AU4903399A - Benzimidazoles, production thereof and use thereof as medicaments - Google Patents

Benzimidazoles, production thereof and use thereof as medicaments Download PDF

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AU4903399A
AU4903399A AU49033/99A AU4903399A AU4903399A AU 4903399 A AU4903399 A AU 4903399A AU 49033/99 A AU49033/99 A AU 49033/99A AU 4903399 A AU4903399 A AU 4903399A AU 4903399 A AU4903399 A AU 4903399A
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group
alkyl
carboxy
substituted
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AU763094C (en
AU763094B2 (en
Inventor
Norbert Hauel
Iris Kauffmann
Herbert Nar
Henning Priepke
Uwe Ries
Jean-Marie Stassen
Wolfgang Wienen
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Boehringer Ingelheim Pharma GmbH and Co KG
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BOEHRINGER INGELHEIM PHARMA
Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE1998129964 external-priority patent/DE19829964A1/en
Priority claimed from DE1998157202 external-priority patent/DE19857202A1/en
Priority claimed from DE1999112690 external-priority patent/DE19912690A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
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  • Diabetes (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Description

WO 00/01704 - 1 - PCT/EP99/04531 S018842pct.203 Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions 5 The present invention relates to benzimidazoles of general formula Ra A-B-Ar-Re 10 Rb their tautomers, their stereoisomers, the mixtures thereof, their prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and 15 the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties. The compounds of the above general formula I wherein Rc 20 denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I wherein Re denotes one of the following amidino groups, as well as their tautomers, their stereoisomers, the mixtures 25 thereof, their prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and their salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, and the 30 stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity.
WO 00/01704 - 2 - PCT/EP99/04531 The present application thus relates to the new compounds of the above general formula I as well as the preparation thereof, the pharmaceutical compositions containing the pharmacologically active compounds, the preparation and 5 use thereof. In the above general formula Ar denotes a phenylene or naphthylene group optionally 10 substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 1 3 -alkyl or C 1 3 -alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally 15 substituted in the carbon skeleton by a C 1 ,-alkyl group, A denotes a C 1 3 -alkylene group, B denotes an oxygen or sulphur atom, a methylene, 20 carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C 1 3 -alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, 25 Ra denotes an R 1
-CO-C
3
-
5 -cycloalkyl group wherein R denotes a Cl- 3 -alkoxy, amino, C 1 4 -alkylamino or di
(C
1
-
4 -alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, 30 a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two C 1 .- alkyl groups, whilst an alkyl substituent may simultaneously be substituted 35 by a hydroxy, C 1
.
3 -alkoxy, carboxy, carboxy-Cl.
3 -alkoxy, carboxy-C.
3 -alkylamino, N- (C 1 -- alkyl) -N- (carboxy
C
1 3 -alkyl) -amino, carboxy-Cl.
3 -alkylaminocarbonyl, WO 00/01704 - 3 - PCT/EP99/04531 N- (C 1 3 -alkyl) -N- (carboxy-C 1 3 -alkyl) -aminocarbonyl, carboxy-C 1 3 -alkylaminocarbonylamino, 1- (C 1 3 -alkyl) 3- (carboxy-C 1 3 -alkyl) -aminocarbonylamino, 3-(C 1 3 -alkyl) 3- (carboxy-C.
3 -alkyl) -aminocarbonylamino or 1,3-di 5 (C 1 3 -alkyl)-3-(carboxy-C. -alkyl) -aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 10 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C 1 3 -alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, 15 a morpholino, piperazino, N-(C 13 -alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R 2
-CX-C
3 ,-cycloalkyl group wherein 20 R 2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a
C
1
.
3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group 25 optionally substituted by a C 1
.
3 -alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C 1
.
3 -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy 30 C 1
-
3 -alkoxy, carboxy-C.
3 -alkylamino or N- (C.
3 -alkyl) carboxy-C 1 3 -alkylamino group, and X denotes an oxygen atom, a Cl -alkylimino, Cl.-alkoxyimino,
C
1 .- alkylhydrazino, di- (Cl 1 3 -alkyl) 35 hydrazino, C 2 .-alkanoylhydrazino, N-(C 1 3 -alkyl)
C
2 .- alkanoylhydrazino or C 1 3 -alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety WO 00/01704 - 4 - PCT/EP99/04531 or in the alkyl and alkanoyl moieties by a carboxy group, a C 1 3 -alkyl or C 3 5 -cycloalkyl group substituted by an 5 imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C 13 -alkyl groups or by one, two or three C 1 3 -alkyl groups, wherein the 10 substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C 24 -alkanoylamino, Cl- 3 -alkylamino, N- (C 2 4 -alkanoyl) -C 1 3 -alkylamino or di 15 (C 1
.
3 -alkyl)-amino group, and the imidazolone ring may be substituted by a C 1
.
3 -alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an 20 amino, C 24 -alkanoylamino, C 1
_
3 -alkylamino, N- (C 2 4 -alkanoyl) -Cl- 3 -alkylamino or di- (C 1
-
3 -alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to 25 the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C 1
.
3 -alkyl groups, whilst at the 30 same time an alkyl substituent may be substituted by a carboxy group, a C 14 -alkyl group which is substituted 35 by a C 1 3 -alkyl-YI-C - alkyl, HOOC-Cl.-alkyl-Yi-C 1 3 -alkyl, tetrazolyl-C 3 -alkyl-Y 2 , R 3
NR
4 - or R 3
NR
4
-C
1 3 -alkyl group and * WO 00/01704 - 5 - PCT/EP99/04531 by an isoxazolidinylcarbonyl group optionally substituted by a Cs--alkyl group, by a pyrrolino carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl 5 carbonyl, carboxy, aminocarbonyl, Cl--alkylaminocarbonyl, di-(C 1 3 -alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or 10 two C 1 3 -alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned
C
1 3 -alkylaminocarbonyl, di-(C 1 3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the 15 Cl- 4 -alkyl group may be wholly or partially replaced by fluorine atoms wherein
R
3 denotes a hydrogen atom or a Cl-,-alkyl group optionally substituted by a carboxy group and 20
R
4 denotes a hydrogen atom, a C 1 3 -alkyl
YI-C
1 3 - alkyl-Y 2 , carboxy-C 1 3 -alkyl-Y 1
-C
3 -alkyl-Y 2 ,
C
1
-
3 -alkyl-Y 2 or carboxy-C 1 3 -alkyl-Y 2 group or 25 R 3 and R 4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C 1
.
3 -alkyl or carboxy-C.
3 -alkyl group wherein 30 Y 1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and
Y
2 denotes a carbon-nitrogen bond or a carbonyl, 35 sulphonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the R 3
NR
4 - group, and the imino groups occurring WO 00/01704 - 6 - PCT/EP99/04531 in the definition of the groups Y, and Y 2 may each additionally be substituted by a C 1 3 -alkyl or carboxy
C
1 3 -alkyl group, 5 a C 1 3 -alkyl or C 3 .- cycloalkyl group substituted by a RNR 6 group wherein R. denotes a hydrogen atom, a C 1 3 -alkyl, C 5 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 10
R
6 denotes a C 1 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy
C
1 3 -alkylcarbonyl group, a C 1 3 -alkyl group which is substituted by a C 2 -alkanoyl 15 or C 5 7 -cycloalkanoyl group and by a C 1 3 -alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C 1 3 -alkyl group and 20 Rc denotes a cyano group or an amidino group optionally substituted by one or two Cl-,-alkyl groups. The carboxy groups mentioned in the definitions of the abovementioned groups may also be replaced by a group 25 which can be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, or the amino and imino groups mentioned in the definitions of 30 the abovementioned groups may also be substituted by a group which can be cleaved in vivo. Groups of this kind are described, for example, in WO 98/46576 and by N.M. Nielson et al. in International Journal of Pharmaceutics 39, 75-85 (1987). 35 WO 00/01704 - 7 - PCT/EP99/04531 A group which can be converted in vivo into a carboxy group may be, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, wherein the alcoholic moiety is preferably a C,-,-alkanol, a phenyl-C 1 3 -alkanol, 5 a C 3 9 -cycloalkanol, whilst a Cs- 8 -cycloalkanol may additionally be substituted by one or two C 1 3 -alkyl groups, a C 58 ,-cycloalkanol wherein a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C 1 3 -alkyl, 10 phenyl-CI- 3 -alkyl, phenyl-Cl--alkoxycarbonyl or
C
2
-
6 -alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C 1 3 -alkyl groups, a C 47 -cycloalkenol, a C 35 -alkenol, a phenyl
C
3 _,-alkenol, a C 3
_
5 -alkynol or phenyl-C 3
-
5 -alkynol, with the 15 proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a
C
3 8 -cycloalkyl-C 1 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 20 C 1 3 -alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula Rd-CO-0- (R 8 CRr) -OH, 25 wherein Rd denotes a Cl 8 -alkyl, C,-,-cycloalkyl, phenyl or phenyl C1- alkyl group, R. denotes a hydrogen atom, a C 1 3 -alkyl, C 5
.
7 -cycloalkyl or 30 phenyl group and R, denotes a hydrogen atom or a C 13 -alkyl group, a group which is negatively charged under physiological 35 conditions may be a tetrazol-5-yl, phenylcarbonylamino carbonyl, trifluormethylcarbonylaminocarbonyl, C.-.-alkylsulphonylamino, phenylsulphonylamino, WO 00/01704 - 8 - PCT/EP99/04531 benzylsulphonylamino, trifluoromethylsulphonylamino,
C
16 -alkylsulphonylaminocarbonyl, phenylsulphonylamino carbonyl, benzylsulphonylaminocarbonyl or perfluoro
C-
6 -alkylsulphonylaminocarbonyl group 5 and a group which can be cleaved in vivo from an imino or amino group may be, for example, a hydroxy group, an acyl group such as a benzoyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine 10 atoms, by C 1 -alkyl or C 13 -alkoxy groups, wherein the substituents may be identical or different, a pyridinoyl group or a C,- 3 ,-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3 trichloropropionyl or allyloxycarbonyl group, a 15 C 1 1 -alkoxycarbonyl or Cl 1 6 -alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl, pentoxycarbonyl, 20 hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, 25 tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C..-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl 30 or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by
C
1 6 -alkyl or C 3 ,-cycloalkyl groups and the substituents may be identical or different, a C.
3 -alkylsulphonyl
C
2 -- alkoxycarbonyl, Cl.
3 -alkoxy-C 24 -alkoxy 35 C 2 -- alkoxycarbonyl, Rd-CO-O- (RdCRf) -O-CO-, C 1 6 -alkyl-CO-NH- WO 00/01704 - 9 - PCT/EP99/04531 (RgCRh) -O-CO- or C 1 6 -alkyl-CO-0- (RCRh) - (RgCRh) -O-CO- group wherein Rd to Rf are as hereinbefore defined, Rg and Rh, which may be identical or different, denote 5 hydrogen atoms or C 1 3 -alkyl groups. Moreover, the saturated alkyl and alkoxy moieties which contain more than 2 carbon atoms mentioned in the above definitions also include the branched isomers thereof, 10 such as, for example, the isopropyl, tert.butyl, isobutyl group etc. Preferred compounds are those of general formula Ra A-B Re (Ia), -O:N 151 15 Rb wherein A denotes a C 1 3 -alkylene group, 20 B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C 1 .- alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, 25 Ra denotes an R 1
-CO-C
3
-
5 -cycloalkyl group wherein R denotes a C 1
.
3 -alkoxy, amino, C 1 4 -alkylamino or di (C,--alkyl) -amino group wherein each alkyl moiety may be 30 substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by WO 00/01704 - 10 - PCT/EP99/04531 one or two C 1
-
3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy,
C,
3 e-alkoxy, carboxy, carboxy-C 1 3 -alkoxy, carboxy
C
1 3 -alkylamino, N- (C.
3 -alkyl) -N- (carboxy-C 1 3 -alkyl) 5 amino, carboxy-C 1 3 -alkylaminocarbonyl, N-(C 1 3 -alkyl) N-(carboxy-C 1 3 -alkyl)-aminocarbonyl, carboxy
C
1 -alkylaminocarbonylamino, 1-(C 1 3 -alkyl)-3-(carboxy
C
1 3 -alkyl) -aminocarbonylamino, 3-(CI- 3 -alkyl)-3-(carboxy Ca 3 -alkyl)-aminocarbonylamino or 1,3-di-(C- 3 -alkyl) 10 3-(carboxy-p 1 3 -alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 15 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C 1
_
3 -alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C 1 3 -alkyl) -piperazino, 20 pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R 2
-CX-C
3 5 -cycloalkyl group wherein
R
2 denotes a phenyl, naphthyl or monocyclic 5- or 25 6-membered heteroaryl group optionally substituted by a
C,-
3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1
_
3 -alkyl group, an oxygen 30 or sulphur atom or an imino group optionally substituted by a C 1 3 -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy
C
1 - -alkoxy, carboxy-Cl.
3 -alkylamino or N- (C 1 3 -alkyl) 35 carboxy-C 3 -alkylamino group, and WO 00/01704 - 11 - PCT/EP99/04531 X denotes an oxygen atom, a C 1 3 -alkylimino, Cl- 3 -alkoxyimino, C 1 3 -alkylhydrazino, di- (Cl 1 3 -alkyl) hydrazino, C 24 -alkanoylhydrazino, N-(C 1 3 -alkyl)
C
2 4 -alkanoylhydrazino or C 1 -- alkylidene group each of 5 which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C 1 3 -alkyl or C 3 5 -cycloalkyl group substituted by an 10 imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C 1
.
3 -alkyl groups or by one, two or three Cl--alkyl groups, wherein the 15 substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C 2 --alkanoylamino,
C
1
-
3 -alkylamino, N- (C 2 .- alkanoyl) -C 1 3 -alkylamino or di 20 (Cl.
