HK1025096B

HK1025096B - Disubstituted bicyclic heterocycles, their production and use as medicaments

Info

Publication number: HK1025096B
Application number: HK00104207.1A
Authority: HK
Inventors: 诺伯特‧豪尔; 尤维‧里斯; 亨宁‧普里普克; 沃尔夫冈‧威尼恩; 琼‧M‧史塔生
Original assignee: 贝林格尔英格海姆法玛公司
Priority date: 1997-02-18
Filing date: 1998-02-16
Publication date: 2002-11-01

Description

Disubstituted bicyclic heterocycles, process for their preparation and their use as medicaments

The subject of the invention is novel disubstituted bicyclic heterocycles of the general formula,

R_a-a-Het-B-Ar-E' (I) its tautomers, stereoisomers and mixtures thereof, and salts thereof, especially physiologically acceptable salts with organic or inorganic acids or bases, which have valuable properties.

Compounds of formula I wherein E is cyano, wherein E is R, are valuable intermediates for the preparation of other compounds of formula I_bThe compounds of general formula I of the NH-C (═ NH) -group, their tautomers and stereoisomers are useful pharmacological properties, in particular their thrombin inhibiting and thrombin time prolonging action.

The subject of the present application is therefore the compounds of the general formula I mentioned above, their preparation, pharmaceutical compositions containing the pharmacologically active compounds, and their use.

In the above general formula

A is a carbonyl or sulfonyl group attached to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the Het group, and each of the foregoing moieties may be free of R₁A group.

B is ethylene, in which the methylene group which is also attached to Het or to the group Ar may be replaced by an oxygen or sulfur atom, or by a sulfinyl, sulfonyl, carbonyl or-NR group₁Group substitution, wherein

R₁Refers to a hydrogen atom or C_1-6-an alkyl group,

e is cyano or R_bAn NH-C (═ NH) -group, wherein

R_bIs a hydrogen atom, a hydroxyl group, C_1-3-an alkyl group or a group cleavable in vivo,

ar is phenylene or naphthylene, optionally substituted by fluorine, chlorine or bromine atoms, or by trifluoromethyl, C_1-3-alkyl or C_1-3-an alkoxy group substitution,

thienylene, thiazolyl, pyridinylene, pyrimidinyl, pyrazinylene or pyridazinylene, if desired by C in the carbon skeleton_1-3-an alkyl substitution,

het denotes a bicyclic heterocycle of formulaWherein

X is a nitrogen atom, and

y is an oxygen or sulfur atom or optionally C_1-6-alkyl or C_3-7A nitrogen atom substituted by a cycloalkyl group, while one or two other non-angular methines (non-angularmethyl groups) of the phenyl moiety in the above bicyclic heterocycle may each be substituted by a nitrogen atom,

or X is optionally substituted by R₁A radical substituted alkynyl, wherein R₁The definition of (a) is as described above,

y is optionally substituted by C_1-6-alkyl or C_3-7-a nitrogen atom substituted by cycloalkyl, or Het is a radical of formula

R₁The definition of (a) is as described above,

z is an oxygen or sulfur atom,

one of the D or G groups being a nitrogen atom and the other D or G group being a methine group, R_aIs C_1-6Alkyl, if necessary by C_1-3-alkyl substituted C_3-7-cycloalkyl, wherein C_1-3Alkyl may additionally be substituted by carboxyl or by a group which can be converted in vivo to carboxyl, or R₂NR₃A group in which

R₂Finger C_1-4Alkyl which may be substituted by carboxyl, C_1-6Alkoxycarbonyl, benzyloxycarbonyl, C_1-3-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluoromethanesulfonylamino, trifluoromethanesulfonylaminocarbonyl or 1H-tetrazolyl,

C_2-4alkyl, the alkyl being hydroxy, phenyl C_1-3-alkoxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3Alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino is substituted, while in the above groups the carbon atom alpha to the adjacent nitrogen atom is unsubstituted,

if necessary by C_1-3-alkyl-substituted piperidinyl and

R₃is a hydrogen atom, C_1-6Alkyl, if necessary by C_1-3-alkyl substituted C_3-7-cycloalkyl radical, C_3-6-alkenyl or C_3-6-alkynyl, wherein the unsaturated moiety may not be directly linked to R₂NR₃-on the nitrogen atom of the radical,

optionally substituted by fluorine, chlorine or bromine atoms or by C_1-3-alkyl or C_1-3Phenyl substituted by alkoxy, by C_1-3Alkyl-substituted benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, or imidazolyl, or

R₂And R₃Cycloalkyleneimino which is common and between which the nitrogen atom is 5-to 7-membered, which may be optionally substituted by carboxyl or C_1-4An alkoxycarbonyl group, to which a further phenyl ring can also be fused.

The compounds of the formula I mentioned above which contain one in vivo cleavable group are so-called prodrugs, and the compounds of the formula I mentioned above which contain two in vivo cleavable groups are so-called prodrugs (doubleprodrugs).

The term "group convertible in vivo into a carboxyl group" means, for example, a hydroxymethyl group, a carboxyl group esterified with an alcohol, wherein the alcohol moiety is preferably C_1-6-alkanol, phenyl-C_1-3-alkanol, C_3-9-cycloalkanol, wherein C_5-8The cycloalkanol may additionally be substituted by one or two C_1-3-alkyl-substituted, C_5-8Cycloalkanols in which the methylene group in the 3-or 4-position is replaced by an oxygen atom or, if desired, by C_1-3Alkyl, phenyl-C_1-3Alkyl, phenyl-C_1-3Alkoxycarbonyl or C2-6-alkanoyl substituted imino, and the cycloalkanol moiety may in turn be replaced by one or two C_1-3-alkyl substituted is C_4-7-Cycloalkenol, C_3-5Enol, phenyl-C_3-5Enol, C_3-5-alkynols or phenyl-C_3-5Alkynols, with the proviso that the carbon atom carrying the double or triple bond is not attached to an oxygen atom, is C_3-8-cycloalkyl-C_1-3Alkanols, bicyclic alkanols having a total number of 8 to 10 carbon atoms, the bicyclic portion of which may additionally be substituted by one or moreTwo C_1-3-alkyl-substituted, 1, 3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

R₄-CO-O-(R₅CR₆)-OH，

Wherein

R₄Is C_1-8-alkyl radical, C_5-7-cycloalkyl, phenyl or phenyl-C_1-3-an alkyl group,

R₅is a hydrogen atom, C_1-3-alkyl radical, C_5-7-cycloalkyl or phenyl, and

R₆is a hydrogen atom or C_1-3The term "alkyl group" or "group cleavable in vivo by an imino or amino group" means, for example, a hydroxyl group, an acyl group, and optionally C_1-3Alkyl-substituted benzoyl or pyridyl radicals, e.g. benzoyl, p-ethyl-benzoyl, p-isopropyl-benzoyl or nicotinoyl, or C_1-16Alkanoyl, such as formyl, acetyl, propionyl, butyryl, pentanoyl, or hexanoyl, allyloxycarbonyl, C_1-16Alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl, phenyl-C_1-6Alkoxycarbonyl, such as benzyloxycarbonyl, phenylethoxycarbonyl, or phenylpropoxycarbonyl, C_1-3-alkylsulfonyl-C_2-4Alkoxycarbonyl radical, C_1-3-alkoxy-C_2-4-alkoxy-C_2-4-alkoxycarbonyl or R₄CO-O-(R₅CR₆) -O-CO-group, wherein R₄To R₆Is as defined above.

Preferred prodrug groups for carboxyl groups include C_1-6Alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butylOxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl, or phenyl-C_1-3Alkoxycarbonyl, such as benzyloxycarbonyl, and

preferred prodrugs for imino or amino groups include C_1-9Alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl, phenyl-C_1-3Alkoxycarbonyl, e.g. benzyloxycarbonyl, optionally substituted by C_1-3Alkyl-substituted phenylcarbonyl, such as benzoyl or 4-ethyl-benzoyl, pyridinoyl, such as nicotinoyl, C_1-3-alkylsulfonyl-n-C_2-3-alkoxycarbonyl or C_1-3-alkoxy-C_2-3-alkoxy-C_2-4Alkoxycarbonyl such as 2-methylsulfonylethoxycarbonyl or 2- (2-ethoxy) -ethoxycarbonyl.

In addition, saturated alkyl and alkoxy moieties containing two or more carbon atoms and alkanoyl and unsaturated alkyl moieties containing 3 or more carbon atoms in the above definitions also include branched isomers thereof, such as isopropyl, tert-butyl, isobutyl, and the like.

Preferred compounds of the above formula I are those in which

A is a carbonyl or sulfonyl group attached to a benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the Het group, and each of the above moieties is free of R₁The radical(s) is (are),

b is an ethylene radical, in which the methylene radical which is also bonded to Het or Ar is replaced by an oxygen or sulfur atom, or by a sulfinyl, sulfonyl, carbonyl or-NR₁-is replaced by a group wherein

R₁Refers to a hydrogen atom or C_1-4-an alkyl group,

e denotes R_bNH-C (═ NH) -group, whichIn

R_bDenotes a hydrogen atom, a hydroxyl group, C_1-3-an alkyl group or a group cleavable in vivo,

ar is optionally substituted by fluorine, chlorine or bromine atoms or by trifluoromethyl, C_1-3-alkyl or C_1-3-an alkoxy-substituted phenylene group,

if necessary on the carbon skeleton by C_1-3An alkyl-substituted thienylene, thiazolyl, pyridinylene, pyrimidinylene, pyrazinylene, or pyridazinylene group,

het denotes a bicyclic heterocycle of formulaWherein

X is a nitrogen atom, and X is a nitrogen atom,

y is an oxygen or sulfur atom or optionally C_1-6-alkyl or C_3-7-a nitrogen atom substituted by a cycloalkyl group, while one or two non-angular methine groups of the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom,

or X is optionally substituted by R₁Methine substituted by radicals in which R₁Is as defined above, and

y is optionally substituted by C_1-6-alkyl or C_3-7-a nitrogen atom substituted by cycloalkyl, or Het is a group of formula;

R₁the definition of (a) is as described above,

z is an oxygen or sulfur atom,

one of the D or G groups is a nitrogen atom and the other D or G group is methine, and R_aIs C_1-6Alkyl, if necessary by C_1-3-alkyl substituted C_3-7-cycloalkyl, wherein C_1-3Alkyl radicals which may also be substituted by carboxyl groups or be convertible in vivoSubstituted by a carboxyl-forming group, or R₂NR₃A group in which

R₂Finger C_1-4Alkyl which may be substituted by carboxyl, C_1-6-alkyloxycarbonyl, benzyloxycarbonyl, C_1-3-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl,

C_2-4alkyl, the alkyl being substituted by hydroxy, phenyl C_1-3-alkoxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_{1- 3}-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino is substituted, while in the above groups the carbon atoms in the alpha-position to adjacent carbon atoms may be unsubstituted, or

If necessary by C_1-3-alkyl-substituted pyridyl and

R₃is a hydrogen atom, C_1-6Alkyl, if necessary by C_1-3-alkyl substituted C_3-7-cycloalkyl radical, C_3-6-alkenyl or alkynyl, wherein the unsaturated moiety cannot be directly linked to R₂NR₃On the nitrogen atom of the radical, optionally substituted by fluorine, chlorine or bromine atoms, or by C_1-3-alkyl or C_1-3Phenyl substituted by alkoxy, by C_1-3Alkyl-substituted benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl or piperidinyl, or

R₂And R₃Cycloalkyleneimino which together with the nitrogen atom between them is 5-to 7-membered, which may be optionally substituted by carboxyl or C_1-4Alkoxycarbonyl substituents, to which a further phenyl ring may also be fused, in particular those compounds in which

Het is the aforementioned benzimidazolylene group, benzothiazolyl group, benzoxazolyl group, indolyl group, quinazolinylene group (chinoxazolinylene), imidazo [4, 5-b ] pyridylene group, imidazo [1, 2-a ] pyridylene group, thiazolo [5, 4-b ] pyridylene group, or thieno [2, 3-d ] imidazolyl group, its tautomers, prodrugs, stereoisomers and salts thereof.

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

A is a carbonyl or sulfonyl group attached to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the Het group, and each of the foregoing moieties is further free of R₁The radical(s) is (are),

b is an ethylene radical in which the methylene radical bonded to Ar may be replaced by an oxygen or sulfur atom, or by-NR₁-is substituted by a group, wherein

R₁Refers to a hydrogen atom or C_1-4-an alkyl group,

e is R_bAn NH-C (═ NH) -group, wherein

R_bIs a hydrogen atom, a hydroxyl group, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C_1-3Alkoxycarbonyl, benzoyl, p-C_1-3-alkyl-benzoyl or pyridinoacyl with C above_1-9The ethoxy moiety in the 2-position of the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl-substituted,

ar is 1, 4-phenylene which is optionally substituted by chlorine atoms or by methyl, ethyl or methoxy, or is 2, 5-thienylene,

het is 1- (C)_1-3-alkyl) -2, 5-benzimidazolylene, 1-cyclopropyl-2, 5-benzimidazolylene, 2, 5-benzothiazolyl, 1- (C)_1-3-alkyl) -2, 5-indolyl, 1- (C)_1-3-alkyl) -2, 5-imidazo [4, 5-b]Pyridinylene, 3- (C)_1-3-alkyl) -2, 7-imidazo [1, 2-a]Pyridylene or 1- (C)_1-3Alkyl) substituted benzene2, 5-thieno [2, 3-d ]]An imidazolyl group, and

R_ais R₂NR₃A group in which

R₂Is a carboxyl group, C_1-6-alkyloxycarbonyl, benzyloxycarbonyl, C_1-3-alkylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl substituted C_1-4-an alkyl group,

C_2-4alkyl, by alkyl being by hydroxy, benzyloxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino is substituted, while in the above groups the carbon atom alpha to the adjacent nitrogen atom is unsubstituted,

R₃is C_3-7-cycloalkyl, propargyl, wherein the unsaturated moiety cannot be directly linked to R₂NR₃On the nitrogen atom of the radical, phenyl optionally substituted by fluorine or chlorine atoms, or by methyl or methoxy, pyrazolyl, pyridazinyl or pyridyl optionally substituted by methyl, or

R₂And R₃Cycloalkyleneimino together with which the nitrogen atom is 5-to 7-membered, optionally carboxy or C_1-4Alkoxycarbonyl, onto which a further phenyl ring, its tautomers, its stereoisomers and its salts can also be fused.

Most preferred compounds of the above formula I are those wherein

A is a carbonyl or sulfonyl group attached to the benzo, pyrido, or thieno moiety of the Het group and each of the above moieties is free of R₁The radical(s) is (are),

b is an ethylene radical in which the methylene radical bonded to the Ar radical may be replaced by an oxygen or sulfur atom, or by-NR₁-is substituted by a group, wherein

R₁Is a hydrogen atom or a methyl group,

e is R_bAn NH-C (═ NH) -group, wherein

R_bDenotes a hydrogen atom, a hydroxyl group, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C_1-3Alkyl-benzoyl or nicotinoyl radicals, together with C above_1-9The ethoxy moiety in the 2-position of the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl-substituted,

het is 1-methyl-2, 5-benzimidazolylene, 1-cyclopropyl-2, 5-benzimidazolylene, 2, 5-benzothiazolyl, 1-methyl-2, 5-indolyl, 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 ] imidazolyl, and

R_ais R₂NR₃A group in which

R₂Is a carboxyl group, C_1-6-alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl substituted C_1-3-an alkyl group,

C_2-3alkyl, the alkyl being substituted by hydroxy, benzyloxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3Alkylamino, while in the above groups the carbon atom alpha to the adjacent nitrogen atom may be unsubstituted,

R₃is propargyl, wherein the unsaturated moiety is not directly linked to R₂NR₃Nitrogen of radicalOn the ring, phenyl optionally substituted by fluorine or chlorine atoms, or phenyl substituted by methyl or methoxy, or pyridyl,

in particular compounds wherein

A is a carbonyl group attached to the benzo or thieno moiety of the Het group,

b is ethylene, wherein the methylene group bonded to the Ar group may be replaced by-NR₁Substituted by radicals in which

R₁Refers to a hydrogen atom or a methyl group,

e denotes R_bAn NH-C (═ NH) -group, wherein

R_bIs a hydrogen atom, a hydroxyl group, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C_1-3Alkyl-benzoyl or nicotinoyl radicals, together with C above_1-9The ethoxy moiety in the 2-position in the alkoxycarbonyl group may also be substituted by methylsulfonyl or 2-ethoxy-ethyl,

ar is 1, 4-phenylene, optionally substituted by methoxy, or 2, 5-thienylene,

het is 1-methyl-2, 5-benzimidazolylene, 2, 5-benzothiazolyl, 1-methyl-2, 5-indolyl, or 1-methyl-2, 5-thieno [2, 3-d ] imidazolyl, and

R_ais R₂NR₃A group in which

C_2-3alkyl, the alkyl being substituted by hydroxy, benzyloxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxy radicalRadical carbonyl-C_1-3-alkylamino is substituted, while in the above groups the carbon atom alpha to the adjacent nitrogen atom is unsubstituted,

R₃is phenyl optionally substituted by fluorine atoms, or is 2-pyridyl, its tautomers, its stereoisomers and its salts.

The following are examples of particularly preferred compounds: (a)2- [ N- (4-carbamimidophenyl) -aminomethyl ] -benzothiazole-5-carboxylic acid-N-phenyl-N- (2-carboxyethyl) -amide, (b)2- [ N- (4-carbamimidophenyl) -N-methyl-aminomethyl ] -benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl) -amide, (c) 1-methyl-2- [ N- (4-carbamimidophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl) -amide, (d) 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide, (e) 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide, (f) 1-methyl-2- [2- (2-amidinophenylthio-5-yl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl-) Amide, (g) 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, (h) 1-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -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-pyridinylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl Yl) -N- (2-hydroxycarbonylethyl) -amide, (m) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, (N) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide, (o) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazole-5-yl -yl-carboxylic acid-N-phenyl-N- [ (N-hydroxycarbonylethyl-N-methyl) -2-amino-ethyl ] -amide, (p) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid-N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide, (q) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid-N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide, (r) 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide,(s) 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide, (t) 1-methyl-2- [ N- (4-carbamimidoyl) 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, tautomers, prodrugs, stereoisomers and salts thereof.

These novel compounds can be prepared by known methods, for example, as follows: a. preparation of a Compound of the general formula I wherein E is R_bNH-C (═ NH) -groups, wherein R_bIs a hydrogen atom, a hydroxyl group or C_1-3When it is an alkyl group

Reacting a compound of the formula II, which may optionally be formed in the reaction mixture, with an amine of the formula III

R_a-A-Het-B-Ar-C(＝NH)-Z₁(II) A, B, Ar, Het and R in formula II_aIs as defined above, and Z₁Is alkoxy or aralkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy, or is alkylthio or aralkylthio, such as methylthio, ethylthio, n-propylthio or benzylthio,

H₂N-R_b′ ' (III) formula III wherein R_b' is a hydrogen atom or a hydroxyl group or C_1-3-an alkyl group.

The reaction is carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane, at a temperature of from 0 to 150 c, preferably from 20 to 120 c, with a compound of formula III or a corresponding acid addition salt thereof, such as ammonium carbonate.

The compounds of formula II can be prepared, for example, by reacting a compound of the formula I in which E is cyano with the corresponding alcohol, such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol, in the presence of an acid, such as hydrochloric acid, or by reacting the corresponding amide with a trialkyloxonium salt, such as triethyloxonium tetrafluoroborate, in a solvent, such as dichloromethane, tetrahydrofuran or dioxane, at a temperature of between 0 and 50 ℃, preferably at 20 ℃, or by reacting the corresponding nitrile with hydrogen sulfide in a solvent, such as pyridine or dimethylformamide, in the presence of a base, such as triethylamine, and then alkylating the resulting thioamide with the corresponding alkyl or aralkyl halide. b. Preparation of a Compound of the general formula I, wherein R_aThe groups A-and E are as defined above, with the proviso that R_aThe A-group contains a carboxyl group and E is as defined above, or R_aThe radical-A-is as defined above and E is NH₂-C (═ NH) -group, or is R_aThe radical-A-containing a carboxyl group and E denotes NH₂-C (═ NH) -group:

converting a compound of the formula:

R_a' -A-Het-B-Ar-C-E ' ' (IV) wherein A, B, Ar and Het are as defined above, R_a' -A-group and E are as defined above for R_aa-A-group and E, with the proviso that R_a'-A-groups contain groups which can be converted into carboxyl groups by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis, E is as defined above, or E' is a group which can be converted into NH by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis₂-C (═ NH) -group, R_aOf the' -A-groupAs defined above for R_a-A-group is as defined below, or R_a'-A-groups contain groups which can be converted into carboxyl groups by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis, E' is a group which can be converted into NH by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis₂The radical of the-C (═ NH) -group is converted into the compounds of the general formula I by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis, where R is_aThe definition of the groups A-and E is as described above, with the proviso that R_aThe A-group contains a carboxyl group and E is as defined above, or R_aThe radical-A-is as defined above and E is NH₂-C (═ NH) -group, or is R_aThe A-group containing a carboxyl group and E is NH₂-C (═ NH) -group.

The carboxyl group which may be converted into a carboxyl group, for example, protected by a protecting group such as a functional derivative thereof, for example, an unsubstituted or substituted amide, ester, thio ester, trimethylsilyl ester, orthoester or imino ester, may be converted into a carboxyl group by hydrolysis, an ester thereof with a tertiary alcohol, for example, a tert-butyl ester, may be converted into a carboxyl group by treatment with an acid or decomposition with heat, an ester thereof with an aralkyl alcohol, for example, a benzyl ester, may be converted into a carboxyl group by hydrogenolysis.

The hydrolysis is preferably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or a mixture thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at a temperature of from-10 to 120 ℃, for example from room temperature to the boiling temperature of the reaction mixture.

If R in the compound of formula IV_athe'-A-group and/or E' contain a tert-butyl or tert-butyloxycarbonyl group, which group can then be cleaved, for example, by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as dichloromethane, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane at temperatures of-10 to 120 ℃Cleavage, for example at a temperature of from 0 to 60 ℃ or thermal decomposition in an inert solvent such as dichloromethane, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably in the presence of catalytic amounts of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid at the boiling temperature of the solvent used, for example at a temperature of from 40 to 120 ℃.

If R of the compound of the formula IV_athe'-A-groups and/or E' contain, for example, a benzyloxy or benzyloxycarbonyl group, these compounds can also be subjected to a hydrocracking in the presence of a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at a temperature of from 0 to 50 ℃, for example at room temperature, under a hydrogen pressure of from 1 to 5 bar. c. Preparation of a Compound of the general formula I, wherein R_aThe group-A-contains the above-mentioned R_aAn ester of the group A-by reacting a compound of the formula with an alcohol of the formula VI

R_a"-A-Het-B-Ar-E' (V) formula V wherein B, E, Ar and Het are as defined above, R_aThe definition of the "-A-group is as given above for R_a"-A-with the proviso that R_aThe group "-A-contains a carboxyl group or a group which can be converted with an alcohol into the corresponding ester,

HO-R₇(VI) formula V1R₇Is an alkyl part of the above-mentioned in vivo cleavable group, but not with R₄-CO-O-(R₅CR₆) The radical giving a carboxyl group, or with its carboxamide acetal, or with a compound of the formula

Z₂-R₈(VII) wherein R₈Refers to the alkyl portion of the groups described above which are cleavable in vivo, but not with R₄-CO-O-(R₅CR₆) The radical giving a carboxyl group, Z₂Refers to a leaving group, and is a substituent,such as a halogen atom, for example chlorine or bromine.

The reaction with the alcohol of the formula VI is conveniently carried out in a solvent or solvent mixture, such as dichloromethane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, or dioxane, but preferably in the presence of an acid, such as hydrochloric acid, or in the presence of a dehydrating agent, such as isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N ' -dicyclohexylcarbodiimide/N-hydroxysuccinimide, N, N ' -carbonyldiimidazole or N, N ' -sulfinyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethylazodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylaminopyridine, at a temperature of between 0 and 150 ℃, preferably between 0 and 80 ℃.

The reaction with the compounds of the formula VII is generally carried out in a solvent such as dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide, or in the presence of a base such as sodium or potassium carbonate, or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may also be used as solvent at the same time, or optionally in the presence of silver carbonate or silver oxide, at a reaction temperature of from-30 to 100 ℃ and preferably from-10 to 80 ℃. d. Preparation of a Compound of the general formula I, wherein R_bIs a group that is cleavable in vivo,

reacting a compound of formula VIII with a compound of formula IX

R_aA-Het-B-Ar-C(＝NH)-NH₂' (VIII) formula (VIII) wherein R_aA, Het, B and A are as defined above,

Z₂-R₇ (IX) R in formula (IX)₇Is a group cleavable in vivo, Z₂Is a nucleofugic leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as methanol, ethanol, dichloromethane, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at a temperature of from 20 ℃ to the boiling temperature of the solvent used.

In the reaction with a compound of the formula IX (wherein Z₂Referred to as a nucleofugic leaving group), the reaction is preferably carried out in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium hydroxide, potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at 0 to 60 ℃. e. Preparing a compound of the general formula I, wherein B is ethylene and one of the methylene groups is replaced by a sulfinyl or sulfonyl group,

oxidizing a compound of the formula

R_a-A-Het-B' -Ar-E, (X) wherein A, E, Ar, Het and R_aAs defined above, B' is ethylene wherein one methylene group is replaced by a sulfinyl or sulfonyl group.

The oxidation is preferably carried out in a solvent or solvent mixture, for example water, water/pyridine, acetone, dichloromethane, glacial acetic acid/acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, and, depending on the oxidizing agent used, at a temperature of from-80 to 100 ℃.

