CA2435492A1 - Antithrombotic compounds, the preparation thereof and their use as pharmaceutical compositions - Google Patents

Abstract

The invention relates to anti-thrombotic compounds of general formula (I), where R1 to R4, Ar, A, m and n are as de-fined in claim 1, the tautomers, stereoisomers, mixtures, pro-drugs and salts thereof which have worthwhile properties. Compounds of the above general formula (I), in which Ar = a phenyl or naphthyl group substituted with the groups R5, R6 and R7 and R5 = a CN group, represent worthwhile intermediate products in the synthesis of the corresponding compounds of general formula (I), in which R5 = an amidino group substituted with one or two C1-3 alkyl groups. The compounds of the above general formula (I), with the exception of those compounds in which Ar = a phenyl or naphthyl group substituted with the groups R5, R6 and R7 and R5 = a CN group, have worthwhile pharmacological properties, in particular an anti-thrombotic effect and a factor Xa-inhibiting effect.

Description

Boehringer Ingelheim Pharma KG Case 5/1312 '~' ' D-55216 Ingelheim/Rhein foreign filing text 74917fft.205 Antithrombotic compounds, the preparation thereof and their use as pharmaceutical compositions The present invention relates to the compounds of general formula (CH2)m (CO)~ NR4-A-Ar (I), the tautomers, the stereoisomers, the mixtures, the prodrugs, the derivatives thereof which contain a group that is negatively charged under physiological conditions instead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable 1 s properties.
The compounds of the above general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group, are valuable intermediate products for preparing the corresponding 2o compounds of general formula I wherein R5 denotes an amidino group optionally substituted by one or two C~_3-alkyl groups. The compounds of the above general formula I with the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group, as well as the tautomers, the stereoisomers, the mixtures, the prodrugs, the 2s derivatives thereof which contain a group that is negatively charged under physiological conditions instead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, and the stereoisomers thereof, have valuable pharmacological properties, particularly an antithrombotic activity and an inhibiting effect on factor Xa.

t Case 511312 . - . Auslandstext The present application thus relates to the new compounds of the above general formula I and the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, their preparation and use.
In the above general formula (i) rn denotes the number 0, n denotes the number 1 and to A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)P-Rf, while p denotes one of the numbers 0, 1, 2 or 3 and Rf denotes a hydroxycarbonyl, C~_3-alkoxycarbonyl, aminocarbonyl, 2o C~_3-alkylaminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, C3_~-cycloalkylamino-carbonyl, N-(C~_3-alkoxy-carbonylmethyl)-N-(C~_3-alkyl)-aminocarbonyl, N-(carboxymethyl)-N-(C~_3-alkyl)-aminocarbonyl or a 4- to 7-membered cycloalkyleneimino-carbonyl group, or (ii) m denotes the number 1, n denotes the number 1 and A denotes a bond or (iii) m denotes the number 0 or 1, n denotes the number 0 and . w t Case 511312 . -. , Auslandstext A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group, or (iv) m denotes the number 2, n denotes the number 0 and A denotes a bond, R~ denotes an amino, C~_5-alkylamino, C3_7-cycloalkylamino or phenyl-C~_3-alkylamino to group each of which may be substituted at the amino nitrogen atom by a phenylcarbonyl or phenylsulphonyl group or by a C~_3-alkyl or C~_3-alkyl-carbonyl group optionally substituted in the alkyl moiety by a carboxy group, a group which may be converted in vivo into a carboxy group, an amino, C~_3-alkylamino or di-(G~_3-alkyl)-amino group, a di-(C~_5-alkyl)amino or N-(C3_~-cycloalkyl)-C~_5-alkylamino group, while the C~_5-alkyl moiety with the exception of the 1 position may be substituted in each case by a hydroxy, C~_3-alkoxy, amino, C~_3-alkyl-amino or di-(C~_3-alkyl)-amino group, 2 o a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl group optionally substituted by a C~_3-alkyl, amino-C~_3-alkyl, C~_a-alkylamino-C~_3-alkyl, di-(C~_3-alkyl)-amino-C1_3-alkyl, aminocarbonyl, C1_3-alkylamino-carbonyl or di-(C~_3-alkyl)-aminocarbonyl group, a 2,5-dihydropyrrol-1-yl-carbonyl group, an aminosulphonyl group optionally substituted by one or two C,_3-alkyl groups, a C3_~-cycloalkyl-carbonyl group, whilst the methylene group in the 3 or 4 position in a C5_~-cycloalkyl-carbonyl group may be replaced by an -NH group wherein Case 511312 . , " Auslandstext the hydrogen atom of the -NH group may be replaced by a C~_3-alkyl, C~_3-alkyl-carbonyl, phenylcarbonyl or phenylsulphonyl group, a phenylcarbonyl or heteroarylcarbonyl group, or a C~_3-alkyl group optionally monosubstituted by an amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, hydroxy, phenyl or a 4- to 7-membered cycloalkyleneimino group or terminally disubstituted by a phenyl group and a hydroxy group, while to the phenyl substituents may be substituted by an amidino group optionally substituted by one or two C~_3-alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C~_3-alkyl or C~_3-alkoxy group, R2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C~_3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2_3-alkenyl, C2_3-alkynyl, hydroxy, C~_3-alkoxy or trifluoromethoxy group, R3 denotes a hydrogen atom or a C~_3-alkyl group, 2 o R4 denotes a hydrogen atom or a C~_3-alkyl group optionally substituted by a carboxy group or a group which may be converted in vivo into a carboxy group and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while 2 s R5 denotes a cyano group, an amidino group optionally substituted by one or two C~_3-alkyl groups, an amino-C,_3-alkyl, C~_3-alkylamino-C~_3-alkyl or di-(C~_3-alkyl)amino-C~_3-alkyl group, R6 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, 3 o C,_3-alkyl, hydroxy, hydroxy-C1_3-alkyl, C~_3-alkoxy, C~_3-alkoxy-C,_3-alkyl, carboxy, carboxy-C~_3-alkyl, carboxy-C~_3-alkoxy, C~~-alkoxy-carbonyloxy, C~_4-alkoxy-carbonyl-C~_3-alkoxy, phenyl-C~_3-alkoxy, amino, C,_3-alkylamino or dl-(C~_3-alkyl)amino group and Case 511312 . , , Auslandstext R7 denotes a hydrogen, fluorine, chlorine or bromine atom or a C~_3-alkyl group, or a thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted in the carbon skeleton by a C~_3-alkyl group, while the term heteroaryl group mentioned above denotes a 5-membered heteroaryl group bound via a carbon or nitrogen atom which contains to an imino group optionally substituted by a C»-alkyl or C,_4-alkyl-carbonyl group, an oxygen or sulphur atom, an imino group optionally substituted by a C~.4-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom, an imino group optionally substituted by a C»-alkyl group and two nitrogen atoms or an oxygen or sulphur atom and two nitrogen atoms, or a 6-membered heteroaryl group which contains one or two nitrogen atoms, while a phenyl ring may be fused to the abovementioned 5- or 6-membered heteroaryl groups via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed may be bound via the heteroaromatic or carbocyclic moiety, and the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned groups, or the unsubstituted or monosubstituted phenyl moieties contained in these groups, as well as the abovementioned heteroaryl 3 o groups may additionally be substituted at a carbon atom in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C~_3-alkyl or C~_3-alkoxy group, unless otherwise stated.

. .
Case 511312 ~ . . Auslandstext The carboxy groups mentioned in the definition of the abovementioned groups may be replaced by a group which may be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, s and moreover the amino and imino groups mentioned in the definition of the abovementioned groups may be substituted by a group which can be cleaved in vivo.
Such groups are described for example in WO 98146576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
to By a group which can be converted in vivo into a carboxy group is meant, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a C~_6-alkanol, a phenyl-C~_3-alkanol, a C3_9-cycloalkanol, while a C5_e-cycloalkanol may additionally be substituted by one or two C~_3-alkyl groups, a C5_e-cycloalkanol wherein a methylene group in the 3 or 4 15 position is replaced by an oxygen atom or by an imino group optionally substituted by a C~_3-alkyl, phenyl-C~_3-alkyl, phenyl-C~_3-alkoxycarbonyl or C2_6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C~_3-alkyl groups, a C4_~-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C3_5-alkynol with the proviso that no bonds to the oxygen atom start from a 2o carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-C~_3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C~_3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula 2 5 Ra-CO-O-(RbCR~)-OH, wherein Ra denotes a C~_$-alkyl, C5_~-cycloalkyl, phenyl or phenyl-C~_3-alkyl group, 3 o Rb denotes a hydrogen atom, a C,_3-alkyl, C5_~-cycloalkyl or phenyl group and R~ denotes a hydrogen atom or a C~_3-alkyl group, ,, Case 5/1312 . . . Auslandstext by a group which is negatively charged under physiological conditions is meant, for example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C~_6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, s C~_s-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C~_s-alkylsulphonylaminocarbonyl group and by a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as a phenylcarbonyl group to optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C~_3-alkyl or C~_3-alkoxy groups, while the substituents may be identical or different, a pyridinoyl group or a C~_~s-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C~_~s-alkoxycarbonyl or C~_~s-alkylcarbonyloxy group, wherein hydrogen 15 atoms may be wholly or partially replaced by fluorine or chlorine atoms such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2 0 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C~_s-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or 2s phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C~_6-alkyl or C3_~-cycloalkyl groups and the substituents may be identical or different, a C~_3-alkylsulphonyl-CZa-alkoxycarbonyl, C~_3-alkoxy-C2~-alkoxy-C2~,-alkoxycarbonyl, Ra-CO-O-(RbCR~)-O-CO-, C~_s-alkyl-CO-NH-(RdCRe)-O-CO- or C~_s-alkyl-CO-O-(RdCRe)-(RdCRe)-O-CO- group, wherein Ra to o R~ are as hereinbefore defined, Rd and Re, which may be identical or different, denote hydrogen atoms or C,_3-alkyl groups.

Case 5/1312 Auslandstext _g_ Moreover, the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms mentioned in the definitions above also include the branched isomers thereof such as the isopropyl, tert.butyl, isobutyl group, etc.
Preferred compounds of the above general formula I are those wherein (i) m denotes the number 0, n denotes the number 1 and to A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-Rf, while p denotes one of the numbers 0, 1, 2 or 3 and Rf denotes a hydroxycarbonyl, C~_3-alkoxycarbonyl, aminocarbonyl, C~_3-alkylaminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, 2o C3_~-cycloalkylamino-carbonyl, N-(C~_3-alkoxy-carbonylmethyl)-N-(C~_3-alkyl)-aminocarbonyl, N-(carboxymethyl)-N-(C~_3-alkyl)-aminocarbonyl or a 4- to 7-membered cycloalkyleneimino-carbonyl group, or (ii) m denotes the number 0 or 1, n denotes the number 0 and A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-3 o alkyl group, R, denotes an amino, C~_3-alkylamino or C3_~-cycloalkylamino group each of which may be substituted at the amino nitrogen atom by a C~_3-alkyl, C~_3-alkylcarbonyl, Case 511312 r , . Auslandstext _g_ carboxy-C~_3-alkyl, carboxy-C~_3-alkylcarbonyl, C~_6-alkoxy-carbonyl-C~_3-alkyl-carbonyl or amino-C~_3-alkyl-carbonyl group, a di-(C~_3-alkyl)amino or N-(C5_~-cycloalkyl)-C~_3-alkylamino group, a 4- to 7-membered cycloalkyleneiminocarbonyl group optionally substituted by a C~_3-alkyl, amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl, aminocarbonyl or C~_3-alkylamino-carbonyl group, while 1 o a hydrogen atom bound to a nitrogen atom may be replaced by an acetyl, phenylcarbonyl or tert.-butoxycarbonyl group, or a 2,5-dihydropyrrol-1-yl-carbonyl group, i5 R2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C~_3-alkyl, C2_3-alkenyl, C2_3-alkynyl, trifluoromethyl, C~_3-alkoxy or trifluoromethoxy group, R3 denotes a hydrogen atom or a C,_3-alkyl group, 2 o R4 denotes a hydrogen atom or a C~_3-alkyl group and Ar denotes a phenyl group substituted by the groups R5, R6 and R7, while R5 denotes a cyano group, an amidino group optionally substituted by one or two 25 C~_3-alkyl groups, a hydroxy, C~_6-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or an amino-C~_3-alkyl or C~_3-alkylamino-C~_3-alkyl group, R6 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C,_3-3 o alkyl, hydroxy, hydroxy-C~_3-alkyl, C,_3-alkoxy, carboxy, C~_3-alkoxy-carbonyloxy, carboxy-C,_3-alkoxy or C~~-alkoxy-carbonyl-C~_3-alkoxy group and R7 denotes a hydrogen atom or a C~_3-alkyl group, Case 5/1312 . , , Auslandstext while the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned groups, or the unsubstituted or monosubstituted phenyl moieties contained in these groups, as well as the abovementioned heteroaryl s groups may additionally be substituted at a carbon atom in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C~_3-alkyl or C~_3-alkoxy group, unless otherwise stated, but particularly those compounds wherein Zo (i) m denotes the number 0, n denotes the number 1 and A denotes a methylene group wherein one or two hydrogen atoms independently of one another may be replaced 15 in each case by a C~_3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-Rf, while p denotes one of the numbers 0, 1, 2 or 3 and Rf denotes a hydroxycarbonyl, C~_3-alkoxycarbonyl, N-(C~_3-alkyl)-aminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, N-(C~_3-alkoxy-carbonyl-methyl)-N-(C~_3-alkyl)-aminocarbonyl, N-(carboxymethyl)-N-(C~_3-alkyl)-aminocarbonyl or a 4- to 7-membered cycloalkyleneimino-carbonyl group or (ii) m denotes the number 0, 3 o n denotes the number 0 and A denotes a -CHZ-CH2- group, or (iii) m denotes the number 1, Case 511312 .. , Auslandstext n denotes the number 0 and A denotes a -CH2- group, the groups R~ to R4 are as hereinbefore defined, but R~ in the 4 position is bound to s the phenyl group contained in formula I and Ar denotes a phenyl group disubstituted by the groups R5 and R6, while R5 is bound in the 3 position if R6 denotes a hydrogen atom, or is bound in the 5 to position if R6 assumes a meaning other than the hydrogen atom, and denotes an amidino group optionally substituted by one or two C~_3-alkyl groups, a hydroxy, C~~-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or an amino-C~_3-alkyl or C~_3-alkylamino-C~_3-alkyl group and 15 R6 denotes a hydrogen atom or a hydroxy, C~_3-alkoxy, carboxy-C~_3-alkoxy, C~_3-alkoxy-carbonyloxy- or C~_4-alkoxy-carbonyl-C~_3-alkoxy group bound in the 2 position, the stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I are those wherein (i) m denotes the number 0, n denotes the number 1 and 2 s A denotes a methylene group wherein a hydrogen atom may be replaced by a methyl, hydroxycarbonyl, C~_3-alkoxy-carbonyl, C~_3-alkylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-yl-carbonyl, C~_3-alkylaminocarbonylmethyl, N-{hydroxy-3 o carbonyl-methyl)-N-(C~_3-alkyl)-amino-carbonyl-methyl, N-(C~_3-alkoxy-carbonyl-methyl)-N-(C~_3-alkyl)-amino-carbonyl-methyl, hydroxycarbonylmethyl, C~_3-alkoxy-carbonylmethyl or dimethylamino-carbonylmethyl group, Case 5/1312 Auslandstext ,, R~ is bound in the 4 position of the phenyl group of formula I and denotes a C5_~-cycloalkylamino group which may be substituted at the amino nitrogen atom by s a C~_3-alkyl, C~_3-alkylcarbonyl, amino-C~_3-alkylcarbonyl, carboxy-G~_3-alkylcarbonyl or C~~-alkoxy-carbonyl-C~_3-alkyl-carbonyl group, a 4- to 7-membered cycloalkyleneiminocarbonyl group to or a 2,5-dihydropyrrol-1-yl-carbonyl group, R2 denotes a hydrogen atom or a C1_3-alkyl, ethenyl, ethynyl, trifluoromethyl or trifluoromethoxy group bound in the 3 position or, if R3 denotes a C~_3-alkyl group, in the 5 position of the phenyl group in formula I or a chlorine or bromine atom bound in 15 the 3 position, R3 denotes a hydrogen atom or a C~_3-alkyl group bound in the 2 position of the phenyl group in formula I, 2 o R4 denotes a hydrogen atom and Ar denotes a phenyl group disubstituted by the groups R5 and R6, while R5 is bound in the 3 position if R6 denotes a hydrogen atom, or is bound in the 5 25 position if R6 assumes a meaning other than the hydrogen atom, and denotes an amidino group optionally substituted by a C~_6-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or a aminomethyl group and 3 o R6 denotes a hydrogen atom or a hydroxy or C1_3-alkoxy-carbonyloxy group bound in the 2 position, as well as those compounds wherein Case 511312 , , , Auslandstext (i) m denotes the number 0, n denotes the number 0 and A denotes a -CH2-CHZ- group, or (ii) m denotes the number 1, n denotes the number 0 and A denotes a -CHZ- group, to R~ denotes a 4- to 7-membered cycloalkyleneiminocarbonyl or 2,5-dihydropyrrol-1-yl-carbonyl group bound in the 4 position of the phenyl group of formula I, R2 denotes a hydrogen atom or a substituent selected from fluorine, chlorine, bromine, C~_3-alkyl and trifluoromethyl bound in the 3 position or, if R3 denotes a z5 C~_3-alkyl group, bound in the 5 position of the phenyl group in formula I, R3 denotes a hydrogen atom or a C~_3-alkyl group bound in the 2 position of the phenyl group in formula I, 2 o R4 denotes a hydrogen atom and Ar denotes a phenyl group disubstituted by the groups R5 and R6, wherein R5 is bound in the 5 position and denotes an amidino group optionally substituted 2 s by one or two C~_3-alkyl groups, a C,_6-alkoxy-carbonyl or phenylcarbonyl group and R6 denotes a hydroxy group bound in the 2 position, 3 o the stereoisomers and the salts thereof.