3 -alkyl)-amino group, and the imidazolone ring may be substituted by a C 1 ,-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an 25 amino, C 2
-
4 -alkanoylamino, Cl.
3 -alkylamino, N- (C 2 4 -alkanoyl) -C 1 3 -alkylamino or di- (C 1 .- alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to 30 the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C 1 3 -alkyl groups, whilst at the 35 same time an alkyl substituent may be substituted by a carboxy group, WO 00/01704 - 12 - PCT/EP99/04531 a C 14 -alkyl group which is substituted by a C 13 -alkyl-YI-C 1 3 -alkyl, HOOC-C 1 3 -alkyl-YI-C 1 3 -alkyl, tetrazolyl-C 3 -alkyl-Y 2 , R 3
NR
4 - or R 3
NR
4
-C
13 -alkyl group 5 and by an isoxazolidinylcarbonyl group optionally substituted by a C 13 -alkyl group, by a pyrro linocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol 10 1-yl-carbonyl, carboxy, aminocarbonyl,
C,
3 -alkylaminocarbonyl, di- (C- 3 -alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or 15 two C 13 -alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned
C
13 -alkylaminocarbonyl, di- (C- 3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the 20 C 14 -alkyl group may be wholly or partially replaced by fluorine atoms wherein
R
3 denotes a hydrogen atom or a C 13 -alkyl group optionally substituted by a carboxy group and 25
R
4 denotes a hydrogen atom, a CI--alkyl
Y
1
-C
1 -alkyl-Y 2 , carboxy-Cl.
3 -alkyl-YI-Cl- 3 -alkyl-Y 2 ,
C
1
-
3 -alkyl-Y 2 or carboxy-Cl.
3 -alkyl-Y 2 group or 30 R 3 and R 4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C 13 -alkyl or carboxy-C 1 3 -alkyl group wherein 35 Y 1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and WO 00/01704 - 13 - PCT/EP99/04531
Y
2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen 5 atom of the R 3 NR- group, and the imino groups occurring in the definition of the groups Y, and Y 2 may each additionally be substituted by a C 1 3 -alkyl or carboxy
C
1 3 -alkyl group, 10 a C 1 3 -alkyl or C 3 .- cycloalkyl group substituted by a R 5
NR
6 group wherein R. denotes a hydrogen atom, a Cl -alkyl, C 5 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 15
R
6 denotes a C 1 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy
C
1 3 -alkylcarbonyl group, a C 13 -alkyl group which is substituted by a C 2
_
4 -alkanoyl 20 or C 5 7 -cycloalkanoyl group and by a C 1 3 -alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C 1
-
3 -alkyl group and 25 RC denotes a cyano group or an amidino group which may be substituted by a hydroxy group, by one or two C 13 -alkyl groups, or by one or two Cl-B-alkoxycarbonyl groups, wherein the carboxy, amino and imino groups mentioned in 30 the definition of the abovementioned groups may also be substituted by a group which can be cleaved in vivo, the tautomers, stereoisomers and salts thereof. 35 WO 00/01704 - 14 - PCT/EP99/04531 Particularly preferred compounds of the above general formula Ia are those wherein A denotes a Cl- 3 -alkylene group, 5 B denotes an oxygen atom, a methylene, imino or N-(Cl3 alkyl)-imino group wherein the alkyl moiety may be substituted by a carboxy group, 10 Ra denotes an ,C 3 .- cycloalkyl group substituted by the R 1 -CO group in the i position wherein R denotes a C 1 3 -alkoxy, amino, C 1 4 -alkylamino or di
(C,
4 -alkyl)-amino group wherein each alkyl moiety may be 15 substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C 1 --alkyl groups, whilst an alkyl substituent may 20 simultaneously be substituted by a hydroxy, Cl.
3 -alkoxy, carboxy, carboxy-Cl 3 -alkoxy, carboxy-C 1 3alkylamino, N- (C 1 3 -alkyl) -N- (carboxy-C 1 3 -alkyl) -amino, carboxy Cl--alkylaminocarbonyl, N- (Cl 1 3 -alkyl) -N- (carboxy
C
13 -alkyl)-aminocarbonyl, carboxy 25 CI 3 -alkylaminocarbonylamino, 1- (C 1 3 -alkyl) -3- (carboxy
C
1 3 -alkyl)-aminocarbonylamino, 3-(C 1 3 -alkyl)-3-(carboxy Cl- 3 -alkyl)-aminocarbonylamino or 1,3-di-(C 13 -alkyl) 3-(carboxy-Cl.
3 -alkyl)-aminocarbonylamino group, 30 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C 1 3 -alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (Cl- 3 -alkyl) -piperazino, 35 pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, WO 00/01704 - 15 - PCT/EP99/04531 a C 35 -cycloalkyl group substituted in the 1 position by the R 2 -CX- group, wherein
R
2 denotes a phenyl, naphthyl or monocyclic 5- or 5 6-membered heteroaryl group optionally substituted by a
C
1
-
3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a CI 3 -alkyl group, an oxygen 10 or sulphur atom or an imino group optionally substituted by a CI 3 -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy
C
1 --alkoxy, carboxy-C.
3 -alkylamino or N- (Cl 13 -alkyl) 15 carboxy-C 13 -alkylamino group, and X denotes an oxygen atom, a C 13 -alkylimino,
C
13 -alkoxyimino or C 13 -alkylidene group, each of which may be substituted in the alkyl or alkanoyl moiety by a 20 carboxy group, a C 13 -alkyl group substituted in the 1 position by an imidazole or imidazolone group wherein 25 the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C 13 -alkyl groups or by one, two or three C 1
-
3 -alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously 30 be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C 2 .-alkanoylamino, Cl- 3 -alkylamino, N- (C 2 .-alkanoyl) -C 13 -alkylamino or di
(C
13 -alkyl)-amino group, and 35 the imidazolone ring may be substituted by a C 1 .-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an WO 00/01704 - 16 - PCT/EP99/04531 amino, C 24 -alkanoylamino, C 13 -alkylamino,
N-(C
2 4 -alkanoyl) -C 1
.
3 -alkylamino or di- (C 1 3 -alkyl) -amino group, and 5 additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be 10 substituted by one or two C 1 3 -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, a C 1 4 -alkyl group which is substituted in the 1 position 15 by an R 3
NR
4 - or R 3
NR
4
-C
3 -alkyl group and by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, 20 C 13 -alkylaminocarbonyl, di-(C 1 3 -alkyl)-aminocarbonyl, isoxazolidin-1-ylcarbonyl or 4- to 7-membered cyclo alkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C 1
.
3 -alkyl groups and at the 25 same time each alkyl moiety or alkyl substituent in the abovementioned C 1 3 -alkylaminocarbonyl, di- (C 1 3 -alkyl) aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C.
1
.
4 -alkyl group may be wholly or 30 partially replaced by fluorine atoms, wherein
R
3 denotes a hydrogen atom or a C 1 3 -alkyl group optionally substituted by a carboxy group and 35 R 4 denotes a hydrogen atom, a C 1 3 -alkyl-Y 2 or carboxy
C
13 -alkyl-Y 2 group or WO 00/01704 - 17 - PCT/EP99/04531
R
3 and R 4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1 position by a carboxy, C- alkyl or carboxy-C 1 3 -alkyl group, wherein 5
Y
2 denotes a carbon-nitrogen bond or a carbonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the
R
3
NR
4 - group, and the imino group occurring in the 10 definition of the groups Y 2 may additionally be substituted by a CI_ 3 -alkyl or carboxy-C 3 -alkyl group, a C 1 3 -alkyl or C 3 -- cycloalkyl group substituted in the 1 position by an RNR 6 - group, wherein 15
R
5 denotes a hydrogen atom, a C-3-alkyl, C 5 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and
R
6 denotes a Cl_ 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy 20 C 13 -alkylcarbonyl group, a C 13 -alkyl group which is substituted by a C 2
_
4 -alkanoyl or C 5 7 -cycloalkanoyl group and by a C 13 -alkyl group substituted by a chlorine, bromine or iodine atom, 25 Rb denotes a CI 3 -alkyl group and Rc denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, 30 C 1 .s-alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 13 -alkyl or C_- alkoxy groups and the substituents may be identical or 35 different, p WO 00/01704 - 18 - PCT/EP99/04531 the C1 -alkanol esters, the tautomers, stereoisomers and salts thereof. Most particularly preferred compounds of general formula I 5 are those wherein A denotes a methylene group, B denotes an oxygen atom or an imino group, 10 Ra denotes a cyclopropyl group substituted by the R-CO group in the 1 position, wherein R denotes a pyrrolidino or piperidino group optionally 15 substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C 1 3 -alkoxy, carboxy-C.
3 -alkylamino or N- (Cl- 3 -alkyl) -carboxy-C 1 3 -alkylamino group, 20 a cyclopropyl group substituted in the 1 position by the
R
2 -CX- group, wherein
R
2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C 1
.
3 -alkyl group and 25 X denotes an oxygen atom, a C 13 -alkoxyimino or
C
1 3 -alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, 30 a C 1 2 -alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C 13 -alkyl groups or by one, two or three C 1
.
3 -alkyl groups, wherein the substituents may be identical or 35 different and one of the abovementioned alkyl substituents may simultaneously be substituted by a A WO 00/01704 - 19 - PCT/EP99/04531 carboxy group or may be substituted in the 2 or 3 position by an amino, C 2 4 -alkanoylamino, C 1 .- alkylamino, N- (C 2 4 -alkanoyl) -C 1 3 -alkylamino or di- (C 1
-
3 -alkyl) -amino group, whilst additionally a phenyl or pyridine ring may 5 be fused to the abovementioned imidazole rings via two adjacent carbon atoms, a C 1 2 -alkyl substituted in the 1 position by a benzimidazolon-1-yl group, whilst the imidazolone ring may 10 be substituted by a methyl or ethyl group optionally substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 position 15 by an R 3
NR
4 - or R 3 NR-C-alkyl group and by a di-(C 1 3 -alkyl)-aminocarbonyl group, by an isoxazolidin-1-ylcarbonyl group, by a pyrrolidino 20 carbonyl or piperidinocarbonyl group substituted by a
C
1
.
3 -alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent in the abovementioned groups may be substituted by a carboxy group, wherein 25
R
3 denotes a hydrogen atom or a C 1 3 -alkyl group optionally substituted by a carboxy group and
R
4 denotes a hydrogen atom, a C 1 3 -alkyl-Y 2 or carboxy 30 C 1 3 -alkyl-Y 2 group or
R
3 and R 4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy group, wherein 35 A WO 00/01704 - 20 - PCT/EP99/04531
Y
2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a C 1 3 -alkyl group, 5 a C 1 2 -alkyl group substituted in the 1 position by an
R
5 NR,- group, wherein
R
5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and 10
R
6 denotes a C 1 3 -alkyl or carboxy-C 1 3 -alkyl group, an n-propyl group substituted in the 3 position by a chlorine atom, which is substituted in the 1 position by a 15 cyclopentylcarbonyl group, a cyclopropyl group substituted in the 1 position by a cyclopentylamino group, which is substituted at the nitrogen atom by a carboxy-Cl.-alkylcarbonyl group, 20 Rb denotes a methyl group and Re denotes an amidino group which may optionally be substituted by a C,- 8 -alkoxycarbonyl, 25 acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, particularly those compounds of general formula Ia wherein 30 A denotes a methylene group, B denotes an imino group, Ra denotes a cyclopropyl group substituted by the R-CO 35 group in the 1 position, wherein WO 00/01704 - 21 - PCT/EP99/04531 R denotes a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C 1 3 -alkoxy, carboxy-C 1 3 -alkylamino or 5 N- (C 1 3 -alkyl) -carboxy-C -- alkylamino group, a cyclopropyl group substituted in the 1 position by the
R
2 -CX group, wherein 10 R 2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C 1 3 -alkyl group and X denotes an oxygen atom, a C 13 -alkoxyimino or
C
1 3 -alkylidene group, each of which is substituted in 15 the alkyl or alkoxy moiety by a carboxy group, a C 1 2 -alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring may be substituted by one to three methyl groups or by two 20 methyl groups and an ethyl group, whilst additionally one of the abovementioned methyl or ethyl substituents may simultaneously be substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 25 position by an R 3
NR
4 - or R 3
NR
4
-CH
2 - group and by a di-(Cl.
3 -alkyl)-aminocarbonyl, by a pyrro 30 lidinocarbonyl or piperidinocarbonyl group optionally substituted by a C 1
.
3 -alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent may be substituted by a carboxy group, wherein 35
R
3 denotes a hydrogen atom or a C 1
.
