the starting material. Then the solvent is distilled off at a bath temperature of no more than 30oC, the oily product is taken up in 80 ml of absolute ethanol and mixed with 1.0 g (10.5 mmol) of ammonium carbonate. After 18 hours, the solvent is distilled off in a vacuum and the obtained crude product is purified by vacuum chromatography (silica gel; methylene chloride/ethanol = 19:1 to 10:1).

Yield: 78% of theoretical, light beige solid,

C28H29N5O3S (515.63)

Rf-value: 0.19 (silica gel; methylene chloride/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 516

(M+H+Na)++ = 269.7

(M+2H)++ = 258.7

Example 131

1-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-

hydrochloride

It is produced analogously to example 10 from 1-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkali.

Utilization: 57% of the theoretical,

C26H25N5O3S (487.58),

Rf-value: 0.23 (silica gel PR-8 reverse phases; methanol/5% table salt solution = 6:4)

EKA-mass spectrum: (M+H)+ = 488

(M+Na)+ = 510

(M+Na+H)+ = 255.6

Example 132

1-methyl-2-[(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utilization: 81% of the theoretical,

C25H28N6O3 (460.6),

Rf-value: 0.094 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 461

(M+H+Na)++ = 242

(M+2H)+ = 231

Example 133

1-methyl-2-[2-[(4-n-hexyloxycarbonylamidino)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[2-[(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 72% of the theoretical,

C35H42N6O5 (626.8),

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

EKA-mass spectrum: (M+H)+ = 627

(M+Na)+ = 649

Example 134

1-methyl-2-[2-[4-(N-benzoylamidino)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- hydrochloride and benzoyl chloride.

Utilization: 79% of the theoretical,

C35H34N6O4 (602.7),

Rf-value: 0.52 (silica gel; dichloromethane/ethanol = 9:1)

EKA-mass spectrum: (M+H)+ = 603

(M+Na)+ = 625

Example 135

1-methyl-2-[2-[4-(N-nicotinoylamidino)phenyl]ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy-

carbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[2-[4-(N-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) -amide hydrochloride and nicotinic acid chloride.

Utilization: 56% of the theoretical,

C34H33N7O4 (603.7),

Rf-value: 0.52 (silica gel; dichloromethane/ethanol = 9:1)

EKA-mass spectrum: (M+H)+ = 604

(M+Na)+ = 626

Example 136

1-cyclopropyl-2-[N-(4-amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-cyclopropyl-2-[N-(4-cyanophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 31% of the theoretical,

C30H33N6O3 (524.6),

Rf-value: 0.40 (silica gel; dichloromethane/methanol = 5:1)

EKA-mass spectrum: (M+H)+ = 525

(M+H+Na)++ = 274

(M+2H)++ = 263

Example 137

1-cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-

hydrochloride and sodium lye.

Utilization: 64% of the theoretical,

C28H28N6O3 (496.6),

EKA-mass spectrum: (M+H)+ = 497

(M+H+Na)++ = 260

(M+Na)+ = 519

(M+2Na)++ = 271

Example 138

1-methyl-2-[N-(4-amidinophenyl)-N-(n-butyl)-aminomethyl]-benz-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2- ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 62% of the theoretical,

C32H38N6O3 (554.7),

EKA-mass spectrum: (M+H)+ = 555

(M+H+Na)++ = 289

(M+2H)++ = 278

Example 139

1-Methyl-2-[N-(4-amidino-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)-amide -hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyano-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 82% of the theoretical,

C28H29ClN6O3 (533.1),

EKA-mass spectrum: (M+H)+ = 533/5

(M+H+Na)++ = 278/9

Example 140

1-methyl-2-[N-[4-(n-octyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

It is produced analogously to example 90 from 1-methyl-2-[N-(4-

amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-ethyl)amide hydrochloride and chloroformic acid-n-octyl ester.

Utilization: 34% of the theoretical,

C37H46N6O5 (654.8),

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

EKA-mass spectrum: (M+H)+ = 655

(M+H+Na)++ = 339

(M+Na)+ = 677

Example 141

1-methyl-2-[N-(4-amidino-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-

ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyano-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 61% of the theoretical,

C30H34N6O3 (526.6),

EKA-mass spectrum: (M+H)+ = 527

(M+H+Na)++ = 275

(M+2H)++ = 264

Example 142

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide-hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 63% of the theoretical,

C24H24N6O (412.5),

Rf-value: 0.76 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 413

Example 143

1-methyl-2-[N-[4-(N-(2-(2-ethoxyethoxy)ethyloxy)-carbonyl-amidino)-phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2 -pyridyl)-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and diethyleneglycolmonoethylether ester of chloroformic acid.

Utilization: 43% of the theoretical,

C34H41N7O7 (659.8),

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

EKA-mass spectrum: (M+H)+ = 660

(M+H+Na)++ = 341

Example 144

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 60% of the theoretical,

C26H30N8O3 (502.6),

Rf-value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 503

(M+H+Na)++ = 263

(M+2H)++ = 252

Example 145

3-methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

It is produced analogously to example 1 from 3-methyl-2-[(4-cyanophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 88% of the theoretical,

C27H28N6O3S (516.63),

Rf-value: 0.23 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 517

(M+H+Na)++ = 270

Example 146

3-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonyl-ethyl)-amide-hydrochloride

It is produced analogously to example 1 from 3-methyl-2-[(4-cyanophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 82% of the theoretical,

C27H29N7O3 (499.58),

Rf-value: 0.20 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 500

(M+H+Na)++ = 261.7

Example 147

3-Methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

It is produced analogously to example 2 from 3-methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide hydrochloride and sodium alkali.

Utilization: 88% of the theoretical,

C25H24N6O3S (488.56),

Rf-value: 0.21 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 489

(M+Na)+ = 511

Example 148

3-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-imidazo[4,5-b]-pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-hydroxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 2 from 3-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2- of ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 80% of the theoretical,

C25H25N7O3 (471.52),

Rf-value: 0.19 (silica gel; acetic ester/ethanol/ammonia = 50:45:5)

EKA-mass spectrum: (M+H)+ = 472

(M+Na)+ = 494

(M+2Na)++ = 258.6

Example 149

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

2.54 g (6.2 mmol) of 3-nitro-4-methylamino-benzene-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide is hydrogenated at room temperature under a hydrogen pressure of 5 bar over palladium/ of coal (10%) in a mixture of 75 ml of ethanol and 75 ml of dichloromethane. The thus obtained crude 3-amino-4-methylamino-benzenesulfonic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide is taken up without purification in 30 ml of phosphorus oxychloride, then 1.1 g (6 .2 mmol) of N-(4-cyanophenyl)-glycine and the mixture is boiled for two hours under reflux. When it has cooled to room temperature, the reaction mixture is introduced into approx. 70 ml of water with cooling and in this way excessive phosphorus oxychloride is decomposed. The solution thus obtained is neutralized with solid sodium carbonate and extracted three times with 30 ml of acetic ester each. The crude product, obtained after evaporation of the solvent, is purified by column chromatography (100 g silica gel; eluant: cyclohexane/acetic ester = 2:3).

Yield: 860 mg (26.8% of theoretical),

melting point: 188-191oC,

C27H27N5O3S (517.6),

Rf-value: 0.52 (silica gel; dichloromethane/methanol = 9:1),

EKA-mass spectrum: (M+H)+ = 518

(M+Na)+ = 540

b) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxy-carbonylethyl)-amide hydrochloride

It was produced analogously to example 25g from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid , ethanol and ammonium carbonate.

Utilization: 87% of the theoretical,

C27H30N6O4S (534.6),

Rf-value: 0.13 (silica gel; dichloromethane/ethanol = 9:1),

EKA-mass spectrum: (M+H)+ = 535

(M+H+Na)++ = 279

Example 150

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2- ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 38% of the theoretical,

C25H30N8O4S (538.6),

Rf-value: 0.09 (silica gel; dichloromethane/ethanol = 9:1),

EKA-mass spectrum: (M+H)+ = 539.

Example 151

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-(2,3-dihydro-indol-1-yl-sulfonyl)-benzimidazole hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(2,3-dihydroindol-1-yl-sulfonyl)-benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate .

Utilization: 15% of the theoretical,

C24H24N6O2S (460.6),

EKA-mass spectrum: (M+H)+ = 461

Example 152

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride and sodium alkalis.