In the preparation of the corresponding sulfinyl compounds of the formula I, the oxidation is suitably carried out using one equivalent of an oxidizing agent, for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at from 0 to 20 ℃ or in acetone at from 0 to 60 ℃, or with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at from 0 to 50 ℃, or with m-chloroperbenzoic acid in dichloromethane, chloroform or dioxane at from-20 to 80 ℃, or with sodium meta-periodate in aqueous methanol or ethanol at from-15 to 25 ℃, or with bromine in aqueous glacial acetic acid or acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butylhypochlorite in methanol at from-80 to-30 ℃, with iodobenzene and dichloro in aqueous pyridine at from 0 to 50 ℃, with nitric acid in glacial acetic acid at 0 to 20 ℃, with chromic acid in glacial acetic acid or acetone at 0 to 20 ℃ and with sulfuryl chloride in dichloromethane at-70 ℃, the thioether-chlorine complex obtained being preferably hydrolyzed with aqueous ethanol.

To prepare the sulfonyl compounds corresponding to formula I, the oxidation is carried out starting with the corresponding sulfinyl compound, preferably with one or more equivalents of oxidizing agent, or starting with the corresponding sulfinyl compound, preferably with two or more equivalents of oxidizing agent, for example with hydrogen peroxide in glacial acetic acid/acetic anhydride, trifluoroacetic acid or formic acid at 20 to 100 ℃, or in acetone at 0 to 60 ℃, with a peracid such as performic acid or with m-chloroperbenzoic acid in acetic acid, trifluoroacetic acid, dichloromethane or chloroform at 0 to 60 ℃, with nitric acid in glacial acetic acid at 0 to 20 ℃, with chromic acid or potassium permanganate in glacial acetic acid, water/sulfuric acid or in acetone at 0 to 20 ℃. Thus, for example, the sulfonyl compounds of the formula I prepared by oxidation of the corresponding sulfinyl compounds, preferably in dichloromethane, with a corresponding amount of m-chloroperbenzoic acid at between 20 ℃ and the reflux temperature of the reaction mixture may still contain small amounts of the corresponding sulfinyl compounds. f. Preparation of a compound of the general formula I, in which E is cyano, B is ethylene, in which the methylene group which is also bonded to Het or Ar is a radical of an oxygen or sulfur atom, or a sulfinyl, sulfonyl, carbonyl or-NR₁When a radical is substituted

By using compounds of the formula

R_a-A-Het-U' (XI) with a compound of the general formula

V-Ar-CN' (XII) wherein R_aA, Ar and Het are as defined above, one of the U or V groups being HO-, HS-, HOSO₂-or HNR₁A radical, another radical being Z₃CH₂-, wherein R₁Is as defined above, Z₃Is a nucleofugic leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent, such as methanol, ethanol, dichloromethane, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide, optionally in the presence of an inorganic or tertiary-organic base such as triethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine, preferably at a temperature between 20 ℃ and the boiling temperature of the solvent, wherein Z is₃Compounds of the formula XI to XII which are halogen atoms can also be prepared in the reaction mixture. g. Preparation of a Compound of the general formula I, wherein E is cyano, R_aIs R₂NR₃When a group is

By using compounds of the formula

H-A-Het-B-Ar-CN' (XIII) (wherein A, B, Het and Ar are as defined above) with an amine of the general formulaWherein R is₂And R₃As defined above, or with a reactive derivative thereof.

The reaction of the compounds of the formula XIII is optionally carried out in a solvent or solvent mixture, for example in dichloromethane, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or in the corresponding amines of the formula III, optionally in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetramethoxysilane, sulfuryl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N, N' -dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyl * tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyl * tetrafluoroborate/1-hydroxybenzotriazole, N, N' -carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at a temperature of from 0 to 150 deg.C, preferably from 0 to 100 deg.C.

The reaction of the corresponding reactable compounds of the formula XIII, such as esters, imidazoles or halogen compounds, with the amines of the formula XIV is preferably carried out in the corresponding amine solvents, optionally in the presence of further solvents such as dichloromethane or ethers, preferably in the presence of tertiary organic bases such as triethylamine, N-ethyldiisopropylamine or N-methyl-morpholine at temperatures of from 0 to 150 ℃, preferably from 50 to 100 ℃. h. Preparing a benzimidazolyl, benzothiazolyl or benzoxazolyl compound of formula I wherein B is ethylene:

a compound of the following formula(wherein R is_aA and Y are as defined above) with a compound of the formula

HO-CO-CH₂CH₂-Ar-E' (XVI) wherein Ar and E are as defined above, or with a reactive derivative thereof.

The reaction is preferably carried out in a solvent or solvent mixture, for example in dichloromethane, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetramethoxysilane, sulfuryl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N, N' -dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyl * tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyl * tetrafluoroborate/1-hydroxybenzotriazole, N, N' -carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at a temperature of from 0 to 150 deg.C, preferably from 0 to 100 deg.C.

The reaction of the corresponding reactable compounds of the formula XVI, such as esters, imidazoles or halogen compounds, with the amines of the formula XV is preferably carried out in a solvent such as dichloromethane, ether or tetrahydrofuran, preferably in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methyl-morpholine, which may also be used as solvent, at temperatures of from 0 to 150 ℃, preferably from 50 to 100 ℃. i. In preparing the quinoxalin-2-one compounds of formula 1:

by using compounds of the formula(wherein R is_a，R₁And A is as defined above) with a compound of the formula

HO-CO-COCH₂-Ar-E (xviii) wherein Ar and E are as defined above, or with a reactive derivative thereof.

The reaction is suitably carried out in a solvent or solvent mixture, such as dichloromethane, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, ethanol or dioxane, optionally in the presence of a dehydrating agent, such as isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetramethoxysilane, sulfuryl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N, N' -dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1, 3, 3-tetramethyl * tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyl * tetrafluoroborate/1-hydroxybenzotriazole, N, N' -carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at a temperature of from 0 to 150 deg.C, preferably from 0 to 100 deg.C.

However, the reaction is particularly preferably carried out with the corresponding reactable compounds of the formula XVIII, such as esters, imidazoles or halides thereof, and amines of the general formula XVII in a solvent, such as dichloromethane, ether, ethanol or tetrahydrofuran, preferably in the presence of a tertiary organic base, such as triethylamine, N-ethyldiisopropylamine or N-methyl-morpholine, which may also be used as solvent, at temperatures of from 0 to 150 ℃, preferably from 50 to 100 ℃. j. To prepare compounds of the general formula I, in which R₂Is C substituted by alkylsulfonylaminocarbonyl_1-4-alkyl, when

A compound of the formula(wherein R is₃A, B, E, and Het are as defined above, R₂' is C substituted by carboxyl_1-4-alkyl) or a reactive derivative thereof, with a salt of a compound of the formula

C_1-3-alkyl-SO₂-NH₂ (XX)

The reaction is preferably carried out in a solvent, for example in dichloromethane, ether, ethanol or tetrahydrofuran or dimethylformamide, at a temperature of from 0 to 150 ℃ and preferably from 50 to 100 ℃, with the corresponding reactable compound of the formula IXX, for example an ester, imidazole or halide thereof, and a salt, preferably an alkali metal salt, for example a sodium salt, of the compound of the formula XX.

In the above-mentioned reactions, the reactive groups present, such as hydroxyl, carboxyl, amino, alkylamino or imino, can optionally be protected during the reaction with customary protecting groups, which are then removed after the reaction.

For example, the protecting group for the hydroxyl group may be trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl, the protecting group for the carboxyl group may be trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, the protecting group for the amino, alkylamino or imino group may be acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl, and the protecting group for the p-amino group may also be phthalyl.

The protecting group is then cleaved, for example, by hydrolysis in an aqueous solvent such as water, isopropanol/water, tetrahydrofuran/water or dioxane/water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleavage, for example in the presence of iodotrimethylsilane at a temperature of 0 to 100 ℃, preferably 10 to 50 ℃.

However, benzyl, methoxybenzyl or benzyloxycarbonyl may, for example, be cleaved by hydrogenation, for example in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at from 0 to 50 ℃ and preferably at room temperature under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.

The methoxybenzyl group may also be cleaved in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as dichloromethane, acetonitrile or acetonitrile/water at 0 to 50 ℃, preferably at room temperature.

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

Cleavage of the tert-butyl or tert-butoxycarbonyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally in a solvent such as dichloromethane, dioxane, or an alcohol.

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

The cleavage of the allyloxycarbonyl group is carried out with catalytic amounts of tetrakis- (triphenylphosphine) palladium (O), preferably treated in a solvent such as tetrahydrofuran, and preferably in the presence of an excess of a base such as morpholine or 1, 3-dimedone at 0 to 100 ℃, preferably at room temperature, under an inert gas, or with catalytic amounts of tris (triphenylphosphine) rhodium (I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1, 4-diazabicyclo (2.2.2] octane at a temperature of 20 to 70 ℃.

The compounds of the formulae II to XX, some of which are known from the literature, can be prepared by processes described in the literature and their preparation is illustrated in the examples below.

For example, compounds of formula II can be prepared by reacting the corresponding nitrile (which can be prepared by the methods f to h) with the corresponding thiol or alcohol in the presence of hydrogen chloride or hydrogen bromide.

The compounds of the formulae IV, V, VIII, X, and IXX used as starting materials can suitably be prepared by the process of the present invention.

Starting compounds of the formula XI in which U is halomethyl can suitably be prepared by cyclizing the corresponding esters which are substituted in the ortho position by the appropriate halogen atom and methoxyacetylamino group to give the corresponding bicyclic 2-alkoxymethyl compounds, optionally further hydrolyzing and optionally amidating the carboxylic acids formed with the corresponding amines, converting the alkoxymethyl compounds obtained into the corresponding halomethyl compounds, which are, if desired, converted into the desired compounds with the corresponding compounds. If cyclization is to be effected with an appropriate carbonic acid derivative, the starting compounds of the formula XI are prepared, where U is hydroxy, mercapto, or amino.

The starting compounds of the formula XIII are prepared by cyclizing the corresponding ortho-disubstituted ester, saponifying the resulting ester and amidating the resulting carboxylic acid with the corresponding amine.

Furthermore, imidazopyridines substituted in the 5-position with a methyl group and prepared by cyclization can be converted via the corresponding N-oxide into the corresponding hydroxymethyl compound and then reoxidized to the desired carboxylic acid of the formula XIII.

The compounds of the formulae III, VI, VII, IX and XII used as starting materials can be prepared in a customary manner, for example by reduction of aromatic esters which are optionally substituted in the ortho position by amino and nitro groups and if desired cyclization of the resulting ortho-diamino compound with the corresponding carboxylic acid.

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

For example, the compounds of the formula I obtained in racemic form are separated by known methods (see: Allinger N.L. and Eliel E.L.: Topics in Stereochemistry, Vol.6, Wiley Interscience, 1971) into their optical enantiomers, whereas compounds of the formula I having at least 2 asymmetric carbon atoms can be separated by known methods on the basis of their physico-chemical differences, for example by chromatographic separation and/or fractional crystallization, into their diastereomers and, if in racemic form, into their enantiomers by the methods described above.

The separation of the enantiomers is preferably carried out by column separation of the chiral phase or by recrystallization from optically active solvents or by reaction with optically active substances, in particular acids and their activated derivatives or alcohols, which form salts or derivatives, such as esters or amides, with the racemic compounds, the diastereomeric salt mixtures or derivatives thus obtained being separated on the basis of their different solubilities, and the enantiomers being obtained in free form from the pure diastereomeric salts or derivatives by the action of suitable reagents. The most commonly used optically active acids are, for example, d-or l-tartaric acid, and dibenzoyl tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, and quinic acid. Examples of optically active alcohols include, for example, (+) -or (-) -methanol, and examples of optically active acyl groups within amides include, for example, (+) -or (-) -methyloxycarbonyl.

In addition, the compounds of the general formula I obtained can also be converted into their salts, in particular into their physiologically acceptable salts for pharmaceutical use with inorganic or organic acids. Examples of suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.

Furthermore, the novel compounds of the formula I thus prepared, if they contain carboxyl groups, can be converted, if desired, with inorganic or organic bases into their salts, in particular into their physiologically acceptable salts for pharmaceutical use. Examples of suitable bases include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

As mentioned above, the novel compounds of the general formula I and their salts have valuable properties. Thus, compounds of formula I wherein E is cyano are valuable intermediates for the preparation of other compounds of formula I wherein E is R_bThe compounds of general formula I and tautomers, stereoisomers and physiologically acceptable salts thereof, NH-C (═ NH) -, have valuable pharmacological properties, in particular a thrombin-inhibiting effect, an effect which prolongs thrombin time, and an inhibitory effect on the relevant serine proteases, such as trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI, and factor XII, some of which, for example the compounds of example 16, also have a mild inhibitory effect on platelet aggregation.

For example, the following compounds: a ═ 2- [ N- (4-amidinophenyl) -aminomethyl ] -benzothiazole-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-hydroxy)

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

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

Hydroxycarbonylethyl) -amide, E ═ 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridine)

Yl) -N- (hydroxycarbonylmethyl) -amide, F ═ 1-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-

Tetrazol-5-yl) ethyl ] -amide, and G ═ 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridine)

The group) -N- (2-hydroxycarbonylethyl) -amide, for which the thrombin time was investigated as follows: materials: blood plasma, citrated blood taken from human body

Test Thrombin (bovine), 30 units/ml, from Behring Werke, Marburg

Diethylbarbiturate acetate buffer, ORWH 60/61, from Behring Werke,

Marburg

biomatic B10 coagulometer, Sarstedt method:

the thrombin time was measured by using a Biomatic B10 thrombin meter manufactured by Sarstedt.

The test substance 0.1 ml of human citrate-containing plasma and 0.1 ml of diethylbarbiturate acetate buffer (DBA buffer) were added to the test strips specified by the manufacturer. The mixture was incubated at 37 ℃ for one minute. The clotting reaction was initiated by adding 0.3 units of test thrombin in 0.1 ml of DBA buffer. The clotting time of the mixture was determined with a coagulometer starting from the addition of thrombin. The control was made with a mixture to which 0.1 ml of DBA buffer was added.

By definition, the effective concentration of the substance is determined by a dose-activity curve and compared to the control, the thrombin time is twice the concentration.

The following table lists the results found:

substance(s)	Thrombin time (ED)₂₀₀Expressed in μ M)
substance(s)	Thrombin time (ED)₂₀₀Expressed in μ M)	A	0.04
B	0.06	A	0.04
B	0.06	C	0.15
D	0.03	C	0.15
D	0.03	E	0.09
F	0.03	E	0.09
F	0.03	G	0.03

For example, no acute toxic side effects were observed when compounds a, D, E and G were administered intravenously to mice at a dose of 1 mg/kg. These compounds are therefore well tolerated.

Based on their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the prophylaxis and treatment of venous and arterial thrombotic disorders, for example for the treatment of deep-leg venous thrombosis, for the prophylaxis of reocclusion after bypass surgery or angioplasty (PT (C) A), for the prophylaxis of peripheral arterial disorders such as pulmonary embolism, intravascular coagulation spread, for the prophylaxis of coronary thrombosis, stroke, and for the prophylaxis of collateral circulation obstruction. Furthermore, the compounds of the invention are useful as antithrombotic agents in the treatment of thrombolysis, for example in combination with rt-PA or streptokinase, for the prevention of long-term restenosis after PT (C) A, for the prevention of metastasis and growth of clot-dependent tumors and for the progression of fibrin-dependent inflammation.

The dosages required to achieve this effect are suitably from 0.1 to 30 mg/kg, preferably from 0.3 to 10 mg/kg, for intravenous administration and from 0.1 to 50 mg/kg, preferably from 0.3 to 30 mg/kg, for oral administration, in each case from 1 to 4 times a day. To this end, the compounds of the formula I prepared according to the invention can, if desired together with other active ingredients, be formulated into the usual pharmaceutical preparations, such as tablets in general or coated tablets, capsules, powders, suspensions or suppositories, with one or more customary inert carriers and/or diluents, for example corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethyl cellulose, or fatty substances such as hard fat or suitable mixtures thereof.

The following examples illustrate the invention: front note

Unless otherwise indicated, R_fThe values were determined on a multichannel physiometer-silica gel plate manufactured by E.Merck of Darmstadt.

EKA mass spectrometry (cationic electrospray mass spectrometry) is described, for example, in "Chemie unseser Zeit 6, 308-316 (1991)".

Example 13-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 (7.4mMol) methyl 6-chloro-5-nitronicotinate (Bernie et al, J.chem.Soc.1951, 2590) are stirred in 20 ml of 40% aqueous methylamine solution at room temperature for 30 minutes. The reaction mixture was then diluted with ice water and the yellow precipitate formed was filtered off and dried. Yield: 1.2 g (80% of theory) of R_fThe value: 0.66 (silica gel, ethyl acetate/ethanol/acetic acid ═ 90: 5) b) 5-amino-6-methylamino-nicotinic acid methyl ester

To a solution of 3.1 g (15mMol) of 6-methylamino-5-nitro-nicotinic acid methyl ester in 100 ml of ethanol/dichloromethane (3: 1) was added 1g of palladium on carbon (10%), and the resulting suspension was hydrogenated at room temperature under 5 bar of hydrogen pressure for 1.5 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The crude oil was taken directly to the next reaction. Yield: 2.4 g (92% of theory) R_fThe value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia 90: 10: 1). c)5- [2- (4-cyanophenyl) ethylcarbonylamino]-6-methylamino-nicotinic acid methyl ester

A solution of 2.6 g (15mMol) of 3- (4-cyanophenyl) propionic acid in 25 ml of dry tetrahydrofuran and a mixture of 2.4 g (15mMol) of N, N' -carbonyldiimidazole are stirred at room temperature for 20 minutes. The imidazole compound is then mixed with a solution of 2.3 g (13mMol) 5-amino-6-methylamino-nicotinic acid methyl ester in 25 ml dimethylformamide and heated to 100 ℃ for 3 hours. After removal of the solvent in vacuo, the crude product is dissolved in ethyl acetate, the organic phase is washed with water and, after drying over sodium sulfate, the solvent is removed again. The resulting residue was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol 19: 1). Yield: 2.1 g (50% of theory) of a beige solid. R_fThe value: 0.54 (silica; ethyl acetate/ethanol/ammonia: 90: 10: 1) d) 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]Pyridine-6-carboxylic acid methyl ester

2.0 g (5.9mMol) of 5- [2- (4-cyanophenyl) ethyl acetateAminocarbonylamino]A solution of-6-methylamino-nicotinic acid methyl ester in 50 ml of glacial acetic acid was heated to 100 ℃ for one hour. After removal of the solvent, the residue was dissolved in dichloromethane, washed with sodium bicarbonate solution, dried over sodium sulfate and distilled again to remove the solvent. Yield: 1.7 g of a brown solid (89% of theory) R_fThe value: 0.50 (silica; ethyl acetate/ethanol/ammonia ═ 90: 10: 1) e) 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]Pyridine-6-carboxylic acids

3.2 g (10mMol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]A solution of methyl pyridine-6-carboxylate in 150 ml of methanol and a solution of 1.5 g of lithium hydroxide in 20 ml of water were mixed and stirred at room temperature for 24 hours. The mixture is then diluted with 50 ml of water, the alcohol is distilled off and the aqueous phase is washed with ethyl acetate. The mixture is acidified with dilute hydrochloric acid, extracted several times with dichloromethane/methanol (9: 1), the organic phase is dried over sodium sulfate and the solvent is distilled off. Yield: 2.1 g of beige solid (70% of theory) R_fThe value: 0.38 (silica; ethyl acetate/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

2.0 g (6.5mMol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]A solution of pyridine-6-carboxylic acid in 100 ml of dichloromethane and 20 ml of sulfuryl chloride are mixed and refluxed for 2 hours. After distilling off the liquid component, the crude product was dissolved twice in dichloromethane, and the solvent was distilled off each time. The acid chloride thus obtained (2 g) is suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g (6.5mMol) of N- (2-ethoxycarbonylethyl) aniline. Then 0.73 g (7.2mMol) of triethylamine was added dropwise over 5 minutes. After stirring for 1 hour, the solvent was distilled off in vacuo, the residue was dissolved in ethyl acetate, and the organic phase was washed with water and dried over sodium sulfate. After distillation of the solvent and flash chromatography (silica gel; dichloromethane to dichloromethane/ethanol 49: 1), the desired product is isolated as a brown oil. Yield: 1.9 g (65% of theory) of R_fThe value: 0.44 (silica gel, ethyl acetate/ethanol/ammonia 90: 10: 1) g) 3-methyl-2- [2- (4-amidinophenyl) ethyl esterBase of]Imidazo [4, 5-b)]Pyridine-6-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.8 g (3.7mMol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]Pyridine-6-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide is stirred into 100 l of ethanol saturated with hydrogen chloride for 16 hours, first at 0 ℃ and then at room temperature until no starting material is detectable by TLC. The solvent was then distilled off and the oil residue was dissolved in 50 ml of absolute ethanol and mixed with 3.6 g (37mMol) of ammonium carbonate. After 4 hours, the solvent is distilled off in vacuo and the crude product is purified by flash chromatography (silica gel; gradient; dichloromethane/ethanol 19: 1 to 4: 1) and evaporated. Yield: 1.6 g (80% of theory) of R_fThe value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia: 90: 5)

Example 23-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -imidazo [4, 5-b ] -pyridine-6-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

535 mg (1.0mMol) of 3-methyl-2- [2- (4-amidinophenyl) ethyl]Imidazo [4, 5-b)]A solution of pyridine-6-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide in 10 ml ethanol and 5 ml 2N sodium hydroxide solution were mixed and stirred at room temperature for 2 hours. The mixture 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, whereupon the desired product precipitates as white crystals. Yield: 375 mg (74% of theory) R_fThe value: 0.23 (silica; ethyl acetate/ethanol/ammonia 90: 5) C₂₆H₂₆N₆O₃(470.54) Mass Spectrometry: (M + H)⁺＝471

Example 33-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -imidazo [4, 5-b ] pyridin-6-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride

In analogy to example 1 using 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]Preparation of pyridin-6-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide by methanolizing hydrochloric acid, methanol and ammonium carbonate. Yield: 75% C of theory₂₆H₂₇N₇O₃(485.55)R_fThe value: 0.31 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝486

Example 43-methyl-2- [2- (4-amidinophenyl) ethyl ] -imidazo [4, 5-b ] pyridin-6-yl-carboxylic acid N-phenyl-N-ethoxycarbonylmethyl-amide-hydrochloride

In analogy to example 1 using 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [4, 5-b)]Pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide, methanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 84% C of theory₂₆H₂₈N₆O₃(484.56)R_fThe value: 0.44 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝485

Example 53-methyl-2- [2- (4-amidinophenyl) ethyl ] -imidazo [4, 5-b ] pyridin-6-yl-carboxylic acid N-phenyl-N-hydroxycarbonylmethyl-amide-hydrochloride

In a manner analogous to example 2 using 3-methyl-2- [2- (4-amidinophenyl) ethyl]Imidazo [4, 5-b)]Pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide-hydrochloride and sodium hydroxide solution. Yield: 85% C of theory₂₅H₂₄N₆O₃(456.51)R_fThe value: 0.19 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝457

Example 62- [2- (4-Amidinophenyl) ethyl ] -3-methyl-6- (2-methoxycarbonyl-2, 3-indolin-1-yl-carbonyl) -imidazo [4, 5-b ] pyridine-hydrochloride

In a manner analogous to example 1 with 2- [2- (4-cyanophenyl) ethyl]-3-methyl-6- (2-methoxycarbonyl-2, 3-indolin-1-yl-carbonyl) -imidazo [4, 5-b]Pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 20% C of theory₂₇H₂₆N₆O₃(482.54)R_fThe value: 0.30 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝483

Example 72- [2- (4-Amidinophenyl) ethyl ] -3-methyl-6- (2-carboxy-2, 3-indolin-1-yl-carbonyl) -imidazo [4, 5-b ] pyridine-hydrochloride

In a manner analogous to example 2 with 2- [2- (4-amidinophenyl) ethyl]-3-methyl-6- (2-methoxycarbonyl-2, 3-indolin-1-yl-carbonyl) -imidazo [4, 5-b]Pyridine-hydrochloride and sodium hydroxide solution. Yield: 90% C of theory₂₆H₂₄N₆O₃(468.52)R_fThe value: 0.24 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝469

(M+Na)⁺＝491

Example 81-methyl-2- [2- (4-amidinophenyl) oxymethyl ] -imidazo [4, 5-b ] pyridin-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide a) 2-amino-3-methylamino-6-methyl-pyridine

8.35 g (50mMol) of 2-methyl-5-methylamino-6-nitro-pyridine (Heterocycles 38, 529(1994)) are dissolved in 300 l of ethyl acetate and hydrogenated with 1.5 g of Raney nickel at room temperature for 3.5 h. The catalyst was then filtered off and the filtrate was evaporated. The residue obtained is recrystallized from petroleum ether to give 5.75 g (84% of theory) of olive green crystals. C₇H₁₁N₃(137.20) melting Point: 112 ℃ and 113 ℃ b)1, 5-dimethyl-2- [ (4-cyanophenyl) oxymethyl]Imidazo [4, 5-b)]-pyridine