3 -alkyl group optionally substituted by a carboxy group and WO 00/01704 - 22 - PCT/EP99/04531
R
4 denotes a C 1
-
3 -alkyl-Y 2 or carboxy- C 1 3 -alkyl-Y 2 group wherein 5 Y 2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a C 1 3 -alkyl group, Rb denotes a methyl group and 10 Rc denotes an amidino group which may optionally be substituted by a C 18 -alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, 15 whilst the abovementioned compounds in which the group Ra is in the 5 position are particularly preferred, the Cl -alkanol esters, the tautomers, stereoisomers and 20 salts thereof. The following are mentioned as examples of particularly preferred compounds: 25 (a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (pyrrolidin-1-yl-carbonyl)-cyclopropyl]-benzimidazole, (b) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-2-yl)-(carboxymethyloxyimino)methylene] 30 cyclopropyl)-benzimidazole, (c) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole, 35 WO 00/01704 - 23 - PCT/EP99/04531 (d) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2 carboxyethyl)-pyrrolidin-l-yl-carbonyl]cyclopropyl] benzimidazole, 5 (e) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[2-(2 carboxyethyl) -4, 5-dimethyl-imidazol-1-yl-methyl] benzimidazole (f) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxy 10 methylamino) -1- (pyrrolidin-1-yl-carbonyl) -ethyl] benzimidazole and (g) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl carboxymethylcarbonylaminomethyl) -1-methyl-1- (pyrrolidin 15 1-yl-carbonyl) -ethyl] -benzimidazole and the C 13 -alkanol esters, the N-(C 18 -alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl-amidines, the tautomers, stereoisomers and salts thereof. 20 According to the invention, the compounds of general formula I are prepared by methods known per se, for example by the following methods: 25 a) In order to prepare a compound of general formula I wherein Re denotes a cyano group: cyclising a compound of general formula zi Z 2 NH-C -A-B -Ar -CN Ra I (II), NH 30 Rb WO 00/01704 - 24 - PCT/EP99/04531 optionally formed in the reaction mixture, wherein Ra, Rb, Ar, A and B are as hereinbefore defined, Zi and Z 2 , which may be identical or different, denote 5 amino, hydroxy or mercapto groups optionally substituted by alkyl groups with 1 to 6 carbon atoms or Zi and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or 10 alkylenedithig group with 2 or 3 carbon atoms. The cyclisation is expediently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, 15 glycol, glycol monomethyl ether, diethyleneglycol dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of general formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for 20 example at temperatures between 0 and 250*C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid, p-toluenesulphonic 25 acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N-dicyclohexyl-carbodiimide or optionally in the presence of a base such as potassium ethoxide or potassium tert. butoxide. However, the cyclisation may also be 30 carried out without a solvent and/or condensing agent. It is particularly advantageous to perform the reaction by preparing a compound of general formula II in the reaction mixture by reduction of a corresponding o-nitro compound 35 optionally in the presence of a carboxylic acid of general formula WO 00/01704 - 25 - PCT/EP99/04531 HO-CO-A-B-Ar-CN (III), wherein Ar, A and B are as hereinbefore defined, by acylation of a corresponding amino compound optionally formed in the 5 reaction mixture. b) In order to prepare a compound of general formula I wherein Radenotes an R 2 -CX' -C 3 -s-cycloalkylene group, wherein R 2 is as hereinbefore defined and X' denotes one 10 of the imino groups mentioned for X hereinbefore: reacting a compound of general formula Ra' I \>A-B-Ar--Rc (IV), N Rb 15 wherein Rb, Ar, A and B are as hereinbefore defined and Ra' denotes an R 2
-CO-C
3 .-cycloalkylene group, where
R
2 is as hereinbefore defined, 20 with an amine of general formula
H
2 X' (V), 25 wherein X' denotes one of the imino groups mentioned for X hereinbefore. The reaction is preferably carried out in a solvent such 30 as methanol/toluene, ethanol, isopropanol or xylene and expediently in the presence of a dehydrating agent such as molecular sieve, sodium sulphate or calcium chloride optionally in the presence of a base such as triethylamine WO 00/01704 - 26 - PCT/EP99/04531 at temperatures between 50 and 100 0 C, preferably at the boiling temperature of the reaction mixture. c) In order to prepare a compound of general formula I 5 wherein Radenotes an R 2 -CX" -C 3
_
5 -cycloalkylene group, wherein R 2 is as hereinbefore defined and X" denotes one of the alkylidene groups mentioned for X hereinbefore: reacting a compound of general formula 10 Ra' >-A-B-Ar-R (IV), N Rb wherein Rb, Ar, A and B are as hereinbefore defined and Ra' denotes an R 2
-CO-C
3
_
5 -cycloalkylene group, where 15
R
2 is as hereinbefore defined, with a phosphone of general formula 20 Z 3 -HX" (VI), wherein X" denotes one of the alkylidene groups mentioned for X hereinbefore and 25 Z 3 denotes a triphenylphosphono or di
(C
13 -alkoxy)phosphono group such as the triethoxyphosphono group. The reaction is preferably carried out under protective 30 gas in a solvent such as tetrahydrofuran, dimethylformamide, dioxane, diethylether or dimethyl sulphoxide in the presence of a base such as potassium tert. butoxide, sodium ethoxide or sodium hydride at WO 00/01704 - 27 - PCT/EP99/04531 temperatures between -25 and 50 0 C, preferably at temperatures between -15' and ambient temperature. d) In order to prepare a compound of general formula I 5 wherein Re denotes an amidino group which may be substituted by one or two C 1 3 -alkyl groups: reacting a compound of general formula Ra - B -Ar- C= (NH) Z 4 (VII), Rb 10 optionally formed in the reaction mixture wherein Ra, Rb, Ar, A and B are as hereinbefore defined and 15 Z 4 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula 20 H - R 7
NR
8 , (VIII) wherein
R
7 and R 8 , which may be identical or different, each 25 denote a hydrogen atom or a C 1
-
3 -alkyl group, or with the salts thereof. The reaction is expediently carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or 30 dioxane at temperatures between 0 and 150*C, preferably at temperatures between 0 and 80 0 C, with an amine of general formula VIII or with a corresponding acid addition salt WO 00/01704 - 28 - PCT/EP99/04531 such as for example ammonium carbonate or ammonium acetate. A compound of general formula VII is obtained for example 5 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 10 triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 500C, but preferably at 20*C, or a corresponding nitrile with hydrogen sulphide expediently in a solvent such as pyridine or 15 dimethylformamide and in the presence of a base such as triethylamine and subsequently alkylating the thioamide formed with a corresponding alkyl or aralkyl halide. e) In order to prepare a compound of general formula I 20 wherein Ra denotes an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two C 13 -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or C 1 3 -alkoxycarbonyl group: 25 cyclising a compound of general formula N Ra" I A-B-Ar - CN (IX), N If Rb optionally formed in the reaction mixture 30 wherein Rb, Ar, A and B are as hereinbefore defined and WO 00/01704 - 29 - PCT/EP99/04531 Ra" denotes an aminocarbonylamino group, substituted in the 3 position by a CI 3 -alkoxycarbonyl-CI- 3 -alkyl group. The reaction is preferably carried out in a solvent such 5 as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at temperatures between 0 and 500C, but preferably at 200C. 10 f) In order to prepare a compound of general formula I wherein Rc denotes a hydroxyamidino group: reacting a nitrile of general formula N R~ -- >-A-B -Ar -CN W Ra N- -- r- N(X) , Rb 15 wherein Ra, Rb, Ar, A and B are as hereinbefore defined, with hydroxylamine or the salts thereof. 20 The reaction is expediently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran, tetrahydrofuran/water, dioxane or dioxane/water at temperatures between 0 and 150 0 C, preferably at temperatures between 0 and 80 0 C. 25 g) In order to prepare a compound of general formula I wherein Ra contains a carboxy group and Rc is as hereinbefore defined or Ra is as hereinbefore defined and Re denotes an amidino group optionally substituted by a 30 hydroxy group or by one or two CI 3 -alkyl groups: converting a compound of general formula WO 00/01704 - 30 - PCT/EP99/04531 Ra' '>-A-B-Ar- R ' (XI), N Rb wherein Rb, Ar, A and B are as hereinbefore defined and Ra'" and Re' have the meanings given for Ra and Rc with the 5 proviso that Ra contains a group which may be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and Rc is as hereinbefore defined or Re denotes a group which may optionally be converted by hydrolysis, treatment with an 10 acid or base, thermolysis or hydrogenolysis into an amidino group substituted by a hydroxy group or by one or two C 1 3 -alkyl groups and Ra is as hereinbefore defined, is converted by hydrolysis, treatment with an acid or 15 base, thermolysis or hydrogenolysis into a compound of general formula I wherein Ra contains a carboxy group and Re is as hereinbefore defined or Ra is as hereinbefore defined and RC denotes an amidino group optionally substituted by a hydroxy group or by one or two C 1
.
3 -alkyl 20 groups. A group which may be converted into a carboxy group might be, for example, a carboxyl group protected by a protecting group, such as the functional derivatives 25 thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters thereof which are expediently converted by hydrolysis into a carboxyl group, 30 the esters thereof with tertiary alcohols, e.g. the tert.butyl ester, which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and WO 00/01704 - 31 - PCT/EP99/04531 the esters thereof with aralkanols, e.g. the benzylester, which are expediently converted into a carboxyl group by hydrogenolysis. 5 The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or the mixtures thereof or in the 10 presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures 15 between -10 and 120 0 C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. If a compound of formula XI for example contains the 20 tert.butyl or tert.butyloxycarbonyl group, these may also be cleaved by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such 25 as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 0 C, e.g. at temperatures between 0 and 60 0 C, or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, 30 toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures 35 between 40 and 120 0
C.
WO 00/01704 - 32 - PCT/EP99/04531 If a compound of formula XI contains, for example, a benzyloxy or benzyloxycarbonyl group, these may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a 5 suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 0 C, e.g. at ambient temperature, and at a hydrogen pressure of from 1 to 5 bar. 10 h) In order to prepare a compound of general formula I wherein Rc denotes an amidino group which is substituted by one or two C,-,-alkoxycarbonyl groups or by a group which can be cleaved in vivo: 15 reacting a compound of general formula I Ra >-A-B-Ar-Ren (XII), Rb wherein 20 Ra, Rb, Ar, A and B are as hereinbefore defined and Re" denotes an amidino group, with a compound of general formula Z5 - R 9 (XIII), 25 wherein
R
9 denotes a Ci,-alkoxycarbonyl group or the acyl group of one of the groups which can be cleaved in vivo mentioned hereinbefore and 30 Z 5 denotes a nucleofugic leaving group such as a halogenatom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
WO 00/01704 - 33 - PCT/EP99/04531 The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulphoxide or dimethylformamide 5 optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20*C and the boiling temperature of the solvent used. With a compound of general formula XIII wherein Z 5 denotes 10 a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethyl sulphoxide, optionally in the presence of a base such as sodium hydride, potassium 15 carbonate, potassium tert. butoxide or N-ethyl diisopropylamine at temperatures between 0 and 600C. If according to the invention a compound of general formula I is obtained which contains a (R 3
NR
4
)-C-
3 -alkyl 20 group wherein at least one of the groups R 3 or R 4 denotes a hydrogen atom, this may subsequently be converted with a corresponding isocyanate or carbamoyl halide into a corresponding urea compound of general formula I and/or 25 if a compound of general formula I is obtained which contains an NH 2
-C-
3 -alkyl group, this may subsequently be converted with a corresponding acrylic acid ester into a corresponding 2- (C 1 3 -alkoxycarbonyl) -ethyl compound of general formula I and/or 30 if a compound of general formula I is obtained which contains an (R 3
NR
4 ) -C 1 3 -alkyl group wherein R 3 and R 4 each denote a hydrogen atom, this may subsequently be converted with a corresponding dihaloalkane into a corresponding 35 compound of general formula I wherein R 3 and R 4 together with the nitrogen atom between them [denote] a WO 00/01704 - 34 - PCT/EP99/04531 corresponding 4- to 7-membered cycloalkyleneimino group and/or if a compound of general formula I is obtained wherein Rc 5 denotes an amidino group, this may subsequently be converted by reaction with a haloacetic acid derivative and subsequent hydrolysis and decarboxylation into a corresponding amidino compound substituted by one or two methyl groups and/or 10 if a compound of general formula I is obtained wherein Rc denotes a hydroxyamidino group, this may subsequently be converted into a corresponding amidino compound by catalytic hydrogenation and/or 15 if a compound of general formula I is obtained wherein Ra contains a carboxy group, this may subsequently be converted into a corresponding ester by esterification. 20 The subsequent preparation of a corresponding urea compound of general formula I is expediently carried out with a corresponding isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such 25 as triethylamine at temperatures between 0 and 50 0 C, preferably at ambient temperature,. The subsequent preparation of a corresponding 2-(Cl--alkoxy-carbonyl) -ethyl-compound is carried out with 30 a corresponding acrylic acid ester, preferably in a solvent such as methanol, ethanol or isopropanol at temperatures between 50 and 100 0 C, preferably at the boiling temperature of the reaction mixture. 35 The subsequent preparation of a corresponding 4- to 7 membered cycloalkyleneimino compound of general formula I is expediently carried out with a corresponding WO 00/01704 - 35 - PCT/EP99/04531 dihaloalkane, preferably in a solvent such as methanol, ethanol or isopropanol in the presence of a base such as sodium carbonate at temperatures between 50 and 1000C, preferably at the boiling temperature of the reaction 5 mixture. The subsequent alkylation is expediently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone 10 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, 15 which may simultaneously act as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 1000C, but preferably at temperatures between -10 and 80 0 C. 20 The subsequent hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium 25 hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane and subsequent decarboxylation in the presence of an acid as hereinbefore 30 described at temperatures between -10 and 120*C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. The subsequent esterification is carried out with a 35 corresponding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, WO 00/01704 - 36 - PCT/EP99/04531 benzene/tetrahydrofuran or dioxan, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl 5 chloroformate, thionyl chloride, trimethylchlorosilane, sulphuric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, 10 N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonylaiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, 15 N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine expediently at temperatures between 0 and 150 0 C, preferably at temperatures between 0 and 80 0 C, or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, 20 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 25 diisopropylamine or N-methyl-morpholine, which may simultaneously act as 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. 30 In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by 35 conventional protecting groups which are cleaved again after the reaction.
WO 00/01704 - 37 - PCT/EP99/04531 For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, 5 protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protecting groups for an amino, alkylamino or imino group 10 may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group. 15 Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid 20 or in the presence of an alkali 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 0 C, preferably at temperatures between 10 and 50 0 C. 25 However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, 30 ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 0 C, but preferably at ambient temperature, and at a hydrogen 35 pressure of 1 to 7 bar, but preferably 3 to 5 bar.