Case 5/1312 . . . Auslandstext The following preferred compounds are mentioned by way of example:
(1) 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine, (2) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine, (3) N-(5-carbamirnidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-to benzylamine, ;' (4) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (5) N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dirnethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (6) N-(3-carbamimidoyl-benzyl)-3-methyl-4-{pyrrolidin-1-yl-carbonyl)-benzamide, (7) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (8) N-(5-aminomethyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (9) 2-(3-aminomethyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetic acid-N-ethylamide, (10) 3-(3-aminomethyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-3 o amino]-propionic acid-N-ethylamide, (11) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-ethoxy-carbonyl-propionyl)amino]-benzamide, Case 5/1312 ~ . . Auslandstext (12) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-acetyl-N-cyclobutyl-amino)-benzamide, (13) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-cyclopentyl-N-methyl-amino)-benzamide, (14) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-carboxy-propionyl)amino]-benzamide, to (15) N-(5-carbamimidoyl-2-hydroxy-benzyl)-4-cyclopentylamino-3-methyl-benzamide, (16) ethyl2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetate, (17) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid, (18) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-N-cyclopentyl-amino]-benzamide, (19) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4.-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzamide, (20) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (21 ) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbony1)-3 o benzoylamino]-propionate, (22) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbony1)-benzoylamino]-propionate, Case 5/1312 , . Auslandstext (23) ethyl 3-(3-carbamimidoyl-phenyl)-3-{3-methyl-4-[N-(3-amino-propionyl)-N-cyclo-pentyl-amino]-benzoylamino}-propionate, s (24) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (25) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbanyl)-benzoylamino]-propionate, (26) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, {27) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-1 s amino]-propionate, (28) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (29) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (30) 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, (31 ) 3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (32) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-3 o benzoylamino]-propionic acid, (33) 3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, Case 511312 Auslandstext (34) 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (35) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionic acid-N-methyl-N-(hydroxycarbonylmethyl)-amide, {36) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionic acid-N-(hydroxycarbonylmethyl)-N-(n-propyl)-amide, (37) 3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (38) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid-N,N-dimethylamide, (39) N-[1-(3-carbamimidoyl-phenyl)-2-oxo-2-(pyrrolidin-1-yl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (40) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-N,N-dimethylamide, (41) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-N-ethylamide, (42) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid-N-ethylamide, (43) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-3 o phenyl)-propionic acid-N-(ethoxycarbonylmethyl)-N-(n-propyl)-amide, (44) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-benzamide, Case 5/1312 ~ . ~ Auslandstext (45) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (46) N-(1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (47) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (48) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4.-(pyrrolidin-1-yl-carbonyl)-benzamide, (49) 3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, (50) ethyl 3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (51) ethyl 3-[3-N-(n-hexyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (52) n-propyl 3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (53) ethyl 3-[3-N-(2,2,2-trichloroethyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (54) N-{5-[N-(n-hexyloxycarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-3 0 1-yl-carbonyl)-benzamide, (55) N-(5-[N-(phenylcarbonyl)-amidino]-2-hydroxy-benzyl~-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, Case 5/1312 ~ . , Auslandstext (56) N-[5-(N-hydroxy-amidino)-2-hydroxy-benzyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide and (57) N-{5-[N-(phenylcarbonyl)-amidino]-2-(ethyloxycarbonyloxy)-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, wherein any amidino group present may additionally be substituted by a C~_6-alkoxy-carbonyl or phenylcarbonyl group, and the salts thereof.
According to the invention, the compounds of general formula I are obtained by methods known per se, e.g. by the following processes:
a) In order to prepare a compound of general formula I wherein (i) m denotes the number 0, n denotes the number 1 and A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced 2o in each case by a C~_3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)P-Rf, while p and Rf are as hereinbefore defined, 2 5 or (ii) m and n each denote the number 1 and A denotes a bond and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while 3 o R6 and R7 are as hereinbefore defined and R5 denotes an amidino group:

Case 5/1312 . , , Auslandstext acylating a compound of general formula H- N R4 -A-Ar ( I I), s wherein R4 is as hereinbefore defined, A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-Rf, while p and Rf are as hereinbefore defined, or denotes a bond and to Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R~, while R5 denotes a cyano group and R6 and R7 are as hereinbefore defined, with a carboxylic acid or a reactive carboxylic acid derivative of general formula RZ O
(CH2)m C (III), X
15 Rs wherein m denotes the number 0 or 1, X denotes a hydroxy or C~~-alkoxy group or a chlorine atom and R~ to R3 are as hereinbefore defined, or with the reactive derivatives thereof and subsequently converting the cyano compound thus obtained 2 o into an amidino compound.
The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile, dimethylformamide, sodium 2 s hyd-roxide solution or sulpholane optionally in the presence of an inorganic or organic base at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160°C.

Case 511312 Auslandstext The acylation may however also be carried out with the free acid optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus s trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-carbodiimidelN-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate/N-methylmorpholine, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate/N-ethyldiisopropylamine, N,N'-thionyldiimidazole or 1 o triphenylphosphine/carbon tetrachloride, at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160°C.
The subsequent conversion of the cyano group into an amidino group takes place as described in process e).
b) In order to prepare a compound of general formula I wherein m denotes the number 0 or 1, n denotes the number 0, A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms 2 o independently of one another may be replaced in each case by a C~_3-alkyl group, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R~ are as hereinbefore defined and RS denotes an amidino group:
2 s alkylating a compound of general formula Rz (Cl."Iz~ NR4 I"I (IV).

wherein R~ to R4 are as hereinbefore defined and m denotes the number 0 or 1, with a compound of general formula Case 511312 Auslandstext Z~ A-Ar M.
wherein A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen s atoms independently of one another may be replaced in each case by a C~_3-alkyl group, Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R~, while Rs and R7 are as hereinbefore defined and R5 denotes a cyano group, and Z~ denotes a leaving group such as a halogen atom or a sulphonyloxy group, to e.g. a chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group, and subsequently converting the cyano compound thus obtained into an amidino compound.
The alkylation is optionally carried out in a solvent or mixture of solvents such as 15 methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetra-hydrofuran, benzene/tetrahydrofuran, dioxan, dimethylsulphoxide or sulpholane with an alkylating agent such as a corresponding halide or sulphonic acid ester, e.g. with methyl iodide, ethyl bromide, dirnethylsulphate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, 2 o conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.
The subsequent conversion of the cyano group into an amidino group is carried out as described in process e).
c) In order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R~ are as hereinbefore defined and R5 denotes an amidino group, m denotes the number 1, n denotes the number 0 and Case 511312 Auslandstext A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group, or m denotes the number 2, n denotes the number 0 and A denotes a bond:
s alkylating a compound of general formula HNR4 A-Ar (II'), wherein R4 is as hereinbefore defined, to A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group, or denotes a bond, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are as hereinbefore defined and R5 denotes a cyano group, with a compound of general formula R~

(CH2)m Z2 (VI), 2 o wherein R~ to R3 are as hereinbefore defined, m denotes the number 1 or 2 and ZZ
denotes a leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group, and subsequently converting the resulting cyano compound into an amidino compound.
2 s The alkylation is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzeneltetrahydrofuran, dioxan, dimethylsulphoxide or sulpholane with an alkylating agent such as a corresponding halide or sulphonic acid ester, e.g.
with methyl iodide, ethyl bromide, dimethylsulphate or benzyl chloride, optionally in Case 511312 Auslandstext the presence of a tertiary organic base or in the presence of an inorganic base conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.
s The subsequent conversion of the cyano group into an amidino group is carried out as described in process e).
d) In order to prepare a compound of general formula I wherein Zo Ar denotes a phenyl or naphthyl group substituted by the groups R5, Rs and R7, while R6 and R~ are as hereinbefore defined and R5 denotes an amidino group, m denotes the number 0 or 1, n denotes the number 0 and A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms i5 independently of one another may be replaced in each case by a C~_3-alkyl group, or m denotes the number 2, n denotes the number 0 and A denotes a bond:
reductive alkylation of an amine of general formula RZ
(CHZ~NR4 H (IV'), 2 0 Rs wherein R~ to R4 are as hereinbefore defined and m denotes the number 0, 1 or 2, with an aldehyde of general formula O
A-Ar (VII), H

Case 511312 . , . Auslandstext _2b_ wherein A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group, or denotes a bond, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while s R6 and R~ are as hereinbefore defined and R5 denotes a cyano group, and subsequently converting the resulting cyano compound into an amidino compound.
The reductive alkylation is however preferably carried out in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium to cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride or borane/pyridine conveniently at a pH of 1-7 optionally in the presence of a dehydrating agent such as molecular sieve or titanium-IV-isopropoxide and at ambient temperature or with hydrogen in the presence of a hydrogenation catalyst, e.g. in the presence of palladiumlcharcoal, at a hydrogen pressure of 1 to 5 bar, preferably at temperatures 15 between 20°C and the boiling temperature of the solvent used. It may also be advantageous during the reaction if reactive groups are protected during the reaction by conventional protecting groups which are cleaved again by conventional methods after the reaction.
2o The subsequent conversion of the cyano group into an amidino group is carried out as described in process e).
e) In order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are as 2s hereinbefore defined and R5 denotes an amidino group optionally substituted by one or two C~_3-alkyl groups:
reacting a compound of general formula Case 511312 Auslandstext R~

(CHz)m (CO)~ NR4-A-Ar C(NH)-Z3 (VIII), optionally formed in the reaction mixture , wherein s R~ to R4, m, n and A are as hereinbefore defined, Ar denotes a phenyl or naphthyl group substituted by the groups R6 and R~, while R6 and R7 are as hereinbefore defined, and Z3 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, iso-propoxy or benzyloxy group or an alkylthio or aralkylthio group such as the Zo methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula H - R8NR9 , (IX) 15 wherein R$ and R9, which may be identical or different, each denote a hydrogen atom or a C~_3-alkyl group, or with the salts thereof.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, 2o n-propanol, tetrahydrofuran or dioxan at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C, with an amine of general formula IX
or with a corresponding acid addition salt such as for example ammonium carbonate or ammonium acetate.