11.4 g (63mMol) of 4-cyano-phenoxyacetic acid are dissolved in 200 ml of anhydrous tetrahydrofuran and mixed at room temperature with 10.2 g (63mMol) of N, N' -carbonyldiimidazole. After 15 minutes at 60 ℃ 5.70 g (41.5mMol) 2-amino-3-methylamino-6-methyl-pyridine are added. After standing at 60 ℃ for 2 hours, the solvent is distilled off, the crystalline residue is mixed with water, washed with water and dried. Recrystallization from ethanol gives 9.95 g (91% of theory) of white crystals. C₁₆H₁₄N₄O (278.32) mass spectrum: m⁺278c)1, 5-dimethyl-2- [ (4-cyanophenyl) oxymethyl]Imidazo [4, 5-b)]-pyridine-4-N-oxide(s)

2.62 g (10mMol) of 1, 5-dimethyl-2- [ (4-cyanophenyl) -oxymethyl]Imidazo [4, 5-b)]Pyridine was suspended in 125 ml dichloromethane and mixed with 2.62 g (12.7mMol) m-chloroperbenzoic acid to give a clear solution. After standing at room temperature for 2 hours, the solvent was distilled off, and the resulting residue was mixed with a sodium hydrogencarbonate solution. After 30 minutes suction filtration gave the product as a white crystal which was washed with water and dried at 40 ℃. Yield: 2.45 g (83% of theory) of C₁₆H₁₄N₄O₂(294.30) Mass Spectrometry: m⁺294d) 1-methyl-2- [ (4-cyanophenyl) oxymethyl group]-5-hydroxymethyl-imidazo [4, 5-b]Pyridine compound

2.40 g (8.2mMol) of 1, 5-dimethyl-2- [ (4-cyanophenyl) oxymethyl]Imidazo [4, 5-b)]pyridine-4-N-oxide was suspended in 75 ml dichloromethane and mixed with 2.4 ml trifluoroacetic anhydride (16.9mMol) to give a clear solution. After 16 hours at room temperature, the solvent was distilled off and the resulting viscous residue was dissolved in 50 ml of dichloromethane and covered with 50 ml of 2M sodium bicarbonate solution. After stirring vigorously for 3 hours, the precipitate formed is filtered off with suction, washed with water and dried at 40 ℃. Yield: 1.85 g of white powder (78% of theory) C₁₆H₁₄N₄O₂(294.30) melting Point: 172 ℃ e) 1-methyl-2- [ (4-cyanophenyl) oxymethyl]Imidazo [4, 5-b)]-pyridine-5-carbaldehyde

3.65 g (12.5mMol) of 1-methyl-2- [ (4-cyanophenyl) -oxymethyl]-5-hydroxymethyl-imidazo [4, 5-b]Pyridine was dissolved in 500 ml of dichloromethane and mixed with 15.0 g of manganese dioxide. After standing at room temperature for 96 hours, the mixture was filtered through celite, and the solvent was distilled off. The filtrate was evaporated and the crystalline precipitate was triturated with ether, filtered with suction and dried. Yield: 3.05 g of white powder (84% of theory) C₁₆H₁₂N₄O₂(292.30) melting Point: 231 ℃ 234 ℃ f) 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-5-carboxy-imidazo- [4, 5-b]-pyridine

1.25 g (4.3mMol) of 1-methyl-2- [ (4-cyanophenyl) oxymethyl]Imidazo [4, 5-b)]Pyridine-5-carbaldehyde in10 ml of formic acid, mixed with hydrogen peroxide (33%) at 0 ℃. After standing at 4 ℃ for 12 hours, the resulting white precipitate was suction filtered, washed with water and dried at 40 ℃. Yield: 0.81 g (61% of theory) of C₆H₁₂N₄O₃(308.7) g) 1-methyl-2- [ (4-cyanophenyl) oxymethyl group]Imidazo [4, 5-b)]Pyridin-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-methoxycarbonylethyl) -amide

308 mg (1.0mMol) of 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-5-hydroxy-imidazo [4, 5-b]Pyridine was suspended in 5 ml of dimethylformamide and mixed with 303 mg (3.0mMol) of N-methylmorpholine and 321 mg (1.0mMol) of O- (benzotriazol-1-yl) -N-, N, N ', N' -tetramethyl * tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2mMol) of methyl N- (2-pyridyl) -3-amino-propionate in 2 ml of dimethylformamide is added to give a clear solution. After 12 hours at room temperature, the reaction solution was stirred into ice water. After three extractions with ethyl acetate, the combined organic extracts were washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained is chromatographed on silica gel using dichloromethane/ethanol (90: 1 to 25: 1). Yield: 165 mg of white powder (35% of theory) C₂₅H₁₂N₆O₄(407.50) melting Point: 139 ℃ and 140 ℃ h) 1-methyl-2- [ (4-amidinophenyl) oxymethyl]Imidazo [4, 5-b)]-pyridin-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) amide

With 140 mg (0.3mMol) of 1-methyl-2- [ (4-cyanophenyl) oxymethyl]Imidazo [4, 5-b)]Pyridin-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide was reacted with ethanol saturated with hydrogen chloride and ammonium carbonate/ethanol in analogy to example 1 g. The product obtained is purified on silica gel using dichloromethane/ethanol (19: 1 to 4: 1) as the chromatography layer. Yield: 48 mg of a white powder (36% of theory) C₂₆H₂₇N₇O₄(501.57) Mass Spectrometry: (M + H)⁺＝502

Example 92- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide a) 4-fluoro-3-methoxyacetylamino-benzoic acid ethyl ester

A solution of 2.8 g (15.3mMol) of 3-amino-4-fluoro-benzoic acid ethyl ester (reference l.s.fosdick, a.f.dodds, j.amer.chem.soc.65, 2305(1943)) and 1.56 ml (1.85 g ═ 17.0mMol) of methoxyacetyl chloride in 50 ml of chlorobenzene was stirred at 50 ℃ for 1 hour and then refluxed for 15 minutes. The solvent was then removed by distillation in vacuo and the crude product was purified by flash chromatography (silica gel; dichloromethane/ethanol 100: 1). The desired compound starts as an oil body and cures after a few days. Yield: 3.8 g (98% of theory) R_fThe value: 0.38 (silica gel: dichloromethane/ethanol ═ 19: 1) b) ethyl 2-methoxymethyl-benzothiazole-5-carboxylate

3.0 g (11.7mMol) of 4-fluoro-3-methoxyacetamido-benzoic acid and 2.1 g (5.2mMol) of Dictyophora Indusiata (Lawesson's reagent) were refluxed in 90 ml of toluene for 6 hours, mixed with 1.0 Dictyophora Indusiata reagent and heated to 120 ℃ for 6 hours. After the solvent had been exchanged for xylene, the mixture was heated at 180 ℃ for a further 8 hours in a pressurized reactor. The solvent was then removed by distillation in vacuo and the crude product was purified by flash chromatography (silica gel; ethyl acetate/petroleum ether 5: 95) and evaporated. Yield: 2.1 g of yellow crystals (72% of theory) R_fThe value: 0.55 (silica; ethyl acetate/petroleum ether ═ 3: 7) c) 2-methoxymethyl-benzothiazole-5-carboxylic acid

A mixture of 2.1 g (8.36mMol) of ethyl 2-methoxymethyl-benzothiazole-5-carboxylate and 16 ml of 2N sodium hydroxide solution is stirred at room temperature into 60 ml of ethanol for 1 hour. The alcohol was then distilled off, the crude product was dissolved in 20 ml of water, washed with 50 ml of diethyl ether and the aqueous phase was acidified with concentrated hydrochloric acid while cooling with ice. The beige compound thus obtained is filtered off with suction, washed with water and dried. Yield: 1.6 g (86% of theory) R_fThe value: 0.12 (silica; dichloromethane/ethanol ═ 29: 1) d) 2-methoxymethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A suspension of 1.6 g (7.2mMol) 2-methoxymethyl-benzothiazole-5-carboxylic acid in 60 ml dichloromethane and 1.6 ml (2)2mMol) of sulfuryl chloride and refluxing for 1 hour. After 20 minutes the solid dissolved. After distilling the liquid content, the crude product was dissolved twice more in dichloromethane and the solvent was distilled off each time. The crude acid chloride obtained was dissolved in 50 ml of tetrahydrofuran and added dropwise to a mixture of 1.4 g (7.2mMol) of N- (2-ethoxycarbonylethyl) aniline and 3.0 ml (21mMol) of triethylamine in 50 ml of tetrahydrofuran and stirred at room temperature overnight. The solvent is then distilled off in vacuo, the residue is dissolved in 30 ml of dichloromethane, the solution is washed with water and dried over sodium sulfate. The solvent was distilled off and flash-separated (silica; gradient; dichloromethane/ethanol 98.5: 1.5 to 80: 20) to isolate the desired product as a brown oil. Yield: 2.05 g (72% of theory) of R_fThe value: 0.40 (silica; ethyl acetate/petroleum ether ═ 1: 1) e)2- [ N- (4-cyanophenyl) -aminomethyl]-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A mixture of 2.05 g (5.14mMol) 2-methoxymethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) amide and 5.7 ml (5.7mMol) of a 1M solution of boron tribromide in dichloromethane was redissolved in 60 ml dichloromethane and stirred at room temperature for 16 hours. The mixture is then washed with 40ml of saturated sodium bicarbonate solution, the organic phase is dried over sodium sulfate and the solvent is evaporated off. The resulting crude 2-bromomethyl-benzothiazole-5-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide (2.4 g) is dissolved in 5.0 ml of N, N-di-isopropyl-ethylamine and mixed with 0.64 g (5.4mMol) of 4-aminobenzonitrile. After heating at 130 ℃ for 1h, the solvent is evaporated off in vacuo and the crude product is chromatographed (silica gel; gradient: ethyl acetate/petroleum ether 1: 3 to 1: 1) and the eluant evaporated to give an orange foam. Yield: 1.1 g (44% of theory) of R_fThe value: 0.35 (silica; ethyl acetate/petroleum ether ═ 7: 3) f)2- [ N- (4-carbamimidophenyl) -aminomethyl]-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.1 g (2.27mMol) of 2- [ N- (4-cyanophenyl) -aminomethyl]Benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide in 100 ml of hydrogen chloride saturated ethaneThe alcohol is stirred for 5 hours at 0 ℃ and then at room temperature until no starting material is detectable by TLC. The solvent was then distilled off at a maximum bath temperature of 30 ℃ and the oil residue was dissolved in 100 ml of absolute ethanol and mixed with 1.6 g (22mMol) of ammonium carbonate. After stirring at room temperature for 18 h, the solvent was removed by distillation in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol-19: 1 to 4: 1). The eluate was re-evaporated to give the desired compound as a white foam. Yield: 0.77 g (63% of theory) of R_fThe value: 0.19 (silica; dichloromethane/ethanol ═ 3: 7) C₂₇H₂₇N₅O₃S (501.60) mass spectrum: (M + H)⁺＝502

Example 102- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazole-5-carboxylic acid N-phenyl-N- (2-carboxyethyl) -amide

0.45 g (0.84mMol) of 2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide is dissolved in 15 ml ethanol and mixed with 2 ml 2N sodium hydroxide solution and stirred at room temperature for 4 hours. The mixture is then acidified with 3 ml of 2N hydrochloric acid and the solvent is distilled off. The crude product was dissolved in 5 ml of dichloromethane/ethanol (2: 1) and the insoluble sodium chloride was removed by filtration. The desired product was obtained as a yellow foam after removal of the solvent by distillation. Yield: 0.26 g (67% of theory) R_fThe value: 0.47 (silica; methanol/5% aqueous sodium chloride solution ═ 6: 4) C₂₅H₂₃N₅O₃S (473.55) mass spectrum: (M + H)⁺＝474

Example 112- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-dihydrochloride

In analogy to example 9 using 2- [ N- (4-cyanophenyl) -aminomethyl]-benzothiazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide, methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 68% C of theory₂₅H₂₄N₆O₃S(488.57)R_fThe value: 0.13 (silica gel; two)Methyl chloride/ethanol 4: 1+ drops of acetic acid) EKA mass spectrum: (M + H)⁺489 example 122- [2- (4-amidinophenyl) -ethyl]-benzothiazol-5-yl-carboxylic acid N- (2-pyridinyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride

In an analogous manner to example 9, using 2- [2- (4-cyanophenyl) ethyl]-benzothiazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 95% C of theory₂₆H₂₅N₅O₃S(487.58)R_fThe value: 0.20 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝488

Example 132- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride

In an analogous manner to example 9, using 2- [ N- (4-cyanophenyl) -aminomethyl]-benzothiazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 68% C of theory₂₅H₂₄N₆O₃S(488.57)R_fThe value: 0.14 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝489

Example 142- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide-dihydrochloride

In an analogous manner to example 10, using 2- [ N- (4-amidinophenyl) -aminomethyl]-benzothiazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride and sodium hydroxide solution. Yield: 90% C of theory₂₃H₂₀N₆O₃S(460.52)R_fThe value: EKA Mass Spectrometry: (M + H)⁺＝461

(M+Na)⁺＝483

(M+2Na)⁺⁺＝253

Example 152- [ N- (4-amidinophenyl) - -N-methyl-aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride a)2- [ N- (4-cyanophenyl) -N-methyl-aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

Prepared in analogy to example 9 using 4-cyano-N-methyl-aniline and 2-methoxymethyl-benzothiazole-5-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide. Yield: 57% R of theory_fThe value: 0.46 (silica gel; dichloromethane/ethanol ═ 19: 1) b)2- [ N- (4-carbamimidophenyl) -N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 9 using 2- [ N- (4-cyanophenyl) -N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 73% C of theory₂₈H₂₉N₅O₃S(515.64)R_fThe value: 0.90 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺516

Example 162- [ N- (4-Amidinophenyl) -N-methyl-aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In analogy to example 10 using 2- [ N- (4-amidinophenyl) -N-methyl-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 96% C of theory₂₆H₂₅N₅O₃S(487.58)R_fThe value: 0.48(Merck RP-8; methanol/5% NaCl solution 6: 4) EKA Mass Spectrometry: (M + H)⁺＝488

(M+2Na)⁺⁺＝266.5

Example 172- [ (4-Amidinophenyl) sulfanylmethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 9 using 2- [ (4-cyanophenyl) thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 61% C of theory₂₇H₂₆N₄O₃S₂(518.66)R_fThe value: 0.27 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA mass spectrum: (M + H)⁺＝519

Example 182- [ (4-Amidinophenyl) sulfanylmethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 10, using 2- [ (4-amidinophenyl) thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 95% C of theory₂₅H₂₂N₄O₃S₂(490.61)R_fThe value: 0.25(Merck RP-8; methanol/5% NaCl solution 6: 4) EKA Mass Spectrometry: (M + H)⁺＝491

(M+Na)⁺⁺＝513

Example 192- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 9, using 2- [ N- (4-cyanophenyl) -aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylmethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 82% C of theory₂₆H₂₅N₅O₃S(487.58)R_fThe value: 0.21 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝488

Example 202- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide-hydrochloride

In analogy to example 10 using 2- [ N- (4-amidinophenyl) -aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 75% C of theory₂₄H₂₁N₅O₃S(459.53)R_fThe value: 0.14 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝460

(M+Na)⁺⁺＝482

Example 212- [2- (4-Amidinophenyl) ethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 9, using 2- [2- (4-cyanophenyl) ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 80% C of theory₂₈H₂₈N₄O₃S(500.62)R_fThe value: 0.30 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝501

Example 222- [2- (4-Amidinophenyl) ethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 10, starting from 2- [2- (4-amidinophenyl) ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 77% C of theory₂₆H₂₄N₄O₃S(472.57)R_fThe value: 0.18 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA mass spectrum: (M + H)⁺＝501

(M+Na)⁺＝495

(M+N+Na)⁺⁺259

Example 232- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 9, using 2- [ N- (4-cyanophenyl) -carbamic acidBase of]-benzothiazol-5-yl-carboxylic acid-N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 83% C of theory₂₄H₂₉N₅O₃S(467.59)R_fThe value: 0.31 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝468

(2M+H)⁺＝935

Example 242- [ N- (4-Amidinophenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 10, using 2- [ N- (4-amidinophenyl) -aminomethyl]-benzothiazol-5-yl-carboxylic acid-N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 75% C of theory₂₂H₂₅N₅O₃S(439.54)R_fThe value: 0.14 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝440

(M+H+Na)⁺⁺＝231.6

Example 251-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 4-methyloxy-3-nitro-benzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

13.1 g (0.13Mol) of triethylamine are added dropwise to a solution of 24.7 g (0.115Mol) of 4-methylamino-3-nitrobenzoyl chloride and 22.3 g (0.115Mol) of N- (2-ethoxy-carbonylethyl) -aniline in 300 ml of tetrahydrofuran at room temperature over 15 minutes with stirring. After stirring for 2 hours, the solvent was distilled off in a water-jet vacuum and the residue and 700 ml of water were mixed with stirring. The mixture is extracted three times with 200 ml of dichloromethane and the organic extracts are washed twice with 200 ml of 2N hydrochloric acid and twice with 300 ml of water and dried over sodium sulfate. The solvent was then distilled off and the oil product obtained was purified by flash chromatography (1 kg of silica gel; eluent: petroleum ether/ethyl acetate 2: 1).Yield: 35.0 g (82% of theory) R_fThe value: 0.28 (silica gel; dichloromethane/ethanol ═ 50: 1) b) 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide

12.1 g (0.0326Mol) 4-methylamino-3-nitro-benzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide are hydrogenated in 300 ml ethanol and 150 ml dichloromethane after addition of 4 g palladium on carbon (10%) at room temperature under a hydrogen pressure of 5 bar. The catalyst was then filtered off and the filtrate was evaporated. The crude product obtained is used without purification. Yield: 10.6 g (95% of theory) of R_fThe value: 0.19 (silica; dichloromethane/ethanol ═ 50: 1) c) 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide

6.17 g (0.035Mol) of N- (4-cyanophenyl) glycine and 5.68 g (0.035Mol) of N, N' -carbonyldiimidazole are heated under reflux in 300 ml of tetrahydrofuran for 30 minutes, then 10.6 g (0.032Mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonylethyl) amide are added and the mixture is heated under reflux for five hours. The solvent was then distilled off in vacuo and the residue was dissolved in 150 ml of glacial acetic acid and heated under reflux for one hour. The glacial acetic acid is then removed by vacuum distillation, the residue is dissolved in about 300 ml of dichloromethane, and the solution is washed twice with about 150 ml of water and then dried over sodium sulfate. The crude product obtained after removal of the solvent by evaporation was purified by column chromatography (800 g silica gel; eluent: dichloromethane and 1-2% ethanol) yield: 8.5 g (57% of theory) R_fThe value: 0.51 (silica; dichloromethane/ethanol ═ 19: 1) d) 1-methyl-2- [ N- (4-carbamimidophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

1.2 g (2.49mMol) of 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide was stirred in 100 ml of saturated ethanolic hydrochloric acid at room temperature for 6 hours. The mixture was evaporated to dryness in vacuo and the residue was dissolved in 100 ml of ethanol, mixed with 2.5 g (26mMol) of ammonium carbonate and the mixture was evaporated in a chamberStir warm overnight. After removal of the solvent by distillation, the crude product obtained is purified by column chromatography (100 g of silica gel; eluent; dichloromethane/ethanol 4: 1). The eluent was concentrated to give the desired compound as a white solid. Yield: 1.10 g (83% of theory) of R_fThe value: 0.18 (silica; dichloromethane/ethanol 4: 1) C₂₈H₃₀N₆O₃xHCl (498.6) EKA Mass Spectrometry: (M + H)⁺＝499

(M+2H)⁺⁺＝250

(M+H+Na)⁺⁺＝261

Example 261-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

300 mg (0.56mMol) of 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]A mixture of-benzoimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride, 15 ml ethanol, 4 ml water and 120 mg (3.0mMol) sodium hydroxide was stirred at room temperature for two hours. The mixture was then diluted with about 20 ml of water and made weakly acidic with glacial acetic acid. The crystallized product was suction filtered, washed with water and dried in vacuo at 60 ℃. Yield: 250 mg (95% of theory) C₂₆H₂₆N₆O₃(470.5) EKA Mass Spectrometry: (M + H)⁺＝471

(M+H+Na)⁺⁺＝247

(M+2Na)⁺⁺＝258

Example 271-methyl-2- [ (4-amidinophenyl) thiomethyl ] -benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 4-methylamino-3-chloroacetylamino-benzoic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide

1.8 g (5.9mMol) 3-amino-4-methylamino-benzoic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide [ are used analogously to the process for preparing 3-amino-4-ethylamino-benzoic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amidePreparation of]A solution of 1.1 g (6.8mMol) of N, N' -carbonyldiimidazole and 0.65 g (6.9mMol) of chloroacetic acid in 75 ml of tetrahydrofuran is stirred at room temperature for 1 hour. The solvent was then distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; dichloromethane/ethanol 49: 1). Yield: 1.7 g (77% of theory) of yellow oil bodies R_fThe value: 0.58 (silica; ethyl acetate/ethanol/ammonia ═ 90: 10: 1) b) 2-chloromethyl-1-methyl-benzoimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide

1.6 g (4.3mMol) 4-methylamino-3-chloroacetylamino-benzoic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide are heated in 25 ml acetic acid at 100 ℃ for 30 minutes. The solvent was then distilled off and the crude product was dissolved in 40ml of dichloromethane/ethanol (9: 1) and washed with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and evaporated. Yield: 1.5 g (100% of theory) of brown oil bodies R_fThe value: 0.63 (silica; ethyl acetate/ethanol/ammonia ═ 90: 10: 1) c) 1-methyl-2- [ (4-cyanophenyl) thiomethyl]-benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide

A mixture of 1.5 g (4.1mMol) 2-chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide and 0.65 g (4.8mMol) p-cyanothiophenol is heated to 100 ℃ for 1 hour in 10 ml dimethylformamide and 10 ml diisopropylethylamine. The solvent is distilled off in vacuo, the crude product is dissolved in 30 ml of ethyl acetate, washed with 30 ml of water and concentrated and purified by flash chromatography (silica gel; dichloromethane/ethanol (49: 1 to 19: 1); yield: 1.5 g (70% of theory) of brown oil R_fThe value: 0.65 (silica; ethyl acetate/ethanol/ammonia ═ 90: 10: 1) d) 1-methyl-2- [ (4-amidinophenyl) sulfanylmethyl]-benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

1.4 g (3.01mMol) of 1-methyl-2- [ (4-cyanophenyl) -sulfanylmethyl]-benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide in 50 ml of ethanol saturated with hydrogen chloride are stirred at 0 ℃ for 5 hours, after whichStir at room temperature until no starting material was detectable by tlc analysis. The solvent was then distilled off at a maximum bath temperature of 30 ℃ and the oil residue was dissolved in 40ml of absolute ethanol and mixed with 2.8 g of ammonium carbonate. After 18 h the solvent was evaporated in vacuo and flash-chromatographed (silica; dichloromethane/ethanol (19: 1 to 4: 1)). Yield: 1.3 g (83% of theory) of a pale beige solid R_fThe value: 0.29 (silica; ethyl acetate/ethanol/ammonia: 50: 45: 5) C₂₅H₃₁N₆O₃S (481.62) EKA mass spectrum: (M + H)⁺＝482

Example 281-methyl-2- [ (4-amidinophenyl) sulfanylmethyl ] -benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-hydroxycarbonylethyl) -amide-hydrochloride

0.52 g (1.0mMol) of 1-methyl-2- [ (4-carbamimidoylphenyl) -sulfanylmethyl]-benzimidazol-5-yl-carboxylic acid-N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride is dissolved in 15 ml of ethanol and mixed with 5 ml of 2N sodium hydroxide solution and stirred at room temperature for 2 hours. Then 5 ml of water were added, the alcohol was distilled off and acidified with concentrated hydrochloric acid. The water was removed by distillation in vacuo, the crude product was dissolved in 5 ml of ethanol and the insoluble sodium chloride was removed by filtration. The title compound was obtained as a white solid after distillation of the solvent. Yield: 0.43 g (88% of theory) of R_fThe value: 0.19 (silica; ethyl acetate/ethanol/ammonia: 50: 45: 5) C₂₃H₂₇N₅O₃S (453.57) EKA mass spectrum: (M + H)⁺＝454

(M+Na)⁺⁺476

Example 291-methyl-2- [ (4-amidinophenyl) sulfanylmethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methylpropyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 27 using 1-methyl-2- [ (4-cyanophenyl) thiomethyl]-benzimidazol-5-yl-carboxylic acid- (N- (2-methylpropyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate-yield 83% C of theory₂₅H₃₁N₆O₃S(495.65)R_fThe value: 0.30 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝496

Example 301-methyl-2- [ (4-amidinophenyl) thiomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 27, using 1-methyl-2- [ (4-cyanophenyl) thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% C of theory₂₈H₅₉N₅O₃S(515.64)R_fThe value: 0.24 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝516

(M+H+Na)⁺⁺＝269.7

Example 311-methyl-2- [ (4-amidinophenyl) thiomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 28, using 1-methyl-2- [ (4-amidinophenyl) thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide. Yield: 76% C of theory₂₆H₂₅N₅O₃S(487.58)R_fThe value: 0.31 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝488

(M+Na)⁺＝510

Example 321-methyl-2- [ (4-carbamimidoylphenyl) oxymethyl ] -benzimidazol-5-yl-sulfonic acid N- (1-methyl-piperidin-4-yl) -N-methyl-amide-hydrochloride a) 4-chloro-3-nitrobenzenesulfonic acid N- (1-methyl-piperidin-4-yl) -N-methyl-amide