Utilization: 24% of the theoretical,

Rf-value: 0.55 (silica gel RP-18 reverse phases; methanol/15% table salt solution = 3:2)

C25H26N6O4S (506.6),

EKA-mass spectrum: (M+H)+ = 507

(M+Na)+ = 529

(M+2Na)++ = 276

Example 153

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-(isoindolin-2-yl-sulfonyl)-benzimidazole hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(isoindolin-2-yl-sulfonyl)-benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 32% of the theoretical,

Rf-value: 0.32 (silica gel; dichloromethane/methanol = 4:1)

C24H24N6O2S (460.6),

EKA-mass spectrum: (M+H)+ = 461

Example 154

2-[2-(4-amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 4-methyl-3-nitro-benzoic acid-ethyl ester

4.9 g (0.03 mol) of p-tolylic acid-ethyl ester are added dropwise to a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulfuric acid with stirring at 5oC and the mixture is stirred for another hour while cooling in an ice bath. When it warms up to room temperature, it is poured over ice water and extracted with acetic ester. The organic extracts are washed with sodium hydrogen carbonate solution, dried and evaporated.

Yield: 5.7 g (90% of theoretical),

Rf-value: 0.81 (silica gel; acetate/cyclohexane = 1:1).

b) 4-(2-dimethylaminovinyl)-3-nitro-benzoic acid methyl ester

1.0 g (4.8 mmol) a) 4-methyl-3-nitro-benzoic acid-ethyl ester, 0.74 g (6.2 mmol) dimethylformamide-dimethylacetal and 2 ml of dimethylformamide are heated with stirring for 3 hours at 140oC. Then the solvent is distilled off and the crude product thus obtained is further converted without purification.

Yield: 1.2 g (100% of theoretical),

Rf-value: 0.54 (silica gel; acetate/cyclohexane = 1:1).

c) 4-formyl-3-nitro-benzoic acid-methyl ester

1.2 g (4.8 mmol) of 4-(2-dimethylaminovinyl)-3-nitro-benzoic acid-methyl ester is dissolved in 120 ml of tetrahydrofuran/water (1:1) and after the addition of 3.0 g ( 14.3 mmol) of sodium periodate is stirred for 20 hours at room temperature. The suspension is then diluted with water and methylene chloride and extracted with methylene chloride. The combined organic extracts are washed with sodium hydrogen carbonate solution, dried and evaporated. The residue is purified by chromatography on silica gel eluting with ethyl acetate/cyclohexane (1:3).

Yield: 0.6 g (63% of theoretical),

Rf-value: 0.3 (silica gel; acetic ester/cyclohexane = 1:1).

d) 3-amino-4-formyl-benzoic acid-methyl ester

0.6 g (2.9 mmol) of 4-formyl-3-nitro-benzoic acid methyl ester, 1.2 g ( 21.4 mmol) of iron powder and 0.01 ml of concentrated hydrochloric acid and heated under reflux for 15 minutes with stirring. Then the iron is removed, the solution is diluted with water and extracted with methylene chloride. The combined organic extracts are washed with water, dried and evaporated.

Yield: 0.3 g (58% of theoretical),

Rf-value: 0.74 (silica gel; methylene chloride/methanol = 9.5:0.5).

e) 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-benzoic acid

1.0 g (5.6 mmol) of 3-amino-4-formyl-benzoic acid methyl ester and 1.1 g (5.6 mmol) of 4-cyanophenyl-propionic acid chloride are dissolved in 50 ml of methylene chloride and after the addition of 0.7 g (5.6 mmol) of N-ethyl-diisopropylamine, it is stirred for 24 hours at room temperature. It is then extracted with sodium hydrogen carbonate solution, the combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel eluting with ethyl acetate/cyclohexane (1:3).

Yield: 0.6 g (32% of theoretical),

Rf-value: 0.60 (silica gel; acetic ester/cyclohexane (1:3).

f) 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid-methyl ester

0.6 g (1.8 mmol) of 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-benzoic acid and 10 ml of methanolic ammonia solution were stirred for 36 hours in a pressure vessel. Then the solvent is distilled off, and the residue is chromatographed on silica gel by washing with methylene chloride containing from 0 to 1% ethanol.

Yield: 0.35 g (62% of theoretical),

Rf-value: 0.38 (silica gel; acetate/cyclohexane (1:3).

g) 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid

0.3 g (0.94 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid methyl ester is dissolved in 4.7 ml of 1N lithium hydroxide solution and 4 ml of tetrahydrofuran and mixed 3 hours at room temperature. Then 4.7 ml of 1N hydrochloric acid is added and stirred for 30 minutes. The secreted product is filtered off with suction, washed with water and dried.

Yield: 0.30 g (100% of theoretical),

Rf-value: 0.1 (silica gel; acetic ester/cyclohexane (1:3).

h) 2-[2-(4-cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

0.4 g (1.3 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid and 5 ml of thionyl chloride are mixed for 60 minutes at 50°C. Then thionyl chloride is distilled off, the residue is dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of 3-(N-phenylamino)-propionic acid-methyl ester and 0.22 ml (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 hours at room temperature. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel eluting with methylene chloride containing 1% methanol.

Utilization: 230 mg (37% of theoretical),

Rf-value: 0.64 (silica gel; methylene chloride/methanol = 9:1).

i) 2-[2-(4-amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-

hydrochloride

230 mg (0.5 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N-(2-methoxy-carbonylethyl)-amide is stirred for 8 hours at room temperature in 30 ml of saturated ethanolic hydrochloric acid. It is then concentrated in vacuo to dryness, the residue is taken up in 20 ml of ethanol, mixed with 0.5 g (5.0 mmol) of ammonium carbonate and stirred overnight at room temperature. After evaporation of the solvent, the crude product is chromatographed on silica gel by washing with methylene chloride/ethanol (4:1).

Yield: 100 mg (39% of the theoretical),

Rf-value: 0.5 (silica gel; methylene chloride/ethanol = 4:1).

C29H29N5O3 (495.59)

Mass spectrum: (M+H)+ = 496

Example 155

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2-hydroxy-carbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-(1-methylpyrazol-4-yl)-N-(2- of ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 95% of the theoretical,

C23H26N8O4S (510.6)

Rf-value: 0.53 (silica gel RP-18 reverse phases, methanol + 5% table salt solution)

Mass spectrum: (M+H)+ = 511

(M+Na)+ = 533

(M+2Na)++ = 278

Example 156

1-methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

a) 3-[N-(tert.butoxycarbonyl-amino)acetylamino]-4-methyl-amino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxy-

carbonylethyl)-amide

19.2 g (0.11 mol) of N-tert.butyloxycarbonylglycine are dissolved in 175 ml of dimethylformamide, mixed with 35.2 g (0.11 mol) of O-benzotriazol-1-yl)-N,N,N' ,N'-tetramethyl-uronium tetrafluoroborate, 11.0 g of triethylamine and 34.2 g (0.10 mol) of 3-amino-4-methyl-amino-benzoic acid-N-(2-pyridyl)-N-(2 -ethoxycarbonylethyl)-amide and stirred for 2.5 hours at room temperature. The reaction mixture is then mixed with 5 l of ice water and stirred for 2 hours. The resulting gray precipitate is filtered off, washed with water, dried and, with the addition of activated carbon, recrystallized from acetic ester.

Yield: 39.85 g (80% of theoretical),

C25H33N5O6 (499.6)

Rf-value: 0.55 (silica gel; methylene chloride/ethanol = 19:1).

b) 1-methyl-2-(N-tert.butoxycarbonyl-aminomethyl)-benzimidazole-5-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy-

carbonylethyl)-amide

10.0 g (0.02 mol) 3-[N-(tert.butoxycarbonyl-amino)-acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl) -amide is dissolved in 50 ml of glacial acetic acid and heated under reflux for one hour. Then the solvent is distilled off, the residue is mixed with ice water and adjusted to pH 8 with the addition of 2N ammonia. After triple extraction with acetic ester, the combined organic phases are washed with common salt solution and dried over sodium sulfate. After evaporation of the solvent, the crude product is chromatographed on silica gel, where it is washed first with methylene chloride, and later with methylene chloride/ethanol (50:1) and (25:1). The desired fractions are combined and evaporated.

Yield: 5.85 g (61% of theoretical),

C25H31N5O5 (481.6)

Rf-value: 0.70 (silica gel; methylene chloride/ethanol = 9:1).

c) 1-methyl-2-aminomethyl-benzimidazole-5-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-trifluoro-

acetate

4.81 g (0.10 mol) 1-methyl-2-(N-tert.butoxycarbonyl-aminomethyl)-benzimidazole-5-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide it is dissolved in 25 ml of methylene chloride, mixed with 5 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. The solvent is then evaporated and the residue is mixed with ether. The resulting crystals are filtered off, washed with ether and dried.

Yield: 3.15 g (68% of theoretical),

C20H23N5O3 (381.4)

Rf-value: 0.18 (silica gel; methylene chloride/ethanol = 9:1).

d) 1-methyl-2-[N-(3-cyano-pyridin-6-yl)-aminomethyl]-benz-imidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxycarbonylethyl)-amide

1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazole-5-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-ethyl)-amide-trifluoroacetate was mixed in 10 ml of N-ethyl-diisopropylamine and heated for 15 minutes at 100oC. After adding 720 mg (5.25 mmol) of 2-chloro-5-cyano-pyridine, the reaction mixture is heated for 2 hours at 125oC. When cooled to room temperature and mixed with approx. 20 ml of water, adjusted to pH 4 with the addition of 1N hydrochloric acid and extracted three times with acetic ester. The combined organic phases are washed with common salt solution and dried over sodium sulfate. After evaporation of the solvent, the crude product is chromatographed on silica gel, where it is washed first with methylene chloride and later with methylene chloride/ethanol (25:1) and (19:1). The desired fractions are combined and evaporated.