25 A compound of general formula VIII is obtained for example by reacting a corresponding cyano compound with a 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 a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, Case 5/1312 . , - Auslandstext tetrahydrofuran or dioxan at temperatures between 0 and 50°C, but preferably at 20°C, or a corresponding nitrite with hydrogen sulphide conveniently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequently alkylating the thioamide formed with a corresponding alkyl or aralkyl halide.
f) In order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are as hereinbefore defined and R5 denotes an aminomethyl, C~_3-alkylaminomethyl or to di-(C~_3-alkyl)aminomethyl group:
Catalytic hydrogenation of a compound of general formula (CH2)rt, (CO)n NR4-A-Ar (I'), wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, R~ to R4, R6, R7, A, m and n are as hereinbefore defined and R5 denotes a cyano group, and optionally subsequent alkylation with a compound of formula 2 o R,o - Z4 (X), wherein Rio denotes a C~_3-alkyl group and Z4 denotes a leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group.
The catalytic hydrogenation is carried out with hydrogen in the presence of a catalyst such as palladium/charcoal, platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures Case 511312 ~ .. ' Auslandstext between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar, or for example with Raney nickel preferably in methanolic ammonia solution.
The alkylation which optionally follows is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzeneltetrahydrofuran, dioxan, dimethylsulphoxide or sulpholane with an alkylating agent such as a corresponding halide or sulphonic acid ester, e.g. with methyl iodide, ethyl bromide, to dimethylsulphate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C.
g) In order to prepare a compound of general formula I wherein°
m denotes the number 0, n denotes the number 0, A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group, and 2 o Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are as hereinbefore defined and R5 denotes an amidino group:
coupling a compound of general formula R~
Rz \ / Z5 (x1), 2 5 Ra wherein R~ to R3 are as hereinbefore defined and Z5 denotes a leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group, Case 511312 ~ . - Auslandstext with a compound of general formula HNR4 A-Ar (II"), wherein R4 is as hereinbefore defined, A denotes a straight-chain C~_3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C~_3-alkyl group, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R~, while so R6 and R7 are as hereinbefore defined and R5 denotes a cyano group, and subsequently converting the resulting cyano compound into an amidino compound.
The coupling reaction is conveniently carried out in a solvent such as toluene, dioxan, dimethoxyethane or tetrahydrofuran using a suitable catalyst, for example bis-(tri-o-tolylphosphine)-palladium-(II)-chloride, tris-(dibenzylideneacetone)-di-palladium(0)Itris-o-tolylphosphine, tris-(dibenzylideneacetone)-dipalladium(0)Itris-(2-furyl)phosphan, tris-(dibenzylideneacetone)-dipalladium(0)12,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, tetrakis-(triphenylphosphine)-palladiurn(0), 1,1'-bis-(diphenylphosphino)-ferrocene-palladium-dichloride or palladium-II-acetate/ 1,3-2 o bis-(triphenylphosphino)-propane, preferably in the presence of a base such as sodium-tert.butoxide, bis-(trimethylsilyl)-lithium amide, potassium carbonate, caesium carbonate or triethylamine at a temperature between 0 and 150°C, preferably 20 to 100°C.
2s The subsequent conversion of the cyano group into an amidino group is carried out as described in process e).
If according to the invention a compound of general formula I is obtained which contains an amino or imino group, this may subsequently be converted with a 3 0 corresponding acyl derivative into a corresponding acyl compound of general formula I andlor Case 5/1312 Auslandstext if a compound of general formula I is obtained which contains an esterified carboxy group, this may be converted by hydrolysis into a corresponding carboxylic acid of general formula I andlor s if a compound of general formula I is obtained which contains a carboxy group, this may subsequently be converted by esterification into a corresponding ester.
The subsequent acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, to ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or sulpholane optionally in the presence of an inorganic or organic base at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160°C.
This may however also be carried out with the free acid, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, 15 thionylchloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole or triphenylphosphinelcarbon 2o tetrachloride, at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160°C.
The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, 2s trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, waterlethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or waterldioxan and the subsequent decarboxylation in the presence of an acid as hereinbefore described at 3 o temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

Case 511312 . , Auslandstext The subsequent esterification is carried out with a corresponding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, but preferably in an excess of the alcohol used, optionally in the presence of an acid s such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimidelN-hydroxysuccinimide, N,N'-carbonyldiimidazole or to N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenyl-phosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine, conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C, or with a corresponding halide in a solvent such as methylene 15 chloride, tetrahydrofuran, dioxan, dirnethylsulphoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may also simultaneously serve as 2 o the solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100°C, but preferably at temperatures between -10 and 80°C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, 2 s carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and Case 511312 .. Auslandstext protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tent-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
s Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanollwater, acetic acid/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali to metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for Zs example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladiumlcharcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamidelacetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 2 o bar, but preferably 3 to 5 bar.
A rnethoxybenzyl group may also be cleaved in the presence of a oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrilelwater at temperatures between 0 and 50°C, but preferably 25 at ambient temperature.
A methoxy group is conveniently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25°C.
3 o A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

Case 511312 Auslandstext A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan or ether.
s A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50°C.
to An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladiurn(O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100°C, preferably at ambient temperature and under inert gas, or by treating with a catalytic amount of tris-15 (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 temperatures between 20 and 70°C.
The compounds of general formulae II to XI used as starting materials, some of 2 o which are known from the literature, are obtained by methods known from the literature and their preparation is also described in the Examples.
The chemistry of the compounds of general formula II, II', II" IV and IV' is described, for example, by Schroter in Stickstoffverbindungen II, pages 341-730, Methoden der 2s organischen Chemie (Houben-Weyl), 4'" edition, Verlag Thieme, Stuttgart 1957. The preparation of carboxylic acid derivatives of general formula III is described in Methoden der organischen Chemie (Houben-Weyl), Volume E5, Carbonsauren and Carbonsaurederivate, 4t" edition, Verlag Thieme, Stuttgart 1985.
3 o Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.

Case 511312 Auslandstext Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E.
L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical enantiomers and compounds of general formula I with at least 2 asymmetric carbon s atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
1 o The enantiomers are preferably separated by column separation on chiral phases or by recrystaliisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus 15 obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active 2 o alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with 2 s inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
3 o Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, Case 511312 Auslandstext potassium hydroxide, cyclohexylamine, ethanolarnine, diethanolamine and triethanolamine.
As already mentioned, the new compounds of general formula I and the salts thereof s have valuable properties. Thus, the compounds of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7 and denotes a cyano group are valuable intermediates for preparing the corresponding compounds of general formula I wherein R5 denotes an amidino group optionally substituted by one or two C~_3-alkyl groups. The compounds of general formula I with 1 o the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R~ and R5 denotes a cyano group, as well as the tautomers, the stereoisomers and the physiologically acceptable salts thereof, have valuable pharmacological properties, particularly an antithrombotic activity which is preferably based on an effect on thrombin or factor Xa, on a prolonging 15 effect on aPTT time and on an inhibitory effect on related serine proteases such as e.g. trypsin, urokinase, factor Vlla, factor IX, factor XI and factor XII.
For example, the compounds 20 (1) 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine-hydrochloride, (2) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride, (3) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxy-carbonylpropionyl)amino]-benzamide-hydrochloride, (4) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-3 o benzamide and (5) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbony1)-benzoylamino]-propionic acid, Case 511312 Auslandstext were investigated for their effect on the inhibition of factor Xa as follows:
Method: Enzyme-kinetic measurement with chromogenic substrate. The quantity of s anp-nitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance I
(in relation to the solvent control) is determined at various concentrations of test substance and from this the ICSO is calculated, as the concentration which inhibits the to factor Xa used by 50 %.
t Material:
Tris(hydroxymethyl)-aminornethane buffer (100 mmol) and sodium chloride (150 mMol), pH 8.0 Factor Xa (Roche), spec. activity: 10 U10.5 ml, final concentration: 0.175 U/ml for each reaction mixture Substrate Chromozym X (Roche), fiinal concentration: 200 pMolll for eachreaction 2o mixture Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 pMolll Procedure:
10 p.1 of a 23.5-times concentrated starting solution of the test substance or solvent (control), 175 p.1 of tris(hydroxymethyl)-arninomethane buffer and 25 ~I of a 1.65 Ulml Factor Xa working solution are incubated for 10 minutes at 37°C. After the addition of 25 ~I of Chrornozyrn X working solution (1.88 p.Molll) the sample is measured in a 3 o photometer (SpectraMax 250) at 405 nm for 150 seconds at 37°C.
Evaluation:

Case 511312 Auslandstext 1. Determining the maximum increase (deItaODlminutes) over 3 measuring points.
2. Determining the % inhibition based on the solvent control.
3. Plotting a dosage/activity curve (% inhibition vs substance concentration).
4. Determining the ICSO by interpolating the X value (substance concentration) of the dosagelactivity curve at Y = 50 % inhibition.
to The following Table shows the results obtained:
Substance Inhibition of factor Xa (ICSO in NM) (1 ) 0.084 (2) 0.014 (3) 0.075 (4) 0.01 (5) 0.031 The compounds prepared according to the invention are well tolerated, as no toxic side effects could be observed at therapeutic doses.
In view of their pharmacological properties the new compounds, with the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group, and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and 2 o arterial thrombotic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT(C)A, for the prevention and treatment of ischaemic incidents in patients with unstable angina or non-transmural cardiac Case 511312 Auslandstext infarct, for preventing metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes, e.g. in the treatment of pulmonary fibrosis, for the prevention and treatment of rheumatoid arthritis, for preventing fibrin-dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes. The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with P2T receptor antagonists (e.g. cangrelor) or with combined thromboxane to receptor antagonistslsynthetase inhibitors (e.g. terbogrel).
The dosage required to achieve such an effect is appropriately 3 to 30 mg/kg, preferably 1 to 10 mglkg by intravenous route, and 5 to 50 mg/kg, preferably 3 to 30 mglkg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers andlor diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, waterlethanol, water/glycerol, waterlsorbitol, waterlpolyethylene glycol, propylene 2 o glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples which follow are intended to illustrate the invention:

Case 511312 Auslandstext Example 1 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phen~rll-ethylamine-hydrochloride a. 2-methyl-4-bromo-benzoic acid-pyrrolidinamide 35 g (0.163 mol) of 2-methyl-4-bromo-benzoic acid are dissolved in 1 I
tetrahydrofuran and 100 ml water and combined with 57.8 g (0.18 mol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 22.0 g (0.163 io mol) of N-hydroxybenzotriazole and 62.7 ml (0.36 mol) of ethyl-dicyclohexylamine.
After 10 minutes at ambient temperature 13.9 ml (0.167 mol) of pyrrolidine are added. The reaction mixture is stirred for 24 hours and evaporated down. The residue is combined with 5 % saline solution/methylene chloride and extracted.
The aqueous phase is extracted three times with methylene chloride, the combined organic phases are dried and evaporated down. The residue is purified on silica gel, eluting with methylene chloride plus ethanol (0-3%). The uniform fractions are combined and evaporated down.
Yield: 42 g (77 % of theoretical), Rf value: 0.45 (dichloromethanelethanol = 95:5) b N-L~5-bromo-2-methoxy-phenyly-ethyl]-acetamide 1.9 g (9.8 mmol) of N-[2-(2-methoxy-phenyl)-ethyl]-acetamide are dissolved in 50 ml acetonitrile and after the addition of 2 g (11 mmol) of N-bromosuccinimide stirred for 4 hours at ambient temperature. Then the solvent is distilled off, the residue is stirred with dichloromethane and suction filtered. The mother liquor is evaporated down and chromatographed on silica gel, eluting with dichloromethanelmethanol/ammonia (50:0.9:0.1 ).
Yield: 2.6 g (99 % of theoretical), Rf value: 0.47 (silica gel; dichloromethane/methanol/ammonia = 24:0.9:0.1 ) c N-j2 ~5-cyano-2-methoxy-phenyl)-ethylJ-acetamide 12.5 g (45.9 mmol) of N-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-acetamide are dissolved in 50 ml dimethylformamide and after the addition of 8.2 g (91 mmol) of Case 511312 ' . ' Auslandstext copper cyanide, 577 mg (0.5 mmol) of tetrakis-triphenylphosphine-palladium-(0) and 11.6 g aluminium oxide stirred for 20 hours under a nitrogen atmosphere at 140°C.
The warm suspension is suction filtered and the mother liquor is evaporated down.
The residue is chromatographed on silica gel, eluting with dichloromethanelethanol (0-3%).
Yield: 4.9 g (49 % of theoretical), Rf value: 0.35 (silica gel; dichloromethane/methanol/ammonia = 19:0.9:0.1 ) ~5-cyano-2-methoxy-phern~)-ethylamine l0 4.9 g (22.4 mmol) of N-[2-(5-cyano-2-methoxy-phenyl)-ethyl]-acetamide are dissolved in 20 ml glacial acetic acid and after the addition of 60 ml of 3 molar hydrochloric acid refluxed for 15 hours. Then the solvent is distilled off, the residue is triturated in acetone and suction filtered. The crude product is dissolved in water, made alkaline with conc. ammonia and extracted with ethyl acetate. The organic phase is dried and i s evaporated down.
Yield: 2.6 g (66 % of theoretical), Rf value: 0.51 (silica gel; dichloromethane/methanol/ammonia = 4:0.9:0.1 ) a 2-(5-cyano-2-methoxy-phenyl)-N ~3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyll-2 o ethylamine A solution of 2.0 g (6.7 mmol) of 2-methyl-4-bromo-benzoic acid-pyrrolidinamide and 1.9 g (8.5 mmol) of (5-cyano-2-methoxy-phenyl)-ethylamine in 75 ml toluene is combined under a nitrogen atmosphere with 5.7 g (17.5 mmol) of caesium carbonate, 120 mg (0.27 mmol) of palladium-II-acetate and 240 mg (0.385 mmol) of 2,2'-bis-25 (diphenylphosphino)-1,1'-binaphthyl (BINAP) and heated to 130°C for 18 hours. After cooling the reaction mixture is stirred with ice water and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated down. The crude product is purified on silica gel, eluting with methylene chloridelmethanollammonia (11010; 50/0.9/0.1 and 33/0.9/0.1 ).
3 o Yield: 0.9 g (37 % of theoretical), Rf value: 0.71 (silica gel; dichloromethane/methanol/ammonia = 9:0.9:0.1 ) . CA 02435492 2003-07-22 Case 511312 Auslandstext f. 2-(5-cyano-2-hydroxy-phenyl)-N-[3-methyl-4={pyrrolidin-1-yl-carbonyl) phenyl ethylamine 0.5 g (1.3 mmol) of 2-(5-cyano-2-methoxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl!-ethylamine are dissolved in 40 ml dichloromethane and combined with 7 ml (7 mmol) of boron tribromide (1 M solution in dichloromethane) at -45 to -25°C. The reaction mixture is stirred for 20 hours at ambient temperature, combined with ice and conc. ammonia and extracted with dichloromethanelmethanol (19:1).
The combined organic extracts are evaporated down and chromatographed on silica gel, eluting with dichloromethane/ethanol (0-3%).
to Yield: 0.2 g (46 % of theoretical), Rf value: 0.42 (silica gel; ethyl acetateltoluene/ammonia = 9:0.9:0.1 ) g. 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-(3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phernr~IlethLrlamine-h~idrochloride 0.2 g (0.63 mmol) of 2-(5-cyano-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine are dissolved in ethanolic hydrochloric acid and stirred for 4.75 hours at ambient temperature. The reaction mixture is evaporated down, taken up in 25 ml ethanol and combined with 0.9 g (9.5 mmol) of ammonium carbonate. After 18 hours at ambient temperature the undissolved material is filtered off and the filtrate evaporated down. The residue is triturated with ether, filtered, washed with ether and dried.
Yield: 0.2 g (87 % of theoretical), Rf value: 0.58 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
1:2) C2~HZgN4O2 X HCI (366.47/402.93) 2s Mass spectrum : {M+H)+ = 367 (M+CI)' = 401103 (CI) Case 5/1312 Auslandstext Example 2 N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine-hydrochloride a. 3-methy~pyrrolidin-1-~-carbonyl)-benzonitrile Prepared analogously to Example 1.c. from 2-methyl-4-bromo-benzoic acid-pyrrolidinamide, copper cyanide, tetrakis-triphenylphosphine-palladium-(0) and aluminium oxide in dimethylformamide.
Z o Yield: 39 % of theoretical, Rf value: 0.22 (silica gel; cyclohexanelethyl acetate = 1:1 ) b. 3-meth~~p_yrrolidin-1 yl-carbonyl -benzylamine 2.3 g 3-methyl-4-{pyrrolidin-1-yl-carbonyl)-benzonitrile are dissolved in 75 ml ethanolic ammonia and after the addition of 0.4 g Raney nickel hydrogenated for 3 hours at 70°C with hydrogen. Then the catalyst is filtered off and the filtrate is evaporated down.
Yield: 2.3 g (100 % of theoretical), Rf value: 0.45 (silica gel; dichloromethanelethanol = 9:1 ) c. N-(5-cyano-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine A solution of 1.1 g (5 mmol) of 3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine in 10 ml methanol is combined with 0.3 ml (5 mmol) of glacial acetic acid and 0.2 g (3.5 mmol) of sodium cyanoborohydride. After 15 minutes 0.5 g (3.4 mmol) of 3-formyl-4-hydroxy-benzonitrile are added. The reaction mixture is stirred for 2 hours at ambient temperature and combined with ice and hydrochloric acid. By adding conc.
ammonia the solution is adjusted to pH 8 and extracted with dichloromethane. The organic phase is evaporated down and chromatographed over silica gel, eluting with ethyl acetate.
3 o Yield: 0.6 g {32 % of theoretical), Rf value: 0.33 (silica gel; dichloromethane/ethanol = 19:1 ) Case 5!1312 Auslandstext d. N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylarnine-hydrochloride Prepared analogously to Example 1.g. from N-(5-cyano-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine and hydrochloric acidlammonium carbonate s in ethanol.
Yield: 98 % of theoretical, Rf value: 0.66 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
1:1 ) C2~H26N402 x HCI (366.47/402.93) Mass spectrum : (M+H)+ = 367 i o (M-H)- = 365 (M+CI)- = 401103 (CI) The following compound is prepared analogously to Example 2:
15 (1) N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine-dihydrochloride Yield: 27 % of theoretical, Rf value: 0.6 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C22H28N4O2 X 2 HCI (380.491453.41 ) 2 o Mass spectrum : (M+H)+ = 381 Example 3 N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-2 s benzamide-hydrochloride a 4-benzyloxv-3-hydroxymethyl-benzonitrile A solution of 1.7 g (6.9 mmol) of 4-benzyloxy-3-forrnyl-benzonitrile in 10 ml tetrahydrofuran at 5-10°C is added dropwise to a solution of 0.15 g (3.9 mrnol) of 3 o sodium borohydride in 20 ml tetrahydrofuran. After 1.5 hours at 10°C the solvent is distilled off. The residue is combined with 0.5 N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried, evaporated down and crystallised with ether/petroleum ether.