To a solution of 2.2 ml (15mMol) of 1-methyl-4-methylamino-piperidine in 60 ml of pyridine were added in portions 3.8 g (15mMol) of 4-chloro-3-nitro-benzenesulfonyl chloride under ice-cooling. The mixture was then stirred for 2 hours with cooling, evaporated to dryness and leftThe residue was mixed with about 50 ml of water and made basic with concentrated ammonia while stirring vigorously. The crude product precipitated was filtered off with suction and purified by column chromatography (250 g of silica gel, eluent: dichloromethane and 1.5% ethanol). Yield: 1.6 g (31% of theory) of C₁₃H₁₈ClN₃O₄S(347.8)R_fThe value: 0.19 (silica; dichloromethane/ethanol ═ 19: 1) b) 4-methylamino-3-nitrobenzenesulfonic acid-N-methyl-N- (1-methyl-piperidin-4-yl) -amide

1.6 g (4.6mMol) of 4-chloro-3-nitrobenzenesulfonic acid-N-methyl-N- (1-methyl-piperidin-4-yl) -amide and 30 ml of a 40% methylamine solution are mixed and stirred in a sealed flask at room temperature for four hours. The mixture was diluted with about 40ml of water, and the precipitated crude product was suction filtered, washed with water and dried. Yield: 1.5 g (95% of theory) of C₁₄H₂₂N₄O₄S(343.4)R_fThe value: 0.45 (silica; dichloromethane/ethanol ═ 4: 1) c) 3-amino-4-methylaminobenzenesulfonic acid-N-methyl-N- (1-methyl-piperidin-4-yl) -amide

1.5 g (4.4mMol) of 4-methylamino-3-nitrobenzenesulfonic acid-N-methyl-N- (1-methyl-piperidin-4-yl) -amide are dissolved in 100 ml of methanol and catalytically hydrogenated at room temperature under a hydrogen pressure of 5 bar (10% palladium on carbon). The catalyst was then removed by filtration and the filtrate was evaporated. The crude product formed is used without purification. Yield: 1.4 g (100% of theory) of C₁₄H₂₄N₄O₂S(312.4)R_fThe value: 0.33 (silica; 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 (3.0mMol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0mMol) of 1, 1' -carbonyldiimidazole are dissolved in 40ml of tetrahydrofuran and heated under reflux for 15 minutes. 700 mg (2.24mMol) of 3-amino-4-methylaminobenzenesulfonic acid-N-methyl-N- (1-methyl-piperidin-4-yl) -amide are then added and boiling is continued for a further 8 hours. The mixture was then evaporated and the resulting oil residue refluxed in 30 ml of glacial acetic acid for one hour. The glacial acetic acid is distilled off and the residue is taken up with 30 mmThe water is mixed with liters and made basic with concentrated ammonia and the solution is extracted three times with about 20 ml of dichloromethane each time. The organic phase was dried and evaporated. The product obtained is used without purification. Yield: 400 mg (39% of theory) C₂₃H₂₇N₅O₃S(453.6)R_fThe value: 0.37 (silica; dichloromethane/ethanol ═ 4: 1) e) 1-methyl-2- [ (4-amidinophenyl) oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N- (1-methyl-piperidin-4-yl) -amide-hydrochloride

In a manner analogous to example 25d, using 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. Yield: 370 mg (83% of theory) of C₂₃H₃₀N₆O₃S (470.6) EKA mass spectrum: (M + H)⁺＝471

(M+2H)⁺⁺＝236

Example 331-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-sulfonic acid N-methyl-N-phenyl-amide-hydrochloride

In analogy to example 32, using 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl-sulfonic acid-N-methyl-N-phenyl-amide and ethanolic hydrochloric acid, ethanol with ammonium carbonate. Yield: 46% C of theory₂₃H₂₃N₅O₃S (449.5) EKA mass spectrum: (M + H)⁺450

(M + H + methanol)⁺＝482

(M+2H)⁺⁺＝223

Example 341-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-sulfonic acid N- (3-ethoxycarbonyl-N-propyl) -N-phenyl-amide-hydrochloride

In analogy to example 32, using 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl-sulfonic acid-N- (3-ethoxycarbonyl-N-propyl) -N-phenyl-amide and ethanolic hydrochloric acid, ethanol and carbonic acidAnd (4) preparing ammonium. Yield: 57% C of theory₂₈H₃₁N₅O₅S (549.7) EKA mass spectrum: (M + H)⁺＝550

Example 351-methyl-2- [ (3-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-sulfonic acid-pyrrolidinamide (pyrrolidid) -hydrochloride

In analogy to example 32, using 1-methyl-2- [ (3-cyanophenyl) oxymethyl]-benzimidazol-5-yl-sulfonic acid-pyrrolidinamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: theoretical yield 71% C₂₀H₂₃N₅O₃S (413.5) EKA mass spectrum: (M + H)⁺Example 361-methyl-2- [2- (4-amidinophenyl) ethyl ═ 414]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-methoxycarbonylpropyl) -amide-dihydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [2- (4-cyanophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-tert-butoxycarbonylpropyl) -amide, methanolic hydrochloric acid, methanol with ammonium carbonate. Yield: 83.5% R of theory_fThe value: 0.17 (silica; dichloromethane/ethanol 4: 1) C₂₉H₃₁N₅O₃(497.6) EKA Mass Spectrometry: (M + H)⁺＝498

(M+H+Na)⁺⁺＝260.7

Example 371-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide-hydrochloride

In analogy to example 26 using 1-methyl-2- [ (4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-methoxycarbonylpropyl) -amide-dihydrochloride and sodium hydroxide solution. Yield: 92% R of theory_fThe value: 0.09 (silica; dichloromethane/ethanol 4: 1) C₂₈H₂₉N₅O₃(483.6) EKA Mass Spectrometry: (M + H)⁺＝484

(M+Na)⁺＝506

(M+H+Na)⁺⁺＝253.7

Example 381-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-ethoxycarbonylpropyl) -amide-dihydrochloride a) 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide

Prepared in analogy to example 25c using N- (4-cyanophenyl) -glycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide. Yield: 65% R of theory_fThe value: 0.17 (silica; dichloromethane/methanol ═ 19: 1) b) 1-methyl-2- [ N- (4-carbamimidophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-ethoxycarbonylpropyl) -amide-dihydrochloride

In analogy to example 25d using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-tert-butyloxycarbonylpropyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 68% R of theory_fThe value: 0.12 (silica; dichloromethane/ethanol 4: 1) C₂₉H₃₂N₆O₃(512.6) EKA Mass Spectrometry: (M + H)⁺＝513

(M+H+Na)⁺⁺＝268

Example 391-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide-hydrochloride

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-ethoxycarbonylpropyl) -amide-dihydrochloride and sodium hydroxide solution. Yield: 73.5% C of theory₂₇H₂₈N₆O₃(484.6) EKA Mass Spectrometry: (M + H)⁺＝485

(M+2H)⁺⁺＝243

(M+H+Na)⁺⁺＝254

Example 401-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [2- (4-cyanophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 73% R of theory_fThe value: 0.15 (silica; dichloromethane/ethanol 4: 1) C₂₈H₂₉N₅O₃(483.6) EKA Mass Spectrometry: (M + H)⁺＝484

(M+H+Na)⁺⁺＝253.7

Example 411-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 26, using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 97% C of theory₂₆H₂₅N₅O₃(455.5) EKA Mass Spectrometry: (M + H)⁺＝456

(M+Na)⁺＝478

(M+2Na)⁺⁺＝250.6

Example 421-methyl-2- [ (4-carbamimidoylphenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride

In analogy to example 25d, using 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 76% R of theory_fThe value: 0.17 (silica; dichloromethane/ethanol 4: 1) C₂₇H₂₇N₅O₄(485.6) EKA Mass Spectrometry: (M + H)⁺＝486

(M+H+Na)⁺⁺＝254.7

Example 431-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide-hydrochloride

In a manner analogous to example 26, using 1-methyl-2- [ (4-amidinophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 58% C of theory₂₅H₂₃N₅O₄(457.5) EKA Mass Spectrometry: (M + H)⁺＝458

(M+Na)⁺＝480

(M+2Na)⁺⁺＝251.6

Example 441-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% R of theory_fThe value: 0.12 (silica; dichloromethane/ethanol 4: 1) C₂₇H₂₈N₆O₃(484.6) EKA Mass Spectrometry: (M + H)⁺＝485

(M+H+Na)⁺⁺＝254

Example 451-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (hydroxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (ethoxycarbonylmethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 84% C of theory₂₅H₂₄N₆O₃(456.5) EKA Mass Spectrometry: (M + H)⁺＝457

(M+Na)⁺＝479

(M+2Na)⁺⁺＝251

Example 461-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N- (4-pyrimidinyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d, using 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N- (4-pyrimidinyl) -N- (2-ethoxycarbonylethyl) amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 14% C of theory₂₆H₂₇N₇O₄(501.6) EKA Mass Spectrometry: (M + H)⁺＝502

Example 471-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride

In analogy to example 25d, using 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 44% R of theory_fThe value: 0.12 (silica; dichloromethane/ethanol 4: 1) C₂₆H₂₆N₆O₄(486.5) EKA Mass Spectrometry: (M + H)⁺＝487

(M+2H)⁺⁺＝244

(M+H+Na)⁺⁺＝255

Example 481-methyl-2- [ (4-carbamimidoylphenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide-hydrochloride

In a manner analogous to example 26, using 1-methyl-2- [ (4-amidinophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride and sodium hydroxide solution. Yield: 85% C of theory₂₄H₂₂N₆O₄(458.5) EKA Mass Spectrometry: (M + H)⁺＝459

(M+Na)⁺＝481

(M+2Na)⁺⁺＝252

Example 491-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride a) 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide

Prepared in analogy to example 25c using N- (4-cyanophenyl) -glycine and 3-amino-4-methylamino-benzoic acid-N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide. Yield: 24% R of theory_fThe value: 0.56 (silica; dichloromethane/methanol ═ 4: 1) b) 1-methyl-2- [ N- (4-carbamimidophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 70% R of theory_fThe value: 0.16 (silica; dichloromethane/ethanol 4: 1) C₂₆H₂₇N₇O₃(485.6) EKA Mass Spectrometry: (M + H)⁺＝486

(M+2H)⁺⁺＝243.7

(M+H-Na)⁺⁺＝254.6

Example 501-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide dihydrochloride and hydrogen hydroxideSodium solution preparation. Yield: 91% C of theory₂₄H₂₃N₇O₃(457.5) EKA Mass Spectrometry: (M + H)⁺＝458

(M+Na)⁺＝480

(M+2Na)⁺⁺＝251.7

Example 511-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [2- (4-cyanophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% R of theory_fThe value: 0.17 (silica; dichloromethane/ethanol 4: 1) C₂₇H₂₈N₆O₃(484.6) EKA Mass Spectrometry: (M + H)⁺＝485

(M+2H)⁺⁺＝243

(M+H+Na)⁺⁺＝254

Example 521-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 26, using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-dihydrochloride and sodium hydroxide solution. Yield: 89% C of theory₂₅H₂₄N₆O₃(456.5) EKA Mass Spectrometry: (M + H)⁺＝457

(M+Na)⁺＝479

Example 531-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d, with 1-methyl-2-[ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 87% R of theory_fThe value: 0.11 (silica; dichloromethane/ethanol 4: 1) C₂₇H₂₈N₆O₃(484.6) EKA Mass Spectrometry: (M + H)⁺＝485

(M+2H)⁺⁺＝243

(M+H+Na)⁺⁺＝254

Example 541-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d, using 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 79.5% C of theory₂₈H₂₉N₅O₄(499.6)R_fThe value: 0.15 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝500.0

(M+H+Na)⁺⁺＝261.7

Example 551-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 26, using 1-methyl-2- [ (4-amidinophenyl) oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 82% C of theory₂₆H₂₅N₅O₄(471.5)R_fThe value: 0.11 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝472

(M+H+Na)⁺⁺＝247.6

(M+Na)⁺＝494

(M+2Na)⁺⁺＝258.6

Example 561-methyl-2- [2- (2-amidinophenylthio-5-yl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 1-methyl-2- [2- (2-cyanophenylthio-5-yl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethylhydroxycarbonylethyl) -amide

Prepared in analogy to example 25c using 3- (2-cyanophenylthio-5-yl) -propionic acid and 3-amino-4-methylamino-benzoic acid-N- (2-pyridyl) N- (2-ethoxycarbonylethyl) amide. Yield: 18% R of theory_fThe value: 0.66 (silica; dichloromethane/methanol ═ 9: 1) b) 1-methyl-2- [2- (2-amidinophenylthio-5-yl) ethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d using 1-methyl-2- [2- (2-cyanophenylthio) -5-yl ] ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 53% C of theory₂₆H₂₂N₆O₃S(504.6)R_fThe value: 0.22 (silica; dichloromethane/ethanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝505

(M+H+Na)⁺⁺＝264

Example 571-methyl-2- [2- (2-amidinophenylthio-5-yl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-methyl-2- [2- (2-amidinophenylthio-5-yl) ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 98% C of theory₂₄H₂₄N₆O₃S (476.6) EKA mass spectrum: (M + H)⁺＝477

(M+Na)⁺＝499

(M+2H)⁺⁺＝239

Example 581-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Prepared in analogy to example 25c using N- (4-cyanophenyl) -glycine and 3-amino-4-methylamino-benzoic acid-N- (2-pyridinyl) N- (2-ethoxycarbonylethyl) -amide. Yield: 61% R of theory_fThe value: 0.62 (silica gel; dichloromethane/ethanol ═ 19: 1) b) 1-methyl-2- [ N- (4-carbamimidophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In a similar manner to example 25d-, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 71% C of theory₂₇H₂₉N₇O₃(499.6)R_fThe value: 0.28 (silica; dichloromethane/ethanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝500

(M+H+Na)⁺⁺＝261.8

(M+2H)⁺⁺＝250.8

Example 591-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 91% C of theory₂₅H₂₅N₇O₃(471.5) EKA Mass Spectrometry: (M + H)⁺＝472

(M+H+Na)⁺⁺＝247.6

(M+2H)⁺⁺＝236.7

(M+2Na)⁺⁺＝258.6

Example 601-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 1-methyl-2- [2- (4-cyanophenyl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Prepared in analogy to example 49a using 3- (4-cyanophenyl) -propionic acid and 3-amino-4-methylamino-benzoic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide. Yield: 22% R of theory_fThe value: 0.68 (silica; dichloromethane/methanol ═ 19: 1) b) 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d using 1-methyl-2- [2- (4-cyanophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 85% C of theory₂₈H₃₀N₆O₃(498.6)R_fThe value: 0.30 (silica; dichloromethane/methanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝499

(M+H+Na)⁺⁺＝261

Example 611-methyl-2- [2- (4-carbamimidoylphenyl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-methyl-2- [2- (4-carbamimidoylphenyl) -ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 97% C of theory₂₆H₂₆N₆O₃(470.5) EKA Mass Spectrometry: (M + H)⁺＝471

(M+H+Na)⁺⁺＝247

(M+Na)⁺＝493

Example 621-methyl-2- [2- (4-carbamimidoylphenyl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride

In an analogous manner to example 25d using 1-methyl-2- [2- (4-cyanophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% C of theory₂₉H₃₁N₅O₃(497.6)R_fThe value: 0.11 (silica; dichloromethane/methanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝498

(M+2H)⁺⁺＝249.8

Example 631-methyl-2- [2- (4-carbamimidoylphenyl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 26, using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide solution. Yield: 71% C of theory₂₇H₂₇N₅O₃(469.6) EKA Mass Spectrometry: (M + H)⁺＝470

(M+H+Na)⁺⁺＝246.6

(M+Na)⁺＝492

(M+2H)⁺⁺＝235.6

Example 641-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (methoxycarbonylmethyl) -amide-dihydrochloride

In analogy to example 25d using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (methoxycarbonylmethyl) -amide andmethanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 73% C of theory₂₅H₂₅N₇O₃(471.5)R_fThe value: 0.12 (silica; dichloromethane/methanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝472

(M+H+Na)⁺⁺＝247.8

Example 651-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 78% C of theory₂₆H₂₇N₇O₃(485.6)R_fThe value: 0.31 (silica; dichloromethane/methanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝486

(M+H+Na)⁺⁺＝254.8

Example 661-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

Prepared in analogy to example 25c using 3- (4-cyanophenyl) -propionic acid and 3-amino-4-methylamino-benzoic acid-N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl ] -amide. Yield: 67% IR value (KBr) of theoretical: characteristic zone is located 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

In a manner analogous to example 25d, using1-methyl-2- [2- (4-cyanophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl]Amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 92% C of theory₂₇H₂₇N₉O₃(493.6) EKA Mass Spectrometry: (M + H)⁺＝494

(M+Na)⁺＝516

(M+2H)⁺⁺＝258.7

Example 671-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl ] -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 29% C of theory₂₆H₂₆N₁₀O (494.6) EKA mass spectrum: (M + H)⁺＝495

Example 681-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-N-hexyloxycarbonylethyl) -amide-hydrochloride

0.60 g (1.1mMol) of 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride was added to about 30 ml of N-hexanol saturated with hydrogen chloride and the mixture was stirred at room temperature for 19 hours. The hexanol was then distilled off in vacuo and the residue was mixed with about 5 ml of 1N ammonia solution with stirring and evaporated again. The crude product was purified by column chromatography (silica gel, 5: 1 dichloromethane/methanol). Yield: 53% C of theory₃₁H₃₇N₇O₃(555.7)R_fThe value: 0.36 (silica gel, 5: 1 dichloromethane/methanol) EKA mass spectrum: (M + H)⁺＝556

Example 691-methyl-2- [ N- (4-amidinophenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 1-methyl-2- [ N- (4-cyanophenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Prepared in analogy to example 25c using N- (4-cyanophenyl) -N-methylglycine and 3-amino-4-methylamino-benzoic acid-N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) -amide. Yield: 71% R of theory_fThe value: 0.66 (silica gel, 19: 1. dioxymethane/methanol) b) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 77% C of theory₂₈H₃₁N₇O₃(513.6) EKA Mass Spectrometry: (M + H)⁺＝514

(M+H+Na)⁺⁺＝268.7

Example 701-methyl-2- [ N- (4-amidinophenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 66% C of theory₂₆H₂₇N₇O₃(485.6) EKA Mass Spectrometry: (M + H)⁺＝486

(M+Na)⁺＝508

(M+2Na)⁺⁺＝265.6

Example 711-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 65% C of theory₂₈H₃₅N₅O₃(489.6) EKA Mass Spectrometry: (M + H)⁺490

Example 721-methyl-2- [2- (4-amidinophenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-hydroxycarbonylethyl) -amide

In analogy to example 26 using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 89% C of theory₂₆H₃₁N₅O₃(461.6) EKA Mass Spectrometry: (M + H)⁺＝462

(M+H+Na)⁺⁺＝242.6

(M+Na)⁺＝484

(M+2H)⁺⁺＝231.6

Example 731-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 60% C of theory₂₇H₃₄N₆O₃(490.6) EKA Mass Spectrometry: (M + H)⁺＝491

Example 741-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-cyclopentyl-N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-methyl-2- [ N- (4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acids-N-cyclopentyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 45% C of theory₂₅H₃₀N₃O₄(462.6) EKA Mass Spectrometry: (M + H)⁺＝463

(M+H+Na)⁺⁺＝243

(M+Na)⁺＝485

(M+2Na)⁺⁺＝254

Example 751-methyl-2- [ N- (4-amidinophenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 54% C of theory₂₇H₂₉N₇O₄(499.6) EKA Mass Spectrometry: (M + H)⁺＝400

(M+2H)⁺⁺＝250.7

Example 761-methyl-2- [ N- (4-amidinophenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylmethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (ethoxycarbonylmethyl) -amide-hydrochloride and sodium hydroxide. Yield: 68% C of theory₂₅H₂₅N₇O₄(471.5) EKA Mass Spectrometry: (M + H)⁺＝472

(M+Na)⁺＝243

(M+2Na)⁺⁺＝258.6

Example 771-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [2- (4-cyanophenyl) -ethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 91% C of theory₂₈H₃₀N₆O₃(498.6)R_fThe value: 0.19 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝499

Example 781-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-dihydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% C of theory₂₇H₂₉N₇O₃(499.6)R_fThe value: 0.09 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝500

Example 791-methyl-2- [ N- (4-carbamimidoylphenyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-dihydrochloride and sodium hydroxide solution. Yield: 85% C of theory₂₅H₂₅N₇O₃(471.5) EKA Mass Spectrometry: (M + H)⁺＝472

(M+2H)⁺⁺＝236.6

(M+2Na)⁺⁺＝258.6

Example 801-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d using 1-methyl-2- [ N- (4-cyanophenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 64% C of theory₂₈H₃₁N₇O₃(513.6) EKA Mass Spectrometry: (M + H)⁺＝514

Example 811-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 70% C of theory₂₆H₂₇N₇O₃(485.6) EKA Mass Spectrometry: (M + H)⁺＝486

(M+Na)⁺＝.508

(M+2Na)⁺⁺＝265.6

Example 821-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 1-methyl-2- [ N- (4-cyanophenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

Prepared in analogy to example 25c using N- (4-cyanophenyl) -N-methylglycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide. Yield: 71% R of theory_fThe value: 0.38 (silica; dichloromethane/methanol ═ 19: 1) b) 1-methyl-2- [ N- (4-carbamimidophenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -N-methylRadical-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% C of theory₂₉H₃₂N₆O₃(512.6) EKA Mass Spectrometry: (M + H)⁺＝513

(M+H+Na)⁺⁺＝268

(M+2H)⁺⁺＝257

Example 831-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 80% C of theory₂₇H₂₈N₆O₃(484.6) EKA Mass Spectrometry: (M + H)⁺＝485

(M+H+Na)⁺⁺＝254

(M+Na)⁺＝507

(M+2Na)⁺⁺＝265

Example 841-Ethyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d using 1-ethyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 85% C of theory₂₈H₃₁N₇O₃(513.6)R_fThe value: 0.21 (silica; dichloromethane/ethanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝514

(M+H+Na)⁺⁺＝268.6

(M+2H)⁺⁺＝257.7

Example 851-Ethyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-ethyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and 2N sodium hydroxide solution. Yield: 49% C of theory₂₆H₂₇N₇O₃(485.6) EKA Mass Spectrometry: (M + H)⁺＝486

(M+H+Na)⁺⁺＝254.6

(M+2H)⁺⁺＝243.6

(M+2Na)⁺⁺＝265.7

Example 861-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 88% C of theory₂₈H₂₉FN₆O₃(516.6)R_fThe value: 0.08 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝517

(M+H+Na)⁺⁺＝270

(M+2H)⁺⁺＝259

Example 871-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-fluorophenyl)) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 45% C of theory₂₆H₂₅N₆O₃(488.5)R_fThe value: 0.05 (silica; dichloromethane/ethanol 4: 1) EKA mass spectrum: (M + H)⁺＝489

(M+H+Na)⁺⁺＝267

(M+2H)⁺⁺＝256

Example 881-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 79% C of theory₂₉H₃₂N₆O₃(512.6)R_fThe value: 0.10 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝513

(M+H+Na)⁺⁺＝268

Example 891-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-methylphenyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-methylphenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 62% C of theory₂₇H₂₈N₆O₃(484.6) EKA Mass Spectrometry: (M + H)⁺＝485

(M+H+Na)⁺⁺＝254

(M+Na)⁺＝507

(M+2Na)⁺⁺＝265

Example 901-methyl-2- [ N- (4- (N-N-hexyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.1 g (2.06mMol) of 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride was dissolved in a mixture of 40ml of tetrahydrofuran and 10 ml of water, and then 570 mg (4.12mMol) of potassium carbonate and 362 mg (2.2mMol) of N-hexyl chloroformate were added and stirred at room temperature for two hours. The solvent is then distilled off, the residue is mixed with about 50 ml of saturated aqueous saline solution and the resulting solution is extracted three times with 20 ml of dichloromethane each time. The extract was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (100 g silica; dichloromethane + 5% ethanol). Yield: 78% C of theory₃₅H₄₂N₆O₅(626.8)R_fThe value: 0.49 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝627

(M+H+Na)⁺⁺＝325

(M+2H)⁺⁺＝314

Example 911-methyl-2- [ N- [4- (N-methoxycarbonylamidino) phenyl ] -amino-methyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and methyl chloroformate. Yield: 41% C of theory₃₀H₃₂N₆O₅(566.6)R_fThe value: 0.85 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝557

(M+H+Na)⁺⁺＝290

(M+Na)⁺＝579

Example 921-methyl-2- [ N- [4- (N-ethoxycarbonylamidino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride and ethyl chloroformate. Yield: 62% C of theory₃₀H₃₂N₆O₅(556.6)R_fThe value: 0.51 (silica; 19: 1 dichloromethane/ethanol) EKA Mass Spectrometry: (M + H)⁺＝557

(M+H+Na)⁺⁺＝290

(M+2H)⁺⁺＝279

Example 931-methyl-2- [ N- [4- (N-cyclohexyloxycarbonylamino) phenyl ] - [ aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride and cyclohexyl chloroformate. Yield: 25% C of theory₃₄H₃₈N₆O₃(610.7)R_fThe value: 0.44 (silica; 19: 1 dichloromethane/ethanol) EKA Mass Spectrometry: (M + H)⁺＝611

(M+2H)⁺⁺＝306

Example 941-methyl-2- [ N- [4- [ N- [2- (methylsulfonyl) ethoxycarbonyl ] amidino ] phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and 2- (methylsulfonyl) -ethyl chloroformate. Yield: 66% C of theory₃₂H₃₆N₆O₇S(648.8)R_fThe value: 0.44 (silica gel; dichloromethane/ethyl acetate)Alcohol 19: 1) EKA mass spectrum: (M + H)⁺＝649