Yield: 1.05 g (67% of theoretical),

C26H25N7O (483.6)

Mass spectrum: (M+H)+ = 484

e) 1-methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(3-cyano-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 38% of the theoretical,

C28H28N8O3 (500.6)

Mass spectrum: (M+H)+ = 501

Example 157

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-

hydroiodide

a) 4-nitro-benzoic acid-N-phenyl-N-(2-methoxy-carbonylethyl)-amide

16.7 g (0.1 mol) of 4-nitrobenzoic acid in 50 ml of thionyl chloride and 3 drops of dimethylformamide are boiled for 1 hour under reflux. The solvent is distilled off under vacuum and the crude product is dissolved in 150 ml of tetrahydrofuran and added dropwise to a solution of 18 g (0.1 mol) of N-(2-methoxycarbonylethyl)-aniline in 250 ml of tetrahydrofuran and 42 ml (0.3 mol) of triethylamine . It is stirred for one hour at room temperature and then diluted with 250 ml of ethyl acetate and washed twice with 200 ml of a 14% table salt solution. The solvent is distilled off and after chromatography (silica gel; methylene chloride) a yellow oil is isolated which slowly solidifies.

Yield: 32.6 g (100% of theoretical),

Rf-value: 0.37 (silica gel; methylene chloride/methanol = 50:1)

b) 4-amino-benzoic acid-N-phenyl-N-(2-methoxy-carbonylethyl)amide

22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide is hydrogenated in 500 ml of methanol with 2 g of 10% palladium on charcoal for 3 hours under a hydrogen pressure of 3 bar . After filtration and removal of the solvent by distillation, it is washed with 100 ml of ether and the white crystalline product is directly further chemically converted.

Yield: 18.6 g (94% of theoretical),

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

c) 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide

26.8 g (91 mmol) of 4-amino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide is dissolved in 500 ml of methylene chloride, cooled to -70oC and mixed with freshly prepared tert .butyl hypochlorite (M.J. Mintz et al., Organic Synthesis, Coll. Vol. 5, p. 184). It is stirred for 2 hours at -70oC, then 9.46 g (91 mmol) of methylthioacetone in 40 ml of methylene chloride are added dropwise over 10 minutes and stirred for another 1.5 hours. Then 12.7 ml (9.1 g, 91 mmol) of triethylamine in 25 ml of methylene chloride was added. It is kept for 30 minutes at -78oC and then slowly warmed up to room temperature overnight. After two washings with 50 ml of water each, the organic phase is separated and dried with sodium sulfate. After removing the solvent in a vacuum and after purification by chromatography (silica gel, acetic ester/petroleum ether = 2:8 to 3:7), a white amorphous substance is obtained.

Yield: 24.1 g (69% of theoretical),

Rf-value: 0.58 (silica gel; acetic ester/petroleum ether = 1:1)

C21H22N2O3S (382.49)

Mass spectrum: (M)+ = 382

d) 1-tert.butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

8.9 g (23 mmol) of 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide are dissolved in 600 ml of ethanol, mixed with approx. 150 mg of Raney-nickel and stirred for 2 hours at room temperature (analogous to P.G. Gassman et al., Organic Synthesis Col. Vol. 6, p. 601). It is then filtered and the solvent is removed under vacuum. The thus obtained crude product (8 g) is dissolved in 200 ml of absolute tetrahydrofuran, mixed with 150 ml of dimethylaminopyridine and 6.84 g (32 mmol) of pyrocarbonic acid-di-tert.butyl ester and stirred for 2.5 hours at 50oC. Then the solvent is distilled off in a vacuum and the crude product is purified by chromatography (silica gel, acetic ester/petroleum ether = 1:4).

Yield: 10.0 g (98% of theoretical),

Rf-value: 0.40 (silica gel; acetic ester/petroleum ether = 3:7).

e) 2-[N-(4-cyano-phenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide

3.5 g (8 mmol) of 1-tert.butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy-carbonylethyl)-amide are dissolved in 80 ml of carbon tetrachloride, mixed with 1.5 g (8.4 mmol) of N-bromosuccinimide and 20 mg of azobisisobutyronitrile and refluxed for 2.5 hours. Then the still warm solution is filtered, the resulting filtrate is washed with a saturated solution of sodium hydrogen carbonate and dried with sodium sulfate. The crude product, after distillation of the solvent, is dissolved in 30 ml of N-ethyl-diisopropyl-amine, mixed with 1.0 g (8 mmol) of 4-aminobenzonitrile and heated for 2.5 hours under reflux. The solvent is distilled off in a vacuum and the resulting residue is purified by chromatography (silica gel, acetic ester/petroleum ether = 1:4 to 1:1).

Yield: 1.1 g (30% of theoretical),

Rf-value: 0.21 (silica gel; acetic ester/petroleum ether = 1:1).

f) 1-methyl-2-[N-(4-thiocarbamoyl-phenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-

amide

1.5 g (3.3 mmol) of 2-[N-(4-cyanophenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonyl-ethyl)-amide is dissolved in 60 ml of xylene, mixed with 0.45 g (3.3 mmol) of potassium carbonate and 0.5 ml (3.3 mmol) of p-toluenesulfonic acid-methyl ester and boiled for 4 hours under reflux. Then, an equal amount of potassium carbonate and p-toluenesulfonic acid-methyl ester is added once more and heated under reflux overnight. It is filtered and washed with acetone. The residue obtained after thickening the thus obtained filtrate is purified by chromatography (silica gel, acetic ester/petroleum ether = 1:4 to 2:3). The thus obtained N-methylated indole (yield: 0.64 g, 41% of theory) was dissolved in 20 ml of pyridine and mixed with 0.67 ml (1.37 mmol) of triethylamine. Hydrogen sulfide gas is then introduced into the solution thus obtained. After 4.5 days, nitrogen is passed through the reaction mixture for 30 minutes, the solvent is distilled off and the resulting residue is purified by chromatography (silica gel, methylene chloride/ethanol 99:1 to 98:2).

Yield: 0.30 g (43% of theoretical),

C28H28N4O3S (500.62)

EKA-mass spectrum: (M+H)+ = 501

(M+Na)+ = 523

g) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-

amide hydroiodide

0.30 g (0.60 mmol) 1-methyl-2-[N-(4-thiocarbamoyl-phenyl)-aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy- carbonylethyl)-amide together with 075 ml (12 mmol) of methyl iodide are dissolved in 20 ml of acetone and stirred for 2 hours at room temperature. Then the solvent is distilled off and the crude product together with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of methylene chloride is stirred for 20 hours at 40oC. The solvent is distilled off in vacuo and the resulting residue is purified by chromatography (silica gel, methylene chloride/ethanol 9:1 to 4:1).

Utilization: 55% of the theoretical,

C28H29N5O3 (483.58)

Rf-value: 0.20 (silica gel; methylene chloride/ethanol = 4:1 + 1 drop of acetic acid)

EKA-mass spectrum: (M+H)+ = 484

Example 158

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

a) Methoxyacetic acid-iminoethyl ester-hydrochloride

A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 ml (23 g, 0.50 mol) of ethanol and 30 ml of absolute diethyl ether is cooled to 0°C and 22.5 g (0.62 mol) of ) of hydrogen chloride gas, whereby the reaction product crystallizes towards the end of the introduction of the gas. To complete the precipitation, it is mixed with 130 ml of diethyl ether and the colorless needles are filtered off.

Yield: 66.4 g (86% of theoretical),

melting point: 117-118oC.

b) 4-hydroxymethyl-2-methoxymethyl-imidazole

A mixture of 30.6 g (0.20 mol) of methoxy-acetic acid-iminoethyl-ester-hydrochloride, 18 g (0.20 mol) of 1,3-dihydroxyacetone and 200 ml of liquid ammonia is heated for 3 hours in an autoclave with a stirrer under with a pressure of 27 bar at 68oC (analogously: P. Dziuron et al., Arch. Pharm. 307, 1974, p. 470). Then the ammonia is removed and mixed with 200 ml of methylene chloride. The secreted white precipitate is filtered off and washed with methylene chloride. The filtrate is concentrated and the resulting residue is purified by chromatography (alumina; methylene chloride/ethanol 90:10 to 85:15).