Case 5/1312 ~ - Auslandstext Yield: 1.5 g (91 % of theoretical), Rf value: 0.2 (silica gel; petroleum ether/ethyl acetate = 8:2) b 4-benzyloxy-~1 3-dioxo-1 3-dihydro-isoindol-2-yl)-methyl-benzonitrile s A solution of 2.6 g (15 mmol) of diethyl azodicarboxylate in 5 ml tetrahydrofuran is added dropwise at ambient temperature to a solution of 0.9 g (6.2 mmol) of phthalimide potassium salt, 1.5 g (6.2 mmol) of 4-benzyloxy-3-hydroxymethyl-benzonitrile and 3.9 g (15 mmol) of triphenylphosphine in 50 ml tetrahydrofuran, while the temperature rises to 42°C. After 24 hours the solvent is distilled off, the to residue is taken up in sodium chloride solutionlethyl acetate and extracted with ethyl acetate. The combined organic extracts are dried and chromatographed on silica gel, eluting with petroleum etherlethyl acetate (10:0, 9:1 and 8:2).
Yield: 0.7 g (31 % of theoretical), Rf value: 0.45 (silica gel; petroleum ether/ethyl acetate = 7:3) c. 4-benzyloxy-3-aminomethyl-benzonitrile 0.7 g (1.9 mmol) of 4-benzyloxy-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-methyl-benzonitrile are dissolved in 20 ml isopropanol and refluxed for 30 minutes with the addition of 1.5 ml of hydrazine hydrate. Then the reaction solution is evaporated 2o down, the residue is stirred with ice water, suction filtered and dried.
Yield: 0.3 g (71 % of theoretical), Rf value: 0.1 (silica gel; petroleum ether/ethyl acetate = 1:1 ) d 3-methyl-4-(pvrrolidin-1-carbonyl)-benzoic acid 2s 26.8 g (0.1 mol) of 3-methyl-4-(pyrrolidin-1-carbonyl)-bromobenzene, 11.9 ml (0.13 mol) of n-butanol, 1 g (0.004 mol) of palladium-II-acetate, 4.2 g (0.016 mol) of tri-phenylphosphine and 15.5 ml (0.12 mol) of N-ethyl-diisopropylamine are placed in a steel bomb and after the addition of carbon monoxide heated for 50 hours to 100°C.
After cooling and evaporating off the carbon monoxide the reaction solution is stirred 3 o into ice water and extracted with ethyl acetate. The organic phase is dried and evaporated down. The residue is taken up in sodium hydrogen carbonate solution and ethyl acetate, the aqueous phase is adjusted to pH 4 with hydrochloric acid and extracted with ethyl acetate. The organic phases are dried and evaporated down.

Case 5/1312 ~ ~ Auslandstext Yield: 0.8 g (3.4 % of theoretical), Rf value: 0.4 (silica gel; dichloromethane/ethanol = 19:1) e. N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-s benzamide-hydrochloride Prepared analogously to Example 1.a. from 3-methyl-4-(pyrrolidin-1-carbonyl)-benzoic acid, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-methylmorpholine and 4-benzyloxy-3-aminomethyl-benzonitrile in dimethylformamide.
2o Yield: 93 % of theoretical, Rf value: 0.5 (silica gel; dichloromethane/ethanol = 9:1) f. N-(5-carbamimidoyl-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride 15 Prepared analogously to Example 1.g. from N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 0.3 g (77 % of theoretical), Rf value: 0.3 (silica gel; dichloromethanelethanollglacial acetic acid = 8:2 +

2 o glacial acetic acid) g. N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride 0.3 g (0.5 mmol) of N-(5-carbamimidoyl-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-2 s yl-carbonyl)-benzamide-hydrochloride are dissolved in 50 ml methanol and after the addition of 200 mg palladium on activated charcoal (10%) hydrogenated with 5 atmospheres of hydrogen at ambient temperature. Then the catalyst is filtered off, the filtrate is evaporated down and triturated with petroleum etherlether (1:1).
Yield: 120 mg (58 % of theoretical), 3 o C2~ H24N4O3 X HCI (380.45/416.91 ) Mass spectrum : (M+H)+ = 381 (M-H)' = 379 Case 5/1312 Auslandstext The following compounds are prepared analogously to Example 3:
(1) N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4.-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride s Yield: 81 % of theoretical, Rf value: 0.55 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C22HzsNa03 x HCI (394.48/430.94) Mass spectrum : (M+H)+ = 395 (M-H)' = 393 (M+CI)' = 429/31 (CI) (2) N-(3-carbamimidoyl-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-I~drochloride Yield: 88 % of theoretical, Rf value: 0.53 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C2~ H25N4O2 X HCI (364.451400.91 ) Mass spectrum : (M+H)+ = 365 (M+CI)' = 399101 (CI) (3) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride Yield: 87% of theoretical, Rf value: 0.7 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:8) C2~H2~F3N4O3 X HCI (434.421470.88) 2 s Mass spectrum : (M+H)+ = 435 (M-H)' = 433 Examele 4 3o N (5 aminomethyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide Prepared analogously to Example 2.b. from N-(5-cyano-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide in methanolic amrnonia/Raney nickellhydrogen and subsequent reaction analogously to Example 3.g. with hydrogen in methanol with the addition of palladium on activated charcoal.