WO 00/01704 - 38 - PCT/EP99/04531 A methoxybenzyl group may also be cleaved in the presence of an oxidant such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50*C, but 5 preferably at ambient temperature. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol. 10 A tert.butyl gr 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. 15 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. 20 An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine) palladium(0), preferably in a solvent such as 25 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 an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I) 30 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 70C. 35 The compounds of general formulae II to XIII used as starting materials, some of which are known from the literature, may be obtained by methods known from the WO 00/01704 - 39 - PCT/EP99/04531 literature and in addition their preparation is described in the Examples. The chemistry of the compounds of general formula III is 5 described, for example, by Jack Robinson in J. Chem. Soc. 1941, 744, that of the benzimidazoles is described by Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, and by Schaumann in Hetarene III, Methoden der organischen Chemie (Houben 10 Weyl), 4 th edition, Verlag Thieme, Stuttgart 1993. Thus, for example, a compound of general formula II is obtained by acylating a corresponding o-diamino compound with a corresponding reactive derivative of a compound of 15 general formula III, a compound of general formulae IV, VII, IX, X, XI and XII is obtained by cyclisation of a corresponding substituted compound according to process a) and if necessary 20 subsequent reduction of any nitro group present in the phenyl moiety, followed by acylation, amidation and/or halogenation. Moreover, the compounds of general formula I obtained may 25 be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by 30 methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on 35 the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or WO 00/01704 - 40 - PCT/EP99/04531 fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above. 5 The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation 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 10 compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric 15 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 20 quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl. 25 Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, 30 hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Moreover, if the new compounds of formula I contain a 35 carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the WO 00/01704 - 41 - PCT/EP99/04531 physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanol amine, diethanolamine and triethanolamine. 5 As already mentioned hereinbefore, the new compounds of general formula I and the salts thereof have valuable properties. Thus, the compounds of general formula I wherein Re denotes a cyano group are valuable intermediate 10 products for preparing the other compounds of general formula I, and the compounds of general formula I wherein Rc denotes one of the abovementioned amidino groups, and the tautomers, stereoisomers and the physiologically acceptable salts thereof have valuable pharmacological 15 properties, particularly an antithrombotic activity, which is preferably based on an activity which influences thrombin or factor Xa, for example on a thrombin inhibiting or factor Xa-inhibiting activity, on an activity which extends the aPTT time and on an inhibiting 20 effect on related serine proteases such as, for example, trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII. For example, the compounds 25 A = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride, 30 B = (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-2-yl)-(carboxymethyloxyimino)methylene] cyclopropyl]-benzimidazole-hydrochloride, C = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 35 carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole-hydrochloride, WO 00/01704 - 42 - PCT/EP99/04531 D = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-[2-(2 carboxyethyl)-pyrrolidin-l-yl-carbonyl]cyclopropyl] benzimidazole-hydrochloride, 5 E = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2 carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl] benzimidazole-hydrochloride, F = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-(carboxy 10 methylamigo)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benz imidazole-hydrochloride and G = 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl carboxymethylcarbonylaminomethyl)-1-methyl-l-(pyrrolidin 15 1-yl-carbonyl)-ethyl]-benzimidazole-dihydrochloride were investigated for their effect on extending the aPTT time as follows: 20 Materials: - Plasma, from human citrated blood, - PTT reagent, Boehringer Mannheim (524298), - calcium solution (0.025 Mol/l), Behring Werke, Marburg (ORH 056/57), 25 - diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61), -Biomatic B10 coagulometer, Desaga, Wiesloch. Method: 30 The aPTT time was determined using a Biomatic B10-coagulometer made by Messrs. Desaga. The test substance was added to the test vessels 35 prescribed by the manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of PTT reagent. The mixture was incubated for three minutes at 370C. The clotting reaction WO 00/01704 - 43 - PCT/EP99/04531 was started by the addition of 0.1 ml of calcium solution. Because of the design of the apparatus, the time taken for the mixture to clot was measured as the calcium solution was added. Mixtures to which 0.1 ml of DBA buffer had been 5 added were used as controls. According to the definition the effective concentration of substance at which the aPTT time was double that of the control was determined by means of a dosage/activity 10 curve. The following Table contains the values found: substance APTT time
(ED
2 0 0 in pM) A 0.12 B 0.42 C 0.31 D 0.29 E 0.29 F 0.20 G 0.17 15 The compounds prepared according to the invention are well tolerated, since no toxic side effects could be detected at therapeutic doses. 20 In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the 25 treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases WO 00/01704 - 44 - PCT/EP99/04531 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 5 support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes, e.g. in the treatment of pulmonary 10 fibrosis. The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50 mg/kg, preferably 0.3 15 to 30 mg/kg 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 and/or diluents, e.g. 20 with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, 25 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. 30 The Examples which follow are intended to illustrate the invention: WO 00/01704 - 45 - PCT/EP99/04531 Example 1 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin 1-vl-carbonvl)cvcloprolpyll-benzimidazole-hydrochloride 5 a. 1-(4-chloro-3-nitro-phenyl)-1-cyclopropanecarboxylic acid To 350 ml of fuming nitric acid are added, in batches, at -25 0 C, 50.0 g (0.21 mol) of 1-(4-chlorophenyl)-1 10 cyclopropanecarboxylic acid. The solution is stirred for 15 minutes at -25 0 C and subsequently poured onto ice water. The product precipitated is suction filtered, washed with water and dried. Yield: 58.5 g (95 % of theory), 15 Rf value: 0.45 (silica gel; methylene chloride/methanol = 9.5:0.5) b. 1-(4-methylamino-3-nitro-phenyl)-1 cyclopropanecarboxylic acid 20 20.0 g (0.083 mol) of 1-(4-chloro-3-nitro-phenyl)-1 cyclopropanecarboxylic acid and 100 ml of methylamine solution (40% in H2O) are heated to 80 0 C in a pressure vessel for five hours. The contents are evaporated to dryness, dissolved in water and acidified with glacial 25 acetic acid. The product precipitated is suction filtered, washed with water and dried. Yield: 16.9 g (93 % of theory), Rf value: 0.58 (silica gel; methylene chloride/methanol = 9:1) 30 c. 4-[l-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-nitro-N methyl-aniline 2.4 g (0.01 mol) of 1-(4-methylamino-3-nitro-phenyl)-1 cyclopropanecarboxylic acid are dissolved in 50 ml 35 dimethylformamide and after the addition of 3.2 g (0.01 mol) of 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 0.7 g (0.01 mol) of pyrrolidine and 1.1 WO 00/01704 - 46 - PCT/EP99/04531 g (0.01 mol) of N-methyl-morpholine stirred for 20 hours at ambient temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are concentrated 5 by evaporation, triturated with ether, suction filtered and dried. Yield: 1.8 g (61 % of theory), Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) 10 d. 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-amino-N methyl-aniline 1.8 g (6.2 mmol) of 4-[l-(pyrrolidin-1-yl 15 carbonyl)cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 40 ml methanol and 40 ml methylene chloride and after the addition of 0.4 g of palladium on activated charcoal (10%) hydrogenated for 4 hours at ambient temperature. Then the catalyst is filtered off and the 20 residue is concentrated by evaporation. Yield: 1.6 g (100 % of theory), Rf value: 0.26 (silica gel; methylene chloride/methanol = 9:1) 25 e. 4-[l-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-(4 cyanophenvl)aminomethvlcarbonylamino-N-methyl-aniline Prepared analogously to Example 1c from 4-[1-(pyrrolidin 1-yl-carbonyl)cyclopropyl]-2-amino-N-methyl-aniline, 0 (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 30 tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 66 % of theory, Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) 35 f. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin 1-vl-carbonyl)cyclopropyll-benzimidazole WO 00/01704 - 47 - PCT/EP99/04531 1.7 g (0.004 mol) of 4-[l-(pyrrolidin-1-yl carbonyl)cyclopropyl]-2-(4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline are refluxed in 7 ml of glacial acetic acid for 2 hours. The solvent is 5 distilled off, the residue dissolved in water and extracted with methylene chloride. The organic phase is dried, concentrated by evaporation and subsequently chromatographed on silica gel, eluting with methylene chloride + 2 to 3% methanol. 10 Yield: 1.0 g (62 % of theory), Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) g. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1 15 (pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl 5-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole are dissolved in 50 ml saturated ethanolic hydrochloric 20 acid and stirred for 5 hours at ambient temperature. The solvent is distilled off, the residue dissolved in 50 ml absolute ethanol and mixed with 2.3 g (25 mmol) of ammonium carbonate. After 60 hours at ambient temperature the mixture is evaporated to dryness. The residue is 25 chromatographed on silica gel, eluting with methylene chloride/methanol (7:1). Yield: 700 mg (62 % of theory), Rf value: 0.61 (silica gel; methylene chloride/methanol = 4:1) 30 C 24
H
28
N
6 0 x HCl (416.54/453.0) mass spectrum: (M+H)* = 417 The following compounds are obtained analogously to Example 1: 35 WO 00/01704 - 48 - PCT/EP99/04531 (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3 methyl-piperidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride Yield: 45 % of theory, 5 Rf value: 0.25 (silica gel; methylene chloride/methanol = 4:1)
C
26
H
32
N
6 0 x HCl (444.59/481.05) mass spectrum: (M+H)* = 445 10 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (piperidin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride Yield: 57 % of theory, Rf value: 0.23 (silica gel; methylene chloride/methanol = 15 4:1)
C
25
H
30
N
6 0 x HCl (430.56/467.93) mass spectrum: (M+H)* = 431 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(4 20 methyl-piperazin-1-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride Yield: 32 % of theory, Rf value: 0.26 (silica gel; methylene chloride/methanol/ ammonia = 2:1:0.25) 25 C 2 sH 31
N
7 0 x HCl (445.58/482.04) mass spectrum: (M+H)* = 446 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2,3 dihydroindolin-1-yl-carbonyl)cyclopropyl]-benzimidazole 30 hydrochloride Yield: 60 % of theory, Rf value: 0.34 (silica gel; methylene chloride/methanol = 4:1)
C
2 eH 2 ,N.O x HCl (464.58/501.04) 35 mass spectrum: (M+H)* = 465 WO 00/01704 - 49 - PCT/EP99/04531 (5) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[l-((2 ethoxycarbonylethyl)-piperidin-1-yl-carbonyl)cyclopropyl] benzimidazole-hydrochloride Yield: 85 % of theory, 5 R. value: 0.57 (silica gel; methylene chloride/methanol = 4:1)
C
30
H
38 N0 3 x HCl (530.67/567.13) mass spectrum: (M+H)* = 531 10 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-((2 ethoxycarbonylethyl)-pyrrolidin-1-yl carbonyl)cyclopropyl]-benzimidazole-hydrochloride Yield: 60 % of theory,
C
29
H