Yield: 26.7 g (94% of the theoretical,

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

C6H10N2O2 (142.20)

Mass spectrum: (M)+ = 142

c) 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole as a 1:1 mixture with 5-hydroxymethyl-2-methoxymethyl-1-methyl-

imidazole

A mixture of 7.1 g (50 mmol) of 4-hydroxymethyl-2-methoxymethyl-imidazole, 3.0 g (53 mmol) of powdered potassium hydroxide and 3.4 ml (0.55 mmol) of methyl iodide in 100 ml of dimethylformamide is heated for 4 hour at 50oC (analogous to I. Sinclair et al., J. Med. Chem., 29, 1986, 261). The solvent is then distilled off in vacuo and the crude product is purified by column chromatography (alumina; methylene chloride/ethanol 99:1 to 95:5).

Yield: 6.1 g (78% of theoretical; 1:1 mixture of two regioisomers),

Rf-value: 0.32 (silica gel; methylene chloride/ethanol = 19:1).

d) 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole

A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxy-methyl-1-methyl-imidazole, and 7.3 g (55 mmol) of N-chloro-succinimide in 48 ml of ethylene glycol monoethyl ether and 70 ml of dioxane is heated for 10 hours at 50oC. The solvent is then distilled off in vacuo and the crude product is purified by chromatography (silica gel; methylene chloride/ethanol = 99:1 to 90:10) to give the isomerically pure title compound.

Yield: 3.4 g (36% of theoretical),

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

e) 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole

3.4 g (18 mmol) of 5-chloro-4-hydroxymethyl-2-methoxy-methyl-1-methyl-imidazole are dissolved in 100 ml of methylene chloride and mixed with manganese dioxide (2 x 6.0 g, a total of 0.14 moles). After 4 hours, the inorganic component is filtered off and the obtained raw product is further chemically converted without cleaning.

Yield: 3.0 g (89% of theoretical),

Rf-value: 0.44 (silica gel; methylene chloride/ethanol = 50:1).

f) 1-methyl-2-methoxy-methyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid-ethyl ester

1.9 ml (2.1 g, 17 mmol) of thioglycolic acid-ethyl ester was added dropwise to a freshly prepared solution of sodium methanolate (from 391 mg, 17 mmol of sodium) in 15 ml of ethanol. After stirring for one hour at room temperature, 1.6 g (8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole is added to 20 ml of absolute ethanol and heated to 80°C (similar to B. Iddon et al., J. Chem. Soc. Perkin Trans, I, 1987, 1457). The solvent is distilled off after 5 hours, the residue is taken up in 50 ml of methylene chloride and washed with 20 ml of water. The aqueous phase is washed once more with 20 ml of methylene chloride and then the combined organic phases are dried with sodium sulfate. The residue, obtained after removing the solvent in vacuo, is purified by column chromatography (alumina; methylene chloride).

Yield: 1.0 g (46% of theoretical),

Rf-value: 0.48 (silica gel; methylene chloride/ethanol = 50:1),

C11H14N2O3S (254.31)

EKA-mass spectrum: (M+H)+ = 255

(M+Na)+ = 277

g) 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid

To a solution of 0.90 g (3.54 mmol) of 1-methyl-2-methoxy-methyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid-ethyl ester in 30 ml of ethanol, 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then the solvent is distilled off in a vacuum, the residue is taken up in 5 ml of water and washed with 10 ml of diethyl ether. The aqueous phase is acidified with 6 ml of 2N hydrochloric acid, cooled to 0°C and the separated crystals are filtered off.

Yield: 0.50 g (63% of theoretical),

Rf-value: 0.21 (silica gel; methylene chloride/ethanol = 9:1 + a few drops of acetic acid)

C9H10N2O3S (226.26)

Mass spectrum: (M)+ = 226

h) 1-methyl-2-methoxymethyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-

amide

A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-methoxy-methyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid in 20 ml of methylene chloride was mixed with 2.0 ml (3.2 g, 27 mmol) of thionyl chloride and refluxed for 60 minutes. In doing so, the solid substance gradually dissolves. The liquid components are distilled off and the crude product is taken up twice more in methylene chloride. After removing the solvent again, the crude product is taken up in 20 ml of tetrahydrofuran and added dropwise to a mixture of 0.42 g (2.3 mmol) N-(2-methoxy-carbonyl-ethyl)aniline and 0.92 ml (6.6 mmol ) of triethylamine in 30 ml of tetrahydrofuran. It is stirred for 16 hours at 50oC and then the solvent is removed, and the crude product obtained is purified by chromatography (silica gel; methylene chloride/ethanol = 100:1).

Yield: 0.66 g (77% of theoretical),

Rf-value: 0.47 (silica gel; methylene chloride/ethanol = 19:1).

i) 1-methyl-2-(N-4-cyanophenylaminomethyl)-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy-

carbonylethyl)-amide

K solution of 0.73 g (1.88 mmol) 1-methyl-2-methoxy-methyl-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl) )-amide in 30 ml of methylene chloride at 5oC, 2.9 ml (2.9 mmol) of a 1-molar solution of boron tribromide in methylene chloride is added dropwise. It is stirred for 16 hours at room temperature and washed with 20 ml of saturated sodium hydrogen carbonate solution, the organic phase is separated, dried with sodium sulfate and filtered. The filtrate was mixed with 14 ml of N-ethyl-diisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile. Then methylene chloride is distilled off in a vacuum, the obtained residue is heated for 1 hour at 50oC and then the remaining solvent is distilled off in a vacuum. After chromatography (silica gel; methylene chloride/ethanol = 99:1 to 97:3) a yellow oil is obtained which slowly solidifies.

Yield: 0.37 g (42% of theoretical),

Rf-value: 0.29 (silica gel; methylene chloride/ethanol = 50:1 + a few drops of ammonia).

j) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

0.38 g (0.80 mmol) 1-methyl-2-(N-4-cyanophenylamino-methyl)-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-( 2-ethoxycarbonylethyl)-amide in 40 ml of ethanol saturated with hydrogen chloride is stirred first for 5 hours at 0oC and then at room temperature until no plasma material can be demonstrated by thin-layer chromatography. Then the solvent is distilled off at a bath temperature of no more than 28oC, the oily residue is taken up in 40 ml of absolute ethanol and mixed with 1.1 g of ammonium carbonate. After 18 hours, the solvent is distilled off in a vacuum, and the crude product is purified by chromatography (silica gel; methylene chloride/ethanol = 9:1 to 4:1).

Utilization: 57% of the theoretical,

C26H28N6O3S(504.62)

Rf-value: 0.21 (silica gel; methylene chloride/ethanol = 4:1 + a few drops of acetic acid),

EKA-mass spectrum: (M+H)+ = 505

(M+H+Na)++ = 264

Example 159

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 2 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2- of ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 85% of the theoretical,

C24H24N6O3S (476.56)

Rf-value: 0.36 (silica gel RP-8 reverse phases; methanol + a few drops of 5% table salt solution).

EKA-mass spectrum: (M+H)+ = 477

(M+Na)+ = 499

(M+2Na)++ = 250

Example 160

1-methyl-3-[N-(4-amidinophenyl)-thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 1-methyl-3-[N-(4-cyanophenyl)-thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

A solution of 2.5 g (7.6 mmol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and 2.4 g (9.6 mmol) of 3-( 4-cyanophenyl)thio-2-oxo-propionic acid-ethyl ester in 50 ml of ethanol is heated for 30 minutes at boiling point. The crude product, obtained after removing the solvent, is purified by chromatography (silica gel; methylene chloride).

Yield: 1.6 g (40% of theoretical),

Rf-value: 0.63 (silica gel; acetic ester/ethanol/ammonia = 90:10:1).

b) 1-methyl-3-[N-(4-amidinophenyl)-thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-

ethyl)-amide hydrochloride

It is produced analogously to example 1 from 1-methyl-3-[N-(4-cyanophenyl)-thiomethyl]-quinoxalin-2-on-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 23% of the theoretical,

C28H27N5O4S (543.64)

Rf-value: 0.25 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

EKA-mass spectrum: (M+H)+ = 544

(M+Na)+ = 566

Example 161

3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide hydrochloride

a) 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-

amide hydrochloride

1.4 g (4.6 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid (produced from 4-bromo- 1-(4-Cyanophenyl)-1-penten-3-one and 2-amino-pyridin-4-carboxylic acid-methyl ester analogous to Y. Katsura et al., Chem. Pharm. Bull. 1992, 40, 1424-1438 ) is suspended in 15 ml of thionyl chloride and heated for 1 hour at boiling point until complete dissolution. After distillation of thionyl chloride, the acid chloride is dissolved without further purification in 15 ml of pyridine and mixed with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonylethyl)aniline at 0°C. After one hour, the solvent is distilled off, the residue is taken up in 30 ml of methylene chloride, washed with 15 ml of 1N hydrochloric acid and dried with sodium sulfate. The solvent is distilled off and a brown oil is obtained by chromatography (silica gel; methylene chloride/ethanol = 0 to 2).