(M+H+Na)⁺⁺＝336

(M+2H)⁺⁺＝325

Example 951-methyl-2- [ N- [4- (N-N-octyloxycarbonylamino) phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-octyl chloroformate. Yield: 41% C of theory₃₆H₄₄N₆O₅(640.8)R_fThe value: 0.43 (silica; 19: 1 dichloromethane/ethanol) EKA Mass Spectrometry: (M + H)⁺＝641

(M+Na)⁺＝663

Example 961-methyl-2- [ N- [4- (N-hydroxycarbamimidoyl) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.44 g (3.0mMol) of 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, 0.625 g (9.0mMol) hydroxylamine hydrochloride and 0.425 g (4.0mMol) sodium carbonate in 80 ml ethanol and refluxed for 7 hours. 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate are then added, and the mixture is boiled for a further 5 hours and then evaporated in vacuo. The residue was dissolved in about 30 ml of dichloromethane, the solution was washed with 20 ml of water, the organic phase was dried and evaporated. The crude product obtained is purified by column chromatography (200 g of silica gel; dichloromethane + 4% ethanol). Yield: 39% C of theory₂₈H₃₀N₆O₄(514.6)R_fThe value: 0.15 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝515

(M+Na)⁺＝537

(2M+H)⁺＝1029

(2M+Na)⁺＝1051

Example 971-methyl-2- [ N- [4- (N-N-heptyloxycarbonylamidino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-heptyl chloroformate. Yield: 43% C of theory₃₅H₄₂N₆O₅(626.8)R_fThe value: 0.40 (silica; 19: 1 dichloromethane/ethanol) EKA Mass Spectrometry: (M + H)⁺＝627

(M+H+Na)⁺⁺＝325

(M+Na)⁺＝649

Example 981-methyl-2- [ N- [4- (N-benzoylamidino) phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride and benzoyl chloride. Yield: 88% C of theory₃₄H₃₂N₆O₄(588.7)R_fThe value: 0.37 (silica gel; dichloromethane/ethanol ═ 19: 1)¹H-NMR Spectroscopy (D)₆-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 991-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 54% C of theory₃₄H₄₀N₆O₅(612.7)R_fThe value: 0.45 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝613

Example 1001-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-N-propoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-N-propoxycarbonylethyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 31% C of theory₃₆H₄₄N₆O₅(640.8)R_fThe value: 0.42 (silica gel; dichloromethane/ethanol 19: 1) EKA mass spectrum: (M + H)⁺＝641

(M+H+Na)⁺⁺＝332

(M+Na)⁺＝663

Example 1011-methyl-2- [ N- [4- (N-ethoxycarbonylamidino) phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and ethyl chloroformate. Yield: 72% C of theory₂₉H₃₁N₇O₅(557.6)R_fThe value: 0.58 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝558

(M+H+Na)⁺⁺＝290.8

(M+Na)⁺＝580

Example 1021-methyl-2- [ N- [4- (N-N-octyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-octyl chloroformate. Yield: 57% C of theory₃₅H₄₃N₇O₅(641.8)R_fThe value: 0.60 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝642

(M+H+Na)⁺⁺＝332.8

(M+Na)⁺＝664

Example 1031-methyl-2- [ N- [4- (N-methoxycarbonylamidino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and methyl chloroformate. Yield: 48% C of theory₂₉H₃₁N₇O₅(557.6)R_fThe value: 0.62 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝558

(M+H+Na)⁺⁺＝290.7

(M+Na)⁺Example 1041-methyl-2- [ N- [4- (N-octyloxycarbonylamino) phenyl ═ 580]-aminomethyl group]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

0.7 g (1.1mMol) of 1-methyl-2- [ N- [4- (N-N-octylcarbonylamidyl) -phenyl]-aminomethyl group]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide is stirred at room temperature in a mixture of 0.12 g (3.0mMol) sodium hydroxide, 5 ml water and 10 ml methanolFor 1 hour. The mixture was then diluted with 20 ml of water and the pH adjusted to 6 with glacial acetic acid. About 5 ml of diethyl ether were then added and the mixture was stirred vigorously for one hour. The crude product precipitated out was suction filtered, washed with a little water and then diethyl ether and dried. Yield: 80% C of theory₃₄H₄₁N₇O₅(627.8) EKA Mass Spectrometry: (M + H)⁺＝628

(M+H+Na)⁺⁺＝325.7

(M+Na)⁺＝650

(M+2Na)⁺⁺＝337.7

Example 1051-methyl-2- [ N- [4- [ N- (2-methylsulfonyl-ethoxycarbonyl) amidino ] -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and 2- (methylsulfonyl) -ethyl chloroformate. Yield: 65% C of theory₃₁H₃₅N₇O₇S(649.7)R_fThe value: 0.54 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝650

(M+H+Na)⁺⁺＝336.6

(M+Na)⁺＝672

(M+2Na)⁺⁺＝347.6

Example 1061-methyl-2- [ N- [4- (N-N-butyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-butyl chloroformate.Yield: 30% C of theory₃₁H₃₅N₇O₅(585.7)R_fThe value: 0.62 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝586

(M+H+Na)⁺⁺＝304.7

(M+2H)⁺⁺＝293.7

Example 1071-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 51% C of theory₃₃H₃₉N₇O₅(613.7)R_fThe value: 0.56 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝614

(M+H+Na)⁺⁺＝318.7

(M+2H)⁺⁺＝307.6

Example 1081-methyl-2- [ N- [4- (N-N-heptyloxycarbonylamidino) -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-heptyl chloroformate. Yield: 21% C of theory₃₄H₄₁N₇O₅(627.8)R_fThe value: 0.60 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝628

(M+H+Na)⁺⁺＝325.7

(M+2H)⁺⁺＝314.7

Example 1091-methyl-2- [ N- [4- (N-N-pentyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-pentyl chloroformate. Yield: 66% C of theory₃₂H₃₇N₇O₅(599.7)R_fThe value: 0.58 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝600

(M+H+Na)⁺⁺＝311.7

(M+Na)⁺＝622

Example 1101-methyl-2- [ N- [4- (N-N-nonyloxycarbonylamidino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and N-nonyl chloroformate. Yield: 60% C of theory₃₆H₄₅N₇O₅(655.8)R_fThe value: 0.48 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝656

(M+H+Na)⁺⁺＝339.8

(M+Na)⁺＝678

Example 1111-methyl-2- [ N- [4- (N-benzoylamidino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonyl ethylYl) -amide-hydrochloride and benzoyl chloride. Yield: 62% C of theory₃₃H₃₁N₇O₄(589.7)R_fThe value: 0.50 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝590

(M+Na)⁺＝612

Example 1121-methyl-2- [ N- [4- (N-nicotinoylamidino) phenyl ] aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and nicotinic acid chloride. Yield: 40% C of theory₃₂H₃₀N₈O₄(590.7)R_fThe value: 0.47 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝591

(M+H+Na)⁺⁺＝307

(M+Na)⁺＝613

Example 1131-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 51% C of theory₃₄H₄₁N₇O₅(627.8)R_fThe value: 0.53 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝628

(M+H+Na)⁺⁺＝325.7

(M+2H)⁺⁺＝314.7

Example 1141-methyl-2- [ N- [4- (N-N-octyloxycarbonylamino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-octyl chloroformate. Yield: 57% C of theory₃₆H₄₅N₇O₅(655.8)R_fThe value: 0.46 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝656

(M+H+Na)⁺⁺＝339.7

(M+2H)⁺⁺＝328.7

Example 1151-methyl-2- [ N- [4- (N- (2-methylsulfonyl-ethoxycarbonyl) amidino ] -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide-hydrochloride and 2- (methylsulfonyl) -ethyl chloroformate. Yield: 72% C of theory₃₀H₃₃N₇O₇(635.7)R_fThe value: 0.23 (silica; dichloromethane/methanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝636

(M+H+Na)⁺⁺＝329.8

Example 1161-methyl-2- [ N- [4- (N-cyclohexyloxycarbonylamino) -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethyl-amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate. Yield: 40% C of theory₃₂H₃₅N₇O₅(597.7)R_fThe value: 0.26 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝598

(M+Na)⁺＝620

Example 1171-methyl-2- [ N- [4- (N-methoxycarbonylamidino) -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-ethoxycarbonylmethyl-amide-hydrochloride and methyl chloroformate. Yield: 62% C of theory₂₈H₂₉N₇O₅(543.6)R_fThe value: 0.19 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝544

(M+H+Na)⁺⁺＝283.8

(M+Na)⁺＝566

Example 1181-methyl-2- [ N- [4- (N-ethoxycarbonylamidino) -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N-methoxycarbonylmethyl-amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N-methoxycarbonylmethyl-amide-hydrochloride and ethyl chloroformate. Yield: 42% C of theory₂₈H₂₉N₇O₅(543.6)R_fThe value: 0.20 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝544

Example 1191-methyl-2- [ N- [4- (N-N-octyloxycarbonyl-amidino) -phenyl ] aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (3-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and chloroformic acidAnd (3) preparing n-octyl ester. Yield: 35% C of theory₃₆H₄₅N₇O₅(655.8)R_fThe value: 0.28 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝656

(M+2H)⁺⁺＝328.7

Example 1201-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) -phenyl ] -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 58% C of theory₃₅H₄₃N₇O₅(641.2)R_fThe value: 0.42 (silica; 19: 1 dichloromethane/ethanol) EKA Mass Spectrometry: (M + H)⁺＝642

(M+H+Na)⁺⁺＝332.7

Example 1211-methyl-2- [ N- [4- [ N-N-octyloxycarbonylamino) -phenyl ] -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-octyl chloroformate. Yield: 36% C of theory₃₇H₄₇N₇O₅(669.8) EKA Mass Spectrometry: (M + H)⁺＝670

(M+H+Na)⁺⁺＝346.9

(M+2H)⁺⁺＝335.6

Example 1221-methyl-2- [ N- [4- (N-N-butyloxycarbonylamino) -phenyl ] -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-butyl chloroformate. Yield: 34% C of theory₃₃H₃₉N₇O₅(613.7) EKA Mass Spectrometry: (M + H)⁺＝614

(M+H+Na)⁺⁺＝318.7

(M+Na)⁺＝636

Example 1231-methyl-2- [ N- [4- (N-benzoylamidino) phenyl ] -N-methyl-aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and benzoyl chloride. Yield: 63% C of theory₃₅H₃₅N₇O₄(617.7) EKA Mass Spectrometry: (M + H)⁺＝618

(M+H+Na)⁺⁺＝320.7

(M+Na)⁺＝640

Example 1241-methyl-2- [ (4-amidinophenyl) oxymethyl ] -benzimidazol-5-yl- (1-ethoxycarbonylmethyl-cyclohex-1-yl) -one-hydrochloride a) 4-chlorophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -one

8.4 g (40mMol) of 3- (4-chlorobenzoyl) -propionic acid are dissolved in 300 ml of tetrahydrofuran and 5.8 g (120mMol) of sodium hydride (50-60% suspension in paraffin oil) are added in portions. The mixture was then heated to reflux for 1.5 hours with stirring, and 8.9 ml (60mMol) of 1, 5-diiodopentane was added dropwise and boiling was continued for an additional three hours. After cooling, the solution is stirred into 200 ml of ice-water and then the tetrahydrofuran is distilled off, the aqueous solution obtained is acidified with 2N hydrochloric acid and extracted with 150 ml of dichloromethaneTaking three times. The organic phase was dried and evaporated and the crude product was purified by column chromatography (500 g silica gel; eluent: dichloromethane + 1-2% ethanol). Yield: 6.2 g (55% of theory) of oil body product C₁₅H₁₇ClO₃(280.8)R_fThe value: 0.56 (silica; dichloromethane/ethanol ═ 19: 1) b) 4-chloro-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -one

7.0 g (25mMol) of 4-chlorophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -ketone are added portionwise to 80 ml of fuming nitric acid at from-5 to-10 ℃ with stirring. The solution was stirred for a further 10 minutes and then stirred into 200 ml of ice-water, the precipitated product was washed with water and dried. Yield: 7.8 g (96% of theory) of C₁₅H₁₆ClNO₅(325.8)R_fThe value: 0.41 (silica; petroleum ether/ethyl acetate 4: 6) c) 4-methylamino-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -one

7.8 g (23.9mMol) of 4-chloro-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -one are stirred in 100 ml of 40% aqueous methylamine solution at room temperature for 14 hours, then diluted with about 150 ml of water and made slightly acidic with glacial acetic acid. The precipitated product was suction filtered, washed with water and dried. Yield: 7.1 g (93% of theory) of C₁₆H₂₀N₂O₅(320.4)R_fThe value: 0.34 (silica; dichloromethane/ethanol ═ 19: 1) d) 4-methylamino-3-nitrophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one

4.9 g (15mMol) of 4-methylamino-3-nitrophenyl- (1-hydroxycarbonylmethyl-cyclohex-1-yl) -one are dissolved in 100 ml of tetrahydrofuran, 2.4 g (15mMol) of 1, 1' -carbonyl-diimidazole are added and the mixture is heated to reflux for 15 minutes. The solvent was then evaporated off, 30 ml of methanol were added and the mixture was boiled under stirring for three hours. After removal of the methanol by distillation, the product obtained is purified by column chromatography (250 g of silica gel, eluent: dichloromethane +1 to 5% ethanol). Yield: 2.4 g (48% of theory) of C₁₇H₂₂N₂O₅(334.4)R_fThe value: 0.76 (silica; dichloromethane/ethyl)Alcohol 19: 1) e) 3-amino-4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one

2.4 g (7.2mMol) of 4-methylamino-3-nitrophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one are catalytically hydrogenated in 100 ml of methanol at room temperature under a hydrogen pressure of 5 bar (10% palladium on carbon). The crude product obtained is used without purification. Yield: 2.1 g (96% of theory) of R_fThe value: 0.34 (silica; dichloromethane/ethanol ═ 19: 1) f)3- (4-cyanophenyloxyacetylamino) -4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one

620 mg (3.5mMol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5mMol) of 1, 1' -carbonyldiimidazole are heated under reflux in 50 ml of tetrahydrofuran for 15 minutes. Then 1.0 g (3.28mMol) 3-amino-4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -ketone was added and the mixture was boiled for 4 hours. The solvent was removed by evaporation and the crude product was purified by column chromatography (150 g silica gel; eluent: dichloromethane +0 to 2% ethanol). Yield: 1.4 g (93% of theory) of C₂₆H₂₉N₃O₅(463.5)R_fThe value: 0.44 (silica; dichloromethane/ethanol ═ 19: 1) g) 1-methyl-2- [ (4-cyanophenyl) oxymethyl]-benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one

1.4 g (3.02mMol) of 3- (4-cyanophenyloxyacetylamino) -4-methylaminophenyl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one are heated under reflux in 50 ml of glacial acetic acid for one hour. The glacial acetic acid is then distilled off, the residue is mixed with 20 ml of water and made basic with concentrated aqueous ammonia. The solution is extracted three times with 20 ml of dichloromethane each time, and the organic extracts are dried and evaporated. The crude product obtained is purified by column chromatography (100 g of silica gel; eluent; dichloromethane +0 to 2% ethanol). Yield: 700 mg (52% of theory) C₂₆H₂₇N₃O₄(445.5) h) 1-methyl-2- [ (4-amidinophenyl) oxymethyl]-benzimidazol-5-yl- (1-ethoxycarbonylmethyl-cyclohex-1-yl) -one-hydrochloride

Prepared in analogy to example 25d, from 700 mg (1.57mMol) 1-methyl-2- (4-cyanophenyloxymethyl) -benzimidazol-5-yl- (1-methoxycarbonylmethyl-cyclohex-1-yl) -one and ethanolic hydrochloric acid and ammonium carbonate. Yield: 390 mg (50% of theory) C₂₇H₃₂N₄O₄(476.6) EKA Mass Spectrometry: (M + H)⁺＝477¹H-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 (width s, 4H) ppm.

Example 1251-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-tert-butylketone-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-tert-butylketone-hydrochloride, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 59% C of theory₂₁H₂₅N₅O (363.5) EKA mass spectrum: (M + H)⁺＝364

Example 1261-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl- (1-methylcyclopent-1-yl) -one-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl- (1-methylcyclopent-1-yl) -one, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 63.5% C of theory₂₃H₂₇N₅O (389.5) EKA mass spectrum: (M + H)⁺＝390

Example 1272- [ (4-Amidinophenyl) sulfinylmethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

0.15 g (0.27mMol) of 2- [ (4-amidinophenyl) thiomethyl]A solution of-benzothiazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride in 10 ml acetic acid was mixed with 0.09 ml (ca. 0.81mMol) of 30% hydrogen peroxide solution and stirred at room temperature. After 4 days, 0.18 ml of hydrogen peroxide solution is addedThe resulting mixture was stirred for an additional two days. After removal of the solvent in vacuo, the product was purified by flash chromatography (silica gel; dichloromethane/ethanol 10: 1 to 4: 1). Yield: 58% C of theory₂₇H₂₆N₄O₄S₂(534.66)R_fThe value: 0.24 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝535

Example 1281-methyl-2- [ (4-carbamimidoylphenyl) sulfonylmethyl ] -benzimidazol-5-yl-carboxylic acid N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

0.40 g (0.70mMol) of 1-methyl-2- [ (4-amidinophenyl) sulfanylmethyl]A solution of-benzothiazol-5-yl-carboxylic acid-N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride in 10 ml formic acid was mixed with 2 ml 30% hydrogen peroxide solution and stirred at room temperature for 16 h. The solvent was then removed by vacuum distillation to give the desired compound as a beige solid (containing a little 1-methyl-2- [ (4-amidinophenyl) sulfinylmethyl]-benzimidazol-5-yl-carboxylic acid-N- (N-propyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride impurity). Yield: 95% C of theory₂₅H₃₁N₆O₅S(513.62)R_fThe value: 0.50 (silica; ethyl acetate/ethanol/1N hydrochloric acid 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝514

Example 1292- [ N- (4-amidinophenyl) aminomethyl ] -thiazolo- [5, 4-b ] pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) methyl 5-amino-6-chloro-nicotinate

A solution of 1.08 g (5.00mMol) 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 was mixed successively with 0.53 ml (29mMol) of water, 3.2 g (57mMol) of iron powder and 0.030 ml of concentrated hydrochloric acid and heated to boiling for 1 hour. Equal amounts of water, iron powder and hydrochloric acid were then added and the mixture was heated to boiling for 30 minutes. The precipitate formed on cooling was filtered off, washed with ethanol and the solvent was removed by vacuum distillation. Yield: 0.75 g (81% of theory) of a yellowish green solid R_fThe value: 0.31 (silica gel; ethyl acetate/stone)1: 4) C in oleyl ether₇H₇C₁N₂O₂(186.60) YEF Mass Spectrometry: m⁺186 and 188 (chloro isotope) b) 6-chloro-5-methoxyacetylamino-nicotinic acid methyl ester

A solution of 0.75 g (4.02mMol) 5-amino-6-chloro-nicotinic acid methyl ester and 0.43 g ═ 0.35 ml (4.5mMol) methoxyacetyl chloride in 20 ml chlorobenzene was stirred at 110 ℃ for 1 hour. After removal of the solvent in vacuo, the crude product is purified by flash chromatography (silica gel; dichloromethane/ethanol 100: 1), evaporated in vacuo and digested with petroleum ether. Yield: 0.55 g (53% of theory) of a pale yellow amorphous solid R_fThe value: 0.33 (silica; ethyl acetate/petroleum ether ═ 1: 4) c) 2-methoxymethyl-thiazolo [5, 4-b]Pyridin-6-yl-carboxylic acid methyl ester

A mixture of 0.53 g (2.05mMol) 6-chloro-5-methoxyacetylamino-nicotinic acid methyl ester and 0.42 g (1.0mMol) dictyophora phalloidea (Lawessons) reagent was heated under reflux in 25 ml xylene for 16 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (silica gel; dichloromethane/ethanol 100: 1) and the solvent was evaporated in vacuo. Yield: 0.33 g (67% of theory) of a yellow amorphous solid R_fThe value: 0.52 (silica; ethyl acetate/petroleum ether ═ 1: 4) d) 2-methoxymethyl-thiazolo [5, 4-b]Pyridin-6-yl-carboxylic acids

1.1 g (4.62mMol) 2-methoxymethyl-thiazolo [5, 4-b ]]A mixture of pyridin-6-yl-carboxylic acid methyl ester and 9.2 ml of 2N sodium hydroxide solution is stirred at room temperature into 50 ml of ethanol for one hour. 9.2 ml of 2N hydrochloric acid are added, the alcohol is distilled off and diluted with 20 ml of water. The aqueous phase is acidified with concentrated hydrochloric acid while cooling with ice, the beige precipitate formed is filtered off, washed with water and dried. Yield: 1.03 g (100% of theory) of R_fThe value: 0.10 (silica; ethyl acetate/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 (4.62mMol) 2-methoxymethyl-thiazolo (5, 4-b) pyridin-6-yl-carboxylic acid in 40ml dichloromethane was mixed with 1.6 g ═ 1.0 ml (13.5mMol) of sulfuryl chlorideMix and heat at reflux for 90 minutes during which time the solid gradually dissolves. After distilling off the liquid component, the crude product was dissolved twice in dichloromethane and concentrated again. The crude acid chloride (1.2 g) was redissolved in 40ml of tetrahydrofuran and added dropwise to a mixture of 0.94 g (4.86mMol) of N- (2-ethoxycarbonylethyl) aniline and 2.1 ml (13.8mMol) of triethylamine in 30 ml of tetrahydrofuran and stirred at room temperature for 2 hours. Then diluted with 200 ml of ethyl acetate, washed with 100 ml of 14% brine solution and the organic phase dried over sodium sulfate. After removal of the solvent in vacuo, the crude product was purified by flash chromatography (silica gel; dichloromethane/ethanol 100: 1). Yield: 1.57 g (87% of theory) of yellow oil bodies R_fThe value: 0.55 (silica; ethyl acetate/ethyl ester 19: 1) f)2- [ N- (4-cyanophenyl) -aminomethyl]Thiazolo [5, 4-b ]]-pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

1.54 g (3.85mMol) 2-methoxymethyl-thiazolo [5, 4-b ]]A mixture of pyridin-6-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and 4.3 ml (4.3mMol) of a 1M solution of boron tribromide in dichloromethane was dissolved in 30 ml of dichloromethane and stirred at room temperature for 5 hours. The mixture is washed with a further 40ml of saturated sodium bicarbonate solution, the organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The crude product (1.9 g) was dissolved in 15.0 ml of N, N-diisopropylethylamine, mixed with 0.50 g (4.2mMol) of 4-aminobenzonitrile and heated to boiling for one hour. The solvent was then removed in vacuo and the crude product was dissolved in 100 ml of dichloromethane and the organic phase washed with 100 ml of water and dried over sodium sulfate. After removal of the solvent in vacuo, the crude product is purified by flash chromatography (silica gel; ethyl acetate/petroleum ether: 35: 65 to 1: 1) and evaporated in vacuo. Yield: 0.45 g (24% of theory) of a yellow amorphous solid R_fThe value: 0.34 (silica; ethyl acetate/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 (0.803mMol) of 2- [ N- (4-cyanophenyl) -aminomethyl]Thiazolo [5, 4-b ]]Pyridin-6-yl-carboxylic acid N-benzeneThe base N- (2-ethoxycarbonylethyl) -amide is stirred in 40ml of ethanol saturated with hydrogen chloride at 0 ℃ for 5 hours and then at room temperature until no starting material is detectable by TLC. The solvent was then distilled off at a bath temperature of at most 30 ℃ and the resulting oil body was dissolved in 40ml of absolute ethanol and mixed with 0.5 g of ammonium carbonate. After 18 h the solvent was removed in vacuo and the crude product was purified by flash chromatography (silica gel; dichloromethane/ethanol from 9: 1 to 4: 1). Yield: 78% of theory, yellow foam C₂₆H₂₆N₆O₃S(502.60)R_fThe value: 0.19 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝503

Example 1301-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 consisting of 6.5 g (19mMol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and 4.5 g (22.8mMol) of N, N' -thiocarbonyldiimidazole is dissolved in 100 ml of tetrahydrofuran under nitrogen, the solution is heated to 90 ℃ for 4 hours and then left to stand at room temperature for 16 hours. After removal of the solvent in vacuo, the crude product is purified by flash chromatography (silica gel; petroleum ether/ethyl acetate: 100: 0 to 65: 35). Yield: 6.8 g (93% of theory) of a beige crystalline solid R_fThe value: 0.55 (silica; ethyl acetate) b) 1-methyl-2- [ (4-cyanophenyl) methylthio group]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide

A solution of 1.30 g (3.4mMol) 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide, 0.52 g (3.74mMol) potassium carbonate and 0.66 g (3.4mMol) 4-bromo-methylbenzonitrile in 40ml absolute ethanol is stirred at 60 ℃ for 4 hours and at room temperature for 16 hours. The solvent was then distilled off in vacuo and the crude product was dissolved in 30 ml of dichloromethane, washed with 40ml of water and dried over sodium sulfate. After filtration and distillation of the solvent, the product is obtainedThe desired compound was an off-white solid. Yield: 1.8 g (100% of theory) of R_fThe value: 0.64 (silica; ethyl acetate) c) 1-methyl-2- [ (4-amidinophenyl) methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

1.5 g (3.0mMol) of 1-methyl-2- [ (4-cyanophenyl) methylthio group]-benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide is stirred in 80 ml of ethanol saturated with hydrogen chloride at 0 ℃ for 6.5 hours and then at room temperature until no starting material is detectable by TLC. The solvent was then distilled off at a maximum bath temperature of 30 ℃ and the resulting oil residue was dissolved in 80 ml of absolute ethanol and mixed with 1.0 g (10.5mMol) of ammonium carbonate. After 18 h the solvent was removed in vacuo and the crude product was purified by flash chromatography (silica gel; dichloromethane/ethanol 19: 1 to 10: 1). Yield: 78% of theory, pale beige solid C₂₈H₂₉N₅O₃S(515.63)R_fThe value: 0.19 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝516