3 ,N0 3 x HC1 (516.64/553.10) 15 mass spectrum: (M+H)* = 517 (M+2H)** = 259 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(N-(2 ethoxycarbonylethyl)-N-methyl-aminomethyl)-pyrrolidin-1 20 yl-carbonyl]cyclopropyl]-benzimidazole-hydrochloride Yield: 65 % of theory,
C
3 1
H
4 1
N
7 0 3 x HCl (559.72/ 596.18) mass spectrum: (M+H)* = 560 (M+2H)** = 280.6 25 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(2 ethoxycarbonylmethyloxymethyl)-pyrrolidin-1-yl carbonyl]cyclopropyl]-benzimidazole-hydrochloride Yield: 61 % of theory, 30 R. value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % glacial acetic acid)
C
29
H
36
N
6 0 4 x HCl (532.66/569.11) mass spectrum: (M+H)* = 533 (M+2H)** = 267 35 WO 00/01704 - 50 - PCT/EP99/04531 Example 2 2-(4-amidinophenylaminomethyl)-l-methyl-5-(1 cyclopentylcarbonyl-3-chloro-n-propyl)-benzimidazole 5 hydrochloride a. 4-[1-(cyclopentylcarbonyl)cyclopropyll-chlorobenzene 2.4 g (0.1 mol) of magnesium chips are suspended in 10 ml ether. After the addition of a spatula-tip of iodine, 10 14.9 g (0.1 mql) of bromocyclopentane are slowly added dropwise to 40 ml of ether, the reaction being started off initially by gentle heating. After the addition has ended the mixture is refluxed for 30 minutes. Then a solution of 14.0 g (0.08 mol) of 1-(4-chlorophenyl)-1 15 cyclopropanecarbonitrile in 75 ml ether is added and refluxed for a further 3 hours. The reaction solution is poured onto ice water, adjusted to pH 3 with hydrochloric acid and extracted with ether. The organic extracts are dried and concentrated by evaporation. The residue is 20 chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1 and 15:1). Yield: 3.0 g (12 % of theory), Rf value: 0.58 (silica gel; petroleum ether/ethyl acetate = 4:1) 25 b. 4-[1-(cyclopentylcarbonyl)cyclopropyll-2-nitro chlorobenzene Prepared analogously to Example la from 4-[1 (cyclopentylcarbonyl)cyclopropyl]-chlorobenzene and fuming 30 nitric acid. Yield: 87 % of theory, Rf value: 0.60 (silica gel; petroleum ether/ethyl acetate = 9:1) WO 00/01704 - 51 - PCT/EP99/04531 c. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-nitro-N methyl-aniline Prepared analogously to Example lb from 4-[1 (cyclopentylcarbonyl)cyclopropyl]-2-nitro-chlorobenzene 5 and aqueous methylamine solution. Yield: 18 % of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) 10 d. 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-amino-N methyl-aniline 2.3 g (7.9 mmol) of 4-[1-(cyclopentylcarbonyl) cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 125 ml ethyl acetate and 25 ml ethanol and after the addition 15 of 1.0 g Raney nickel hydrogenated for 1.5 hours at ambient temperature. Then the catalyst is filtered off and the residue is concentrated by evaporation. Yield: 2.0 g (98 % of theory), Rf value: 0.15 (silica gel; methylene chloride/ethanol = 20 19:1) e. 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-(4 cyanophenyl-aminomethylcarbonylamino)-N-methyl-aniline Prepared analogously to Example 1c from 4-[1 25 (cyclopentylcarbonyl)cyclopropyl]-2-amino-N-methyl aniline, 0-(benzotriazol-1-yl)-N,N,N',N' tetramethyluroniumtetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 96 % of theory, 30 Rf value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) f. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1 (cyclopentylcarbonyl)-cyclopropyll-benzimidazole 35 Prepared analogously to Example if from 4-[1 (cyclopentylcarbonyl)cyclopropyl]-2-(4-cyanophenyl- WO 00/01704 - 52 - PCT/EP99/04531 aminomethylcarbonylamino)-N-methyl-aniline in glacial acetic acid. Yield: 53 % of theory, Rf value: 0.46 (silica gel; methylene chloride/ethanol = 5 19:1) g. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(1 cyclopentyl-carbonyl-3-chloro-n-propyl)-benzimidazole hydrochloride 10 Prepared analQgously to Example lg from 2-(4 cyanophenylaminomethyl)-1-methyl-5-(1-cyclopentylcarbonyl 3-chloro-n-propyl)-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 61 % of theory, 15 C 25
H
3 ClN 5 0 x HCl (452.00/488.56) mass spectrum: (M+H)* = 452/4 (Cl)) Example 3 20 (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[l [(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino) methylenelcyclopropyll-benzimidazole-hydrochloride a. 1-[(pyridin-3-vl)-carbonyllcyclopropyl-benzene 25 A solution of 21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether is added dropwise at -40 to -50 0 C to 100 ml of butyllithium (1.6 M in hexane) and then stirred for 20 minutes at -40 0 C. The mixture is then cooled to -60 0 C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropane 30 carbonitrile in 125 ml ether is added dropwise. After it has all been added, the reaction mixture is heated to ambient temperature and stirred for 5 hours. The suspension is mixed with 20% hydrochloric acid and heated to 1000C for 30 minutes. After cooling, the mixture is 35 adjusted to pH 8 with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The WO 00/01704 - 53 - PCT/EP99/04531 residue is chromatographed on aluminium oxide, eluting with petroleum ether/ethyl acetate (9:1). Yield: 14.0 g (46 % of theory), R. value: 0.27 (aluminium oxide; petroleum ether/ethyl 5 acetate = 9:1) b. 4-[1-[(pyridin-3-vl)-carbonyllcyclopropyll-nitrobenzene Prepared analogously to Example la from 1-[(pyridin-3-yl) carbonyl]cyclopropyl-benzene and fuming nitric acid. 10 Yield: 53.7 % of theory, Rf value: 0.29 (aluminium oxide; petroleum ether/ethyl acetate = 4:1) c. 4-[l-[(pvridin-3-vl)-carbonyllcyclopropyll-aniline 15 Prepared analogously to Example 2d from 4-[1-[(pyridin-3 yl)-carbonyl]cyclopropyl]-nitrobenzene and Raney nickel in ethyl acetate/ethanol. Yield: 94 % of theory, Rf value: 0.51 (silica gel; methylene chloride/ethanol = 20 19:1) d. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl] trifluoroacetylaniline 25 8.0 g (33.5 mmol) of 4-[1-[(pyridin-3-yl) carbonyl]cyclopropyl]-aniline are dissolved in 100 ml chlorobenzene and after the addition of 15 ml trifluoroacetic anhydride the mixture is stirred for two hours at 110 0 C. The solvent is distilled off, the residue 30 stirred with petroleum ether/ether (9:1), suction filtered and dried. Yield: 10.0 g (88 % of theory), R, value: 0.54 (silica gel; methylene chloride/ethanol = 19:1) 35 WO 00/01704 - 54 - PCT/EP99/04531 e. 4-[l-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro trifluoroacetylaniline 1.7 g (5 mmol) of 4-[l-[(pyridin-3-yl) 5 carbonyl]cyclopropyl]-trifluoroacetylaniline are added batchwise to 13 ml of conc. sulphuric acid and 16 ml of 65% nitric acid at -5 0 C. Then the mixture is stirred for a further 30 minutes without cooling, poured onto ice water and extracted with ethyl acetate. The organic extracts are 10 dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (50:1 and 25:1). The desired fractions are concentrated by evaporation, triturated with ether/petroleum ether, suction filtered and dried. 15 Yield: 1.2 g (75 % of theory), Rf value: 0.70 (silica gel; methylene chloride/ethanol = 19:1) f. 4-[l-[(pyridin-3-yl)-carbonylicyclopropyl]-2-nitro-N 20 trifluoroacetyl-N-methyl-aniline 1.15 g (3.0 mmol) of 4-[l-[(pyridin-3-yl) carbonyl]cyclopropyl]-2-nitro-trifluoroacetylaniline are dissolved in 50 ml acetone and after the addition of 25 2.0 g potassium carbonate and 0.8 ml methyl iodide refluxed for two hours. The insoluble matter is filtered off and the solution is evaporated down. The residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (1:1 and 1:4). 30 Yield: 0.88 g (75 % of theory), R, value: 0.38 (silica gel; petroleum ether/ethyl acetate = 1:1) WO 00/01704 - 55 - PCT/EP99/04531 g. 4-[l-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-N methyl-aniline 7.4 g (18.8 mmol) of 4-[l-[(pyridin-3-yl) 5 carbonyl]cyclopropyl]-2-nitro-N-trifluoroacetyl-N-methyl aniline are stirred in 200 ml of 20% potassium hydroxide solution for one hour at 30 0 C. Then the mixture is diluted with isopropanol, the organic phase is separated off, 10.0 g of aluminium oxide are added and the resulting mixture 10 is evaporated to dryness. The residue is chromatographed on aluminium oxide, eluting with petroleum ether/ethyl acetate (4:1 and 1:1). Yield: 2.6 g (47 % of theory), Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate 15 = 1:1) h. 4-[l-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-amino-N methyl-aniline 20 Prepared analogously to Example 2d from 4-[l-[(pyridin-3 yl)-carbonyl]cyclopropyl]-2-nitro-N-methyl-aniline and Raney nickel in ethyl acetate/ethanol. Yield: 98 % of theory, Rf value: 0.51 (silica gel; methylene chloride/ethanol = 25 19:1) i. 4-El-r[(pyridin-3-vl)-carbonyllcyclopropyll-2-(4-cyano phenyl)-aminomethylcarbonylamino-N-methyl-aniline 30 Prepared analogously to Example 1c from 4-[l-[(pyridin-3 yl)-carbonyl]cyclopropyl]-2-amino-N-methyl-aniline, 0 (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. 35 Yield: 97 % of theory, Rf value: 0.48 (silica gel; methylene chloride/ethanol = 19:1) WO 00/01704 - 56 - PCT/EP99/04531 k. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[(pyridin-3 vl)-carbonyllcyclopropyll-benzimidazole 5 Prepared analogously to Example if from 4-(pyridin-3-yl carbonyl)cyclopropyl-2-(4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid. Yield: 76 % of theory, 10 Rf value: 0.5 (silica gel; methylene chloride/ethanol = 19:1) 1. (E/Z)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1 [(pyridin-3-yl)-(carboxymethyloxyimino)methylene] 15 cyclopropyllbenzimidazole 1.6 g (4.0 mmol) of 2-(4-cyanophenylaminomethyl)-l-methyl 5-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-benzimidazole, 3.0 g (12 mmol) of carboxy-methoxylamine-hemihydrate, 0.84 20 ml of triethylamine, 12 g of molecular sieve 3A and 12 g of molecular sieve 4A are refluxed for 12 hours in 80 ml methanol and 40 ml toluene. Then the molecular sieve is filtered off and the filtrate is concentrated by evaporation. The residue is stirred with water, suction 25 filtered and dried. The crude product is chromatographed on silica gel, eluting with methylene chloride/ethanol/glacial acetic acid (25:1:0 and 8:2:0.2). Yield: 0.9 g (48 % of theory), R. value: 0.34 (silica gel; methylene chloride/ethanol/ 30 glacial acetic acid = 8:2:0.2) m. (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino) methylenelcyclopropyll-benzimidazole-hydrochloride 35 Prepared analogously to Example ig from (E/Z)-2-(4 cyanophenylaminomethyl)-1-methyl-5-[l-[(pyridin-3-yl)- WO 00/01704 - 57 - PCT/EP99/04531 (ethoxycarbonylmethyloxyimino)methylene]cyclopropyl] benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 60 % of theory, 5 Rf value: 0.28 (silica gel; methylene chloride/ethanol/ glacial acetic acid = 8:2:0.2)
C
29
H
3
,N
7 0 3 x HCl (525.62/562.09) mass spectrum: (M+H)* = 526 10 The following compounds are obtained analogously to Example 3: (1) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridine-2-yl)-(ethoxycarbonylmethyloxyimino) 15 methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 52 % of theory, Rf value: 0.21 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0.2)
C
2 9
H
3 1 N,0 3 x HCl (525.62/562.09) 20 mass spectrum: (M+H)* = 526 (2) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [phenyl-(ethoxycarbonylmethyloxyimino)-methylene] cyclopropyl]-benzimidazole-hydrochloride 25 Yield: 18 % of theory,
C
30
H
32
N
6 0 3 x HCl (524.63/561.09) mass spectrum: (M+H)* = 525 (M-H+HCl)^ = 559/61 (Cl) 30 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1 methyl-pyrazol-5-yl-carbonyl)cyclopropyl]-benzimidazole hydrochloride Yield: 10 % of theory,
C
24
H
2 sN 7 0 x HCl (427.51/ 463.97) 35 mass spectrum: (M+H)* = 428 (M+H+HCl) = 464/6 (Cl) WO 00/01704 - 58 - PCT/EP99/04531 (4) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(1-methyl-pyrazol-5-yl-(ethoxycarbonylmethyloxyimino) methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 80 % of theory, 5 Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % glacial acetic acid)
C
2
,H
3 2 N,0 3 x HCl (528.63/565.08) mass spectrum: (M+H)* = 529 10 (5) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [phenyl-(3-ethoxycarbonyl-n-propyloxyimino)methylene] cyclopropyl]-benzimidazole-dihydrochloride Yield: 47 % of theory, Rf value: 0.06 (silica gel; methylene chloride/methanol = 15 9:1)
C
32
H
36
N
6 0 3 x 2 HCl (552.69/625.60) mass spectrum: (M+H)* = 553 Example 4 20 (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridine-2-yl)-(carboxymethyloxyimino)methylene] cyclopropyvll-benzimidazole-hydrochloride 25 150 mg (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl 5-[1-[(pyridin-2-yl-(ethoxycarbonylmethyloxyimino) methylene]cyclopropyl]-benzimidazole-hydrochloride and 2.5 ml of 2N sodium hydroxide solution are stirred in 10 ml ethanol for 5 hours at ambient temperature. The alcohol is 30 distilled off and the residue is adjusted to pH 5 with hydrochloric acid. The crystalline product is suction filtered, washed with water and dried. Yield: 46 % of theory, Rf value: 0.10 (silica gel; methylene chloride/ethanol/ 35 glacial acetic acid = 8:2:0.1)