Yield: 1.48 g (64% of theoretical),

Rf-value: 0.73 (silica gel; acetic ester/ethanol/ammonia = 90:10:1).

b) 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonyl-

ethyl)-amide hydrochloride

It is produced analogously to example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) )-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 62% of the theoretical,

C29H31N5O3 (497.60)

Rf-value: 0.23 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

EKA-mass spectrum: (M+H)+ = 498

Example 162

3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide hydrochloride

It is produced analogously to example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) )-amide hydrochloride and sodium hydroxide solution.

Utilization: 92% of the theoretical,

C27H27N5O3 (469.55)

Rf-value: 0.19 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

EKA-mass spectrum: (M+H)+ = 470

(M+Na)+ = 492

(M+2H)++ = 235.7

(M+H+Na)++ = 246.7

(M+2Na)++ = 257.7

Example 163

1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-

methyl)-2-aminoethyl]-amide dihydrochloride

was prepared analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)- 2-amino-ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 80% of the theoretical,

C31H37N7O3 (555.7)

Rf-value: 0.24 (silica gel; dichloromethane/methanol = 4:1)

EKA-mass spectrum: (M+H)+ = 556

(M+H+Na)++ = 289.8

(M+2H)++ = 278.8

Example 164

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide -dihydrochloride

It is produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)- of 2-amino-ethyl]-amide dihydrochloride and sodium lye.

Utilization: 79% of the theoretical,

C29H33N7O3 (527.6)

Rf-value: 0.43 (silica gel RP-18 reverse phases; methanol/5% aqueous common salt solution = 6:4)

EKA-mass spectrum: (M+H)+ = 528

(M+H+Na)++ = 275.6

(M+2H)++ = 264.6

Example 165

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide dihydrochloride

It is produced from 1-methyl-2-[N-(4-amidinophenyl)-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide- of the hydrochloride by hydrogenation over palladium/charcoal (10%) under a hydrogen pressure of 5 bar and at room temperature.

Utilization: 61% of the theoretical,

C26H28N6O2 (456.6)

Rf-value: 0.70 (silica gel RP-18 reverse phases; methanol/5% aqueous common salt solution = 9:1),

EKA-mass spectrum: (M+H)+ = 457

(M+H+Na)++ = 240

Example 166

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)- amide

It was produced analogously to example 26 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N- (2-ethoxy-carbonyl-ethyl)-amide and sodium lye.

Utilization: 97% of the theoretical,

C32H37N7O5 (599.7)

Rf-value: 0.22 (silica gel; dichloromethane/methanol = 9:1)

EKA-mass spectrum: (M+H)+ = 600

(M+H+Na)++ = 311.7

(M+2H)++ = 300.8

(M+2Na)++ = 322.8

Example 167

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)- amide

It was produced analogously to example 165 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy -n-propyl)-amide by catalytic debenzylation.

Utilization: 26% of the theoretical,

C33H40N6O4 (584.7)

Rf-value: 0.39 (silica gel; dichloromethane/methanol = 9:1)

EKA-mass spectrum: (M+H)+ = 585

(M+H+Na)++ = 304

(M+Na)+ = 607

Example 168

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 42% of the theoretical,

C28H29FN6O3 (516.6)

Rf-value: 0.31 (silica gel; dichloromethane/methanol = 5:1)

EKA-mass spectrum: (M+H)+ = 517

(M+H+Na)++ = 270

Example 169

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonyl-ethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonyl-ethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 90% of the theoretical,

C28H29FN6O3 (516.6)

Rf-value: 0.29 (silica gel; dichloromethane/methanol = 5:1)

EKA-mass spectrum: (M+H)+ = 517

(M+H+Na)++ = 270

Example 170

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and sodium lye.

Utilization: 97% of the theoretical,

C26H25FN6O3 (488.5)

Rf-value: 0.13 (silica gel; dichloromethane/methanol = 4:1)

EKA-mass spectrum: (M+H)+ = 489

(M+Na)+ = 511

(M+2Na)++ = 267

Example 171

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonyl-ethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and sodium lye.

Utilization: 89% of the theoretical,

C26H25FN6O3 (488.5)

Rf-value: 0.15 (silica gel; dichloromethane/methanol = 4:1)

EKA-mass spectrum: (M+H)+ = 489

(M+Na)+ = 511

(M+2Na)++ = 267

Example 172

1-methyl-2-[N-(4-amidino-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyano-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 89% of the theoretical,

C29H32N6O4 (528.6)

Rf-value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 529

(M+H+Na)++ = 276

(M+2H)++ = 265

Example 173

1-methyl-2-[N-[4-(N-4-ethylbenzoylamidino)phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and 4-ethylbenzoyl chloride.

Utilization: 64% of the theoretical,

C36H37N7O4 (631.7)

Rf-value: 0.78 (silica gel; dichloromethane/methanol = 9:1)

EKA-mass spectrum: (M+H)+ = 632

(M+H+Na)++ = 327

(M+Na)+ = 654

Example 174

1-methyl-2-[N-[4-(N-4-benzyloxycarbonylamidino)phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-

pyridyl)-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide -hydrochloride and chloroformic acid-benzyl ester.

Utilization: 64% of the theoretical,

C35H35N7O5 (633.6)

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

EKA-mass spectrum: (M+H)+ = 634

(M+H+Na)++ = 328.8

(M+Na)+ = 656

Example 175

1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxy-carbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide hydrochloride and sodium alkali.

Utilization: 71% of the theoretical,

C27H28N6O4 (500.6)

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

EKA-mass spectrum: (M+H)+ = 501

(M+Na)+ = 523

(M+2Na)++ = 273

Example 176

1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

ethoxycarbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 67% of the theoretical,

C28H31N7O4 (529.6)

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

EKA-mass spectrum: (M+H)+ = 530

Example 177

1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-

hydroxycarbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( of 2-ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 78% of the theoretical,

C26H27N7O4 (501.6)

Rf-value: 0.12 (silica gel; dichloromethane/methanol = 4:1)

EKA-mass spectrum: (M+H)+ = 502

Example 178

1-methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-

N-(2-hydroxycarbonylethyl)-amide

It was produced analogously to example 104 from 1-methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N- (2-ethoxy-carbonylethyl)-amide and sodium lye.

Utilization: 62% of the theoretical,

C33H31N7O5 (605.7)

Rf-value: 0.26 (silica gel; dichloromethane/methanol = 9:1)

EKA-mass spectrum: (M+H)+ = 606

(M+Na)+ = 628

(M-H+2Na)+ = 650

(M+2H)++ = 303.8

(M+H+Na)++ = 314.8

(M+2Na)++ = 325.7

Example 179

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-

amide hydrochloride

It was produced analogously to example 25 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 61% of the theoretical,

C33H34N6O2 (546.7)

Rf-value: 0.19 (silica gel; dichloromethane/ethanol = 4:1)

EKA-mass spectrum: (M+H)+ = 547

(M+H+Na)++ = 285

Example 180

1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide

It is produced analogously to example 90 from 1-methyl-2-[N-(4-

amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide hydrochloride and chloroformic acid-n-hexyl ester.

Utilization: 73% of the theoretical,

C40H46N6O4 (674.9)

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

EKA-mass spectrum: (M+H)+ = 675

(M+H+Na)++ = 349

(M+Na)+ = 697

(M+K)+ = 713

Example 181

3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonyl-

ethyl)-amide hydrochloride

It is produced analogously to example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N- (2-methoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 53% of the theoretical,

C28H30N6O3 (498.59)

Rf-value: 0.42 (silica gel; acetic ester/ethanol/ammonia = 50:45:5).

EKA-mass spectrum: (M+H)+ = 499

(M+2Na)++ = 272

(M+H+Na)++ = 261

(M+2H)++ = 250

Example 182

1-methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy- carbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(3-cyanopyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- hydroxycarbonylethyl)-amide and sodium lye.

Utilization: 40% of the theoretical,

C24H24N8O3 (472.9)

Rf-value: 0.67 (silica gel RP-18 reverse phases; methanol/5% table salt solution = 1:1)

EKA-mass spectrum: (M+H)+ = 473

Example 183

1-methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-

(methanesulfonylaminocarbonyl)-ethyl]-amide

a) 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methane-

sulfonylaminocarbonyl)-ethyl]-amide

2.0 g (4.5 mmol) 1-methyl-2-[N-(4-cyanophenyl)-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-hydroxycarbonylethyl)-amide and 0.73 g (4.7 mmol) of carbonyldiimidazole are dissolved in 5 ml of dimethylformamide and stirred for 30 minutes at room temperature and 2 hours at 90°C. In parallel, 0.55 g (5.8 mmol) of methanesulfonic acid and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred for 2 hours at room temperature. This suspension is then added to the tetrahydrofuran solution at room temperature. After 12 hours at room temperature, add 50 ml of water and adjust the pH value to 6.8. The solution is extracted 4 times with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions are collected and evaporated.