Case 5/1312 Auslandstext Yield: 34 % of theoretical, Rf value: 0.35 (silica gel; dichloromethanelethanol = 8:2) C2~ H25N3O3 (367.45) Mass spectrum : (M-H)- = 366 The following compounds are prepared analogously to Example 4:
(1) 2-(3-aminomethyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetic acid-N-ethylamide-hydrochloride Yield: 91 % of theoretical, 1 o Rf value: 0.13 (silica gel; ethyl acetate/ethanol = 3:2 + 1 % ammonia) C24H3oN4O3 X HCI (422.531458.99) Mass spectrum : (M+H)+ = 423 (2) 3-(3-aminomethyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-i5 propionic acid-N-ethylamide Yield: 28 % of theoretical, Rf value: 0.22 (silica gel; dichloromethane/ethanol = 9:1 + 1 % ammonia) C25H32N4~3 {436.56) Mass spectrum : {M+H)+ = 437 2 0 (M-H)- = 435 Example 5 25 N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-ethoxy-carbonylpropionyl)amino,]-benzamide-hydrochloride a. benzyl 4-cycloaentylamino-3-methyl-benzoate 3.3 g (13.6 mmol) of benzyl 4-amino-3-methyl-benzoate, 1.3 ml (15 mmol) of cyclo-3 o pentanone, 1.2 ml (20.5 mmol) of glacial acetic acid and 0.1 g of p-toluenesulphonic acid are dissolved in 70 ml tetrahydrofuran and stirred for 30 minutes at ambient temperature. Then 4.0 g (17.8 mmol) of sodium triacetoxyborohydride are added.
After 26 hours at ambient temperature the solvent is distilled off and the residue is Case 5/1312 Auslandstext distributed in water/ ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are dried and purified over silica gel, eluting with dichloromethane.
Yield: 0.8 g (19 % of theoretical), s Rf value: 0.78 (silica gel; dichloromethane/ethanol = 95:5) b benzyl4-[cyclopentyl-(3-ethoxycarbonyl-aropionyl)-aminol-3-methyl-benzoate A solution of 0.8 g (2.6 mmol) of benzyl 4-cyclopentylamino-3-methyl-benzoate in 30 ml tetrahydrofuran is combined with 0.1 g (2.6 mmol) of sodium hydride and heated Zo to 40°C for one hour. After the addition of 0.3 ml (2.34 mmol) of ethyl succinate chloride the reaction mixture is stirred for 5 days at ambient temperature.
After evaporation of the solvent the residue is taken up in ethyl acetate, washed with saline solution and dried. The crude product is purified on silica gel, eluting with dichloromethane.
15 Yield: 0.8 g (73 % of theoretical), Rf value: 0.64 (silica gel; dichloromethane/ethanol = 95:5) c 4-[cyclopentYl-y3-ethoxycarbonyl propionyl)-aminol-3-methyl-benzoic acid Prepared analogously to Example 3.g. from benzyl 4-[cyclopentyl-(3-ethoxycarbonyl-2 o propionyl)-amino]-3-methyl-benzoate and palladium on activated charcoal/hydrogen in methanol.
Yield: 91 % of theoretical, Rf value: 0.12 (silica gel; dichloromethanelethanol = 95:5) 2 s d. N-(5-cyano-2-benzyloxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonyl-propionyl)aminol-benzamide Prepared analogously to Example 1.a. from 4-[cyclopentyl-(3-ethoxycarbonyl-propionyl)-amino]-3-methyl-benzoic acid, 4-benzyloxy-3-aminomethyl-benzonitrile, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 3 o N-methylmorpholine in dimethylformamide.
Yield: 95 % of theoretical, Rf value: 0.28 (silica gel; dichloromethane/ethanol = 95:5) Case 5/1312 Auslandstext _4g-e. N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxy-carbonyllaropion~~amino]-benzamide-hydrochloride Prepared analogously to Example 1.g. from N-(5-cyano-2-benzyloxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonylpropionyl)amino]-benzamide and s hydrochloric acidlammonium carbonate in ethanol and subsequent reaction analogously to Example 3.g. with hydrogen in methanol with the addition of palladium on activated charcoal.
Yield: 51 % of theoretical, Rf value: 0.31 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
6:4) to CZ7H34N4O5 X HCI (494.60/531.06) Mass spectrum : (M+H)+ = 495 (M+CI)' = 529131 (CI) The following compounds are prepared analogously to Example 5:
(1 ) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-acetyl-N-cyclobutyl-amino)-benzamide-hydrochloride Yield: 97 % of theoretical, Rf value: 0.12 (silica gel; dichlaromethanelethanol = 4:1 ) 2 o C22H26N4O3 X HCI (394.481430.94) Mass spectrum : (M+H)+ = 395 (M-H)' = 393 (M+CI)' = 429/31 (CI) 2 s (2) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-cyclopentyl-N-methyl-amino)-benzamide-hyd rochloride Yield: 91 % of theoretical, Rf value: 0.30 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C2zH28Na42 x HCI (380.49/416.95) o Mass spectrum : (M+H)+ = 381 (M-H)' = 379 (M+CI)' = 415/17 (CI) Case 511312 ~ , ~ Auslandstext Example 6 N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-carboxy-propionYl amino]-benzamide-hydrochloride s 0.2 g (0.28 mmol) of N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonylpropionyl)amino]-benzamide-hydrochloride are stirred in 5 ml of 6 molar hydrochloric acid at ambient temperature for 4 hours. The solvent is distilled off and the residue is purified on Reversed Phase RP 8, eluting with water/methanol (0 - 50%).
to Yield: 99 % of theoretical, r Rf value: 0.49 (Reversed Phase RP 18; 5% sodium chloride solution/methanol =
6:4) C25H3pN4O5 X HCI (4fi6.541503.00) Mass spectrum : (M+H)+ = 467 (M-H)' = 465 is (M+Na)+ = 489 Example 7 ~5-carbamimidoyl-2-hydroxy-benzy~-4-cyclopentylamino-3-methyl-benzamide-20 ~drochloride a. methyl 4-cyclopenylamino-3-methyl-benzoate Prepared analogously to Example 1.e. from methyl 4-bromo-3-methyl-benzoate, cyclopentylamine, caesium carbonate, palladium-II-acetate and 2,2'-bis-(diphenyl-2 s phosphino)-1,1'-binaphthyl in toluene.
Yield: 95 % of theoretical, Rf value: 0.55 (silica gel; dichloromethane) b. 4-cvclopentylamino-3-methyl-benzoic acid 3 0 3.3 g (14 mmol) of methyl 4-cyclopentylamino-3-methyl-benzoate are dissolved in ml methanol and combined with 30 ml of sodium hydroxide solution (2N). After hours at ambient temperature the reaction mixture is evaporated down and combined with 30 ml hydrochloric acid (2N) with cooling. After 30 minutes the solution is Case 511312 ~ Auslandstext combined with dichloromethane and extracted. The organic phase is dried and evaporated down.
Yield: 0.8 g (26 % of theoretical), Rf value: 0.74 (silica gel; petroleum ether/ethyl acetate = 4:6) c N-(2-benzyloxy-5-cyano-benzyl)-4-cyclopentylamino-3-methyl-benzamide Prepared analogously to Example 1.a. from 4-cyclopentylamino-3-methyl-benzoic acid, O-(benzotriazol-1-yl)-N,N,N'-N'-tetramethyluronium fluoroborate, N-methylmorpholine and 4-benzyloxy-3-aminomethyl-benzonitrile in to dirnethylformamide.
a Yield: 49 % of theoretical, Rf value: 0.77 (silica gel; dichloromethane/ethanol = 95:5) d. N-(5-carbamimidoyl-2-hydroxy-benzyl)-4-cyclopentylamino-3-methyl-benzamide-hydrochloride Prepared analogously to Example 1.g. from N-(2-benzyloxy-5-cyano-benzyl)-4-cyclopentylamino-3-methyl-benzamide and hydrochloric acidlammonium carbonate in ethanol and subsequent reaction with hydrogenlpalladium on activated charcoal in methanol analogously to Example 3.g.
2 o Yield: 78 % of theoretical, Rf value: 0.29 (silica gel; dichloromethanelethanol = 4:1 ) Cz~H26N402 x HCI (366.47/402.93) Mass spectrum : (M+H)+ = 367 (M-H)- = 365 (M+CI)' = 401103 (CI) Case 511312 , Auslandstext Example 8 Ethyl 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbony1)-benzo~ilamino]-acetate a. bend tert-butoxycarbonylamino- 3-cvano-phenyl)-acetate Prepared analogously to Example 1.c. from benzyl tert-butoxycarbonylamino-(3-bromo-phenyl)-acetate and copper-(I)-cyanidel tetrakis-triphenylphosphine-palladium-(0).
1 o Yield: 41 % of theoretical, Rf value: 0.25 (silica gel; cyclohexanelethyl acetate = 4:1 ) b. benz~l amino-l3-cyanophenyl)-acetate Prepared analogously to Example 1.d. from benzyl tert-butoxycarbonylamino-(3-Zs cyano-phenyl)-acetate and hydrochloric acid in dioxan.
Yield: 66% of theoretical, Rf value: 0.4 (silica gel; dichloromethanelmethanol = 95:5 + ammonia) c. benzyl (3-cyano-phenyl)-~[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-2 o carbon~amino,}-acetate Prepared analogously to Example 1.a. from benzyl amino-(3-cyano-phenyl)-acetate and 3-methyl-4-(pyrrolidin-1-carbonyl)-benzoic acid, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide.
Yield: 93% of theoretical, 2 s Rf value: 0.5 (silica gel; ethyl acetate) d. Ethyl (3-carbamimidoyl-phenyl)-{[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-carbonyl-amino acetate Prepared analogously to Example 1.g. from benzyl (3-cyano-phenyl)-{[3-methyl-4-3 0 (pyrrolidin-1-yl-carbonyl)-phenyl]-carbonyl-amino}-acetate and hydrochloric acidlammonium carbonate in ethanol.
Yield: 47% of theoretical, Rf value: 0.46 (Reversed Phase RPB; 5% saline solution/methanol = 2:3) Case 511312 Auslandstext C24H28N40a x CH3COOH (436.521496.57) Mass spectrum : (M+H)+ = 437 (M-H)- = 435 s Example 9 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-hydrochloride Prepared analogously to Example 7.b. from ethyl (3-carbamimidoyl-phenyl)-{[3-lo methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-carbonyl-amino}-acetate and sodium hydroxide solution.
Yield: 91 % of theoretical, Rf value: 0.55 (Reversed Phase RPB; 5% saline solution/methanol = 2:3) CZZH2aNa0a X HCI (408.46/444.92) is Mass spectrum : (M+H)+ = 409 (M+Na)+ = 431 Example 10 2 o N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-N-cyclopentyl-amino)-benzamide-hydrochloride a. rnethyl4-fcyclopentyl-[2-(2,2,2-trifluoro-acetylamino)-acetyl]-amino}-3-methyl-benzoate 2 s Prepared analogously to Example 5.b. from methyl 4-cyclopentylamino-3-methyl-benzoate, (2,2,2-trifluoro-acetylamino)-acetyl chloride and sodium hydride in tetrahydrofuran.
Yield: 46 % of theoretical, Rf value: 0.65 (silica gel; dichloromethane/ethanol = 95:5) b 4-fN-(2-benzyloxycarbonylamino-acetyl-c~clopentyl-aminol-3-methyl-benzoic acid 1.5 g (3.8 mmol) of methyl 4-fcyclopentyl-[2-(2,2,2-trifluoro-acetyl-amino)-acetyl]-amino}-3-methyl-benzoate are stirred in 20 ml methanol and 7.8 ml (7.7 mmol) of 1 Case 5/1312 . . Auslandstext molar sodium hydroxide solution for 2 hours. The solvent is distilled off, the residue is combined with 3.9 ml (3.8 mmol) of 1 molar sodium hydroxide solution. Then 0.6 ml (4.1 mmol) of benzyl chloroformate are added dropwise. After 1.5 hours the mixture is acidified with 1 molar hydrochloric acid and extracted with ethyl acetate.
The s combined organic extracts are dried and evaporated down.
Yield: 1.3 g (80 % of theoretical), Rf value: 0.10 (silica gel; dichloromethane/ethanol = 95:5) c. N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-[N-(2-benzyloxycarbonylamino-acetyl)-to cyclopentyl-amino]-benzamide Prepared analogously to Example 1.a. from 4-[N-(2-benzyloxycarbonyl-amino-acetyl)-cyclopentyl-amino]-3-methyl-benzoic acid, 3-aminomethyl-4-benzyloxy-benzonitrile, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate and N-methylmorpholine in dimethylformamide.
15 Yield: 66% of theoretical, Rf value: 0.68 (silica gel; dichloromethanelethanol = 95:5) d. N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-cyclopentyl-amino~]-benzamide-hydrochloride 2 o Prepared analogously to Example 1.g. from N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-[N-(2-benzyloxycarbonylamino-acetyl)-cyclopentyl-amino]-benzarnide and hydrochloric acidl ammonium carbonate in ethanol followed by reaction with hydrogen/ palladium on activated charcoal in methanol analogously to Example 3.g.
Yield: 55% of theoretical, 2s Rf value: 0.61 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C23H2gN503 X HCI (423.52/459.98) Mass spectrum : (M+H)+ = 424 (M+CI)- = 458/60 (CI) 9~
Case 5/1312 ' , ~ Auslandstext The following compound is prepared analogously to Example 10:
(1 ) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methy!-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzamide-hydrochloride s Yield: 100% of theoretical, Rf value: 0.53 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C24H3~ N5O3 X HCI (437.55/474.01 ) Mass spectrum : (M+H)+ = 438 (M+CI)- = 472/74 (CI) to Example 11 N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride a. 2-Chloro-4-(pyrrolidin-1-yl-carbon,!)-benzoic acid 0.9 g (4.3 mmol) of 2-chloro-terephthalic acid and 0.8 g {4.7 mmol) of N,N'-carbonyldiimidazole are stirred in 10 ml dimethylformamide for 15 minutes.
Then 0.5 ml (6.5 mmol) of pyrrolidine and 1.0 ml (9.5 mmol) of N-methylmorpholine are added.
2 o After 48 hours at ambient temperature the solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane/ethanol/glacial acetic acid 95:5:0.02 and 80:20:0.02.
Yield: 0.3 g (23 % of theoretical), Rf value: 0.21 (silica gel; dichloromethane/ethanol 95:5 + glacial acetic acid) b. N-(2-benzyloxY-5-cyano-benzyl)-3-chloro-4-(,pyrrolidin-1-yl-carbonyl)-benzamide Prepared analogously to Example 1.a. from 2-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid, 3-aminomethyl-4-benzyloxy-benzonitrile, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and N-ethyldiisopropylamine in 3 o tetrahydrofuran.
Yield: 73% of theoretical, Rf value: 0.45 (silica gel; dichloromethane/ethanol = 95:5) Case 5/1312 ~ ~ Auslandstext c. N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride Prepared analogously to Example 1.g. from N-(2-benzyloxy-5-cyano-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide and hydrochloric acidlammonium s carbonate in ethanol followed by reaction with hydrogen/palladium on activated charcoal in methanol analogously to Example 3.g.
Yield: 66% of theoretical, Rf value: 0.54 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C2oH21CIN4O3 X HCI (400.871437.34) to Mass spectrum : (M+H)+ = 401 (M-H)' = 399 (M+CI)' = 435/7/9 (C12) Example 12 is Ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzo~aminoLpropionate -hydrochloride a. 3-amino-3-f3-cyano-phenyl)-propionic acid 13.1 g (0.1 mol) of 3-cyanobenzaldehyde are dissolved in 50 ml of 95% ethanol and 2o after the addition of 15.4 g (0.2 mol) of ammonium acetate stirred for 15 minutes at 45°C. Then 20.8 g (0.2 mol) of malonic acid in 50 ml of 95% ethanol are added dropwise. The reaction mixture is refluxed for 2 hours. The crystalline product is suction filtered and recrystallised from methanol/water.
Yield: 6.5 g (34 % of theoretical), 25 C~oH~oN202 (190.20) Mass spectrum : (M+H)+ = 191 (M-H)' = 189 b. 3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3 o propionic acid 380.4 mg (2 mmol) of 3-amino-3-(3-cyano-phenyl)-propionic acid are added to 2.0 ml of 2 molar sodium hydroxide solution while cooling with ice. After the addition of 500 mg (1.98 mmol) of 3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylchloride the reaction ' Case 511312 ~ . Auslandstext mixture is stirred for 4 hours at ambient temperature. The solution is diluted with water and adjusted to pH 4 with 1 M hydrochloric acid. The precipitate formed is suction filtered and chromatographed on silica gel, eluting with dichloromethane/ethanol (4-10%).
s Yield: 280 mg (35 % of theoretical), Rf value: 0.35 (silica gel; dichloromethane/ethanol = 9:1 ) c. Ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]_propionate ~drochloride to Prepared analogously to Example 1.g. from 3-(3-cyano-phenyl)-3-[3-methyl-4 (pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid and hydrochloric acidlammonium carbonate in ethanol.
Yield: 59 % of theoretical, Rf value: 0.40 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) 15 C25H3pN4O4 X HCI (450.54/487.01 ) Mass spectrum : (M+H)+ = 451 (M-H)- = 449 (M+CI)' = 585/87 (CI) 2o The following compounds are prepared analogously to Example 12:
(1) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbony1)-benzoylamino'Lpro~onate -hydrochloride Yield: 98 % of theoretical, 2 s Rf value: 0.22 (silica gel; dichloromethanelethanol = 4:1 ) C24H27CIN4O4 X HCI (470.69/507.43) Mass spectrum : (M+H)+ = 471173 (CI) (M+CI)' = 50517/9 (C12) 3 0 (2) ethyl 3-(3-carbamimidoyl-phenyl)-3-{3-methyl-4-[N-(3-amino-propionyl)-N-~clopentyl-aminol-benzoYlamino}-propionate -hydrochloride Yield: 100% of theoretical, Rf value: 0.28 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) Case 511312 ' . ' Auslandstext C28H37N5O4 X HCI (507.63/544.11 ) Mass spectrum : (M+H)+ = 508 (M+CI)- = 542/44 (CI) s (3) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate -hydrochloride Yield: 81 % of theoretical, Rf value: 0.70 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
1:4) C24Hz7BrN404 x HCI (515.41/551.87) io Mass spectrum : (M+H)+ = 515117 (Br) (4) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionate -hydrochloride Yield: 45 % of theoretical, 15 Rf value: 0.30 (silica gel; dichloromethane/ethanol = 4:1 + 1 % glacial acetic acid) C25H2gN4O4 x HCI (448.51 /484.91 ) Mass spectrum : (M+H)+ = 449 (M+CI-)' = 483/5 (CI) 20 (5) ethyl 3-(3-carbamirnidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate -hydrochloride Yield: 71 % of theoretical, Rf value: 0.20 (silica gel; dichloromethanelethanol = 3:1 ) C2sHZ8N4O4 X HCI (460.53/497.01 ) 2 s Mass spectrum : (M+H)+ = 461 (M+CI-)- = 495/7 (CI) (6) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminoJ-propionate -hydrochloride 3 o Yield: 38 % of theoretical, Rf value: 0.18 (silica gel; dichloromethane/ethanol = 4:1 ) C2sH32N4Oq x HCI (464.56/501.03) Mass spectrum : (M+H)+ = 465 Case 511312 Auslandstext (M+CI')' = 499/501 (CI) (7) ethyl 3-(3-carbarnimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]_propionate -hydrochloride Yield:
Rf value:
C26H3oN4O4 X HCI (462.55/499.0) Mass spectrum Example 13 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid-hydrochloride Prepared analogously to Example 6 from ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate -hydrochloride and 6 molar hydrochloric acid.
Yield: 85 % of theoretical, 2 o Rf value: 0.50 (Reversed Phase RP 8; 5% sodium chloride solution/methanol = 2:3) C23H26N4O4 X HCI (422.491458.96) Mass spectrum : (M+H)+ = 423 (M-H)' = 421 The following compounds are obtained analogously to Example 13:
(1 ) 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminol-propionic acid-h~rdrochloride Yield: 65 % of theoretical, 3 o R, value: 0.5 (Reversed Phase RP 8; 5% sodiurn chloride solution/methanol = 2:3) C23H23F3N4O4 X HCI (476.46/512,91) Mass spectrum : (M+H)+ = 477 (M-H)' = 475 Case 5/1312 A Auslandstext (2) 3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]_propionic acid-hK,drochloride Yield: 90 % of theoretical, s Rf value: 0.42 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C22H2sCINa04 x HCI (442.9/479.38) Mass spectrum : (M+H)+ = 44315 (CI) (M-H)' = 441/3 (CI) to (3) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzo~amino]=proaionic acid-hydrochloride Yield: 27 % of theoretical, Rf value: 0.40 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C23H2aNaO4 X HCI (420.46/456.93) 15 Mass spectrum : (M+H)'' = 421 (M-H)' = 419 (4) 3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-aminoL~ropionic acid-hydrochloride 2 o Yield: 86 % of theoretical, Rf value: 0.15 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C24H24N4O4 X HCI (432.88/468.95) Mass spectrum : (M+H)+ = 433 (M-H)' = 431 2 s (M+CI)' = 467/9 (5) 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid-hydrochloride Yield: 85 % of theoretical, 3 o Rf value: 0.57 (Reversed Phase RP 8; 5% sodium chloride solution/methanol = 2:3) C24H28N40a x HCI (436.511472.98) Mass spectrum : (M+H)+ = 437 (M-H)' = 435 ~