(M+H+Na)⁺⁺＝269.7

(M+2H)⁺⁺＝258.7

Example 1311-methyl-2- [ (4-amidinophenyl) methylthio ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 10, using 1-methyl-2- [ (4-amidinophenyl) methylthio]-benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 57% C of theory₂₆H₂₅N₅O₃S(487.58)R_fThe value: 0.23 (reverse phase silica RP-8; methanol/5% saline solution 6: 4) EKA Mass Spectrometry: (M + H)⁺＝488

(M+Na)⁺＝510

(M+Na+H)⁺⁺＝255.6

Example 1321-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-propargyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 81% C of theory₂₅H₂₈N₆O₃S(460.6)R_fThe value: 0.094 (silica; dichloromethane/ethanol 4: 1) EKA mass spectrum: (M + H)⁺＝461

(M+H+Na)⁺⁺＝242

(M+2H)⁺⁺＝231

Example 1331-methyl-2- [2- [4- (N-N-hexyloxycarbonylamino) phenyl ] ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 72% C of theory₃₅H₄₂N₆O₅S(626.8)R_fThe value: 0.54 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝627

(M+Na)⁺＝649

Example 1341-methyl-2- [2- [4- (N-benzoylamidino) phenyl ] ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxy-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and benzoyl chloride. Yield: 79% C of theory₃₅H₃₄N₆O₄(602.7)R_fThe value: 0.52 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝603

(M+Na)⁺＝625

Example 1351-methyl-2- [2- [4- (N-nicotinoylamidino) phenyl ] ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [2- (4-amidinophenyl) ethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and nicotinoyl chloride. Yield: 56% C of theory₃₄H₃₃N₇O₄(603.7)R_fThe value: 0.52 (silica; dichloromethane/ethanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝604

(M+Na)⁺＝626

Example 1361-cyclopropyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 31% C of theory₃₀H₃₃N₆O₃S(524.6)R_fThe value: 0.40 (silica; dichloromethane/ethanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝525

(M+H+Na)⁺⁺＝274

(M+2H)⁺⁺＝263

Example 1371-cyclopropyl-2- [ N- [ 4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-cyclopropyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethyl) carboxylic acidOxycarbonylethyl) -amide hydrochloride and sodium hydroxide solution. Yield: 64% C of theory₂₈H₂₈N₆O₃(496.6) EKA Mass Spectrometry: (M + H)⁺＝497

(M+H+Na)⁺⁺＝260

(M+Na)⁺＝519

(M+2Na)⁺⁺＝＝271

Example 1381-methyl-2- [ N- (4-carbamimidoylphenyl) -N- (N-butyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 62% C of theory₃₂H₃₈N₆O₃(554.7) EKA Mass Spectrometry: (M + H)⁺＝555

(M+H+Na)⁺⁺＝289

(M+2H)⁺⁺＝278

Example 1391-methyl-2- [ N- (4-carbamimidoyl-2-chloro-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 82% C of theory₂₈H₂₉ClN₆O₃(533.1) EKA Mass Spectrometry: (M + H)⁺＝533/5

(M+H+Na)⁺⁺＝278/9

Example 1401-methyl-2- [ N- [4- (N-octyloxycarbonylamino) phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and N-octyl chloroformate. Yield: 34% C of theory₃₇H₄₆N₆O₅(654.8)R_fThe value: 0.15 (silica; dichloromethane/ethanol 19: 1) EKA Mass Spectrometry: (M + H)⁺＝655

(M+H+Na)⁺⁺＝339

(M+Na)⁺＝677

Example 1411-methyl-2- [ N- (4-carbamimidoyl-2-ethyl-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 61% C of theory₃₀H₃₄N₆O₃(526.6) EKA Mass Spectrometry: (M + H)⁺＝527

(M+H+Na)⁺⁺＝275

(M+2H)⁺⁺＝264

Example 1421-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid-benzylamide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 63% C of theory₂₄H₂₄N₆O(412.5)R_fThe value: 0.76 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝413

Example 1431-methyl-2- [ N- [4- (N- (2- (2-ethoxyethoxy) ethoxy) carbonylamidyl) -phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and diethylene glycol monoethyl ether chloroformate. Yield: 43% C of theory₃₄H₄₁N₇O₇(659.8)R_fThe value: 0.56 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝660

(M+H+Na)⁺⁺＝341.7

Example 1441-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 60% C of theory₂₆H₃₀N₈O₃(502.6)R_fThe value: 0.13 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝503

(M+H+Na)⁺⁺＝263

(M+2H)⁺＝252

Example 1453-methyl-2- [ (4-carbamimidoylphenyl) -sulfanylmethyl ] -imidazo [4, 5-b ] -pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 1, using 3-methyl-2- [ (4-cyanophenyl) thiomethyl]Imidazo [4, 5-b)]Pyridin-6-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 88% C of theory₂₇H₂₈N₆O₃S(516.63)R_fThe value: 0.23 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝517

(M+H+Na)⁺⁺＝270

Example 1463-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -imidazo [4, 5-b ] -pyridin-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 1, using 3-methyl-2- [ N- (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. Yield: 82% C of theory₂₇H₂₈N₇O₃(499.58)R_fThe value: 0.20 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝500

(M+H+Na)⁺⁺＝261.7

Example 1473-methyl-2- [ (4-carbamimidoylphenyl) -sulfanylmethyl ] -imidazo [4, 5-b ] -pyridin-6-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 2, using 3-methyl-2- [ (4-carbamimidoylphenyl) -sulfanylmethyl]Imidazo [4, 5-b)]Pyridin-6-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide solution. Yield: 88% C of theory₂₅H₂₄N₆O₃S(488.56)R_fThe value: 0.21 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝489

(M+Na)⁺＝511

Example 1483-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -imidazo [4, 5-b ] -pyridin-6-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 2, using 3-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]Imidazo [4, 5-b)]Pyridin-6-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and sodium hydroxide solution. Yield: 80% C of theory₂₅H₂₅N₇O₃(471.52)R_fThe value: 0.19 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝472

(M+Na)⁺＝494

(M+2Na)⁺⁺＝258.6

Example 1491-methyl-2- [ N- (4-carbamimidoylphenyl) -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 (6.2mMol) of 3-nitro-4-methylamino-benzenesulfonic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide are hydrogenated on palladium on carbon (10%) in a mixture of 75 ml of ethanol and 75 ml of dichloromethane at room temperature under 5 bar of hydrogen. The crude product 3-amino-4-methylamino-benzenesulfonic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide obtained was dissolved without further purification in 30 ml of phosphorus oxychloride, 1.1 g (6.2mMol) of N- (4-cyanophenyl) -glycine was then added and the mixture was heated under reflux for two hours. After cooling to room temperature, the reaction mixture was added to about 70 ml of water while cooling to decompose excess phosphorus oxychloride. The resulting solution was neutralized with solid sodium carbonate and extracted three times with 30 ml ethyl acetate. The solvent was removed by evaporation and the crude product was purified by column chromatography (100 g silica gel; eluent: cyclohexane/ethyl acetate 2: 3). Yield: 860 mg (26.8% of theory) melting point: 188-191 ℃ C₂₇H₂₇N₅O₃S(517.6)R_fThe value: 0.52 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝518

(M+Na)⁺540b) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 87% C of theory₂₇H₃₀N₆O₄S(534.6)R_fThe value: 0.13 (silica; dichloromethane/ethanol ═ 9: 1) EKA Mass Spectrometry: (M + H)⁺＝535

(M+H+Na)⁺⁺＝279

Example 1501-methyl-2- [ N- (4-amidinophenyl) -aminomethyl ] -benzimidazol-5-yl-sulfonic acid N- (1-methylpyrazol-4-yl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 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. Yield: 38% C of theory₂₅H₃₀N₈O₄S(538.6)R_fThe value: 0.09 (silica; dichloromethane/ethanol ═ 9: 1) EKA Mass Spectrum: (M + H)⁺＝539

Example 1511-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -5- (2, 3-indolin-1-yl-sulfonic acid) -benzimidazole-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-5- (2, 3-indolin-1-yl-sulfonic acid) -benzimidazole, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 15% R of theory_fThe value: 0.36 (silica; dichloromethane/methanol 4: 1) C₂₄H₂₄N₆O₂S (460.6) EKA mass spectrum: (M + H)⁺＝461

Example 1521-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-sulfonic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl]-benzimidazol-5-yl-sulfonic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 24% R of theory_fThe value: 0.55 (reverse RP-18 silica; methanol/5% aqueous saline 3: 2) C₂₅H₂₆N₆O₄S (506.6) EKA mass spectrum: (M + H)⁺＝507

(M+Na)⁺＝529

(M+2Na)⁺⁺＝276

Example 1531-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -5- (isoindolin-2-yl-sulfonyl) -benzimidazole-hydrochloride

In analogy to example 25d using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-5- (isoindolin-2-yl-sulfonyl) -benzimidazole, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 33% R of theory_fThe value: 0.32 (silica; dichloromethane/methanol 4: 1) C₂₄H₂₄N₆O₂S (460.6) EKA mass spectrum: (M + H)⁺＝461

Example 1542- [2- (4-carbamimidoylphenyl) -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 (0.03Mol) of ethyl p-toluate were added dropwise to a solution of 3 ml of concentrated hydrochloric acid and 4 ml of concentrated sulfuric acid at 5 ℃ while stirring, and stirred for 1 hour under cooling in an ice bath. After heating to ambient temperature, the mixture was poured onto ice water and extracted with ethyl acetate. The organic extracts were washed with sodium bicarbonate solution, dried and evaporated. Yield: 5.7 g (90% of theory) of R_fThe value: 0.81 (silica; ethyl acetate/cyclohexane ═ 1: 1) b)4- (2-dimethylaminoethyl) -3-nitro-benzoic acid methyl ester

1.0 g (4.8mMol) of 4-methyl-3-nitro-benzoic acid ethyl ester, 0.74 g (6.2mMol) of dimethylformamide dimethyl acetal and 2 ml of dimethylformamide are heated to 140 ℃ for 3 hours with stirring. Then theThe solvent was removed by distillation and the crude product obtained was used without further purification. Yield: 1.2 g (100% of theory) R_fThe value: 0.54 (silica; ethyl acetate/cyclohexane ═ 1: 1) c) 4-formyl-3-nitro-benzoic acid methyl ester

1.2 g (4.8mMol) of methyl 4- (2-dimethylaminoethyl) -3-nitro-benzoate are dissolved in 120 ml of tetrahydrofuran/water (1: 1), after addition of 3.0 g (14.3mMol) of sodium metaperiodate, the mixture is stirred at room temperature for 20 hours. The suspension was diluted with water and dichloromethane and extracted with dichloromethane. The combined organic extracts were washed with sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate/cyclohexane (1: 3). Yield: 0.6 g (63% of theory) of R_fThe value: 0.63 (silica; ethyl acetate/cyclohexane ═ 1: 1) d) 3-amino-4-formyl-benzoic acid methyl ester

To a solution of 25 ml ethanol/glacial acetic acid/water (2: 1) were added 0.6 g (2.9mMol) of 4-formyl-3-nitro-benzoic acid methyl ester, 1.2 g (21.4mMol) of iron powder and 0.01 ml of concentrated hydrochloric acid, and the mixture was refluxed for 15 minutes with stirring. The iron was then separated off, the solution diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water, dried and evaporated. Yield: 0.3 g (58% of theory) of R_fThe value: 0.74 (silica gel; dichloromethane/methanol ═ 9.5: 0.5) e)3- [3- (4-cyanophenyl) -propionylamino]-4-formyl-benzoic acid methyl ester

1.0 g (5.6mMol) of methyl 3-amino-4-formyl-benzoate and 1.1 g (5.6mMol) of 4-cyanophenylpropionyl chloride are dissolved in 50 ml of dichloromethane, and after addition of 0.7 g (5.6mMol) of N-ethyl-diisopropylamine, the mixture is stirred at room temperature for 24 hours. Then extracted with sodium bicarbonate solution and the combined organic extracts were dried and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate/cyclohexane (1: 3). Yield: 0.6 g (32% of theory) of R_fThe value: 0.60 (silica; ethyl acetate/cyclohexane ═ 1: 1) f)2- [2- (4-cyanophenyl) -ethyl]-quinazoline-7-carboxylic acid methyl ester

0.6 g (1.8mMol) of 3- [3- (4-cyanophenyl) -propionylAmino group]Ethyl-4-formylbenzoate and 10 ml methanolic ammonia solution were shaken in a pressurized flask for 36 hours. The solvent is then distilled off and the residue is chromatographed on silica gel, eluting with 0 to 1% methanol in dichloromethane. Yield: 0.35 g (62% of theory) of R_fThe value: 0.38 (silica; ethyl acetate/cyclohexane ═ 1: 1) g)2- [2- (4-cyanophenyl) -ethyl]-quinazoline-7-carboxylic acid

0.3 g (0.94mMol) of 2- [2- (4-cyanophenyl) -ethyl]Methyl (E) -quinazoline-7-carboxylate was dissolved in 4.7 ml of 1N lithium hydroxide solution and 4 ml of tetrahydrofuran and stirred at room temperature for 3 hours. Then 4.7 ml of 1N hydrochloric acid were added and the mixture was stirred for 30 minutes. The precipitated product was suction filtered, washed with water and dried. Yield: 0.30 g (100% of theory) of R_fThe value: 0.1 (silica; ethyl acetate/cyclohexane ═ 1: 1) h)2- [2- (4-cyanophenyl) -ethyl]-quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

0.4 g (1.3mMol) of 2- [2- (4-cyanophenyl) -ethyl]-quinazoline-7-carboxylic acid and 5 ml thionyl chloride were stirred at 50 ℃ for 60 minutes. The thionyl chloride was then distilled off, the residue dissolved in dichloromethane and mixed with 0.24 g (1.3mMol) of methyl 3- (N-phenylamino) propionate and 0.22 ml (1.3mMol) of N-ethyldiisopropylamine and stirred at room temperature for 18 h. After removal of the solvent by evaporation in vacuo, the residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane. Yield: 230 mg (37% of theory) R_fThe value: 0.64 (silica; ethyl acetate/methanol ═ 9: 1) i)2- [2- (4-carbamimidophenyl) -ethyl]-quinazolin-7-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

230 mg (0.5mMol) of 2- [2- (4-cyanophenyl) -ethyl]-quinazolin-7-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide was stirred in 30 ml of saturated ethanolic hydrochloric acid at room temperature for 8 hours. The mixture was then evaporated to dryness in vacuo and the residue was dissolved in 20 ml of ethanol, mixed with 0.5 g (5.0mMol) of ammonium carbonate and stirred at room temperature overnight. After removal of the solvent by distillation, the crude product is chromatographed on silica gel, eluting with dichloromethane/diethyl ether (4: 1). Yield:100 mg (39% of theory) R_fThe value: 0.5 (silica; ethyl acetate/ethanol 4: 1) C₂₉H₂₉H₅O₃(495.59) Mass Spectrometry: (M + H)⁺＝496

Example 1551-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-sulfonic acid N- (1-methylpyrazol-4-yl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-sulfonic acid-N- (1-methylpyrazol-4-yl) N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 95% C of theory₂₃H₂₆N₈O₄S(510.6)R_fThe value: 0.53 (reverse phase silica RP-18; methanol + 5% saline solution) EKA Mass Spectrometry: (M + H)⁺＝511

(M+Na)⁺＝533

(M+2Na)⁺⁺＝278

Example 1561-methyl-2- [ N- (3-carbamimidoyl-pyridin-6-yl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride a)3- [ (N-tert-butoxycarbonyl-amino) acetylamino ] -4-methylamino-benzoic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

19.2 g (0.11Mol) of N-tert-butoxycarbonylglycine were dissolved in 175 ml of dimethylformamide and mixed with 35.2 g (0.11Mol) of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyl * tetrafluoroborate, 11.0 g of triethylamine and 34.2 g (0.10Mol) of 3-amino-4-methylamino-benzoic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide and stirred at room temperature for 2.5 hours. The reaction solution was then mixed with 5 liters of ice water and stirred for 2 hours. The resulting grey precipitate was filtered off, washed with water, dried and recrystallized from ethyl acetate with addition of activated carbon. Yield: 39.85 g (80% of theory) C₂₅H₃₃N₅O₆(499.6)R_fThe value: 0.55 (silica; dichloromethane/ethanol ═ 19: 1) b) 1-methyl-2- (N)-tert-butoxycarbonyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

10.0 g (0.02Mol) of 3- [ (N-tert-butoxycarbonyl-amino) acetylamino group was added]-4-methylamino-benzoic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide was dissolved in 50 ml of glacial acetic acid and heated under reflux for one hour. The solvent was then distilled off, the residue was mixed with ice water and the pH was adjusted to 8 by adding 2N aqueous ammonia. After three extractions with ethyl acetate, the combined organic phases were washed with aqueous salt solution and dried over sodium sulfate. After evaporation of the solvent, the crude product is chromatographed on silica gel, eluting first with dichloromethane and then with dichloromethane/ethanol (50: 1) and (25: 1). The desired fractions were combined and evaporated. Yield: 5.85 g (61% of theory) of C₂₅H₃₁N₅O₅(481.6)R_fThe value: 0.70 (silica; dichloromethane/ethanol ═ 9: 1) c) 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-trifluoroacetate

4.81 g (0.10Mol) 1-methyl-2- (N-tert-butoxycarbonyl-aminomethyl) benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide are dissolved in 25 ml of dichloromethane and admixed with 5 ml of trifluoroacetic acid and stirred at room temperature for 5 hours, then the solvent is removed by evaporation and the residue is stirred with ether. The precipitate formed is filtered off, washed with ether, the crystals formed are filtered off, washed with ether and dried. Yield: 3.15 g (68% of theory) of C₂₀H₂₃N₅O₃(381.4)R_fThe value: 0.18 (silica; dichloromethane/ethanol ═ 9: 1) d) 1-methyl-2- [ N- (3-cyano-pyridin-6-yl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

1.5 g (3.25mMol) 1-methyl-2-aminomethyl-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-trifluoroacetate are stirred into 10 ml N-ethyl-diisopropylamine and heated at 100 ℃ for 15 minutes. After addition of 720 mg (5.25mMol) of 2-chloro-5-cyano-pyridine, the reaction mixture is added at 125 ℃The heat was applied for 2 hours. After cooling to room temperature, about 20 ml of water are stirred, the pH is adjusted to 4 by addition of 1N hydrochloric acid, and the mixture is extracted three times with ethyl acetate. The combined organic phases were washed with brine solution and dried over sodium sulfate. After evaporation of the solvent, the crude product is chromatographed on silica gel, eluting first with dichloromethane and then with dichloromethane/ethanol (25: 1) and (19: 1). The desired fractions were combined and evaporated. Yield: 1.05 g (67% of theory) of C₂₆H₂₅N₇O (483.6) mass spectrum: (M + H)⁺484e) 1-methyl-2- [ N- (3-carbamimidoyl-pyridin-6-yl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridinyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (3-cyano-pyridin-6-yl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 38% C of theory₂₈H₂₈N₈O₃(500.6) Mass Spectrometry: (M + H)⁺＝501

Example 1571-methyl-2- [ N- (4-amidinophenyl) aminomethyl ] -indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride a) 4-nitro-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide

16.7 g (0.1Mol) of 4-nitrobenzoic acid are heated under reflux in 50 ml of thionyl chloride and 3 drops of dimethylformamide for 1 hour. After removal of the solvent by distillation in vacuo, the crude product is dissolved in 150 ml of tetrahydrofuran and added dropwise to a solution of 18 g (0.1Mol) of N- (2-methoxycarbonylethyl) -aniline in 250 ml of tetrahydrofuran and 42 ml (0.3Mol) of triethylamine. After stirring at room temperature for 1 hour, the reaction mixture was diluted with 250 ml of ethyl acetate and washed twice with 200 ml of 14% aqueous saline solution. After removal of the solvent by distillation, the residue was chromatographed (silica gel; dichloromethane) to give a yellow oil which solidified slowly. Yield: 32.6 g (100% of theory) R_fThe value: 0.37 (silica; dichloromethane/methanol ═ 50: 1) b) 4-amino-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide

22 g (67mMol) of 4-nitro-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide are hydrogenated in 50 ml of methanol with 2 g of 10% palladium on carbon at 3 bar hydrogen pressure for 3 hours. After filtration and distillation to remove the solvent, the reaction mixture was washed with 100 ml of ether and the white crystalline product was used as such. Yield: 18.6 g (94% of theory) of R_fThe value: 0.70 (silica; dichloromethane/methanol ═ 19: 1) c) 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

26.8 g (91mMol) of 4-amino-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) amide are dissolved in 500 ml of dichloromethane and cooled to-70 ℃ and admixed within 30 minutes with freshly prepared tert-butyl hypochlorite (M.J.Mintz et al, Organic Synthesis, Coll.Vol.5, p.184). The mixture was stirred at-70 ℃ for 2 hours, then a solution of 9.46 g (91mMol) of methyl propanethione in 40ml of dichloromethane was added dropwise over a period of 10 minutes, and stirring was continued for a further 1.5 hours. Then a solution of 12.7 ml (9.1 g, 91mMol) of triethylamine in 25 ml of dichloromethane was added. The mixture was left at-78 ℃ for 30 minutes and then slowly warmed to room temperature overnight. After washing twice with 50 ml of water, the organic phase is separated and dried over sodium sulfate. After removal of the solvent in vacuo, purification by chromatography (silica gel; ethyl acetate/petroleum ether: 2: 8 to 3: 7) gave a white amorphous material. Yield: 24.1 g (69% of theory) R_fThe value: 0.58 (silica; ethyl acetate/petroleum ether ═ 1: 1) C₂₁H₂₂N₂O₃S (382.49) mass spectrum: (M)⁺= 382d) 1-tert-butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide

8.9 g (23mMol) of 2-methyl-3-thiomethyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide are dissolved in 600 ml of ethanol and admixed with about 150 mg of Raney nickel and stirred at room temperature for 2 hours (analogously to P.G.Gassman et al, Organic Synthesis col. Vol.6, p.601). The mixture was then filtered and the solvent removed in vacuo. The crude product obtained (8 g) is dissolved in 200 ml of anhydrous tetrahydrofuran, admixed with 150 mg of dimethylaminopyridine and 6.84 g (32 mMol)) Di-tert-butyl pyrocarbonate was mixed and stirred at 50 ℃ for 2.5 hours. After removal of the solvent in vacuo, the crude product was chromatographed (silica gel; ethyl acetate/petroleum ether 1: 4). Yield: 10.0 g (98% of theory) of R_fThe value: 0.40 (silica; ethyl acetate/petroleum ether ═ 3: 7) e)2- [ N- (4-cyanophenyl) aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide

3.5 g (8mMol) of 1-tert-butoxycarbonyl-2-methyl-indol-5-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide are dissolved in 80 ml of carbon tetrachloride and combined with 1.5 g (8.4mMol) of N-bromo-succinamide and 20 mg of azobisisobutyronitrile and heated under reflux for 2.5 h. The solution was then filtered while hot and the filtrate was washed with saturated sodium bicarbonate solution and dried over sodium sulfate. After the solvent was distilled off, the resulting crude product was dissolved in 30 ml of N-ethyldiisopropylamine, mixed with 1.0 g (8mMol) of 4-aminobenzonitrile, and heated under reflux for 2.5 hours. The solvent was removed by distillation in vacuo and the residue was purified by chromatography (silica gel; ethyl acetate/petroleum ether: 1: 4 to 1: 1). Yield: 1.1 g (30% of theory) of R_fThe value: 0.21 (silica; ethyl acetate/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 (3.3mMol) of 2- [ N- (4-cyanophenyl) aminomethyl]-indol-5-yl-carboxy-N-phenyl-N- (2-methoxycarbonylethyl) -amide was dissolved in 60 ml of xylene, mixed with 0.45 g (3.3mMol) of potassium carbonate and 0.5 ml (3.3mMol) of methyl p-toluenesulfonate and heated under reflux for 4 hours. Then, the same amount of potassium carbonate and methyl tosylate was added thereto, and the mixture was heated under reflux overnight. Filtered and washed with acetone. The filtrate was concentrated and the residue was purified by chromatography (silica gel; ethyl acetate/petroleum ether: 1: 4 to 2: 3). The resulting N-methylated indole (yield: 0.4 g, 41% of theory) was dissolved in 20 ml of pyridine and mixed with 0.67 ml (1.37mMol) of triethylamine. Hydrogen sulphide is then introduced into the solution thus obtained. After 4.5 days, nitrogen was passed in for 30 minutes, the solvent was distilled off, and the residue obtained was subjected toPurification by chromatography (silica gel; dichloromethane/ethanol 99: 1 to 98: 2). Yield: 0.30 g (43% of theory) of C₂₈H₂₈N₄O₃S (500.62) EKA mass spectrum: (M + H)⁺＝501

(M+Na)⁺523g) 1-methyl-2- [ N- (4-amidinophenyl) aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide-hydrochloride

0.30 g (0.60mMol) of 1-methyl-2-N- (4-thiocarbamoyl-phenyl) -aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide was dissolved in 20 ml of acetone together with 0.75 ml (12mMol) of methyl iodide and stirred at room temperature for 2 hours. The solvent is then distilled off and the crude product is stirred with 1.0 g of ammonium acetate in 12 ml of ethanol and 5 ml of dichloromethane at 40 ℃ for 20 hours. The solvent was removed by distillation in vacuo and the residue was purified by chromatography (silica; dichloromethane/ethanol 9: 1 to 4: 1). Yield: 55% C of theory₂₈H₂₉N₅O₃(483.58)R_fThe value: 0.20 (silica; dichloromethane/ethanol ═ 4: 1+1 drops of acetic acid) EKA Mass Spectroscopy: (M + H)⁺＝484