Yield: 1.05 g, (44% of theoretical),

C26H25N7O4S (531.6)

Rf-value: 0.72 (silica gel; dichloromethane/methanol = 9:1)

b) 1-methyl-2-[N-[4-(N-hydroxylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-

(methanesulfonylaminocarbonyl)-ethyl]-amide

It is produced analogously to example 96 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulfonylaminocarbonyl)- ethyl]-amide and hydroxylamine.

Utilization: 27% of the theoretical,

C26H28N8O5S (564.6)

Rf-value: 0.75 (silica gel; dichloromethane/ethanol = 7:1 + 1% glacial acetic acid)

EKA-mass spectrum: (M+H)+ = 565

(M+Na)+ = 587

Example 184

1-methyl-2-[N-(5-amidino-thiazol-2-yl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy-

carbonylethyl]-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(5-cyano-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Example 185

1-methyl-2-[N-(5-amidino-thiazol-2-yl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-

carbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(5-amidino-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( of 2-ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Example 186

1-methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy-

carbonylethyl)-amide hydrochloride

It was produced analogously to example 25d from 1-methyl-2-[N-(2-cyano-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Utilization: 19% of the theoretical,

C25H27N9O3 (501.6)

Rf-value: 0.28 (silica gel; dichloromethane/methanol = 4:1 + 1% glacial acetic acid)

EKA-mass spectrum: (M+H)+ = 502

(M+H+Na)++ = 262.5

Example 187

1-methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-

carbonylethyl)-amide

It was produced analogously to example 26 from 1-methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( of 2-ethoxycarbonylethyl)-amide hydrochloride and sodium hydroxide solution.

Utilization: 11% of the theoretical,

C23H23N9O3 (473.5)

Rf-value: 0.55 (silica gel RP-8 reverse phases; 5% table salt solution/methanol = 6:4)

EKA-mass spectrum: (M+H)+ = 474

(M+Na)+ = 496.6

Example 188

1-methyl-2-[2-[4-(N-n-hexyloxycarbonylamidino)phenyl]-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-

tetrazol-5-yl)-ethyl]-amide

It is produced analogously to example 90 from 1-methyl-2-[2-[4-

amidinophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]-amide and chloroformic acid-n-hexyl ester.

Example 189

1-methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide-hydrochloride and chloroformic acid-n-pentyl ester.

Utilization: 53% of the theoretical,

C35H42N6O6 (642.7)

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

EKA-mass spectrum: (M+H)+ = 643

(M+H+Na)++ = 333.4

Example 190

1-methyl-2-[N-(4-n-heptyloxycarbonylamidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-

phenyl-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl) -amide-hydrochloride and chloroformic acid-n-heptyl ester.

Utilization: 68% of the theoretical,

C37H46N6O6 (670.8)

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

EKA-mass spectrum: (M+H)+ = 671

(M+H+Na)++ = 347.4

Example 191

1-methyl-2-[N-(4-ethoxycarbonylamidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-

pyridyl)-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide-hydrochloride and chloroformic acid-ethyl ester.

Utilization: 43% of the theoretical,

C31H35N7O6 (601.7)

Rf-value: 0.44 (silica gel; dichloromethane/ethanol = 9:1)

EKA-mass spectrum: (M+H)+ = 602

(M+H+Na)++ = 312.8

Example 192

1-methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-

pyridyl)-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-pentyl ester.

Utilization: 72% of the theoretical,

C34H41N7O6 (643.7)

Rf-value: 0.49 (silica gel; dichloromethane/ethanol = 9:1)

EKA-mass spectrum: (M+H)+ = 644

(M+H+Na)++ = 333.9

Example 193

1-methyl-2-[N-(2-methoxy-4-n-heptyloxycarbonylamidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-

(2-Pyridyl)-N-(2-ethoxycarbonylethyl)-amide

It was produced analogously to example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-ethoxycarbonylethyl)-amide hydrochloride and chloroformic acid-n-heptyl ester.

Utilization: 55% of the theoretical,

C36H45N7O6 (671.8)

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

EKA-mass spectrum: (M+H)+ = 672

(M+H+Na)++ = 347.9

Example 194

Dry ampoules with 75 mg of active substance per 10 ml

Composition:

active substance 75.0 mg

mannitol 50.0 mg

water for injection up to 10.0 ml

Preparation:

The active substance and mannitol dissolve in water. After filling, it is dried by freezing. The dilution to prepare the ready-to-use solution is done with water for injection.

Example 195

Dry ampoules with 35 mg of active substance per 2 ml

Composition:

active substance 35.0 mg

mannitol 100.0 mg

water for injection up to 2.0 ml

Preparation:

The active substance and mannitol dissolve in water. After filling, it is dried by freezing.

Dissolving to prepare a ready-to-use solution is done with water for injection.

Example 196

Tablets with 50 mg of active substance

Composition:

(1) active substance 50.0 mg

(2) milk sugar 98.0 mg

(3) corn starch 50.0 mg

(4) polyvinylpyrrolidone 15.0 mg

(5) magnesium stearate 2.0 mg

215.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with aqueous solution (4). (5) is mixed with the dry granulate. Tablets flat on both sides, with both sides and a partial notch on one side, are pressed from this mixture. Tablet diameter: 9 mm.

Example 197

Tablets with 350 mg of active substance

Composition:

(1) active substance 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) polyvinylpyrrolidone 30.0 mg

(5) magnesium stearate 4.0 mg

600.0 mg

Preparation:

(1), (2) and (3) are mixed and granulated with aqueous solution (4). (5) is mixed with the dry granulate. Tablets flat on both sides, with both sides and a partial notch on one side, are pressed from this mixture. Tablet diameter: 12 mm.

Example 198

Capsules with 50 mg of active substance

Composition:

(1) active substance 50.0 mg

(2) dried corn starch 58.0 mg

(3) powdered milk sugar 50.0 mg

(4) magnesium stearate 2.0 mg

160.0 mg

Preparation:

(1) and (3) rub together. This mass is added to the mixture of (2) and (4) with intensive mixing.

With this powdery mixture, plug-in capsules made of hard gelatin size 3 are filled by machine.

Example 199

Capsules with 350 mg of active substance

Composition:

(1) active substance 350.0 mg

(2) dried corn starch 46.0 mg

(3) powdered milk sugar 30.0 mg

(4) magnesium stearate 4.0 mg

430.0 mg

Preparation:

(1) and (3) rub together. This mass is added to the mixture of (2) and (4) with intensive mixing.

With this powder mixture, plug-in capsules made of hard gelatin size 0 are filled by machine.

Example 200

Suppositories with 100 mg of active substance

1 suppository contains:

active substance 100.0 mg

polyethylene glycol (m.m. 1500) 600.0 mg

polyethylene glycol (m.m. 6000) 460.0 mg

polyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Claims (14)