Case 511312 - Auslandstext (M+CI)' = 471/3 (6) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-~hen_yl)-propionic acid-N-meth I-y_N-(h~ d~ roxycarbonylmethyl~ amide-hydrochloride s Yield: 42 % of theoretical, R, value: 0.35 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C26H31N5~5 x HCI (493.561530.03) Mass spectrum : (M+H)+ = 494 (M-H)' = 492 io (M+CI)' = 528/30 (7) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-henvll-aroaionic acid-N-(hvdroxvcarbonvlmethvl)-N-ln-oropvll-amide-hydrochloride 15 Yield: 67 % of theoretical, Rf value: 0.33 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) CZgH35N5O5 X HCI (521.621558.08) Mass spectrum : (M+H)+ = 522 (M-H)' = 520 (8) 3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-aminol-aropionic acid-hydrochloride Yield:
Rf value:
C24H26N4O4 x HCI (434.50/470.95) Mass spectrum Case 511312 - Auslandstext Example 14 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid-N N-dimethylamide-hydrochloride a. 3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid dimethylamide Prepared analogously to Example 1.a. from 3-(3-cyano-phenyl)-3-[3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, dimethylamine, to O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate and N-methylmorpholine in dimethylformamide.
Yield: 36 % of theoretical, Rf value: 0.38 (silica gel; dichloromethanelethanol = 19:1 ) b. 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino -propionic acid dimethylamide-hydrochloride Prepared analogously to Example 1.g. from 3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid-dimethylamide and hydrochloric acidlammonium carbonate in ethanol.
2 0 Yield: 24 % of theoretical, Rf value: 0.17 (silica gel; dichloromethane/ethanol 4:1 + 1 % glacial acetic acid) C25Hg~N5O3 X HCI (449.561486.03) Mass spectrum : (M+H)+ = 450 (M+CI)- = 484/86 (CI) The following are prepared analogously to Example 14:
(1) N-[1-(3-carbamimidoyl-phenyl)-2-oxo-2-(pyrrolidin-1-yl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride Case 5/1312 . Auslandstext O N

C ~ ~ HCI
' H2N NH
Yield: 79 % of theoretical Rf value: 0.40 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) CZgH3~N5O3 X HCI (461.53/498.03) Mass spectrum : (M+H)+ = 462 (2) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-N.N-dimethylamide-hydrochloride Yield: 76 % of theoretical to Rf value: 0.46 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C24H2gN5O3 X HCI (435.53/471.99) Mass spectrum : (M+H)+ = 436 (3) 2-(3-carbarnimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-N-ethylamide-hydrochloride Yield: 56 % of theoretical Rf value: 0.38 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C24H2gN5O3 X HCI (435.53/471.99) 2 o Mass spectrum : (M+H)+ = 436 (4) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]_propionic acid-N-ethKlamide-hydrochloride 2 5 Yield: 43 % of theoretical Rf value: 0.25 (silica gel; dichloromethane/ethanol = 4:1 + 1 % glacial acetic acid) C25H3~N5O3 X HCI (449.55/486.02) Case 511312 Auslandstext Mass spectrum : (M+H)+ = 450 (M-H)' = 448 (M+CI)' = 484/6 (CI) (5) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenvl)-propionic acid-N-(ethoxycarbonylmethvl)-N-(n-propel)-amide-hydrochloride Yield: 91 % of theoretical Rf value: 0.27 (silica gel; dichloromethane/ethanol = 4:1 + 1 % glacial acetic acid) 1 o C3pH3gN5U3 X HCI (549.671586.14) Mass spectrum : (M+H)+ = 550 (M+CI)' = 584/6 (CI) Example 15 N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride a 3-l1-amino-ethyl)-4-benzKloxy-benzonitrile 10.4 g (41.4 mmol) of 3-acetyl-4-benzoyl-benzonitrile are dissolved in 40 ml methanol, combined with 31.0 g (0.4 mol) of ammonium acetate and, after the addition of 1.8 g (28 mmol) of sodium cyanoborohydride, refluxed for 3 days under a nitrogen atmosphere. The solvent is distilled off, the residue is stirred in semiconc.
hydrochloric acid for 30 minutes, neutralised with ammonia and extracted with ethyl 2s acetate. The combined organic extracts are evaporated down and chromatographed on silica gel, eluting with petroleum ether/ethanol 9:1 and with ethyl acetate/ethanol 7:3.
Yield: 1.3 g (12 % of theoretical), Rf value: 0.15 (silica gel; ethyl acetate/ethanol = 9:1 ) , CA 02435492 2003-07-22 Case 511312 . Auslandstext b. N-[1-(2-benzyloxy-5-cyano-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide Prepared analogously to Example 1.a. from 3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid, 3-(1-amino-ethyl)-4-benzyloxy-benzonitrile, O-(benzotriazol-1-yl)-s N,N,N',N'-tetramethyl-uronium tetrafluoroborate and N-methylmorpholine in d imethylformamide.
Yield: 63 % of theoretical, Rf value: 0.45 (silica gel; dichloromethanelethanol = 19:1) to c. N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbon~il)-benzamide-hydrochloride Prepared analogously to Example 1.g. from N-[1-(2-benzyloxy-5-cyano-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide and hydrochloric acidlammonium carbonate in ethanol followed by reaction with hydrogen/palladium 15 on activated charcoal in methanol analogously to Example 3.g.
Yield: 30 % of theoretical, Rf value: 0.35 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) CZZH2sNaOs x HCI (394.48/430.95) Mass spectrum : (M+H)+ = 395 2 0 (M-H)' = 393 (M+CI)- = 429/31 (CI) The following compounds are prepared analogously to Example 15:
2s (1) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-bromo-4-(pyrrolidin-1-yl-carbons)-benzamide-hydrochloride Yield: 3 % of theoretical Rf value: 0.50 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C2~H23BrN4O3 X HCI (459.35/495.82) 3 o Mass spectrum : (M+H)+ = 459161 (Br) Case 511312 Auslandstext (2) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride Yield: 5 % of theoretical Rf value: 0.58 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) C2~H24N4O3 X HCI (380.451416.92) Mass spectrum : (M+H)+ = 381 Example 16 Ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminol-propionate -hydrochloride a. 4-methyl-3-trifluoromethyl-benzonitrile 10.0 g (57 mmol) of 4-methyl-3-trifluoromethyl-aniline are suspended in 50 ml of semiconcentrated hydrochloric acid and at 0°C combined with a solution of 4.2 g (61 mmol) of sodium nitrite in 25 ml of water. The diazonium salt solution formed is then added dropwise at 30°C to a solution of 12.5 g (0.14 mol) of copper-(I)-cyanide and g (0.38 mol) of potassium cyanide in 160 ml of water. The suspension formed is 2 o heated to 78°C for 2 hours. After cooling the undissolved material is filtered off, the filtrate is combined with 250 ml ethyl acetate and extracted. The combined organic phases are washed until neutral, dried and evaporated down. The crude product is purified by sublimation at 40-90°C and 12 mbar.
Yield: 5.5 g (47 % of theoretical), 2 5 R, value: 0.43 (silica gel; cyclohexanelethyl acetate = 4:1 ) b. 4-cyano-2-trifluoromethyl-benzoic acidl4-aminocarbonyl-2-trifluoromethyl-benzoic acid 28 ml of conc. sulphuric acid are added dropwise at ambient temperature to a 3 o suspension of 4.5 g (24.3 mmol) of 4-methyl-3-trifluoromethyl-benzonitrile and 11 g (37.4 mmol) of potassium dichromate in 100 ml glacial acetic acid, while the temperature rises to 80°C. After 1.5 hours at 115°C the reaction mixture is cooled, poured onto a mixture of 300g of ice/ 300 ml of saturated saline solution, adjusted to Case 511312 ~ ~ Auslandstext pH 3.5 with conc. ammonia and extracted with a total of 1000 ml of ethyl acetate. The combined organic phases are evaporated down by half, adjusted to pH 9 with conc.
ammonia and extracted with a total of 400 ml of 0.1 N sodium hydroxide solution. The aqueous phase is adjusted to pH 3.5 by the addition of conc. hydrochloric acid and s extracted with a total of 400 ml of ethyl acetate. The combined organic extracts are washed with saturated saline solution, dried and evaporated down.
Yield: 2.fi g (product mixture in a ratio of 3:7, 47 % of theoretical), Rf values:
4-cyano-2-trifluoromethyl-benzoic acid: 0.3 (silica gel; rnethylene chloridelethanol =
l0 6.5 : 3.5 + glacial acetic acid) 4-aminocarbonyl-2-trifluoromethyl-benzoic acid: 0.2 (silica gel; methylene chloridelethanol = 6.5 : 3.5 + glacial acetic acid) c. 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)- benzonitrilel3-trifluoromethyl-4-1s (pyrrolidin-1-yl-carbonyl)-benzamide Prepared analogously to Example 1.a. from 4-cyano-2-trifluoromethyl-benzoic acidl4-aminocarbonyl-2-trifluoromethyl-benzoic acid, pyrrolidine, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine in dimethylformamide.
2 o Yield: 53 % of theoretical (product mixture), Rf values:
3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzonitrile: 0.35 (silica gel;
ethyl acetatelethanol = 85:15 + glacial acetic acid) 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide: 0.35 (silica gel;
ethyl 2 s acetatelethanol = 85:15 + glacial acetic acid) d. 3-trifluoromethyl-4;~pyrrolidin-1-yl-carbonyl)-benzoic acid 1.65 g of a mixture of 3-trifluoromethyl-4.-(pyrrolidin-1-yl-carbonyl)-benzonitrile and 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide are dissolved in 20 ml ethanol 3 o and combined with 20 ml of 10 N sodium hydroxide solution. After 45 minutes at 80°C the reaction solution is poured onto ice water and adjusted to pH
9 with conc.
hydrochloric acid. The ethanol is distilled off and the residue is extracted with 100 ml Case 5/1312 Auslandstext ether and 50 ml ethyl acetate. The aqueous phase is adjusted to pH 3.5 with conc.
hydrochloric acid, the white precipitate formed is suction filtered and dried.
Yield: 1.05 g (85 % of theoretical), Rf value: 0.43 (silica gel; ethyl acetatelethanol = 85:15 + glacial acetic acid) e. ethyl 3-(3-cyano-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminoJ_propionate Prepared analogously to Example 1.a. from 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium to tetrafluoroborate, N-methylmorpholine and ethyl 3-amino-3-(3-cyano-phenyl)-propionate in dimethylformamide.
Yield: 64 % of theoretical, Rf value: 0.7 (silica gel; ethyl acetate/ethanol = 9:1) f. ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminoJpro~onate -hydrochloride Prepared analogously to Example 1.g. from ethyl 3-(3-cyano-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminoJ-propionate and hydrochloric acidl ammonium carbonate in ethanol.
2 o Yield: 90% of theoretical, Rf value: (Reversed Phase RP 8; 5% sodium chloride solution/methanol = 2:3) C25H27F3N4O4 X HCI (504.511540.97) Mass spectrum : (M+H)+ = 505 Example 17 N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hK,drochloride a 3-trifluoromethoxv-4-(~~yrrolidin-1-vl-carbonyl)-benzoic acid 1.8 g of carbonyldiimidazole (15.6 mmol) and 2.5 ml of N-methylmorpholine (22.7 mmol) are added to a solution of 2.5 g of 2-(trifluoromethoxy)-terephthalic acid (19 ~