Example 1581-methyl-2- [ N- (4-amidinopyridine) aminomethyl ] -thieno [2.3-d ] imidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) iminoethyl methoxyacetate hydrochloride

A solution of 35.5 g (0.50Mol) of methoxyacetonitrile in 29 ml (23 g, 0.50Mol) of ethanol and 30 ml of anhydrous diethyl ether is cooled to 0 ℃ and 22.5 g (0.62Mol) of hydrogen chloride are passed in over 1 hour, the reaction product crystallizing out on completion of the gas passage. To complete the precipitation, the colorless needles were filtered off, mixing with 130 ml of diethyl ether. Yield: melting point of 66.4 g (86% of theory): 117 ℃ C.) -118 ℃ C.) -4-hydroxymethyl-2-methoxymethyl-imidazole

A mixture of 30.6 g (0.20Mol) of iminoethyl methoxyacetate hydrochloride, 18 g (0.20Mol) of 1, 3-dihydroxyacetone and 200 ml of liquid ammonia was heated at 27 bar 68 ℃ for 3 hours in a stirred autoclave (analogously to this)In P.Dziuron et al, Arch pharm.307, 1974, page 470). The ammonia was then removed and mixed with 200 ml of dichloromethane. The resulting white precipitate was filtered off and washed with dichloromethane. The filtrate was evaporated and the resulting residue was purified by chromatography (alumina; dichloromethane/ethanol 90: 10 to 85: 15). Yield: 26.7 g (94% of theory) R_fThe value: 0.43 (silica; dichloromethane/ethanol ═ 9: 1) C₆H₁₀N₂O₂(142.20) Mass Spectrometry: (M)⁺142c) 1: 1 mixtures of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole

A mixture of 7.1 g (50mMol) 4-hydroxymethyl-2-methoxymethyl-imidazole, 3.0 g (53mMol) potassium hydroxide powder and 3.4 ml (0.55mMol) methyl iodide was heated in 100 ml dimethylformamide at 50 ℃ for 4 hours (analogously to i.sinclair et al, j.med.chem., 29, 1986, 261). The solvent was then distilled off in vacuo and the crude product was purified by column chromatography (alumina; dichloromethane/ethanol 99: 1 to 95: 5). Yield: 6.1 g (78 of theory; 1: 1 mixture of the two regioisomers) R_fThe value: 0.32 (silica; dichloromethane/ethanol ═ 19: 1) d) 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methylimidazole

A 1: 1 mixture of 7.7 g (49mMol) of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 7.3 g (55mMol) of N-chloro-succinamide were heated in 48 ml of ethylene glycol monoethyl ether and 70 ml of dioxane at 50 ℃ for 10 hours. The solvent is then distilled off in vacuo and the crude product is purified by column chromatography (silica; dichloromethane/ethanol 99: 1 to 90: 10) to give the isomerically pure title compound. Yield: 3.4 g (36% of theory) R_fThe value: 0.40 (silica; dichloromethane/ethanol ═ 19: 1) e) 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole

3.4 g (18mMol) of 5-chloro-4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole are dissolved in 100 ml of dichloromethane and manganese dioxide (2X 6.0 g, total amount 0.14Mol) is added in two portions at two hour intervals. 4 smallThe inorganic components are filtered out after the reaction, the solvent is removed, and the crude product is used without further purification. Yield: 3.0 g (89% of theory) R_fThe value: 0.44 (silica; dichloromethane/ethanol ═ 50: 1) f) 1-methyl-2-methoxymethyl-thieno [2.3-d]Imidazol-5-ylcarboxylic acid ethyl ester

To a solution of freshly prepared sodium ethoxide (prepared from 391 mg, 17mMol of sodium) in 15 ml of ethanol was added dropwise 1.9 ml (2.1 g, 17mMol) of ethyl thioglycolate. After stirring for 1 hour at room temperature, 1.6 g (8.5mMol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-imidazole in 20 ml of absolute ethanol are added and the mixture is heated at 80 ℃ (analogously to b.iddon et al, j.chem.soc.perkin trans.i, 1987, 1457). After 5 hours the solvent was distilled off and the residue was dissolved in 50 ml of dichloromethane and washed with 20 ml of water. The aqueous phase is washed again with 20 ml of dichloromethane and the combined organic phases are then dried over sodium sulfate. The solvent was removed by distillation in vacuo and the crude product was purified by column chromatography (alumina; dichloromethane). Yield: 1.0 g (46% of theory) of R_fThe value: 0.48 (silica; dichloromethane/ethanol 50: 1) C₁₁H₁₄N₂O₃S (254.31) EKA mass spectrum: (M + H)⁺＝255

(M+Na)⁺277g) 1-methyl-2-methoxymethyl-thieno [2.3-d]Imidazol-5-yl-carboxylic acids

In the presence of 0.90 g (3.54mMol) of 1-methyl-2-methoxymethyl-thieno [2.3-d]A solution of imidazol-5-yl-carboxylic acid ethyl ester in 30 ml of ethanol was added dropwise 5 ml of 2N sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours. The solvent was then distilled off in vacuo and the residue was dissolved 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 ℃ and the precipitate formed is filtered off. Yield: 0.50 g (63% of theory) of R_fThe value: 0.21 (silica; 9: 1+ drops of acetic acid with dichloromethane/ethanol) C₉H₁₀N₂O₃S (226.26) EKA mass spectrum: (M)⁺226h) 1-methyl-2-methoxymethyl-thieno [2.3-d]Imidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl)-amides of

0.50 g (2.2mMol) of 1-methyl-2-methoxymethyl-thieno [2.3-d]A suspension of imidazol-5-yl-carboxylic acid in 20 ml dichloromethane and 2.0 ml (3.2 g, 27mMol) thionyl chloride were mixed and heated at reflux for 60 minutes during which the solid gradually dissolved. After distilling off the liquid component, the crude product was redissolved twice in dichloromethane. After the solvent had been removed again, the crude acid chloride was dissolved in 20 ml of tetrahydrofuran and added dropwise to a solution of 0.42 g (2.3mMol) of N- (2-methoxycarbonylethyl) aniline and 0.92 ml (6.6mMol) of triethylamine in 30 ml of tetrahydrofuran. After stirring at 50 ℃ for 16 h, the solvent was removed and the crude product was purified by chromatography (silica gel; dichloromethane/ethanol 100: 1). Yield: 0.66 g (77% of theory) of R_fThe value: 0.47 (silica; dichloromethane/ethanol ═ 19: 1) i) 1-methyl-2- (N-4-cyanophenylaminomethyl) -thieno [2.3-d]Imidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide

In the presence of 0.73 g (1.88mMol) of 1-methyl-2-methoxymethyl-thieno [2.3-d]To a solution of imidazol-5-yl-carboxylic acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide in 30 ml of dichloromethane at 5 ℃ was added dropwise a solution of 2.9 ml (2.9mMol) of 1M boron tribromide in dichloromethane. After stirring at room temperature for 16 hours, the mixture is washed with 20 ml of saturated sodium bicarbonate solution, the organic phase is separated off, dried over sodium sulfate and filtered. The filtrate was mixed with 14 ml of N-ethyl-diisopropylamine and 0.43 g (3.64mMol) of 4-aminobenzonitrile. The dichloromethane was then distilled off in vacuo, the residue was heated at 50 ℃ for 1 hour and the residual solvent was distilled off in vacuo. Chromatography (silica; dichloromethane/ethanol 99: 1 to 97: 3) gave yellow oil which slowly solidified. Yield: 0.37 g (42% of theory) of R_fThe value: 0.29 (silica gel; dichloromethane/ethanol ═ 50: 1+ 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-ethoxycarbonylethyl) -amide-hydrochloride

0.38 g (0.80mMol) of 1-methyl-2- (N-4-cyanophenylaminomethyl) -thieno [2.3-d]Imidazol-5-yl-carboxylic acidThe acid N-phenyl-N- (2-methoxycarbonylethyl) -amide is stirred in 40ml of ethanol saturated with hydrogen chloride at 0 ℃ for 5 hours and then at room temperature until no starting material is detectable by TLC. The solvent was then distilled off at a bath temperature of maximum 28 ℃ and the oil residue was dissolved in 40ml of absolute ethanol and mixed with 1.1 g of ammonium carbonate. After 18 h the solvent was distilled off in vacuo and the crude product was purified by chromatography (silica gel; dichloromethane/ethanol from 9: 1 to 4: 1). Yield: 57% C of theory₂₆H₂₈N₆O₃S(504.62)R_fThe value: 0.21 (silica; dichloromethane/ethanol 4: 1+ few drops of acetic acid) EKA Mass Spectrometry: (M + H)⁺＝505

(M+H+Na)⁺⁺＝264

Example 1591-methyl-2- [ N- (4-amidinopyridine) aminomethyl ] -thieno [2.3-d ] imidazol-5-yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 2, using 1-methyl-2- [ N- (4-amidinophenyl) aminomethyl]-thieno [2.3-d]Imidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 85% C of theory₂₄H₂₄N₆O₃S(476.56)R_fThe value: 0.36 (reverse phase silica RP-8; methanol + 5% saline solution) EKA Mass Spectrometry: (M + H)⁺＝477

(M+Na)⁺＝499

(M+2Na)⁺⁺＝250

EXAMPLE 1601-methyl-3- [ N- (4-amidinophenyl) thiomethyl ] -quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride a) 1-methyl-3- [ N- (4-cyanophenyl) thiomethyl ] -quinoxalin-2-one-6-yl-carboxylic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide

2.5 g (7.6mMol) 3-amino-4-methylamino-benzoic acid N-phenyl-N- (2-methoxycarbonylethyl) -amide and 2.4 g (9.6mMol)3- (4-cyanophenyl) thioA solution of ethyl-2-oxo-propionate in 50 ml of ethanol was heated to boiling for 30 minutes. After removal of the solvent the crude product was purified by chromatography (silica gel; dichloromethane). Yield: 1.6 g (40% of theory) of R_fThe value: 0.63 (silica; ethyl acetate/ethanol/ammonia ═ 90: 10: 1) b) 1-methyl-3- [ N- (4-amidinophenyl) sulfanylmethyl]-quinoxalin-2-one-6-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 1, using 1-methyl-3- [ N- (4-cyanophenyl) thiomethyl]-quinoxalin-2-one-6-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol, with ammonium carbonate. Yield: 23% C of theory₂₈H₂₇N₅O₄S(543.64)R_fThe value: 0.25 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝544

(M+Na)⁺＝566

Example 1613-methyl-2- [2- (4-carbamimidoylphenyl) 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

1.4 g (4.6mMol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl]Imidazo [1.2-a ]]Pyridin-7-yl-carboxylic acid (prepared in analogy to Y.Katsura et al chem.pharm.Bull.1922, 40, 1424-carboxylic acid methyl ester using 4-bromo-1- (4-cyanophenyl) -1-penten-3-one and 2-aminopyridine-4-carboxylate) was suspended in 15 ml of thionyl chloride and heated to boiling for 1h until all dissolved. After distillative removal of thionyl chloride, the acid chloride was no longer purified in 15 ml of pyridine and mixed with 1.0 g (5.2mMol) of N- (2-ethoxycarbonylethyl) aniline at 0 ℃. After 1 hour the solvent was distilled off and the residue was dissolved in 30 ml of dichloromethane, washed with 15 ml of 1N hydrochloric acid and dried over sodium sulfate. The solvent was distilled off and then subjected to chromatography (silica gel; dichloromethane/ethanol ═ 0 to 2%) to give a brown oil. Yield: 1.48 g (64% of theory) R_fThe value: 0.73 (silica; ethyl acetate/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-ethoxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 1, starting 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. Yield: 62% C of theory₂₉H₃₁N₅O₃(497.60)R_fThe value: 0.23 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝498

Example 1623-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -imidazo [1.2-a ] pyridin-7-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 2, using 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. Yield: 92% C of theory₂₇H₂₇N₅O₃(469.55)R_fThe value: 0.19 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝470

(M+Na)⁺＝492

(M+2H)⁺⁺＝235.7

(M+H+Na)⁺⁺＝246.7

(M+2Na)⁺⁺＝257.7

Example 1631-methyl-2- [ N- (4-amidinophenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [ (N-ethoxycarbonylethyl-N-methyl) -2-aminoethyl ] -amide-dihydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N- [ (N-ethoxycarbonylethyl)-N-methyl) -2-aminoethyl]Amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 80% C of theory₃₁H₃₇N₇O₃(555.7)R_fThe value: 0.24 (silica; dichloromethane/methanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝556

(M+H+Na)⁺⁺＝289.8

(M+2H)⁺⁺＝278.8

Example 1641-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [ (N-hydroxycarbonylethyl-N-methyl) -2-aminoethyl ] -amide-hydrochloride

By the method of example 26 using 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N-phenyl-N- [ (N-ethoxycarbonylethyl-N-methyl) -2-aminoethyl]-amide-dihydrochloride and sodium hydroxide solution. Yield: 79% C of theory₂₉H₃₃N₇O₃(527.6)R_fThe value: 0.43 (reverse phase silica RP-18; methanol/5% saline solution 6: 4) EKA Mass Spectrometry: (M + H)⁺＝528

(M+H+Na)⁺⁺＝275.6

(M+2H)⁺⁺＝264.6

Example 1651-methyl-2- [ N- (4-amidinophenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxy-N-propyl) -amide-hydrochloride

With 1-methyl-2- [ N- (4-amidinophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-benzyloxy-N-propyl) -amide-hydrochloride was prepared by hydrogenation on palladium on carbon (10%) at 5 bar hydrogen pressure at room temperature. Yield: 61% C of theory₂₆H₂₈N₆O₂(456.6)R_fThe value: 0.70 (reverse phase silica RP-18; methanol/5% saline solution 9: 1) EKA Mass Spectrometry: (M + H)⁺＝457

(M+H+Na)⁺⁺＝240

Example 1661-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl]-aminomethyl group]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide solution. Yield: 97% C of theory₃₂H₃₇N₇O₃(599.7)R_fThe value: 0.22 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝600

(M+H+Na)⁺⁺＝311.7

(M+2H)⁺⁺＝300.8

(M+2Na)⁺⁺＝322.8

Example 1671-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxy-N-propyl) -amide

In an analogous manner to example 165, using 1-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl]-aminomethyl group]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-benzyloxy-N-propyl) -amide. Yield: 26% C of theory₃₃H₄₀N₆O₄(584.7)R_fThe value: 0.39 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝585

(M+H+Na)⁺⁺＝304

(M+Na)⁺⁺＝607

Example 1681-methyl-2- [ N- (4-amidinophenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyano)Phenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol with ammonium carbonate. Yield: 42% C of theory₂₈H₂₉FN₆O₃(516.6)R_fThe value: 0.31 (silica; dichloromethane/methanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝517

(M+H+Na)⁺⁺＝270

Example 1691-methyl-2- [ N- [4- (N-carbamimidoylphenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyanophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% C of theory₂₈H₂₉FN₆O₃(516.6)R_fThe value: 0.29 (silica; dichloromethane/methanol 5: 1) EKA Mass Spectrometry: (M + H)⁺＝517

(M+H+Na)⁺⁺＝270

Example 1701-methyl-2- [ N- (4- (amidinophenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-methyl-2- [ N- (4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (3-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 97% C of theory₂₆H₂₅FN₆O₃(488.5)R_fThe value: 0.13 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝489

(M+Na)⁺⁺＝511

(M+2Na)⁺⁺＝267

Example 1711-methyl-2- [ N- (4- (amidinophenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (4-fluorophenyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26, using 1-methyl-2- [ N- (4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (4-fluorophenyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 89% C of theory₂₆H₂₅FN₆O₃(488.5)R_fThe value: 0.15 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝489

(M+Na)⁺⁺＝511

(M+2Na)⁺⁺＝267

Example 1721-methyl-2- [ N- (4- (amidino-2-methoxy-phenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In an analogous manner to example 25d, using 1-methyl-2- [ N- (4-cyano-2-methoxy-phenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 89% C of theory₂₉H₃₂N₆O₄(528.6)R_fThe value: 0.13 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝529

(M+H+Na)⁺⁺＝276

(M+2H)⁺⁺＝265

Example 1731-methyl-2- [ N- (4- (N-4-ethylcarbamoylamidino) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [ N- (4-carbamimidoyl-phenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and 4-ethylbenzoyl chloride. Yield: 64% C of theory₃₆H₃₇N₇O₄(631.7)R_fThe value: 0.78 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝632

(M+H+Na)⁺⁺＝327.8

(M+Na)⁺⁺＝654

Example 1741-methyl-2- [ N- (4- (N-benzyloxycarbonylamidyl) phenyl ] -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In an analogous manner to example 90, using 1-methyl-2- [ N- (4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and benzyl chloroformate. Yield: 64% C of theory₃₅H₃₅N₇O₅(633.6)R_fThe value: 0.60 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝634

(M+H+Na)⁺⁺＝328.8

(M+Na)⁺＝656

Example 1751-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 71% C of theory₂₇H₂₈N₆O₄(500.6)R_fThe value: 0.15 (silica; dichloromethane/methanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝501

(M+Na)⁺＝523

(M+2Na)⁺⁺＝273

Example 1761-methyl-2- [ N- (4-amidino-2-methoxy-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d, using 1-methyl-2- [ N- (4-cyano-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 67% C of theory₂₈H₃₁N₇O₄(529.6)R_fThe value: 0.16 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝530

Example 1771-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 78% C of theory₂₆H₂₇N₇O₄(501.6)R_fThe value: 0.12 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝502

Example 1781-methyl-2- [ N- (4- (N-benzyloxycarbonylamidyl) phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 104 using 1-methyl-2- [ N- (4- (N-benzyloxycarbonylamidyl) phenyl)]-aminomethyl group]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide and sodium hydroxide solution. Yield: 62% C of theory₃₃H₃₁N₇O₅(605.7)R_fThe value: 0.26 (silica; dichloromethane/methanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝606

(M+Na)⁺＝628

(M-H+2Na)⁺＝650

(M+2H)⁺⁺＝303.8

(M+H+Na)⁺⁺＝314.8

(M+2Na)⁺⁺＝325.7

Example 1791-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-benzyloxy-N-propyl) -amide-hydrochloride

In an analogous manner to example 25, using 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. Yield: 61% C of theory₃₃H₃₄N₆O₂(546.7)R_fThe value: 0.19 (silica; dichloromethane/ethanol 4: 1) EKA Mass Spectrometry: (M + H)⁺＝547

(M+H+Na)⁺⁺＝285

Example 1801-methyl-2- [ N- [4- (N-N-hexyloxycarbonylamino) phenyl ] - -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-benzyloxy-N-propyl) -amide

In a manner analogous to example 90, using 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (3-benzyloxy-N-propyl) -amide-hydrochloride and N-hexyl chloroformate. Yield: 73% C of theory₄₀H₄₆N₆O₄(674.9)R_fThe value: 0.46 (silica; dichloromethane/ethanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝675

(M+H+Na)⁺⁺＝349

(M+Na)⁺＝697

(M+K)⁺＝713

Example 1813-methyl-2- [2- (4-carbamimidoylphenyl) ethyl ] -imidazo [1.2-a ] -pyridin-7-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In a manner analogous to example 1, using 3-methyl-2- [2- (4-cyanophenyl) -ethyl]Imidazo [1.2-a ]]Pyridin-7-yl-carboxylic acid-N- (2-pyridyl) -N- (2-methoxycarbonylethyl) -amide-hydrochloride and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 53% C of theory₂₈H₃₀N₆O₃(498.59)R_fThe value: 0.42 (silica; ethyl acetate/ethanol/ammonia 50: 45: 5) EKA Mass Spectrometry: (M + H)⁺＝499

(M+2Na)⁺⁺＝272

(M+H+Na)⁺⁺＝261

(M+2H)⁺⁺＝250

Example 1821-methyl-2- [ N- (3-carbamimidoyl-pyridin-6-yl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In an analogous manner to example 26 using 1-methyl-2- [ N- (3-cyanopyridin-6-yl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide and sodium hydroxide solution. Yield: 40% C of theory₂₄H₂₄N₈O₃(472.9)R_fThe value: 0.67 (reverse phase silica RP-8; methanol/5% saline solution 1: 1) EKA Mass Spectrometry: (M + H)⁺＝473

Example 1831-methyl-2- [ N- [4- (N-hydroxycarbamimidoyl) 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- (methanesulfonylaminocarbonyl) -ethyl ] -amide

2.0 g (4.5mMol) of 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide and 0.73 g (4.7mMol) carbonyldiimidazole in 80 ml tetrahydrofuran and 5 ml dimethylformamide under stirring at room temperatureStirred for 30 minutes and stirred at 90 ℃ for 2 hours. At the same time, 0.55 g (5.8mMol) of methanesulfonic acid amide and 0.28 g (5.8mMol) of sodium hydride are suspended in 15 ml of dimethylformamide and stirred at room temperature for 2 hours. The suspension was then added to the tetrahydrofuran solution at room temperature. After 12 hours, 50 ml of water were added at room temperature and the pH was adjusted to 6.8. The solution was extracted 4 times with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel (dichloromethane/ethanol (40: 1)). The desired fractions were purified and evaporated. Yield: 1.05 g (44% of theory) of C₂₆H₂₅N₇O₄S(531.6)R_fThe value: 0.72 (silica; dichloromethane/methanol ═ 9: 1) b) 1-methyl-2- [ N- [4- (N-hydroxyamidine) -phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- [ (2-methanesulfonylaminocarbonyl) -ethyl]-amides of

In an analogous manner to example 96 using 1-methyl-2- [ N- (4-cyanophenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- [2- (methanesulfonylaminocarbonyl) -ethyl]-amide and hydroxylamine preparation. Yield: 27% C of theory₂₆H₂₈N₈O₅S(564.6)R_fThe value: 0.75 (silica; dichloromethane/ethanol 7: 3+ 1% glacial acetic acid) EKA mass spectrum: (M + H)⁺＝565

(M+Na)⁺＝587

Example 1841-methyl-2- [ N- (5-amidino-thiazol-2-yl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

Prepared in analogy to example 25d using 1-methyl-2- [ N- (5-cyano-thiazol-2-yl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.

Example 1851-methyl-2- [ N- (5-amidino-thiazol-2-yl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

Prepared in analogy to example 26 using 1-methyl-2- [ N- (5-carbamimidoyl-thiazol-2-yl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution.

Example 1861-methyl-2- [ N- (2-carbamimidoyl-pyrazin-5-yl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride

In analogy to example 25d, using 1-methyl-2- [ N- (2-cyano-pyrazin-5-yl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide with ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 19% C of theory₂₅H₂₇N₉O₃(501.6)R_fThe value: 0.28 (silica; dichloromethane/methanol ═ 4: 1+ 1% glacial acetic acid) EKA Mass Spectroscopy: (MH)⁺＝502

(M+H+Na)⁺⁺＝262.5

Example 1871-methyl-2- [ N- (2-amidino-pyrazin-5-yl) aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide

In analogy to example 26, using 1-methyl-2- [ N- (2-carbamimidoyl-pyrazin-5-yl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide-hydrochloride and sodium hydroxide solution. Yield: 11% C of theory₂₃H₂₃N₉O₃(473.5)R_fThe value: 0.55 (reverse phase silica RP-8; 5% saline solution in methanol 6: 4) EKA Mass Spectrometry: (M + H)⁺＝474

(M+H+Na)⁺⁺＝496.6

Example 1881-methyl-2- [2- [4- (N-N-hexyloxycarbonylamino) phenyl ] -ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl ] -amide

Prepared in analogy to example 90 using 1-methyl-2- [2- [ 4-carbamimidoylphenyl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- [2- (1H-tetrazol-5-yl) -ethyl ] -amide and N-hexyl chloroformate.

Example 1891-methyl-2- [ N- (2-methoxy-4-N-pentyloxycarbonylaminophenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

In analogy to example 90, using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and N-pentyl chloroformate. Yield: 53% C of theory₃₅H₄₂N₆O₆(642.7)R_fThe value: 0.54 (silica; dichloromethane/ethanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝643

(M+H+Na)⁺⁺333.4

Example 1901-methyl-2- [ N- (4-N-heptyloxycarbonylamidino-2-methoxy-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (2-ethoxycarbonylethyl) -amide

In analogy to example 90, using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N- (2-ethoxycarbonylethyl) -amide hydrochloride and N-heptyl chloroformate. Yield: 68% C of theory₃₇H₄₆N₆O₆(670.8)R_fThe value: 0.56 (silica; dichloromethane/ethanol ═ 9: 1) EKA Mass Spectrometry: (M + H)⁺＝671

(M+H+Na)⁺⁺＝347.4

Example 1911-methyl-2- [ N- (4-ethoxycarbonylamidino-2-methoxy-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In analogy to example 90, using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride and ethyl chloroformate. Yield: theoretical value43% of C₃₁H₃₅N₇O₆(601.7)R_fThe value: 0.44 (silica; dichloromethane/ethanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝602

(M+H+Na)⁺⁺＝312.8

Example 1921-methyl-2- [ N- (2-methoxy-4-N-pentyloxycarbonylamino-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In analogy to example 90, using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride and N-pentyl chloroformate. Yield: 72% C of theory₃₄H₄₁N₇O₆(643.7)R_fThe value: 0.49 (silica; dichloromethane/ethanol ═ 9: 1) EKA Mass Spectrometry: (M + H)⁺＝644

(M+H+Na)⁺⁺＝333.9

Example 1931-methyl-2- [ N- (2-methoxy-4-N-heptyloxycarbonylamidino-phenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide

In analogy to example 90, using 1-methyl-2- [ N- (4-carbamimidoyl-2-methoxy-phenyl) -aminomethyl]-benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide hydrochloride and N-heptyl chloroformate. Yield: 55% C of theory₃₆H₄₅N₇O₆(671.8)R_fThe value: 0.54 (silica; dichloromethane/ethanol 9: 1) EKA Mass Spectrometry: (M + H)⁺＝672

(M+H+Na)⁺⁺＝347.9

Example 194 dry ampoule ingredients containing 75 mg of active substance per 10 ml: preparation of active substance 75.0 mg mannitol 50.0 mg water for injection to 10 ml:

the active substance and mannitol are dissolved in water. After packaging, the solution was lyophilized. To prepare a ready-to-use solution, the product is dissolved in water for injection.