1. Disubstituted bicyclic heterocycles of the general formula Ra - A - Het - B - Ar - E (I) indicated by that A represents a carbonyl or sulfonyl group connected to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno part of the residue Het, whereby the aforementioned parts may not contain any residue R1, B represents an ethylene group in which one methylene group, which is connected to a Het residue or to an Ar residue, can be substituted with an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NR1-group, whereby R1 represents a hydrogen atom or a C1-6-alkyl group, E is cyano or the group RbNH-C(=NH)-, in which Rb represents a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a residue that can be cleaved in vivo, Ar represents a phenylene or naphthylene group, which can be substituted with a fluorine, chlorine or bromine atom or with a trifluoromethyl, C1-3-alkyl or C1-3-Alkoxy group, a thienylene, thiazolylene, pyridylene, pyrimidylene, pyrazinylene or pyridazinylene group, which can be substituted in the carbon skeleton with a C1-3-alkyl group, if necessary, Het represents the bicyclic heterocycle of the formula [image] where X represents a nitrogen atom, i Y represents an oxygen or sulfur atom or a nitrogen atom optionally substituted with one C1-6-alkyl or C3-7-cycloalkyl group, whereby additionally one or two non-angular methine groups in the phenyl part of the aforementioned bicyclic heterocycle can be substituted with one nitrogen atom, or X represents a methine group optionally substituted with the residue R1, where R1 is defined as previously stated, and Y represents a nitrogen atom optionally substituted with a C1-6-alkyl or C3-7-cycloalkyl group, or Het represents a formula group [image] R1 is defined as previously stated, Z is an oxygen or sulfur atom, one of the residues D or G represents a nitrogen atom, and the other of the residues D or G represents a methine group, i Ra represents a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted with a C1-3-alkyl group, whereby the C1-3-alkyl group can additionally be substituted with one carboxyl group or with one group which in vivo can translate into a carboxy group, or R2NR3-group, in which R2 represents a C1-4-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonyl, amino-carbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl group, C2-4-alkyl group substituted with hydroxy, phenyl- C1-3-Alkoxy, Carboxy, C1-3-Alkylamino, C1-3-Alkoxycarbonyl-C1-3-Alkylamino, N-(C1-3-Alkyl)-carboxy-C1-3-Alkylamino or N-(C1-3 -alkyl)-C1-3-Alkoxycarbonyl-C1-3-alkylamino group, whereby in the previously mentioned group the α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, or a piperidinyl group optionally substituted with a C1-3-alkyl group and R3 represents a hydrogen atom, a C1-6-alkyl group, a C3-7-cycloalkyl group, a C3-6-alkenyl or a C3-6-alkynyl group, which can be substituted with a C1-3-alkyl group if necessary, whereby the unsaturated part cannot be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with fluorine, chlorine or bromine, with a C1-3-alkyl or C1-3-alkoxy group, benzylic, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl , pyrimidinyl, pyrazolyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group, which can be substituted with a C1-3-alkyl group if necessary, or R2 and R3, together with the nitrogen atom located between them, represent a five- to seven-membered cycloalkylenimine group optionally substituted with a carboxy or C1-4-alkoxycarbonyl group, on which one phenyl ring can additionally be condensed, their tautomers, their stereoisomers, their mixtures and their salts. 2. Disubstituted bicyclic heterocycles of the general formula I according to claim 1, characterized in that A represents a carbonyl or sulfonyl group connected to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno part of the residue Het, whereby the aforementioned parts may not contain any residue R1, B represents an ethylene group, in which one methylene group that is connected to a Het or Ar residue can be substituted with an oxygen or sulfur atom, with a sulfinyl, sulfonyl, carbonyl or -NR1-group, whereby R1 represents a hydrogen atom or a C1-4-alkyl group, E is a RbNH-C(=NH)- group, in which Rb represents a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a residue that can be cleaved in vivo, Ar represents a phenylene group substituted as necessary with a fluorine, chlorine or bromine atom or with a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, thienylene, thiazolylene, pyridynylene, pyrimidinylene, pyrazinylene or pyridazinylene group, each of which can be substituted in the carbon skeleton with a C1-3-alkyl group, if necessary, Het represents the bicyclic heterocycle of the formula [image] where X represents a nitrogen atom, Y represents an oxygen or sulfur atom or a nitrogen atom optionally substituted with one C1-6-alkyl or C3-7-cycloalkyl group, whereby additionally one or two non-angular methine groups in the phenyl part of the aforementioned bicyclic heterocycle can be substituted with one nitrogen atom, or X represents a methine group optionally substituted with the residue R1, where R1 is defined as previously stated, and Y represents a nitrogen atom optionally substituted with a C1-6-alkyl or C3-7-cycloalkyl group, or Het represents a formula group [image] R1 is defined as previously stated, Z is an oxygen or sulfur atom, one of the residues D or G represents a nitrogen atom, and the other of the residues D or G represents a methine group, i Ra represents a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted with a C1-3-alkyl group, whereby the C1-3-alkyl group can additionally be substituted with one carboxyl group or with a group that can be convert to a carboxy group, or R2NR3-group, in which R2 represents a C1-4-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonyl, amino-carbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl group, a C2-4-alkyl group substituted with hydroxy, phenyl-C1-3-alkoxy, carboxy, C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, N-(C1-3-alkyl)-carboxy- by a C1-3-alkylamino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whereby in the aforementioned groups the α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, or a piperidinyl group optionally substituted with a C1-3-alkyl group and R3 represents a hydrogen atom, a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted with a C1-3-alkyl group, a C3-6-alkenyl or alkynyl group, whereby the unsaturated part cannot be directly connected to a nitrogen atom groups R2NR3, phenyl group optionally substituted with fluorine, chlorine or bromine, with a C1-3-alkyl or C1-3-alkoxy group, benzylic, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl , pyridazinyl, imidazolyl or piperidinyl group, each of which can be substituted with a C1-3-alkyl group if necessary or R2 and R3, together with the nitrogen atom located between them, represent a five- to seven-membered cycloalkylenimine group, which can be substituted with a carboxy or C1-4-alkoxycarbonyl group, on which one phenyl ring can additionally be condensed, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts. 3. Disubstituted bicyclic heterocycles of the general formula I according to claim 1, characterized in that A represents a carbonyl or sulfonyl group connected to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno part of the residue Het, whereby the aforementioned parts may not contain any residue R1, B represents an ethylene group, in which one methylene group, which is connected to the Ar residue, can be substituted with an oxygen or sulfur atom or -NR1-group, whereby R1 represents a hydrogen atom or a C1-4-alkyl group, E is a RbNH-C(=NH)- group, in which Rb represents a hydrogen atom, a hydroxy group, a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, wherein the ethoxyl part in position 2 of the aforementioned C1- 9-Alkoxycarbonyl groups can additionally be substituted with one C1-3-alkylsulfonyl or 2-(C1-3-Alkoxy)-ethyl group, Ar represents a 1,4-phenylene or 2,5-thienyl group which, if necessary, can be substituted with a chlorine atom, with a methyl, ethyl or methoxy group, Het represents 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-Benzthiazolylene, 1-(C1-3-alkyl)-2,5-indolylene, 1-(C1-3-alkyl)-2,5-imidazo[4,5-b]pyridinylene, 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene or 1- (C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group i Ra represents the group R2NR3 in which R2 represents a C1-4-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonyl-aminocarbonyl or 1H-tetrazol-5-yl group, a C2-4-alkyl group substituted with hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl- C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino, or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, wherein in the previously mentioned α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, R3 represents a C3-7-cycloalkyl group, a propargyl group, whereby the unsaturated part cannot be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted with fluorine or chlorine, with a methyl or methoxy group, a pyrazolyl, pyridazolyl or pyridinyl group, each of which may optionally be substituted with a methyl group or R2 and R3, together with the nitrogen atom located between them, represent a five- to seven-membered cycloalkylenimine group optionally substituted with a carboxy or C1-4-alkoxycarbonyl group, on which one phenyl ring can additionally be condensed, their tautomers, their stereoisomers and their salts. 4. Disubstituted bicyclic heterocycles of the general formula I according to claim 1, characterized in that A represents a carbonyl or sulfonyl group connected to the benzo, pyrido or thieno part of the Het residue, whereby the aforementioned parts may not contain any R1 residue, B represents an ethylene group, in which one methylene group, which is connected to the Ar residue, can be substituted with an oxygen or sulfur atom or with -NR1-group, whereby R1 represents a hydrogen atom or a methyl group, E is a RbNH-C(=NH)- group, in which Rb represents a hydrogen atom, a hydroxy group, a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxy-carbonyl, benzoyl, p-C1-3-alkyl-benzoyl or nicotinoyl group, whereby the ethoxyl part in position 2 of the aforementioned C1-9-alkoxycarbonyl group it can additionally be substituted with one C1-3-alkylsulfonyl or 2-(C1-3-alkoxy)-ethyl group, Ar represents a 1,4-phenylene or 2,5-thienyl group, which, if necessary, can be substituted with a chlorine atom, with a methyl, ethyl or methoxy group, Het represents 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4, 5-b]-pyridinylene, 3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and Ra represents the group R2NR3 in which R2 represents a C1-3-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, C2-3-alkyl group substituted with hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl- C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino, or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, wherein in the previously mentioned group α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, i R3 represents a propargyl group, whereby the unsaturated part cannot be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group or a pyridinyl group, which can be substituted with fluorine or chlorine, with a methyl or methoxy group, if necessary. their tautomers, their stereoisomers and their salts. 