C
2 7
H
2 7
N
7 0 3 x HCl (497.58/534.05) WO 00/01704 - 59 - PCT/EP99/04531 mass spectrum: (M+H)* = 498 (M+Na)* = 520 The following compounds are obtained analogously to 5 Example 4: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-[2-(2 carboxyethyl)-piperidin-l-yl-carbonyl]cyclopropyl] benzimidazole-hydrochloride 10 Yield: 94 % of theory, Rf value: 0.57 (Reversed phase RP 18; methanol/5% sodium chloride solution = 3:2)
C
2
,H
34 N0 3 x HCl (502.62/539.08) mass spectrum: (M+H)* = 503 15 (M+Na)* = 525 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole-hydrochloride 20 Yield: 98 % of theory, Rf value: 0.73 (Reversed phase RP 8; methanol/5% sodium chloride solution = 1:2)
C
26
H
33
N
7 0 3 x HCl (491.60/564.54) mass spectrum: (M+H)* =0492 25 (M+2H)** = 247 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3 carboxypropionylamino)-1-(ethoxycarbonyl)-ethyl] benzimidazole-hydrochloride 30 Yield: 98 % of theory, Rf value: 0.70 (RP 8; methanol/5% sodium chloride solution = 1 :2)
C
25
H
3
ON
6 0 5 x HCl (494.55/531.05) mass spectrum: (M+H)* = 495 35 (2M+H)* = 989 WO 00/01704 - 60 - PCT/EP99/04531 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylamino)-1-(pyrrolidin-1-yl-carbonyl)-methyl] benzimidazole-hydrochloride Yield: 87 % of theory, 5 C 2 4
H
2 9 N,0 3 x HCl (463.54/500.04) mass spectrum: (M+H)* = 464 (M+2H)* = 232.6 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2 10 carboxyethyl) 7 pyrrolidin-1-yl-carbonyl]cyclopropyl] benzimidazole-hydrochloride Yield: 94 % of theory,
C
2
H
32 N6O 3 x HCl (488.59/525.05) mass spectrum: (M+H)* = 489 15 (M+Na)* = 511 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylcarbonylamino)-1-(pyrrolidin-1-yl-carbonyl) methyl]-benzimidazole-hydrochloride 20 Yield: 49 % of theory,
C
2 sH 29 N,0 4 x HCl (491.'55/528.01) mass spectrum: (M+H)* = 492 (M+H+Na)** = 257.7 25 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylcarbonylamino)-1-(pyrrolidin-1-yl-carbonyl) ethyl]-benzimidazole-hydrochloride Yield: 92 % of theory,
C
2
,H
31
N
7 0 4 x HCl (505.58/542.04) 30 mass spectrum: (M+H)* = 506 (M+H+Na)** = 264.7 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3 carboxymethyl-imidazolin-2,4-dion-5-yl)-benzimidazole 35 hydrochloride Yield: 88 % of theory,
C
2 2
H
2 3 N,0 4 x HCl (449.47/485.94) WO 00/01704 - 61 - PCT/EP99/04531 mass spectrum: (M+H)* = 450 (M+2Na)** = 247.7 (9) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 5 [(pyridin-3-yl)-(carboxymethyloxyimino)methylene] cyclopropyl]-benzimidazole-hydrochloride Yield: 54 % of theory,
C
27
H
2
,N
7 0 3 x HC1 (497.56/534.09) mass spectrum: (M+H)* = 498 10 (M+Na)* = 520 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(N (2-carboxyethyl)-N-methyl-aminomethyl)-pyrrolidin-1-yl carbonyl]cyclopropyl]-benzimidazole-hydrochloride 15 Yield: 100 % of theory,
C
2 9
H
37
N
7 0 3 x HC1 (531.66/568.12) mass spectrum: (M+H)* = 532 (M-H) = 530 20 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2 carboxyethyl)-N-(2-pyridyl)-aminomethyl]-benzimidazole hydrochloride Yield: 91 % of theory,
C
2 5
H
2 7 N,0 2 x HCl (457.54/493.96) 25 mass spectrum: (M+H)* = 458 (12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(N benzenesulphonyl-N-carboxymethyl-aminomethyl) benzimidazole-hydrochloride 30 Yield: 84 % of theory,
C
25
H
2
,NO
4 S x HCl (506.59/543.06) mass spectrum: (M+H)* = 507 (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2 35 carboxy-ethyl)-benzimidazole-1-yl-methyl]-benzimidazole hydrochloride Yield: 76% of theory, WO 00/01704 - 62 - PCT/EP99/04531
C
27
H
27
N
7 02 x HC1 (481. 56/518. 05) mass spectrum: (M+H)* = 482 (M+2H) 2 * = 242 (M+Na)* = 504 5 (M+H+Na) 2 . = 253 (M-H+2Na)* = 526 (M+2Na) 2 . = 264 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(2-methyl 10 4-carboxy-imidazol-1-yl-methyl)-benzimidazole hydrochloride Yield: 61% of theory,
C
2 2
H
2 3
N
7 0 2 x HCl (417.47/453.92) mass spectrum: (M+H)* = 418 15 (15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[3-(3 carboxy-n-propyl)-benzimidazol-2-on-1-yl-methyl] benzimidazole-hydrochloride Yield: 86% of theory, 20 C 2
,H
2 9
N
7 0 3 x HCl (511.59/548.04) mass spectrum: (M+H)* = 512 (M+Na)* = 534 (M+H+Na) 2 . = 267.7 (M+2Na) 2 . = 278.8 25 (16) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[3-(2 carboxy-ethyl)-imidazo[4,5-b]pyridin-2-on-1-yl-methyl] benzimidazole-hydrochloride Yield: 83% of theory, 30 C 26
H
26
N
8 0 3 x HCl (498.55/535) mass spectrum: (M+H)* = 499 (M+Na)*= 521 (M-H)~ = 497 (2M-H)~= 995 35 WO 00/01704 - 63 - PCT/EP99/04531 (17) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2 carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl] benzimidazole-hydrochloride Yield: 68% of theory, 5 Rf value: 0.70 (Reversed phase RP 8; methanol/5% sodium chloride solution = 6:4)
C
25
H
2 9
N
7 0 2 x HCl (459.56/496.01) mass spectrum: (M+H)* = 460 (M+Na)* = 482 10 (M+H+Na) 2 . = 241 (18) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [phenyl-(carboxymethyloxyimino)methylene]cyclopropyl] benzimidazole-dihydrochloride 15 Yield: 70% of theory,
C
28
H
2
,N
6 0 3 x 2HC1 (496.57/569.5) mass spectrum: (M+H)* = 497 (M-H)~ = 495 20 (19) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-3-yl)-(carboxymethylidene) methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 37% of theory Rf value: 0.45 (Reversed phase RP 8; methanol/5% sodium 25 chloride solution = 6:4)
C
27
H
26 N.0 2 x HCl (466.55/503.0) mass spectrum: (M+H)* = 467 (20) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 30 [(1-methyl-pyrazol-5-yl)-(carboxymethyloxyimino) methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 30% of theory, Rf value: 0.25 (Reversed phase RP 8; (5% saline solution/methanol = 1:1) 35 C 2
,H
28 N.0 3 x HCl (500.58/537.03) WO 00/01704 - 64 - PCT/EP99/04531 mass spectrum: (M+H)* = 501 (M-H)~ = 499 (M+Cl)* = 535/537 (Cl) 5 (21) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [phenyl-(3-carboxy-n-propyloxyimino)methylene] cyclopropyl]-benzimidazole-dihydrochloride Yield: 37 % of theory, Rf value: 0.35 (Reversed phase RP 8; 5% saline 10 solution/methanol = 3:2)
C
30
H
32
N
6 0 3 x 2 HCl (524.64/597.55) mass spectrum: (M+H)* = 525 Example 5 15 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin 1-vl-carbonyl)-aminomethyll-benzimidazole-hydrochloride a. 5-(4-chlorophenyl)-imidazolidin-2,4-dione 20 15.0 g (0.11 mol) of 4-chlorobenzaldehyde, 51.3 g (0.53 mol) of ammonium carbonate and 7.6 g (0.12 mol) of potassium cyanate are stirred in 150 ml water and 150 ml methanol for 18 hours at 55 C. The solvent is distilled off, the residue dissolved in water and extracted with 25 ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. Yield: 8.6 g (38 % of theory), melting point: 2150 C 30 b. 5-(4-chloro-3-nitro-phenyl)-imidazolidin-2,4-dione Prepared analogously to Example la from 5-(4 chlorophenyl)-imidazolidin-2,4-dione and fuming nitric acid. Yield: 52 % of theory, 35 Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1) WO 00/01704 - 65 - PCT/EP99/04531 c. 4-chloro-3-nitro-phenylalanine-hydrochloride 560 mg (2.2 mmol) of 5-(4-chloro-3-nitro-phenyl) imidazolidin-2,4-dione are refluxed for 24 hours in 20 ml of semiconc. hydrochloric acid. The solvent is distilled 5 off, the residue dissolved in water, filtered to remove the insoluble matter and concentrated by evaporation. The residue is dissolved three times in ethanol, evaporated to dryness, triturated with ether, suction filtered and dried. 10 Yield: 380 mg (65 % of theory), melting point: 186 0 C d. 4-chloro-3-nitro-N-tert.butyloxycarbonyl-phenvlalanine 5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine-hydro 15 chloride are dissolved in 50 ml dioxane and 25 ml water and, after the addition of 5.5 ml (39.1 mmol) of triethylamine and 4.8 g (21.3 mmol) of di-tert.butyl dicarbonate, stirred for 18 hours at ambient temperature. Then the mixture is diluted with 0.5 M potassium hydrogen 20 sulphate solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. Yield: 6.3 g (100 % of theory), Rf value: 0.20 (silica gel; methylene chloride/methanol = 25 9:1) e. 2-(4-chloro-3-nitro-phenyl)-2 tert.butyloxvcarbonylamino-l-(pvrrolidin-1-vl)-ethanone 30 Prepared analogously to Example 1c from 4-chloro-3-nitro N-tert.butyloxycarbonyl-phenylalanine, 0-(benzotriazol-1 yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl-diisopropylamine in tetrahydrofuran. 35 Yield: 68 % of theory, melting point: 203 0
C
A WO 00/01704 - 66 - PCT/EP99/04531 f. 2-(4-methylamino-3-nitro-phenyl)-2 tert.butyloxvcarbonylamino-1- (pvrrolidin-1-vl)-ethanone 5 Prepared analogously to Example lb from 2-(4-chloro-3 nitro-phenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin 1-yl)-ethanone and methylamine solution. Yield: 76 % of theory, Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate = 10 1:1) g. 2-(4-methylamino-3-amino-phenyl)-2 tert.butyloxvcarbonylamino-1-pvrrolidin-1-vl-ethanone 15 Prepared analogously to Example id from 2-(4-methylamino 3-nitro-phenyl)-2-tert.butyloxycarbonylamino-l (pyrrolidin-1-yl)-ethanone and palladium on activated charcoal in methylene chloride/ethanol. Yield: 100 % of theory, 20 Rf value: 0.12 (silica gel; cyclohexane/ethyl acetate = 1:1) h. 2-[4-methylamino-3-(4 cyanophenylaminomethylcarbonylamino)-phenyl]-2 25 tert.butvloxvcarbonylamino-l- (pvrrolidin-l-vl)-ethanone Prepared analogously to Example 1c from 2-(4-methylamino 3-aminophenyl)-2-tert.butyloxycarbonylamino-1-(pyrrolidin 1-yl)-ethanone, 0-(benzotriazol-1-yl)-N,N,N',N' 30 tetramethyluronium tetrafluoroborate, 4-cyano phenylglycine and triethylamine in tetrahydrofuran. Yield: 100 % of theory, Rf value: 0.50 (silica gel; methylene chloride/methanol = 9:1) 35 WO 00/01704 - 67 - PCT/EP99/04531 i. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin 1-vl-carbonyl)-aminomethyll-benzimidazole Prepared analogously to Example lf from 2-[4-methylamino 5 3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2 tert.butyloxycarbonylamino-l-(pyrrolidin-1-yl)-ethanone in glacial acetic acid. Yield: 30 % of theory, Rf value: 0.19 (silica gel; methylene chloride/methanol = 10 9.5:0.5) k. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l (pyrrolidin-1-yl-carbonyl)-aminomethyl]-benzimidazole hydrochloride 15 Prepared analogously to Example lg from 2-(4 cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin-1-yl carbonyl)-aminomethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 27 % of theory, 20 C 22
H
27 N,0 x HCl (405.50/441.96) mass spectrum: (M+H)* = 406 The following compounds are obtained analogously to Example 5: 25 (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (pyrrolidin-1-yl-carbonyl)-N-acetyl-aminomethyl] benzimidazole-hydrochloride Yield: 29 % of theory, 30 C 2
,H
2 9 N,0 2 x HCl (447.54/484.54) mass spectrum: (M+H)* = 448 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (pyrrolidin-1-yl-carbonyl)-N-(2-ethoxycarbonylethyl)-N 35 methyl-aminomethyl]-benzimidazole-hydrochloride Yield: 74 % of theory,
C
2
,H
37
N
7 0 3 x HCl (519.65/556.11) WO 00/01704 - 68 - PCT/EP99/04531 mass spectrum: (M+H)* = 520 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l (pyrrolidin-1-yl-carbonyl)-N-(ethoxycarbonylmethyl) 5 aminomethyl]-benzimidazole-hydrochloride Yield: 76 % of theory,
C
2
,H
3 3 N.0 3 x HCl (491.59/528.05) mass spectrum: (M+H)* = 492 (M+2H)** = 246.7 10 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (pyrrolidin-1-yl-carbonyl)-N,N-di-(ethoxycarbonylmethyl) aminomethyl]-benzimidazole-hydrochloride Yield: 51 % of theory, 15 C 30
H
39
N
7 0 5 x HCl (577.68/614.14) mass spectrum: (M+H)* = 578 (M+Na)* = 600 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 20 (pyrrolidin-1-yl-carbonyl)-N (ethoxycarbonylmethylcarbonyl)-aminomethyl]-benzimidazole hydrochloride Yield: 29 % of theory,
C
2 7
H
33
N
7 0 4 x HCl (519.60/556.06) 25 mass spectrum: (M+H)* = 520 (M+2 H)** = 260.7 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (pyrrolidin-1-yl-carbonyl)-N-(2-ethoxycarbonylethyl) 30 aminomethyl]-benzimidazole-hydrochloride Yield: 84 % of theory,
C
2 7
H
3 5
N