Case 5/1312 Auslandstext mmol) in 40 ml of dimethylformamide at ambient temperature. After 10 minutes 1.3 ml of pyrrolidine (15.6 mmol) are added dropwise. The reaction mixture is stirred for 3 days at ambient temperature, then stirred into ice water, adjusted to pH 4 with 1 N
hydrochloric acid and extracted 3 x with 100 ml of ethyl acetate. The combined s organic phases are washed with saline solution, dried and evaporated down.
The crude product is purified on silica gel, eluting initially with dichloromethane, then with dichloromethane/ethanol 50:1, 25:1, 19:1 and 9:1. The uniform fractions are combined and evaporated down.
Yield: 90 mg (3% of theoretical), 1 o Rf value: 0.27 (silica gel; dichloromethane/ethanol = 9:1 ) b. N-(2-benzyloxy-5-cyano-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide Prepared analogously to Example 1.a. from 3-trifluoromethyl-4.-(pyrrolidin-1-15 carbonyl)-benzoic acid, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-methylmorpholine and 4-benzyloxy-3-aminomethyl-benzonitrile in dimethylformamide.
Yield: 62 % of theoretical, Rf value: 0.5 (silica gel; dichloromethanelethanol = 9:1 ) c. N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonylj-benzamide-hydrochloride Prepared analogously to Example 1.g. from N-(2-benzyloxy-5-cyano-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide and hydrochloric acid/ammonium carbonate in ethanol followed by reaction with hydrogen/palladium on activated charcoal in methanol analogously to Example 3.g.
Yield: 24% of theoretical, Rf value: 0.3 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) CZ~ H2~ F3N4O4 X HCI (450.42/486.88) 3 o Mass spectrum : (M+H)+ = 451 (M-H)- = 449 Case 5/1312 Auslandstext Example 18 3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino,-aropionic acid-hydrochloride s a 4-amino-2-oxo-chroman-6-carbonitrile-hydrochloride 4.6 ml of a 1 N solution of bis-(trimethylsilyl)-lithium amide in tetrahydrofuran (4.6 mmol) are added dropwise to a solution of 750 mg of 2-oxo-2H-chromene-6-carbonitrile (4.4 mmol) at -70 °C. After 5 minutes at -70 °C and 2 hours at -15 °C the reaction mixture is poured onto 180 ml of diethylether and combined with ethereal 1 o hydrochloric acid. The precipitate formed is filtered off, dried and further reacted without purification.
Yield: 1.0 g (56% of theoretical), Rf value: 0.45 (silica gel; ethyl acetate/ethanol = 9:1 + 1 % ammonia)) 15 b.3-(5-cyano-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-aminol-aropionic acid Prepared analogously to Example 12.b. from 4-amino-2-oxo-chromane-6-carbonitrile-hydrochloride, 3-methyl-4-(pyrrolidin-1-carbonyl)-benzoylchloride and triethylamine in tetrahydrofuran.
2 o Yield: 39 % of theoretical, Rf value: 0.5 (silica gel; ethyl acetatelethanol = 4:1 + 1 % glacial acetic acid) c. ethyl 3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbon -benzoylamino~-propionate -hydrochloride 2 s Prepared analogously to Example 1.g. from 3-(5-cyano-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 69 % of theoretical, Rf value: 0.5 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) Case 511312 ~ . Auslandstext d. 3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylaminol-propionic acid-hydrochloride Prepared analogously to Example 11. from ethyl 3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate s hydrochloride and 6 N hydrochloric acid.
Yield: 43 % of theoretical, Rf value: 0.6 (Reversed Phase RP 8; 5% sodium chloride solutionlmethanol =
2:3) C2sH2sN445 X HCI (438.48/474.95) Mass spectrum : (M+H)+ = 439 to Example 19 Ethyl 3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbon r~l -benzoylamino]~~roaionate 15 A suspension of 390 mg (0.8 mmol) of ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate and 1.0 ml triethylamine in 40 ml dichloromethane is combined with 275 mg (1.1 mrnol) of 4-nitrophenyl benzoate and refluxed for 7 hours. The solvent is evaporated off, the residue is taken up in ice water and adjusted to pH 4 with 1 N hydrochloric acid. After extraction with ethyl 2 o acetate the combined organic phases are washed with saline solution and dried. The crude product is purified on silica gel, eluting initially with dichloromethane, then with dichloromethane/ethanol 50:1 and 25:1.
Yield: 55 mg (12 % of theoretical), Rf value: 0.45 (silica gel; dichloromethanelethanol = 19:1 ) 2 5 C32H34N4~5 (554.65) Mass spectrum : (M+H)+ = 555 (M-H)- = 553 The following compounds are prepared analogously to Example 19:
(1) ethyl 3-[3-N-(n-hexyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbons)-benzo,~laminol-~roaionate Yield: 47 % of theoretical, ~

Case 511312 ' , ~ Auslandstext Rf value: 0.45 (silica gel; dichloromethanelethanol = 19:1 + 1 % ammonia) C32H42N4O6 X HCI (578.71/615.18) Mass spectrum : (M+H)+ = 579 s (2) n-propyl 3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonylZ benzoylamino]-propionate Yield: 23 % of theoretical, R~ value: 0.70 (silica gel; ethyl acetatelethanol = 9:1 ) C33H36N4~5 (568.68) 1 o Mass spectrum : (M+H)+ = 569 (M-H)' = 567 (3) ethyl 3-[3-N-(2,2,2-trichloroethyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-~pyrrolidin-1-~-carbonyl)-benz~laminoJ propionate 15 Yield: 45 % of theoretical, Rf value: 0.70 (silica gel; ethyl acetatelethanol = 9:1 ) C28H31CI3N4~6 (625.94) Mass spectrum : (M+H)+ = 6251719 (C13) (M-H)' = 623/517 (C13) 20 (M+HCOO)- = 669171171 (C13) (4) N-~5-[N-(n-hexyloxycarbonyl)-amidinoJ-2-hydroxy-benzyl'~-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide 25 Yield: 11 % of theoretical, Rf value: 0.50 (silica gel; ethyl acetatelethanol = 9:1 ) C28H36N4O5 (508.62) Mass spectrum : (M+H)+= 509 (M-H)- = 507 Case 511312 - Auslandstext (5) N-{5-[N-(phenylcarbonyl)-amidinoJ-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbony~-benzamide Yield: 46 % of theoretical, Rf value: 0.45 (silica gel; ethyl acetate/ethanol = 9:1 ) C28H28N404 (484.56) Mass spectrum : (M+H)+ = 585 (M-H)~ = 583 Example 20 to N-[5-(N-hydroxy-amidino)-2-hydroxy-benzyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride a. N-(5-N-hydroxyamidino-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide is A solution of 482 mg (1.06 mmol) of N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-(pyrrolidin-1-yl-carbonyl)-benzamide in 20 ml methanol/ethanol (1:1) is combined with a solution of 148 mg (2.1 mmol) of hydroxylamine hydrochloride and 174 mg (2.1 mmol) of sodium acetate in 1.0 ml of water and refluxed for 7 hours. After cooling the reaction mixture is combined with ice water and extracted with ethyl acetate.
The 2 o combined organic phases are washed with saline solution, dried and evaporated down. The crude product is purred on silica gel, eluting initially with dichloromethane, then with dichloromethanelethanol 25:1, 19:1 and 9:1.
Yield: 210 mg (41 % of theoretical), Rf value: 0.40 (silica gel; dichloromethanelethanol = 19:1) b. N-(5-N-hydroxyamidino-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride Prepared analogously to Example 3.g. from N-(5-N-hydroxyamidino-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide and hydrogen/palladium on 3 o activated charcoal.
Yield: 41 % of theoretical, R, value: 0.3 (Reversed Phase RP 8; 5% sodium chloride solution/methanol =
2:3) CZ~H24N4O4 X HCI (396.45/432.91) ~

Case 511312 ' - Auslandstext Mass spectrum : (M+H)+ = 397 (M-H)- = 395 Example 21 N-{5-[N-(phenylcarbonyl)-amidino]-2-(ethyloxycarbonyloxy)-benzyl}-3-methyl-4-~pyrrolidin-1-~I-carbonyl)-benzamide 121 mg (0.25 mrnol) of N-(5-phenylcarbonylamidino-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide are dissolved in 10 ml isopropanol with heating 1 o and combined with a solution of 41.5 mg (0.3 mmol) of potassium carbonate in 0.5 ml of water. After 10 minutes a solution of 32.6 mg (0.3 mmol) of ethyl chloroformate in 1 m! of isopropanol is added. After 1 hour at ambient temperature the reaction solution is stirred into ice water. The precipitate formed is suction filtered, washed with water and dried.
Yield: 72 mg (52 % of theoretical), Rf value: 0.50 (silica gel; dichloromethane/ethanoi = 9:1 ) C31 H32N4~6 (556.62) Mass spectrum : (M+H)+ = 557 (M-H)' = 555 Example 22 Dry ampoule containing 75 mg of active substance per 10 ml Composition:
Active substance 75.0 mg Mannitol 50.0 mg 3 o water for injections ad 10.0 ml Case 511312 - Auslandstext Preparation:
Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections.
Example 23 Dry ampoule containing 35 mg of active substance per 2 ml to Composition:
Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is 2 o freeze-dried.
To produce the solution ready for use, the product is dissolved in water for injections.
Example 24 Tablet containing 50 mg of active substance Composition:
(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate2.0 mg 215.0 mg Case 511312 Auslandstext Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) s is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
z o Example 25 Tablet containing 350 mg of active substance 15 Composition:
(1 ) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg 20 (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 ma 600.0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) 2s is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.

Case 5/1312 - Auslandstext Example 26 Capsules containing 50 mg of active substance s Composition:
(1 ) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg to (4) Magnesium stearate2.0 ma 160.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with i5 vigorous mixing.
This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
Example 27 Capsules containing 350 mg of active substance 2 5 Composition:
(1 ) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg 3 0 (4) Magnesium stearate4.0 ma 430.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with 3 s vigorous mixing.

,.
Case 511312 Auslandstext This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
Example 28 Suppositories containing 100 mg of active substance 1 suppository contains:
io Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 ma 2,000.0 mg Preparation:
The polyethyleneglycol is melted together with polyethylenesorbitan monostearate.
At 40°C the ground active substance is homogeneously dispersed in the melt. This is then cooled to 38°C and poured into slightly chilled suppository moulds.

Claims (11)

Claims

1. Compounds of general formula (i) m denotes the number 0, n denotes the number 1 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-R f, while p denotes one of the numbers 0, 1, 2 or 3 and R f denotes a hydroxycarbonyl, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, C3-7-cycloalkylamino-carbonyl, N-(C1-3-alkoxy-carbonylmethyl)-N-(C1-3-alkyl)-aminocarbonyl, N-(carboxymethyl)-N-(C1-3-alkyl)-aminocarbonyl or a 4- to 7-membered cycloalkyleneimino-carbonyl group, or (ii) m denotes the number 1, n denotes the number 1 and A denotes a bond or (iii) m denotes the number 0 or 1, n denotes the number 0 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, or (iv) m denotes the number 2, n denotes the number 0 and A denotes a bond, R1 denotes an amino, C1-5-alkylamino, C3-7-cycloalkylamino or phenyl-C1-3-alkylamino group each of which may be substituted at the amino nitrogen atom by a phenylcarbonyl or phenylsulphonyl group or by a C1-3-alkyl or C1-3-alkyl-carbonyl group optionally substituted in the alkyl moiety by a carboxy group, a group which may be converted in vivo into a carboxy group, an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, a di-(C1-5-alkyl)amino or N-(C3-7-cycloalkyl)-C1-5-alkylamino group, while the C1-5-alkyl moiety with the exception of the 1 position may be substituted in each case by a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl-amino or di-(C1-3-alkyl)-amino group, a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl group optionally substituted by a C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group, a 2,5-dihydropyrrol-1-yl-carbonyl group, an aminosulphonyl group optionally substituted by one or two C1-3-alkyl groups, a C3-7-cycloalkyl-carbonyl group, whilst the methylene group in the 3 or 4 position in a C5-7-cycloalkyl-carbonyl group may be replaced by an -NH group wherein the hydrogen atom of the -NH group rnay be replaced by a C1-3-alkyl, C1-3-alkyl-carbonyl, phenylcarbonyl or phenylsulphonyl group, a phenylcarbonyl or heteroarylcarbonyl group, or a C1-3-alkyl group optionally monosubstituted by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, hydroxy, phenyl or a 4- to 7-membered cycloalkyleneimino group or terminally disubstituted by a phenyl group and a hydroxy group, while the phenyl substituents may be substituted by an amidino group optionally substituted by one or two C1-3-alkyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, R2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2-3-alkenyl, C2-3-alkynyl, hydroxy, C1-3-alkaxy or trifluoromethoxy group, R3 denotes a hydrogen atom or a C1-3-alkyl group, R4 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group or a group which may be converted in vivo into a carboxy group and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R~, while R5 denotes a cyano group, an amidino group optionally substituted by one or two C1-3-alkyl groups, an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl)amino-C1-3-alkyl group, R6 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C1-3-alkyl, hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, carboxy, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy, C1-4-alkoxy-carbonyloxy, C1-4-alkoxy-carbonyl-C1-3-alkoxy, phenyl-C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group and R7 denotes a hydrogen, fluorine, chlorine or bromine atom or a C1-3-alkyl group, or a thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, while the term heteroaryl group mentioned above denotes a 5-membered heteroaryl group bound via a carbon or nitrogen atom which contains an imino group optionally substituted by a C1-4-alkyl or C1-4-alkyl-carbonyl group, an oxygen or sulphur atom, an imino group optionally substituted by a C1-4-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom, an imino group optionally substituted by a C1-4-alkyl group and two nitrogen atoms or an oxygen or sulphur atom and two nitrogen atoms, or a 6-membered heteroaryl group which contains one or two nitrogen atoms, while a phenyl ring may be fused to the abovementioned 5- or 6-membered heteroaryl groups via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed may be bound via the heteroaromatic or carbocyclic moiety, and the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned groups, or the unsubstituted or monosubstituted phenyl moieties contained in these groups, as well as the abovementioned heteroaryl groups may additionally be substituted at a carbon atom in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, unless otherwise stated, the carboxy groups mentioned in the definition of the abovementioned groups may be replaced by a group which may be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, and the amino and imino groups mentioned in the definition of the abovementioned groups may be substituted by a group which can be cleaved in vivo, the stereoisomers and the salts thereof.