Example 195 dry ampoule ingredients containing 35 mg of active substance per 2 ml: active substance 35.0 mg mannitol 100.0 mg water for injection to 2.0 ml preparation:

Example 196 tablet composition containing 50 mg of active substance: (1) active substance 50.0 mg (2) lactose 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mg

215.0 mg preparation:

mixing (1), (2) and (3), and granulating with the aqueous solution of (4). Adding (5) to the dried particulate material. The mixture is pressed into tablets, and the tablets have double sides, both sides are engraved with characters, and one side is provided with a parting line.

Diameter of the sheet: 9mm

Example 197 tablet preparation with 350 mg of active substance: (1) 350.0 mg of (2) lactose 136.0 mg of (3) maize starch 80.0 mg of (4) polyvinylpyrrolidone 30.0 mg of (5) magnesium stearate 4.0 mg

600.0 mg preparation:

Tablet diameter: 12mm

Example 198 capsule ingredients with 50 mg active: (1) active substance 50.0 mg (2) dried corn starch 58.0 mg (3) lactose powder 50.0 mg (4) magnesium stearate 2.0 mg

160.0 mg preparation:

grinding (1) with (3). Adding the ground substance into the mixture of (2) and (4) under strong stirring. The powder mixture was filled into hard gelatin capsules No. 3 with a capsule filling machine.

Example 199 Capsule ingredients containing 350 mg of active substance: (1) 350.0 mg of active substance (2) dried corn starch 46.0 mg of (3) lactose powder 30.0 mg of (4) magnesium stearate 4.0 mg

430.0 mg preparation:

Example 200 suppository 1 containing 100 mg of active substance the suppository contains: active substance 100.0 mg polyethylene glycol (MW 1500) 600.0 mg polyethylene glycol (MW 6000) 460.0 mg polyethylene sorbitol monostearate 840.0 mg

2,000.0 mg

Claims

1. A disubstituted bicyclic heterocycle of the formula, its tautomer, stereoisomer, mixture or salt thereof

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

Wherein A is a carbonyl or sulfonyl group attached to a benzo-, pyrido-, pyrimido-, pyrazino-, pyridazino-or thieno-moiety of a Het group which is R-free of the Het group₁Part of a group, B being ethylene, wherein a Het or Ar group is attachedThe methylene group in (A) may be via an oxygen or sulfur atom or via a sulfinyl, sulfonyl, carbonyl or-NR group₁Group substitution, wherein

R₁Is a hydrogen atom or C_1-6-alkyl radical, E is cyano or R_bAn NH-C (═ NH) -group, wherein

R_bIs a hydrogen atom, a hydroxyl group, C_1-3-an alkyl group or a group cleavable in vivo; the group comprising C_1-6Alkoxycarbonyl radical, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C_1-3-alkoxycarbonyl, optionally substituted by C_1-3Alkyl-substituted phenylcarbonyl, benzoyl, C_1-3-alkylsulfonyl-n-C_2-3-alkoxy-C_2-4Alkoxycarbonyl, p-C_1-3-alkylbenzoyl or pyridinoacyl radicals, together with C as defined above_1-9The ethoxy group in the 2-position on the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl substitution; in the above definitions saturated alkyl and alkoxy moieties containing more than two carbon atoms and alkanoyl and unsaturated alkyl moieties containing more than three carbon atoms also include branched isomers thereof, Ar is phenylene or naphthylene, optionally substituted with fluorine, chlorine or bromine atoms or with trifluoromethyl, C_1-3-alkyl or C_1-3-an alkoxy group substitution,

thienyl, thiazolyl, pyridinylene, pyrimidinyl, pyrazinylene, or pyridazinylene, optionally substituted by C on the carbon skeleton_1-3-an alkyl substitution,

het denotes a bicyclic heterocycle of formulaWherein

X is a nitrogen atom, and

y is an oxygen or sulfur atom, or optionally substituted by C_1-6-alkyl or C_3-7-a nitrogen atom substituted by a cycloalkyl group, furthermore, one or two non-angular methine groups in the phenyl moiety in the above bicyclic heterocycle may each be substituted by a nitrogen atom,

or X is optionally R₁Methine substituted by radicals in which R₁Is as defined above, and

y is renChoosing the place with C_1-6-alkyl or C_3-7-a nitrogen atom substituted by a cycloalkyl group,

or Het is the group

R₁The definition of (a) is as described above,

z is an oxygen or sulfur atom,

one of the D or G groups is a nitrogen atom and the other D or G group is a methine group,

and R_aIs C_1-6-alkyl, optionally with C_1-3-alkyl substituted C_3-7-cycloalkyl, wherein C_1-3The alkyl radical may in turn be substituted by carboxyl groups or groups which can be converted into carboxyl groups in vivo,

or R₂NR₃A group in which

R₂Is C_1-4Alkyl which may be substituted by carboxyl, C_1-6-alkyloxycarbonyl, benzyloxycarbonyl, C_1-3-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl substitution,

by hydroxy, phenyl C_1-3-alkoxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino substituted C_2-4Alkyl, in which the carbon atom in the position alpha to the adjacent nitrogen atom may be unsubstituted, or

Optionally with C_1-3-alkyl-substituted piperidinyl, and

R₃is a hydrogen atom, C_1-6-alkyl, optionally with C_1-3-alkyl substituted C_3-7-cycloalkyl radical, C_3-6-alkenyl or C_3-6-alkynyl, wherein the unsaturated moiety is not directly linked to R₂NR₃-on the nitrogen atom of the radical,

optionally substituted by fluorine, chlorine or bromine atoms, C_1-3-alkyl or C_1-3-alkoxy-substituted benzenesOptionally substituted by C_1-3Alkyl-substituted benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, or imidazolyl, or

R₂Or R₃Together with the nitrogen atom therebetween form a 5-to 7-membered cycloalkylimino group, optionally substituted by carboxyl or C_1-4-alkoxycarbonyl substituted, which may have a phenyl ring fused thereto.

2. The disubstituted bicyclic heterocycle of formula I, its tautomer, its stereoisomer, or its salt according to claim 1, wherein

A is a carbonyl or sulfonyl group which is attached to a benzo-, pyrido-, pyrimido-, pyrazino-, pyridazino-or thieno-moiety of the Het group which is R-free of the Het group₁The moiety of the group(s) is,

b is ethylene, in which the methylene group which is also bonded to Het or Ar may be replaced by an oxygen or sulfur atom or a sulfinyl, sulfonyl, carbonyl or-NR group₁-is substituted by a group, wherein

R₁Is a hydrogen atom or C_1-4-an alkyl group,

e is R_bAn NH-C (═ NH) -group, wherein

R_bAs defined in claim 1, in accordance with claim 1,

ar denotes phenylene, optionally substituted by fluorine, chlorine or bromine atoms or by trifluoromethyl, C_1-3-alkyl or C_1-3-an alkoxy-substituted one or more of,

het denotes a bicyclic heterocycle of formulaWherein

X is a nitrogen atom, and

y is an oxygen or sulfur atom, or optionally substituted by C_1-6-alkyl or C_3-7Nitrogen atoms substituted by cycloalkyl radicals, and bicyclic hetero rings as described aboveOne or two non-angular methines of the phenyl moiety in the ring may each be replaced by a nitrogen atom,

y is optionally substituted by C_1-6-alkyl or C_3-7-a nitrogen atom substituted by a cycloalkyl group,

or Het is the group

Wherein R is₁The definition of (a) is as described above,

z is an oxygen or sulfur atom,

and R_aIs C_1-6-alkyl, optionally substituted by C_1-3-alkyl substituted C_3-7-cycloalkyl, wherein C_1-3The alkyl radical may in turn be substituted by carboxyl groups or groups which can be converted into carboxyl groups in vivo,

or R₂NR₃A group in which

with hydroxy, phenyl C_1-3-alkoxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino substituted C_2-4Alkyl, in which the carbon atom in the position alpha to the adjacent nitrogen atom may be unsubstituted, or

Optionally is covered with C_1-3-alkyl-substituted pyridyl, and

R₃is a hydrogen atom, C_1-6-alkyl, optionally substituted by C_1-3-alkyl substituted C_3-7-cycloalkyl radical, C_3-6-alkenyl or alkynyl, wherein the unsaturated moiety cannot be directly linked to R₂NR₃-on the nitrogen atom of the radical,

optionally substituted by fluorine, chlorine or bromine atoms or by C_1-3-alkyl or C_1-3Phenyl substituted by alkoxy, by C_1-3Alkyl-substituted benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, or piperidinyl or

3. Disubstituted bicyclic heterocycles of the general formula I, their tautomers, their stereoisomers, their mixtures or their salts according to claim 1,

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

wherein

Het is 1- (C)_1-3-alkyl) -2, 5-benzimidazolylene, 1-cyclopropyl-2, 5-benzimidazolylene, 2, 5-benzothiazolyl, 1- (C)_1-3-alkyl) -2, 5-indolyl, 1- (C)_1-3-alkyl) -2, 5-imidazo [4, 5-b]Pyridinylene, 3- (C)_1-3-alkyl) -2, 7-imidazo [1, 2-a]Pyridylene or 1- (C)_1-3-alkyl) -2, 5-thieno [2, 3-d]An imidazolyl group, and

R_ais R₂NR₃A group in which

by hydroxy, benzyloxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino substituted C_2-4-alkyl, wherein in the above groups the carbon atom in the alpha-position adjacent to the nitrogen atom may be unsubstituted, or

R₃Is C_3-7Cycloalkyl, propargyl, wherein the unsaturated moiety may not be directly linked to R₂NR₃Phenyl which is optionally substituted by a fluorine or chlorine atom or by a methyl or methoxy group, pyrazolyl, pyridazinyl or pyridyl which are optionally substituted by a methyl group,

R₂and R₃Together with the nitrogen atom therebetween form a 5-to 7-membered cycloalkylimino group, optionally substituted by carboxyl or C_1-4Alkoxycarbonyl-substituted, optionally fused to a phenyl ring,

b is an ethylene radical, in which the methylene radical bonded to the Ar radical may be interrupted by an oxygen or sulfur atom or by-NR₁-is substituted by a group, wherein

R₁Is a hydrogen atom or C_1-4-an alkyl group,

e is R_bAn NH-C (═ NH) -group, wherein

R_bIs a hydrogen atom, a hydroxyl group, C_1-3-alkyl or C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C_1-3Alkoxycarbonyl, benzoyl, p-C_1-3-alkylbenzoyl or pyridinoacyl radicals, together with C as defined above_1-9The ethoxy group in the 2-position on the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl-substituted,

ar is 1, 4-phenylene, optionally substituted by a chlorine atom or by methyl, ethyl, or methoxy, or is 2, 5-thienylene,

4. the disubstituted bicyclic heterocycle of formula I, its tautomer, stereoisomer, or salt according to claim 1, wherein

A denotes a radical which is not substituted by R on the Het group₁A carbonyl or sulfonyl group attached to the benzo, pyrido, or thieno moiety of a group,

b is an ethylene radical, in which the methylene radical bonded to the Ar radical may be interrupted by an oxygen or sulfur atom or by-NR₁-radical substitution, wherein

R₁Is a hydrogen atom or a methyl group,

e is R_bAn NH-C (═ NH) -group, wherein

R_bDenotes a hydrogen atom, a hydroxyl group, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C_1-3-alkylbenzoyl or nicotinoyl radicals, together with C above_1-9The ethoxy group in the 2-position on the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl-substituted,

ar is 1, 4-phenylene optionally substituted by a chlorine atom or by methyl, ethyl, or methoxy, or is 2, 5-thienylene,

R_ais R₂NR₃A group in which

by hydroxy, benzyloxy, carboxy-C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino substituted C_2-3-alkyl in the above-mentioned group adjacent to the nitrogen atomThe carbon atom in the alpha-position of the son may be unsubstituted, and

R₃refers to propargyl, wherein the unsaturated moiety may not be directly bonded to R₂NR₃A phenyl group, optionally substituted by a fluorine or chlorine atom or by a methyl or methoxy group, or a pyridyl group,

5. the disubstituted bicyclic heterocycle of formula I, its tautomer, stereoisomer, or salt according to claim 1, wherein

A is a carbonyl group attached to a benzo or thieno moiety of the Het group,

b is ethylene, in which the methylene group bonded to the Ar group may be replaced by-NR₁Group substitution, wherein

R₁Is a hydrogen atom or a methyl group,

e is R_bAn NH-C (═ NH) -group, wherein

R_bIs a hydrogen atom, a hydroxyl group, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C_1-3-alkylbenzoyl or nicotinoyl, wherein C is as defined above_1-9The ethoxy group in the 2-position on the alkoxycarbonyl group can also be replaced by methylsulfonyl or 2-ethoxyethyl,

ar is 1, 4-phenylene optionally substituted with methoxy, or is 2, 5-thienylene,

R_ais R₂NR₃A group in which

by hydroxy, benzyloxy, carboxy C_1-3-alkylamino radical, C_1-3-alkoxycarbonyl-C_1-3Alkylamino, N- (C)_1-3-alkyl) -carboxy-C_1-3Alkylamino or N- (C)_1-3-alkyl) -C_1-3-alkoxycarbonyl-C_1-3-alkylamino substituted C_2-3-alkyl, in which the carbon atom in the position alpha to the adjacent nitrogen atom may be unsubstituted, and

R₃is phenyl optionally substituted by a fluorine atom or is 2-pyridyl.

6. Disubstituted bicyclic heterocycles of the general formula I, tautomers, stereoisomers, or salts thereof according to one of claims 1 to 5, wherein R_bIn the definition:

C_1-6-alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl;

said phenyl group-C_1-3-alkoxycarbonyl is benzyloxycarbonyl;

said C is_1-9Alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl,

said optionally substituted C_1-3-alkyl-substituted phenylcarbonyl is benzoyl or 4-ethyl-benzoyl;

said C is_1-3-alkylsulfonyl-n-C_2-3-alkoxycarbonyl or C_1-3-alkoxy-C_2-3-alkoxy-C_2-4-alkoxycarbonyl is 2-methylsulfonylethoxycarbonyl or 2- (2-ethoxy) -ethoxycarbonyl;

the pyridine acyl is nicotinoyl;

the branched isomers are isopropyl, tert-butyl and isobutyl.

7. A compound of the following general formula I, a tautomer thereof, a stereoisomer thereof, or a salt thereof,

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

(b)2- [ N- (4-carbamimidophenyl) -N-methyl-aminomethyl ] -benzothiazol-5-yl-carboxylic acid N-phenyl-N- (2-hydroxycarboxyethyl) -amide,

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

(d) 1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N-phenyl-N- (3-hydroxycarbonylpropyl) -amide,

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

(f) 1-methyl-2- [2- (2-amidinophenylthio-5-yl) -ethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (2-hydroxycarbonylethyl) -amide,

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

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

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

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

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

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

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

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

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

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

(s) 1-methyl-2- [ N- (4-carbamimidoyl-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.

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

1-methyl-2- [ N- (4-carbamimidoylphenyl) -aminomethyl ] -benzimidazol-5-yl-carboxylic acid N- (2-pyridyl) -N- (hydroxycarbonylethyl) -amide.

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

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

12. A prodrug or prodrug of a compound according to claims 7-11, comprising a prodrug group comprising a group which is cleavable in vivo to a carboxyl group and/or an imino or amino group, wherein the prodrug group of the carboxyl group comprises C_1-6-alkoxycarbonyl, or phenyl-C_1-3-alkoxycarbonyl, and

prodrug groups for imino or amino groups include C_1-9Alkoxycarbonyl, phenyl-C_1-3-alkoxycarbonyl, optionally substituted by C_1-3Alkyl-substituted phenylcarbonyl, pyridinoyl, C_1-3-alkylsulfonyl-n-C_2-3-alkoxycarbonyl or C_1-3-alkoxy-C_2-3-alkoxy-C_2-4-an alkoxycarbonyl group;

in addition, saturated alkyl and alkoxy moieties containing more than two carbon atoms and alkanoyl and unsaturated alkyl moieties containing more than 3 carbon atoms in the above definitions also include branched isomers thereof.

13. The prodrug or dual-prodrug of claim 12, wherein said C_1-6-alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl;

said phenyl group-C_1-3-alkoxycarbonyl is benzyloxycarbonyl;

the pyridine acyl is nicotinoyl;

the branched isomers are isopropyl, tert-butyl and isobutyl.

14. A physiologically acceptable salt of a compound according to claims 1 to 11, wherein E is R_bNH — C (═ NH) -groups.

15. A pharmaceutical composition comprising at least one compound of claims 1 to 11, wherein E is R_bAn NH-C (═ NH) -group, or a pharmaceutical composition comprising a salt according to claim 14, optionally together with one or more inert carriers and/or diluents.

16. The compound according to at least one of claims 1 to 11, wherein E is R_bUse of the NH-C (═ NH) -group, or the salt according to claim 14, for the preparation of a pharmaceutical composition having the effect of prolonging thrombin time, the thrombin inhibiting effect and the associated serine protease inhibiting effect.

17. A process for the preparation of a compound according to claims 1 to 11, characterized in that

a. To prepare compounds of the general formula I, in which E is R_bNH-C (═ NH) -groups, wherein R_bIs a hydrogen atom, a hydroxyl group or C_1-3When it is an alkyl group

Is prepared by reacting a compound of the formula (II) with an amine of the formula (III), optionally formed in the reaction mixture,

R_a-A-Het-B-Ar-C(＝NH)-Z₁ (II)

in the formula II

A, B, Ar, Het, and R_aAs defined in claims 1 to 11, and Z₁Is alkoxy, aralkoxy, alkylthio or aralkylthio,

H₂N-R_b′ (III)

in the formula III

R_b' is a hydrogen atom, a hydroxyl group or C_1-3-alkyl, or

b. To prepare compounds of the general formula I, in which R_a-A-groups and E are as defined in claims 1 to 11, with the proviso that R_a-A-group contains a carboxyl group and E is as defined in claims 1 to 11, or R_a-A-is as defined in claims 1 to 11 and E is NH₂-C (═ NH) -group, or R_aThe A-group containing a carboxyl group and E is NH₂-C (═ NH) -group, when:

then the compound of the following general formula (IV)

R_a′-A-Het-B-Ar-C-E′ (IV)

Wherein

A, B, Ar and Het are as defined in claims 1 to 11, R_a'-A-groups and E' are as defined for R given in claims 1 to 10_aa-A-group and E, with the proviso that R_a'-A-groups contain groups which can be converted into carboxyl groups by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis, E is as defined in claims 1 to 11, or E' is a group which can be converted into NH by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis₂-C (═ NH) -group, R_a' -A-group is as defined for R in claim 1_a-A-group, or R_a'-A-group contains a group which can be converted into a hydroxyl group by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis, E' is a group which can be converted into NH by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis₂-a group of-C (═ NH) -groups,

by hydrolysis, acid or base treatment, thermal decomposition or hydrogenolysis into compounds of the general formula I, wherein R_a-A-The radicals and E are as defined in claims 1 to 11, with the proviso that R_a-A-contains a carboxyl group and E is as defined in claims 1 to 11, or R_aThe definition of the radical A-is as defined in claims 1 to 10, and E is NH₂-C (═ NH) -group, or is R_aThe A-group containing a carboxyl group and E is NH₂-C (═ NH) -group, or

c. To prepare compounds of the general formula I, in which R_a-A-group containing R as defined in claims 1 to 11_aAn ester of the A-group

Then reacting the compound of the formula (V) with an alcohol of the formula (VI) or with a compound of the formula VII

R_a″-A-Het-B-Ar-E (V)

In the formula V

B, E, Ar and Het are as defined in claims 1 to 11, R_aThe definition of the "-A-group is given in claims 1 to 11_aWith the proviso that R is_aThe group "-A-contains a carboxyl group or a group which can be converted into the corresponding ester with an alcohol,

HO-R₇ (VI)

in the formula VI

R₇Is an alkyl moiety of an in vivo cleavable group as described in claims 1 to 11, but not with R₄-CO-O-(R₅CR₆) The group giving rise to a carboxyl group, or reacting with its carboxamide acetal,

Z₂-R₈ (VII)

in the formula VII

R₈Is an alkyl moiety of an in vivo cleavable group as described in claims 1 to 11, but not with R₄-CO-O-(R₅CR₆) The radical giving a carboxyl group, and Z₂Is a leaving group, or

d. To prepare compounds of the formula ICompound (I) wherein R_bIs a group cleavable in vivo

Then reacting the compound of the formula (VIII) with a compound of the formula IX

R_a-A-Het-B-Ar-C(＝NH)-NH₂ (VIII)

In the formula (VIII)

R_aA, Het, B and Ar are as defined in claims 1 to 11,

Z₂-R₇ (IX)

in the formula IX

R₇Is a group cleavable in vivo, Z₂Is a nucleofugic leaving group, or

e. To prepare compounds of the general formula I in which B is ethylene and in which methylene is replaced by sulfinyl or sulfonyl

Oxidizing a compound of the formula

R_a-A-Het-B′-Ar-E (X)

Wherein

A, E, Ar, Het and R_aIs as defined in claims 1 to 11, and

b' is ethylene in which methylene is replaced by sulfinyl or sulfonyl, or

f. To prepare compounds of the general formula I in which E is cyano, B is ethylene, where the methylene group which is also attached to Het or Ar is bonded to an oxygen or sulfur atom, or to sulfinyl, sulfonyl, carbonyl or-NR₁-is replaced by a group, when

By reacting a compound of the formula XI with a compound of the formula XII

R_a-A-Het-U (XI)

V-Ar-CN (XII)

In the formula

R_aA, Ar and Het are as defined in claims 1 to 11,

one of the U or V radicals is HO-, HS-, HOSO₂-or HNR₁A radical, another radical being Z₃CH₂-, wherein R₁As defined in claims 1 to 11, Z₃Is a nucleofugic leaving group, or

g. To prepare compounds of the general formula I, in which E is cyano, R_aIs R₂NR₃When a group is

Reacting a compound of formula XIII with an amine of formula XIV

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

In formula XIII

A, B, Het and Ar are as defined in claims 1 to 11,

in the formula XIV

R₂And R₃As defined in claims 1 to 11, or with reactive derivatives thereof, or

h. To prepare a benzimidazolyl, benzothiazolyl or benzoxazolyl compound of formula I, wherein B is ethylene:

by reaction of a compound of the formula XV with a compound of the formula XVI or with a readily reactive derivative thereof

In the formula XV

R_aA and Y are as defined in claims 1 to 11,

HO-CO-CH₂CH₂-Ar-E (XVI)

in the formula XVI

Ar and E are as defined in claims 1 to 11, and

i. to prepare the quinoxalin-2-one compounds of formula 1:

by reacting a compound of formula XVII with a compound of formula XVIII or with a readily reactive derivative thereof,

in the general formula XVII

R_a，R₁And A is as defined in claims 1 to 11,

HO-CO-COCH₂-Ar-E (XVIII)

in the formula XVIII

Ar and E are as defined in claims 1 to 10, or

j. To prepare compounds of the general formula I, in which R₂Is C substituted by alkylsulfonylaminocarbonyl_1-4When it is an alkyl group

By reaction of a compound of formula IXX or a readily reactive derivative thereof with a salt of a compound of formula XX

In the formula IXX

R₃A, B, E, and Het are as defined in claims 1 to 11, R₂' is C substituted by carboxyl_1-4-an alkyl group,

C_1-3-alkyl-SO₂-NH₂ (XX)

And, the protecting groups used in the reaction to protect the reactive groups are cleaved and/or

Optionally resolving the prepared compound of the general formula I into its stereoisomers and/or

Converting the prepared compound of the general formula I into a salt thereof;

the group cleavable in vivo includes C_1-3-an alkyl group or a group cleavable in vivo; the group comprising C_1-6Alkoxycarbonyl radical, C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C_1-3-alkoxycarbonyl, optionally substituted by C_1-3Alkyl-substituted phenylcarbonyl, benzoyl, C_1-3-alkylsulfonyl-n-C_2-3-alkoxy-C_2-4Alkoxycarbonyl, p-C_1-3-alkylbenzoyl or pyridinoacyl radicals, together with C as defined above_1-9The ethoxy group in the 2-position on the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl substitution.

18. A method according to claim 17 wherein the in vivo cleavable group comprises C_1-9Alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C_1-3Alkoxycarbonyl, benzoyl, p-C_1-3-alkylbenzoyl or pyridinoacyl radicals, together with C as defined above_1-9The ethoxy group in the 2-position on the alkoxycarbonyl group may also be replaced by C_1-3-alkylsulfonyl or 2- (C)_1-3-alkoxy) -ethyl substitution.

The process according to claim 17, wherein the conversion of the prepared compound of the general formula I into its salt is carried out with an inorganic or organic acid or base into a pharmaceutically acceptable salt thereof.