5. Disubstituted bicyclic heterocycles of the general formula I according to claim 1, characterized in that A represents a carbonyl group connected to the benzo or thieno part of the Het residue, B represents an ethylene group, in which one methylene group, which is connected to the Ar residue, can be replaced by an -NR1-group, whereby R1 represents a hydrogen atom or a methyl group, E is a RbNH-C(=NH)- group, in which Rb represents a hydrogen atom, a hydroxy group, a C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxy-carbonyl, benzoyl, p-C1-3-alkyl-benzoyl or nicotinoyl group, whereby the ethoxyl part in position 2 of the aforementioned C1-9-alkoxycarbonyl group can additionally be substituted with one methylsulfonyl or 2-ethoxy-ethyl group, Ar represents a 1,4-phenylene or 2,5-thienyl group, which can be substituted with a methoxy group if necessary, Het represents 1-methyl-2,5-benzimidazolylene, 2,5-benzthiazolylene, 1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and Ra represents the group R2NR3 in which R2 represents a C1-3-alkyl group, which can be substituted with one carboxy, C1-6-alkoxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, C2-3-alkyl group substituted with hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl- C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkylamino, or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, wherein in the previously mentioned group α-carbon atom standing immediately next to the nitrogen atom cannot be substituted, i R3 represents a phenyl or 2-pyridinyl group substituted with a fluorine atom, their tautomers, their stereoisomers and their salts. 6. The following compounds of general formula I, indicated by the fact that they belong to the group consisting of: (a) 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide, (b) 2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonyl-ethyl)-amide, (c) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2- hydroxycarbonyl-ethyl)-amide, (d) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3- hydroxycarbonyl-propyl)-amide, (e) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxy-carbonylmethyl)-amide, (f) 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl) -amide, (g) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl)-amide, (h) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxy-carbonylethyl)-amide, (i) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (j) 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl] -amide, (k) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl] -amide, (l) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)- amide, (m) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)- amide, (n) 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (o) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxy-carbonylethyl-N-methyl)-2- aminoethyl]-amide, (p) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, (q) 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide, (r) 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (s) 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl )-amide, (t) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide and (u) 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2,3-d]-imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)- amide, their tautomers, their prodrugs, their double prodrugs, their stereoisomers and their salts. 7. Compound of general formula I, characterized in that it is 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl) -amide, its prodrugs, their double prodrugs and their salts. 8. A compound of the general formula I, characterized in that 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-( 2-Hydroxycarbonyl-ethyl)-amide, its prodrugs, their double prodrugs and their salts. 9. Compound of the general formula I, characterized in that 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2- pyridyl)-N-(2-hydroxycarbonyl-ethyl)-amide, its prodrugs, its double prodrugs and its salts. 10. Physiologically tolerable salts of compounds according to claims 1 to 9, characterized in that E represents the group RbNH-C(=NH). 11. Medicine, characterized by the fact that, in addition to one or more inert carriers and/or diluting agents, if necessary, it contains a compound according to at least one of claims 1 to 9, in which E represents the group RbNH-C(=NH), or a salt according to the claim 10. 12. The use of a compound according to at least one of claims 1 to 9, in which E represents the group RbNH-C(=NH), or a salt according to claim 10, characterized in that it is used for the production of a drug that acts to prolong thrombin time and which has an inhibitory effect on thrombin and related serine proteases. 13. The method for the production of the medicine according to claim 11, characterized in that the compound according to at least one of claims 1 to 9, in which E represents the group RbNH-C(=NH), or the salt according to claim 10, is mixed into one or more inert carriers and/or diluents. 14. Process for the production of compounds according to claims 1 to 10, characterized in that a) for the production of compounds of the general formula I, in which E represents the group RbNH-C(=NH), in which Rb represents a hydrogen atom, hydroxy or C1-3-alkyl group, if necessary, a compound of general formula II is created in the reaction mixture Ra - A - Het - B - Ar -C(=NH) - Z1 (II) where A, B, Ar, Het and Ra have the meaning set forth in claims 1 to 9, a Z1 represents an alkoxy, aralkyl, alkylthio or aralkylthio group, chemically converted from the amino general formula H2N-R'b (III) where Rb' represents a hydroxy or C1-3-alkyl group, or b) for the production of a compound of the general formula I, in which the group Ra-A and E are defined as in claims 1 to 9, provided that the group Ra-A contains a carboxy group and E is defined as in claims 1 to 9, or that is the group Ra-A defined as stated in claims 1 to 9, and E represents the group NH2-C(=NH), or that the group Ra-A contains a carboxy group, and E represents the group NH2-C(=NH), compound of the general formula Ra' - A - Het - B - Ar - C - E' (IV) in which they are A, B, Ar and Het defined as in claims 1 to 9, a the group Ra'-A and E' have the meanings given in claims 1 to 9 for the group Ra-A and E, provided that the group Ra'-A contains a group which can be converted by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis into a carboxyl group, and E is defined as in claims 1 to 9, or E' contains a group that can be converted to the group NH2-C(=NH) by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, and the group Ra'-A has the meaning specified in claims 1 to 9 for the group Ra-A, or the group Ra'-A contains a group that can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, and E' represents a group that can be converted into a carboxyl group by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, it can be converted into the group NH2-C(=NH), is converted into a compound of general formula I by hydrolysis, treatment with acid or base, thermolysis or hydrogenolysis, in which the groups Ra-A and E are defined as in claims 1 to 9, provided that the group Ra-A is defined as in claims 1 to 9, such that the group Ra-A contains a carboxy group, and E is defined as in claims 1 to 9, or the group Ra-A has the meaning specified in claims 1 to 9, and E represents the group NH2-C(=NH), or the group Ra-A contains a carboxy group, and E represents the group NH2-C(=NH), or c) for the production of a compound of the general formula I, in which the group Ra-A contains an ester group specified in claims 1 to 9 in the definition for the group Ra-A, compounds of the general formula Ra'' - A - Het -B - Ar - E (V) in which they are B, E, Ar and Het defined as in claims 1 to 9, a Ra''-A has the meaning given in claims 1 to 9 for the group Ra-A, provided that the group Ra''-A contains a carboxyl group or a group that can be converted into a corresponding ester group by alcohol, it is chemically converted with alcohol of the general formula HO-R7 (VI) where R7 represents the alkyl part of the residue mentioned in claims 1 to 9 which can be cleaved in vivo to a carboxyl group, with the exception of the group R6-CO-O-(R5CR6), or with its formamide acetals, or with a compound of the general formula Z2-R8 (VII) where R8 represents the alkyl part of the residue mentioned in claims 1 to 9 which can be cleaved in vivo to a carboxyl group, with the exception of the group R6-CO-O-(R5CR6), and Z2 represents the output group, or d) for the production of a compound of the general formula I, in which Rb represents a residue that can be cleaved in vivo, compound of the general formula Ra - A - Het - B - Ar - C(=NH) - NH2 (VIII) in which they are Ra, A, Het, B and Ar defined as in claims 1 to 9, it is chemically converted with a compound of the general formula Z2-R5 (IX) where R5 represents a residue that can be cleaved in vivo, a Z2 is a nucleophilic leaving group, or e) for the production of a compound of the general formula I in which B represents an ethylene group, in which one methylene group is replaced by a sulfinyl or sulfonyl group, a compound of the general formula is oxidized Ra - A - Het - B' - Ar - E (X) in which they are A, E, Ar, Het and Ra defined as in claims 1 to 9, a B' represents an ethylene group in which one methylene group is replaced by a sulfenyl or sulfinyl group, or f) for the production of compounds of the general formula I, in which E represents a cyano group, and B is an ethylene group in which one methylene group is connected to a Het residue or an Ar residue, substituted with an oxygen or sulfur atom, or substituted with sulfinyl, sulfonyl , carbonyl or with -NR1 group, compounds of the general formula Ra - A - Het - U (XI) it is chemically converted with a compound of the general formula V - Ar - CN (XII) in which they are Ra, A, Ar and Het defined as stated in claims 1 to 9, one of the residues U or V represents HO-, HS-, HOSO-, HOSO2- or the group HNR1, and the remaining of the residues represents the group Z3CH2, wherein R 1 defined as in claims 1 to 9 and Z 3 is a nucleophilic leaving group, or g) for the production of a compound of the general formula I in which E represents a cyano group and Ra is a group R2NR3, compound of the general formula H - A - Het - B - Ar - CN (XIII) in which they are A, B, Het and Ar as defined in claims 1 to 9, is chemically converted with an amine of the general formula [image] in which they are R2 and R3 defined as in claims 1 to 9, or with its derivatives capable of reaction, or h) for the production of a benzimidazolyl, benzthiazolyl or benzoxazolyl compound of the general formula I, in which B represents an ethylene group, compound of the general formula [image] in which they are Ra, A and Y defined as in claims 1 to 9, it is chemically converted with a compound of the general formula HO-CO-CH2CH2-Ar-E (XVI) in which they are Ar and E defined as in claims 1 to 9, or with their derivatives capable of reaction, or i) for the production of the quinoxalin-2-one compound of the general formula, compound of the general formula [image] in which they are Ra, R1 and A defined as in claims 1 to 9, it is chemically converted with a compound of the general formula HO-CO-COCH2-Ar-E (XVIII) in which they are Ar and E defined as in claims 1 to 9, or with reactive derivatives thereof, or j) for the conversion of the compound of the general formula I in which R2 represents a C1-4-alkyl group, which is substituted with one alkylsulfonylaminocarbonyl group, compound of the general formula [image] in which they are R3, A, B, E and Het defined as in claims 1 to 9, a R2' represents a C1-4-alkyl group, which is substituted with one carboxy group, or its derivative capable of reaction, it is chemically converted with one salt of a compound of the general formula C1-3-alkyl-SO2-NH2 (XX) and if necessary, the protective residue, used to protect reactive groups during chemical conversion, is cleaved off, and/or then, if necessary, the thus obtained compound of the general formula I is separated into its stereoisomers, and/or the thus obtained compound of the general formula I is converted with inorganic or organic acids or bases into its salts, especially for pharmaceutical use into its physiologically tolerable salts.