2. Compounds of general formula I according to claim 1, wherein (i) m denotes the number 0, n denotes the number 1 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-R f, while p denotes one of the numbers 0, 1, 2 or 3 and R f denotes a hydroxycarbonyl, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, C3-7-cycloalkylamino-carbonyl, N-(C1-3-alkoxy-carbonylmethyl)-N-(C1-3-alkyl)-aminocarbonyl, N-(carboxymethyl)-N-(C1-3-alkyl)-aminocarbonyl or a 4- to 7-membered cycloalkyleneimino-carbonyl group, or (ii) m denotes the number 0 or 1, n denotes the number 0 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, R1 denotes an amino, C1-3-alkylamino or C3-7-cycloalkylamino group each of which may be substituted at the amino nitrogen atom by a C1-3-alkyl, C1-3-alkylcarbonyl, carboxy-C1-3-alkyl, carboxy-C1-3-alkylcarbonyl, C1-6-alkoxy-carbonyl-C1-3-alkyl-carbonyl or amino-C1-3-alkyl-carbonyl group, a di-(C1-3-alkyl)amino or N-(C5-7-cycloalkyl)-C1-3-alkylamino group, a 4- to 7-membered cycloalkyleneiminocarbonyl group optionally substituted by a C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, aminocarbonyl or C1-3-alkylamino-carbonyl group, while a hydrogen atom bound to a nitrogen atom may be replaced by an acetyl, phenylcarbonyl or tert.-butoxycarbonyl group, or a 2,5-dihydropyrrol-1-yl-carbonyl group, R2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, trifluoromethyl, C1-3-alkoxy or trifluoromethoxy group, R3 denotes a hydrogen atom or a C1-3-alkyl group, R4 denotes a hydrogen atom or a C1-3-alkyl group and Ar denotes a phenyl group substituted by the groups R5, R6 and R7, while R5 denotes a cyano group, an amidino group optionally substituted by one or two C1-3-alkyl groups, a hydroxy, C1-6-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or an amino-C1-3-alkyl or C1-3-alkylamino-C1-3-alkyl group, R6 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, alkyl, hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, carboxy, C1-3-alkoxy-carbonyloxy, carboxy-C1-3-alkoxy or C1-4-alkoxy-carbonyl-C1-3-alkoxy group and R7 denotes a hydrogen atom or a C1-3-alkyl group, while the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned groups, or the unsubstituted or monosubstituted phenyl moieties contained in these groups, as well as the abovementioned heteroaryl groups may additionally be substituted at a carbon atom in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, unless otherwise stated, the stereoisomers and the salts thereof.

3. Compounds of general formula I according to claim 2, wherein (i) m denotes the number 0, n denotes the number 1 and A denotes a methylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-R f, while p denotes one of the numbers 0, 1, 2 or 3 and R f denotes a hydroxycarbonyl, C1-3-alkoxycarbonyl, N-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, N-(C1-3-alkoxy-carbonyl-methyl)-N-(C1-3-alkyl)-aminocarbonyl, N-(carboxymethyl)-N-(C1-3-alkyl)-aminocarbonyl or a 4- to 7-membered cycloalkyleneimino-carbonyl group or (ii) m denotes the number 0, n denotes the number 0 and A denotes a -CH2-CH2- group, or (iii) m denotes the number 1, n denotes the number 0 and A denotes a -CH2- group, the groups R1 to R4 are defined as in claim 2, but R1 in the 4 position is bound to the phenyl group contained in formula I and Ar denotes a phenyl group disubstituted by the groups R5 and R6, while R5 is bound in the 3 position if R5 denotes a hydrogen atom, or is bound in the 5 position if R6 assumes a meaning other than the hydrogen atom, and denotes an amidino group optionally substituted by one or two C1-3-alkyl groups, a hydroxy, C1-6-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or an amino-C1-3-alkyl or C1-3-alkylamino-C1-3-alkyl group and R6 denotes a hydrogen atom or a hydroxy, C1-3-alkoxy, carboxy-C1-3-alkoxy, C1-3-alkoxy-carbonyloxy- or C1-4-alkoxy-carbonyl-C1-3-alkoxy group bound in the 2 position, the stereoisomers and the salts thereof.

4. Compounds of general formula I according to claim 1, wherein (i) m denotes the number 0, n denotes the number 1 and A denotes a methylene group wherein a hydrogen atom may be replaced by a methyl, hydroxycarbonyl, C1-3-alkoxy-carbonyl, C1-3-alkylaminocarbonyl, dimethylaminocarbonyl, pyrrolidin-1-yl-carbonyl, C1-3-alkylaminocarbonylmethyl, N-(hydroxy-carbonyl-methyl)-N-(C1-3-alkyl)-amino-carbonyl-methyl, N-(C1-3-alkoxy-carbonyl-methyl)-N-(C1-3-alkyl)-amino-carbonyl-methyl, hydroxycarbonylmethyl, C1-3-alkoxy-carbonylmethyl or dimethylamino-carbonylmethyl group, R1 is bound in the 4 position of the phenyl group of formula I and denotes a C5-7-cycloalkylamino group which may be substituted at the amino nitrogen atom by a C1-3-alkyl, C1-3-alkylcarbonyl, amino-C1-3-alkylcarbonyl, carboxy-C1-3-alkylcarbonyl or C1-4-alkoxy-carbonyl-C1-3-alkyl-carbonyl group, a 4- to 7-membered cycloalkyleneiminocarbonyl group or a 2,5-dihydropyrrol-1-yl-carbonyl group, R2 denotes a hydrogen atom or a C1-3-alkyl, ethenyl, ethynyl, trifluoromethyl or trifluoromethoxy group bound in the 3 position or, if R3 denotes a C1-3-alkyl group, in the 5 position of the phenyl group in formula I or a chlorine or bromine atom bound in the 3 position, R3 denotes a hydrogen atom or a C1-3-alkyl group bound in the 2 position of the phenyl group in formula I, R4 denotes a hydrogen atom and Ar denotes a phenyl group disubstituted by the groups R5 and R6, while R5 is bound in the 3 position if R6 denotes a hydrogen atom, or is bound in the 5 position if R6 assumes a meaning other than the hydrogen atom, and denotes an amidino group optionally substituted by a C1-6-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or a aminomethyl group and R6 denotes a hydrogen atom or a hydroxy or C1-3-alkoxy-carbonyloxy group bound in the 2 position, the stereoisomers and the salts thereof.

5. Compounds of general formula I according to claim 1, wherein (i) m denotes the number 0, n denotes the number 0 and A denotes a -CH2-CH2- group, or (ii) m denotes the number 1, n denotes the number 0 and A denotes a -CH2- group, R1 denotes a 4- to 7-membered cycloalkyleneiminocarbonyl or 2,5-dihydropyrrol-1-yl-carbonyl group bound in the 4 position of the phenyl group of formula I, R2 denotes a hydrogen atom or a substituent selected from fluorine, chlorine, bromine, C1-3-alkyl and trifluoromethyl bound in the 3 position or, if R3 denotes a C1-3-alkyl group, bound in the 5 position of the phenyl group in formula I, R3 denotes a hydrogen atom or a C1-3-alkyl group bound in the 2 position of the phenyl group in formula I, R4 denotes a hydrogen atom and Ar denotes a phenyl group disubstituted by the groups R5 and R6, wherein R5 is bound in the 5 position and denotes an amidino group optionally substituted by one or two C1-3-alkyl groups, a C1-6-alkoxy-carbonyl or phenylcarbonyl group and R6 denotes a hydroxy group bound in the 2 position, the stereoisomers and the salts thereof.

6. The following compounds of general formula I according to claim 1:
(1) 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine, (2) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine, (3) N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine, (4) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (5) N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (6) N-(3-carbamimidoyl-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (7) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (8) N-(5-aminomethyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (9) 2-(3-aminomethyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetic acid-N-ethylamide, (10) 3-(3-aminomethyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid-N-ethylamide, (11 ) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-ethoxy-carbonyl-propionyl)amino]-benzamide, (12) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-acetyl-N-cyclobutyl-amino)-benzamide, (13) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-cyclopentyl-N-methyl-amino)-benzamide, (14) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-carboxy-propionyl)-amino]-benzamide, (15) N-(5-carbamimidoyl-2-hydroxy-benzyl)-4.-cyclopentylamino-3-methyl-benzamide, (16) ethyl2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetate, (17) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid, (18) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-N-cyclo-pentyl-amino]-benzamide, (19) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzamide, (20) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (21) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (22) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (23) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzoylamino}-propionate, (24) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (25) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionate, (26) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (27) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate, (28) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (29) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, (30) 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, (31) 3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, (32) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionic acid, (33) 3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (34) 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (35) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionic acid-N-methyl-N-(hydroxycarbonylmethyl)-amide, (36) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionic acid-N-(hydroxycarbonylmethyl)-N-(n-propyl)-amide, (37) 3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid, (38) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid-N,N-dimethylamide, (39) N-[1-(3-carbamimidoyl-phenyl)-2-oxo-2-(pyrrolidin-1-yl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (40) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-N,N-dimethylamide, (41) 2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetic acid-N-ethylamide, (42) 3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionic acid-N-ethylamide, (43) 3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionic acid-N-(ethoxycarbonylmethyl)-N-(n-propyl)-amide, (44) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (45) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (46) N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (47) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (48) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (49) 3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionic acid, (50) ethyl 3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (51) ethyl 3-[3-N-(n-hexyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (52) n-propyl 3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (53) ethyl 3-[3-N-(2,2,2-trichloroethyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate, (54) N-{5-[N-(n-hexyloxycarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (55) N-{5-[N-(phenylcarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, (56) N-[5-(N-hydroxy-amidino)-2-hydroxy-benzyl]-3-methyl-4-(pyrrolidin-1-yl-carbo-nyl)-benzamide and (57) N-{5-[N-(phenylcarbonyl)-amidino]-2-(ethyloxycarbonyloxy)-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide, while any amidino group present may additionally be substituted by a C1-6-alkoxycarbonyl or phenylcarbonyl group, and the salts thereof.

7. Physiologically acceptable salts of the compounds according to claims 1 to 6 with the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group.

8. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 6 with the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group, or a salt according to claim 7 optionally together with one or more inert carriers and/or diluents.

9. Use of a compound according to at least one of claims 1 to 6 with the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group, or a salt according to claim 7 for preparing a pharmaceutical composition with an antithrombotic activity.

10. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 6 with the exception of those compounds wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, and R5 denotes a cyano group, or a salt according to claim 7 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

11. Process for preparing the compounds according to claims 1 to 7, characterised in that a) in order to prepare a compound of general formula I wherein (i) m denotes the number 0, n denotes the number 1 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-R f, while p and R f are defined as in claims 1 to 6, or (ii) m and n each denote the number 1 and A denotes a bond and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an amidino group, a compound of general formula H~NR4~A~Ar (II), wherein R4 is defined as in claims 1 to 6, A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group or a hydrogen atom may be replaced by the group -(CH2)p-R f, while p and R f are defined as in claims 1 to 6, or A denotes a bond, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R5 denotes a cyano group and R6 and R7 are defined as in claims 1 to 6, is acylated with a carboxylic acid or a reactive carboxylic acid derivative of general formula wherein m denotes the number 0 or 1, X denotes a hydroxy or C1-4-alkoxy group or a chlorine atom and R1 to R3 are defined as in claims 1 to 6, or with the reactive derivatives thereof and the resulting cyano compound is then converted into an amidino compound or b) in order to prepare a compound of general formula I wherein m denotes the number 0 or 1, n denotes the number 0, A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an amidino group, a compound of general formula wherein R1 to R4 are defined as in claims 1 to 6 and m denotes the number 0 or 1, is alkylated with a compound of general formula Z1~A~Ar (V), wherein A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes a cyano group, and Z1 denotes a leaving group and the resulting cyano compound is then converted into an amidino compound, or c) in order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an amidino group, m denotes the number 1, n denotes the number 0 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, or m denotes the number 2, n denotes the number 0 and A denotes a bond, a compound of general formula HNR4~A~Ar (II'), wherein R4 is defined as in claims 1 to 6, A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, or denotes a bond, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes a cyano group, is alkylated with a compound of general formula wherein R1 to R3 are defined as in claims 1 to 6, m denotes the number 1 or 2 and Z2 denotes a leaving group, and the resulting cyano compound is then converted into an amidino compound or d) in order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an amidino group, m denotes the number 0 or 1, n denotes the number 0 and A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, or m denotes the number 2, n denotes the number 0 and A denotes a bond, an amine of general formula wherein R1 to R4 are defined as in claims 1 to 6 and m denotes the number 0, 1 or 2, is reductively alkylated with an aldehyde of general formula wherein A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, or denotes a bond, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes a cyano group, and the resulting cyano compound is then converted into an amidino compound, or e) in order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an amidino group optionally substituted by one or two C1-3-alkyl groups, a compound of general formula optionally formed in the reaction mixture wherein R1 to R4, m, n and A are defined as in claims 1 to 6, Ar denotes a phenyl or naphthyl group substituted by the groups R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and Z3 denotes an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with an amine of general formula H~R8NR9 , (IX) wherein R8 and R9, which may be identical or different, each denote a hydrogen atom or a C1-3-alkyl group, or with a salt thereof or f) in order to prepare a compound of general formula I wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R,7 while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an aminomethyl, C1-3-alkylaminomethyl or di-(C1-3-alkyl)aminomethyl group, a compound of general formula wherein Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, R1 to R4, R6, R7, A, m and n are defined as in claims 1 to 6 and R5 denotes a cyano group, is catalytically hydrogenated and optionally then alkylated with a compound of formula R10- Z4 (X), wherein R10 denotes a C1-3-alkyl group and Z4 denotes a leaving group, or g) in order to prepare a compound of general formula I wherein m denotes the number 0, n denotes the number 0, A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes an amidino group, a compound of general formula wherein R1 to R3 are defined as in claims 1 to 6 and Z5 denotes a leaving group, is coupled with a compound of general formula HNR4~A~Ar (II"), wherein R4 is defined as in claims 1 to 6, A denotes a straight-chain C1-3-alkylene group wherein one or two hydrogen atoms independently of one another may be replaced in each case by a C1-3-alkyl group, and Ar denotes a phenyl or naphthyl group substituted by the groups R5, R6 and R7, while R6 and R7 are defined as in claims 1 to 6 and R5 denotes a cyano group, and then the cyano compound thus obtained is converted into an amidino compound, and subsequently, if desired, a compound of general formula I thus obtained which contains an amino or imino group is converted by means of a corresponding acyl derivative into a corresponding acyl compound of general formula I and/or a compound of general formula I thus obtained which contains an esterified carboxy group is converted by hydrolysis into a corresponding carboxylic acid of general formula I and/or a compound of general formula I thus obtained which contains a carboxy group is converted by esterification into a corresponding ester and/or any protecting group used in order to protect reactive groups during the reactions is cleaved and/or a compound of general formula I thus obtained is resolved into its stereoisomers and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically acceptable salts thereof with an inorganic or organic acid or base.