7 0 3 x HCl (505.62/542.62) mass spectrum: (M+H)* = 506 (M+2H)** = 253.7 35 WO 00/01704 - 69 - PCT/EP99/04531 Example 6 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-(2-ethoxy carbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl] 5 benzimidazole-hydrochloride a. 5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidin-2,4 dione To 50 ml of fuming nitric acid are added batchwise at 10 -250 C to -354 C 10.0 g (4.45 mmol) of 5-(4-chloro-phenyl) 5-methyl-imidazolidin-2,4-dione. After 45 minutes at -25 to -20 0 C the reaction mixture is poured onto ice water. The crystalline product is suction filtered, washed with water and dried. 15 Yield: 10.5 g (100 % of theory), melting point: 173-178 C Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate = 1:1) 20 b. 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid 10.5 g (0.044 mol) of 5-(4-chloro-3-nitro-phenyl)-5 methyl-imidazolidine-2,4-dione are refluxed in 200 ml dioxane and 700 ml of 6N hydrochloric acid for 5 days. The solution is concentrated by evaporation, the residue is 25 taken up in water and extracted with ethyl acetate. The aqueous phase is concentrated by evaporation, mixed with toluene and evaporated to dryness. The residue is triturated with ether, suction filtered and dried. Yield: 6.8 g (63 % of theory), 30 R. value: 0.24 (Reversed phase RP8, 5% saline solution/methanol = 1:1) c. 2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro phenyl) -propionic acid 35 Prepared analogously to Example 5d from 2-amino-2-(4 chloro-3-nitro-phenyl)-propionic acid, di-tert.butyl WO 00/01704 - 70 - PCT/EP99/04531 pyrocarbonate and triethylamine in dioxane. Yield: 9.6 g (100 % of theory), Rf value: 0.31 (Reversed phase RP8, 5% saline solution/methanol = 1:2) 5 d. 2-(4-chloro-3-nitro-phenyl)-2 tert.butyloxycarbonylamino-1-(pvrrolidin-1-vl)-propanone Prepared analogously to Example 1c from 2 10 tert.butyloxygarbonylamino-2-(4-chloro-3-nitro-phenyl) propionic acid, 0-(benzotriazol-1-yl)-N,N,N',N' tetramethyluronium tetrafluoroborate, pyrrolidine and N methylmorpholine in dimethylformamide. Yield: 94 % of theory, 15 Rf value: 0.11 (silica gel; cyclohexane/ethyl acetate = 1:1) e. 2-(4-methylamino-3-nitro-phenyl)-2 tert.butvloxvcarbonylamino-l-(pvrrolidin-l-vl)-propanone 20 Prepared analogously to Example lb from 2-(4-chloro-3 nitro-phenyl)-2-tert.butyloxycarbonylamino-l-(pyrrolidin 1-yl)-propanone and methylamine solution in dimethylformamide at 160 0 C. 25 Rf value: 0.79 (silica gel; ethyl acetate/ethanol = 9:1) f. 2-(4-methylamino-3-amino-phenyl)-2 tert.butyloxycarbonylamino-1-pyrrolidin-l-yl-propanone 30 Prepared analogously to Example 1d from 2-(4-methylamino 3-nitro-phenyl)-2-tert.butyloxycarbonylamino-l (pyrrolidin-1-yl)-propanone and palladium on activated charcoal/hydrogen in methanol. Yield: 100 % of theory, 35 Rf value: 0.63 (silica gel; ethyl acetate/ethanol = 9:1) WO 00/01704 - 71 - PCT/EP99/04531 q. 2-[4-methylamino-3-(4-cyanophenylaminomethyl carbonylamino)-phenyll-2-tert.butyloxycarbonylamino-1 (pyrrolidin-l-vl)-propanone 5 Prepared analogously to Example ic from 2-(4-methylamino 3-amino-phenyl)-2-tert.butyloxycarbonylamino-1 (pyrrolidin-1-yl)-propanone, 0-(benzotriazol-1-yl) N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano phenylglycine and N-methylmorpholine in dimethylformamide. 10 Yield: 37 % of theory, Rf value: 0.47 (silica gel; ethyl acetate) h. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1 (N-tert.butyloxycarbonylamino)-1-(pyrrolidin-1-yl 15 carbonyl)-ethyll-benzimidazole Prepared analogously to Example if from 2-[4-methylamino 3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2 tert.butyloxycarbonylamino-1-(pyrrolidin-1-yl)-propanone 20 and glacial acetic acid. Yield: 60 % of theory, Rf value: 0.37 (silica gel; ethyl acetate) i. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-i 25 (pyrrolidin-1-vl-carbonyl)-ethyll-benzimidazole 1.3 g (2.3 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl 5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidin-1-yl carbonyl)-ethyl]-benzimidazole are dissolved in 20 ml 30 dioxane and, after the addition of 40 ml of semiconc. hydrochloric acid, stirred for two hours at ambient temperature. The solution is mixed with ice, made alkaline with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by 35 evaporation. Yield: 0.9 g (98 % of theory), Rf value: 0.14 (silica gel; ethyl acetate/ethanol = 9:1) WO 00/01704 - 72 - PCT/EP99/04531 k. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-[N-(2 ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl) ethyl]-benzimidazole 5 0.4 g (1.04 mmol) of 2-(4-cyanophenylaminomethyl)-1 methyl-5-[1-amino-i-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole are dissolved in 10 ml ethanol and after the addition of 0.3 ml (2.7 mmol) of ethyl acrylate stirred 10 for 24 hours 4t 95 0 C. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride/ethanol (20:1 and 4:1). Yield: 0.16 g (31 % of theory), Rf value: 0.26 (silica gel; ethyl acetate/ethanol = 9:1) 15 1. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N-(2 ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl) ethyll-benzimidazole-hydrochloride 20 Prepared analogously to Example ig from 2-(4 cyanophenylaminomethyl)-1-methyl-5-[1-[N-(2 ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl) ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. 25 Yield: 96 % of theory,
C
2 8
H
3 7
N
7 0 3 x HCl (519.65/556.11) mass spectrum: (M+H)* = 520 (M+Na)* = 542 30 The following compounds are obtained analogously to Example 6: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3 ethoxycarbonylpropionylamino)-1-ethoxycarbonyl-ethyl] 35 benzimidazole-hydrochloride Yield: 69 % of theory,
C
21
H
3 ,NO x HCl (522.62/555.08) WO 00/01704 - 73 - PCT/EP99/04531 mass spectrum: (M+H)* = 523 (M+H+Na)** = 273 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 5 (ethoxycarbonylmethylcarbonylamino)-1-(pyrrolidin-1-yl carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 95 % of theory,
C
2
,H
35
N
7 0 4 x HCl (533.64/570.10) mass spectrum: (M+H)* = 534 10 (M+Na)* = 556 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3 ethoxycarbonylpropionylamino)-1-(pyrrolidin-1-yl carbonyl)-ethyl]-benzimidazole-hydrochloride 15 Yield: 20 % of theory,
C
2 9
H
37
N
7 0 4 x HCl (547.66/584.12) mass spectrum: (M+H)* = 548 (M+H+Na)** = 285.7 20 (4) 2-[4-amidinophenyl-N-(2-ethoxycarbonylethyl) aminomethyl]-1-methyl-5-[1-dimethylamino-1-(pyrrolidin-l yl-carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 91 % of theory,
C
30
H
4
IN
7 0 3 x HCl (547.71/584.17) 25 mass spectrum: (M+H)* = 548 (M-H) = 546 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 ethoxycarbonylethylamino)-1-(dimethylaminocarbonyl) 30 ethyl]-benzimidazole-hydrochloride Yield: 40 % of theory, Rf value: 0.60 (Reversed phase RP 8; 5% saline solution/methanol = 1/1)
C
2
,H
3
N
7 0 3 x HCl (493.63/530.08) 35 mass spectrum: (M+H)* = 494 (M-H+2HCl)~ = 564/566/568 (Cl 2
)
WO 00/01704 - 74 - PCT/EP99/04531 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidin-1-yl-carbonyl) ethyl]-benzimidazole-hydrochloride Yield: 77 % of theory, 5 Rf value: 0.40 (silica gel; methylene chloride/methanol = 4:1 + 1 % glacial acetic acid)
C
27
H
35
N
7 0 3 x HC1 (505.63/542.08) mass spectrum: (M+H)* = 506 10 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 ethoxycarbonylethyl-amino)-1-(N-ethyl-N methylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 85 % of theory, RF value: 0.44 (silica gel; methylene chloride/ethanol = 15 9:1)
C
2
,H
3 ,N,0 3 x HCl (507.64/544.14) mass spectrum: (M+H)* = 508 (M+Cl)~ = 542/4 (Cl) 20 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (methoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole-hydrochloride Yield: 99 % of theory, Rf value: 0.21 (silica gel; methylene chloride/methanol = 25 4:1 + 1 % glacial acetic acid)
C
2
,H
33
N
7 0 3 x HCl (491.60/528.05) mass spectrum: (M+H)* = 492 (M-H+HCl)~ = 526/8 (Cl) (M-H+2HCl)~ = 562/4/8 (Cl 2 ) 30 (9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N,N bis(ethoxycarbonylmethyl)amino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole-hydrochloride Yield: 65 % of theory, 35 Rf value: 0.35 (silica gel; methylene chloride/methanol = 4:1 + 1 % glacial acetic acid)
C
3
,H
41 N,0 5 x HCl (591.72/628.17) WO 00/01704 - 75 - PCT/EP99/04531 mass spectrum: (M+H)* = 592 (M-H+HCl)~ = 626/8 (Cl) (M-H+2HCl)~ = 662/4/6 (Cl 2 ) 5 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(isoxazolidin-1-yl carbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 9% of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/5% saline 10 solution = 3:2)
C
2 6
H
3 3
N
7 0 4 x HCl (507.60/544.05) mass spectrum: (M+H)* = 508 (11) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2 15 ethoxycarbonyl-ethylamino)-1-(isoxazolidin-1-yl-carbonyl) ethyl]-benzimidazole-hydrochloride (12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(N-methyl-N 20 ethylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 58% of theory, Rf value: 0.70 (Reversed phase RP 8; methanol/5% saline solution = 3:2)
C
26
H
35
N
7 0 3 x 2 HCl (493.62/566.52) 25 mass spectrum: (M+H)* = 494 (M+HCl-H)~ = 528/30 (Cl) (13) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-((N,N di-(ethoxycarbonylmethyl)-amino)-1-(N-methyl-N 30 ethylaminocarbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 30% of theory, R. value: 0.40 (Reversed phase RP 8; methanol/5% saline solution = 3:2)
C
30
H
4 ,N,0 5 x 2 HCl (579.71/652.62) 35 mass spectrum: (M+H)* = 580 (M-H)- = 578 WO 00/01704 - 76 - PCT/EP99/04531 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(piperidinocarbonyl)-ethyl] benzimidazole-dihydrochloride 5 Yield: 82% of theory, Rf value: 0.60 (Reversed phase RP 8; methanol/5% saline solution = 3:2)
C
28
H
37
N
7 0 3 x 2 HCl (519.65/592.75) mass spectrum: (M+H)* = 520 10 (M-H+HCl) = 534/6 (Cl) (M-H+2HCl) = 590/2/4 (C12) (15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(diethylaminocarbonyl) 15 ethyl]-benzimidazole-dihydrochloride Yield: 88% of theory, Rf value: 0.60 (Reversed phase RP 8; methanol/5% saline solution = 3:2)
C
2 7
H
3 7
N
7 0 3 x 2 HCl (507.64/580.56) 20 Mass spectrum: (M+H)* = 508 (M-H+2HCl)~ = 578/580/582 (Cl 2 ) (16) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethyl-methylamino)-1-(pyrrolidin-1-yl 25 carbonyl)-ethyl]-benzimidazole-dihydrochloride Yield: 46 % of theory, R, value: 0.43 (silica gel; methylene chloride/methanol = 4:1 + 1% glacial acetic acid)
C
2
,H
37
N
7 0 3 x 2 HCl (519.65/592.56) 30 mass spectrum: (M+H)* = 520 (M+Cl)~ = 554/6 (Cl) (17) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (tetrazol-5-yl-methylamino)-1-(pyrrolidin-1-yl-carbonyl) 35 ethyl]-benzimidazole-dihydrochloride WO 00/01704 - 77 - PCT/EP99/04531 (18) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3 ethoxycarbonyl-propylamino)-1-(pyrrolidin-1-yl-carbonyl) ethyl]-benzimidazole-dihydrochloride Yield: 95 % of theory, 5 R. value: 0.50 (Reversed phase RP 8; methanol/5% saline solution = 1:1)
C
29
H
39
N
7 0 3 x 2 HCl (533.68/606.58) mass spectrum: (M+H)* = 534 10 Example 7 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N cyclopentyl-N-(3-ethoxycarbonylpropionyl) 15 aminolcyclopropyll-benzimidazole-hydrochloride a. 4-((l-tert.butyloxycarbonylamino)cyclopropyl)-2-nitro N-methyl-aniline 20 15.0 g (63.5 mmol) of 4-((l-carboxy)cyclopropyl)-2-nitro N-methyl-aniline and 17.6 ml (127 mmol) of triethylamine are dissolved in 250 ml of dichloromethane and 8.3 g (76 mmol) of ethyl chloroformate are added at 0 0 C. After one hour at ambient temperature 0.75 g tetrabutylammonium 25 bromide are added. Then a solution of 6.3 g (96 mmol) of sodium azide in 20 ml water is added dropwise. After one hour at 0*C the solution is diluted with water and extracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The residue is 30 dissolved in 200 ml tert.butanol and refluxed for two hours. The solvent is concentrated by evaporation, the residue chromatographed on silica gel and eluted with methylene chloride. Yield: 15.5 g (77 % of theory), 35 Rf value: 0.83 (silica gel; methylene chloride/methanol = 9.5:0.5) WO 00/01704 - 78 - PCT/EP99/04531 b. 4-((1-amino)cyclopropyl)-2-nitro-N-methyl-aniline hydrochloride 15.5 g (0.05 mol) of 4-[(1-tert.butyloxycarbonylamino) 5 cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 50 ml ethanol and 50 ml ethanolic hydrochloric acid and stirred for 7 hours at ambient temperature. The solvent is distilled off, the residue triturated with ether, suction filtered and dried. 10 Yield: 98 % of theory, Rf value: 0.44 (silica gel; methylene chloride/methanol = 9.5:0.5) c. 4-[N-(1-cyclopentylamino)cyclopropyl]-2-nitro-N-methyl 15 aniline 12.0 g (0.05 mol) of 4-[(1-amino)cyclopropyl]-2-nitro-N methyl-aniline-hydrochloride are dissolved in 500 ml of tetrahydrofuran and after the addition of 4.1 g (0.05 mol) 20 of cyclopentanone and 3.2 ml of glacial acetic acid, 13.6 g (0.064 mol) of sodium triacetoxyborohydride are added batchwise under a nitrogen atmosphere. After 16 hours at ambient temperature, the mixture is diluted with sodium hydrogen carbonate solution and extracted with ethyl 25 acetate. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with ethyl acetate/cyclohexane (1:1). Yield: 10.8 g (80 % of theory) R, value: 0.56 (silica gel; methylene chloride/methanol = 30 9.5:0.5) d. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl amino)cvclopropvll-2-nitro-N-methyl-aniline 35 1.0 g (3.6 mmol) of 4-[(1-cyclopentylamino)cyclopropyl]-2 nitro-N-methyl-aniline are dissolved in 30 ml tetrahydrofuran and after the addition of 0.45 g (4.4 WO 00/01704 - 79 - PCT/EP99/04531 mmol) of triethylamine, 0.65 g (4.4 mmol) of ethyl succinate chloride are added and the resulting mixture is stirred for four hours at ambient temperature. Then it is diluted with ethyl acetate and sodium hydrogen carbonate 5 solution, the organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/cyclohexane (1:1). Yield: 1.3 g (90 % of theory), Rf value: 0.46 (silica gel; ethyl acetate/cyclohexane = 10 1:1) e. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl amino)cyclopropyll-2-amino-N-methyl-aniline 15 Prepared analogously to Example id 4-[l-(N-(3 ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl] 2-nitro-N-methyl-aniline and palladium on activated charcoal/hydrogen in methylene chloride/ethanol. Yield: 100 % of theory, 20 Rf value: 0.18 (silica gel; ethyl acetate/cyclohexane = 1:1) f. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl amino)cyclopropyl]-2-(4-cyanophenyl) 25 aminomethvlcarbonylamino-N-methyl-aniline Prepared analogously to Example 1c 4-[l-(N-(3 ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl] 2-amino-N-methyl-aniline, 0-(benzotriazol-1-yl)-N,N,N',N' 30 tetramethyluronium tetrafluoroborate, 4-cyano phenylglycine and triethylamine in dimethylformamide. Yield: 96 % of theory, Rf value: 0.54 (silica gel; methylene chloride/methanol = 9.5:0.5) 35 WO 00/01704 - 80 - PCT/EP99/04531 g. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[N cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino] cyclopropyll-benzimidazole 5 Prepared analogously to Example if from 4-[l-(N-(3 ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl] 2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl aniline in glacial acetic acid. Yield: 52 % of theory, 10 Rf value: 0.8, (silica gel; methylene chloride/methanol = 9:1) h. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[N cyclopentyl-N-(3-ethoxycarbonylpropionyl) 15 aminolcyclopropyll-benzimidazole-hydrochloride Prepared analogously to Example lg from 2-(4 cyanophenylaminomethyl)-1-methyl-5-[1-[N-cyclopentyl-N-(3 ethoxycarbonylpropionyl)-amino]cyclopropyl]-benzimidazole 20 and hydrochloric acid/ammonium carbonate in ethanol. Yield: 36 % of theory,
C
30
H
38 N,0 3 x HCl (530.68/567.14) mass spectrum: (M+H)* = 531 25 Example 8 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3 ethoxycarbonylmethyl-imidazolin-2,4-dion 5-vl)benzimidazole-hydrochloride 30 a. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylaminocarbonylamino)-1-(pyrrolidin-1 vl-carbonyl)-ethyll-benzimidazole 35 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl 5-[1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole are dissolved in 10 ml dimethylformamide and WO 00/01704 - 81 - PCT/EP99/04531 after the addition of 0.9 ml (7.9 mmol) of ethyl isocyanatoacetate stirred for 45 minutes at ambient temperature. The solution is poured onto ice water, the crystalline product is suction filtered and dried. The 5 residue is chromatographed on silica gel, eluting with methylene chloride/ethanol/ammonia (20:1:0.01 and 10:1:0.01). Rf value: 0.77 (silica gel; methylene chloride/ethanol/ammonia = 9:1:0.01) 10 b. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(5-methyl-3 ethoxycarbonylmethyl-imidazolin-2,4-dion-5-yl) benzimidazole-hydrochloride 15 Prepared analogously to Example 1g from 2-(4 cyanophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylaminocarbonylamino)-1-(pyrrolidin-1 yl-carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. 20 Yield: 68 k of theory,
C
24
H
27
N
7 0 4 x HCl (477.52/513.99) mass spectrum: (M+H)* = 478 Example 9 25 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl) N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole hydrochloride 30 a. 4-(2-tert.butyloxycarbonylethyl)-2 (pyridylaminomethyl)-2-nitro-chlorobenzene 13.4 g (0.053 mol) of 4-chloro-3-nitro-benzylbromide and 11.8 g (0.053 mol) of 2-tert.butyloxycarbonylethylamino 35 pyridine are stirred in 80 ml of N-ethyl-diisopropylamine for 3 hours at 9 0 C. The solution is concentrated by WO 00/01704 - 82 - PCT/EP99/04531 evaporation, the residue chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (8:2 and 7:3). Yield: 8.2 g (40 % of theory), Rf value: 0.64 (silica gel; petroleum ether/ethyl acetate 5 = 8:2) b. 4-(2-tert.butyloxycarbonylethyl)-2 (pyridylaminomethyl)-2-nitro-N-methyl-aniline 10 Prepared analogously to Example lb from 4-(2 tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2 nitro-chlorobenzene and methylamine solution. Yield: 20 % of theory, Rf value: 0.65 (silica gel; methylene chloride/ethanol = 15 9:1) c. 4-(2-tert.butyloxycarbonylethyl)-2 (pvridylaminomethyl)-2-amino-N-methyl-aniline 20 1.6 g (4 mmol) of 4-(2-tert.butyloxycarbonylethyl)-2 (pyridylaminomethyl)-2-nitro-N-methyl-aniline are dissolved in 200 ml methanol and, after the addition of 2 g of Raney nickel, combined with 1 ml of hydrazine hydrate. The solution is stirred for 30 minutes at ambient 25 temperature and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (95:5). Yield: 1.2 g (82 % of theory), R, value: 0.33 (silica gel; methylene chloride/ethanol = 30 9:1) d. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl) N-(2-ethoxvcarbonylethyl)-aminomethyll-benzimidazole 35 Prepared analogously to Example 1c from 4-(2 tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2 amino-N-methyl-aniline, 0-(benzotriazol-1-yl)-N,N,N',N'- WO 00/01704 - 83 - PCT/EP99/04531 tetramethyluronium tetrafluoroborate, 4-cyano phenylglycine in tetrahydrofuran and glacial acetic acid. Yield: 72 % of theory, R, value: 0.36 (silica gel; methylene chloride/ethanol = 5 9:1) e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(2 pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl] benzimidazole-hydrochloride 10 Prepared analogously to Example ig from 4-[(5-(2 tert.butyloxycarbonylethyl)-2-pyridylaminomethyl-1-methyl benzimidazole-2-yl)-methylamino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol. 15 Yield: 59 % of theory,
C
27
H
31 N,0 2 x HCl (485.59/522.1) mass spectrum: (M+H)* = 486 The following compounds are obtained analogously to 20 Example 9: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5 [N-(ethoxycarbonylmethyl)-benzenesulphonylaminomethyl] benzimidazole-hydrochloride 25 Yield: 53 % of theory,
C
27
H
30
N
6 0 4 S x HCl (534.64/571.1) mass spectrum: (M+H)* = 535 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-(N-methyl 30 phenylcarbonylaminomethyl)]-benzimidazole-hydrochloride Yield: 42 % of theory,
C
2 sH 26
N
6 0 x HCl (426.53/462.96) mass spectrum: (M+H)* = 427 35 WO 00/01704 - 84 - PCT/EP99/04531 Example 10 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-methyl benzimidazol-1-vl)methyll-benzimidazole-hydrochloride 5 a. 1-(4-chloro-3-nitrobenzvl)-2-methyl-benzimidazole Prepared analogously to Example 9a from 2-methyl benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulphoxide. 10 Yield: 78% of,theory,
C
15
H
12 ClN 3 0 2 (3d1.7) mass spectrum: M* = 301/303 b. 1-(4-methylamino-3-nitrobenzvl)-2-methyl-benzimidazole 15 Prepared analogously to Example lb from 1-(4-chloro-3 nitrobenzyl)-2-methyl-benzimidazole and methylamine. Yield: 96% of theory, Rf value: 0.56 (silica gel; methylene chloride/ethanol = 19:1) 20 c. 1-(4-methylamino-3-aminobenzvl)-2-methyl-benzimidazole Prepared analogously to Example 1c from 1-(4-methylamino 3-nitrobenzyl)-2-methyl-benzimidazole and hydrogen/Raney nickel. 25 Yield: 100% of theory, Rf value: 0.34 (silica gel; methylene chloride/ethanol = 19:1) d. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[(2-methyl 30 benzimidazol-l-vl)methyll-benzimidazole A mixture of 1.94 g (11.0 mmol) of N-(4-cyanophenyl) glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole is refluxed in 80 ml of absolute tetrahydrofuran for 15 35 minutes. After the addition of 2.7 g (10.46 mmol) of 1-(4 methylamino-3-aminobenzyl)-2-methyl-benzimidazole the mixture is refluxed for a further 16 hours. Then the WO 00/01704 - 85 - PCT/EP99/04531 solution is evaporated to dryness, the residue is mixed with 80 ml glacial acetic acid and refluxed for 1 hour. It is then evaporated to dryness once more, the residue thus obtained is mixed with 50 ml of water and made alkaline 5 with conc. ammonia (about pH 10). The product which crystallises out is suction filtered, washed with a little water and dried. Yield: 4.1 g (96% of theory), Rf value: 0.30 (silica gel; methylene chloride/ethanol = 10 19:1)
C
25
H
22
N
6 (406.5) mass spectrum: M* = 406 e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-methyl 15 benzimidazol-l-vl)methyll-benzimidazole-hydrochloride Prepared analogously to Example ig from 2-(4 cyanophenylaminomethyl)-1-methyl-5-[(2-methyl benzimidazol-1-yl)methyl]-benzimidazole hydrochloric 20 acid/ammonium carbonate. Yield: 59% of theory,
C
2
,H
2
,N
7 x HCl (423.5/459.9) mass spectrum: (M+H)* = 424 (M+2H) 2 . = 217.7 25 The following compounds are obtained analogously to Example 10: (1) 2-(4-amidinophenyloxymethyl)-1-methyl-5-[(imidazol-l 30 yl)-methyl]-benzimidazole-hydrochloride Yield: 30% of theory,
C
20
H
2 0
N
6 0 x HCl (360.4/396.9) mass spectrum: (M+H)* = 361 (M+2H) 2 . = 181 35 (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (imidazol-1-yl)-ethyl]-benzimidazole-hydrochloride WO 00/01704 - 86 - PCT/EP99/04531 Yield: 70% of theory,
C
2
,H
23 N x HCl (373.46/410) mass spectrum: (M+H)* = 374 (M+2H) 2 . = 187.6 5 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2-ethyl 4-methyl-imidazol-1-yl)-ethyl]-benzimidazole dihydrochloride Yield: 18% of theory, 10 C 24
H
29
N
7 x 2HC1(415.55/488.46) mass spectrum: (M+H)* = 416 (M+2H) 2 . = 208.7 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-ethyl-4 15 methyl-imidazol-1-yl)-methyl]-benzimidazole dihydrochloride Yield: 36% of theory,
C
23
H
27
N
7 x 2HCl (401.52/437.97) mass spectrum: (M+H)* = 402 20 (M+2H) 2 * = 201.7 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[N-(pyridin 2-yl)-N-methyl-aminomethyl]-benzimidazole-dihydrochloride Yield: 78% of theory, 25 C 23
H
25
N
7 x 2HCl (399.5/435.95) mass spectrum: (M+H)* = 400 (M+2H) 2 . = 200.6 (6) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-(2 30 ethoxycarbonyl-ethyl)-benzimidazol-1-yl)-methyl] benzimidazole-dihydrochloride Yield: 61% of theory,
C
29
H
3
N
7 02x HCl (509.62/546.07) mass spectrum: (M+H)* = 510 35 (M+2H) 2 . = 255.7 (M+H+Na) 2 . = 266.7 WO 00/01704 - 87 - PCT/EP99/04531 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(imidazol 1-yl)-methyl]-benzimidazole-hydrochloride Yield: 35% of theory,
C
20
H
21
N
7 x HCl (359.44/395.89) 5 mass spectrum: (M+H)* = 360 (M+2H) 2 . = 180.6 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2 acetylamino-ethyl)-4,5-dimethyl-imidazol-1-yl)-methyll 10 benzimidazole-dihydrochloride Yield: 42% of theory,
C
2
,H
3 2 NO x 2HCl (472.6/545.51) mass spectrum: (M+H)* = 473 (M+2H) 2 * = 237 15 (M+H+Na) 2 . = 248 (9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2 aminocarbonyl-ethyl)-4,5-dimethyl-imidazol-1-yl)-methyl] benzimidazole-dihydrochloride 20 Yield: 68% of theory,
C
2 sH 3 ,NO x 2HCl (458.6/531.51) mass spectrum: (M+H)* = 459 (M+2H) 2 . = 230 25 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-methyl 4-ethoxycarbonyl-imidazol-1-yl)-methyl]-benzimidazole hydrochloride Yield: 34% of theory,
C
2
,H
27 N,0 2 x HCl (445.53/481.98) 30 mass spectrum: (M+H)* = 446 (M+2H) 2 . = 223.5 (M+H+Na) 2 . = 234.5 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(3-(3 35 ethoxycarbonyl-n-propyl)-benzimidazol-2-on-1-yl)-methyl] benzimidazole-hydrochloride Yield: 58% of theory, WO 00/01704 - 88 - PCT/EP99/04531
C
3 0
H
33
N
7 0 3 x HC1 (539.64/576.09) mass spectrum: (M+H)* = 540 (M+H+Na) 2 * = 281.7 5 (12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(3-(2 ethoxycarbonyl-ethyl)-imidazo[4,5-b]pyridin-2-on-1-yl) methyl]-benzimidazole-hydrochloride Yield: 29% of theory,
C
2
,H
3 ,N0 3 x HCl (526.6/563.05) 10 mass spectrum; (M+H)* = 527 (M+2H ) 2 . = 264 (M+H+Na) 2 . = 275 (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-phenyl 15 imidazol-1-yl)-methyl]-benzimidazole-hydrochloride Yield: 58% of theory,
C
26
H
2 N, x HCl (435.54/472) mass spectrum: (M+H)* = 436 (M+Na)* = 218.6 20 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(4,5 dimethyl-2-(2-ethoxycarbonylethyl)-imidazol-1-yl)-methyl] benzimidazole-dihydrochloride Yield: 52% of theory, 25 C 2 7
H
33 N,0 2 x 2HCl (487.61/560.52) mass spectrum: (M+H)* = 488 (M+2H) 2 . = 244.6 Example 11 30 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 ethoxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl carbonyl)-ethyl]-benzimidazole-hydrochloride 35 a. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(2 tert.butyloxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl- WO 00/01704 - 89 - PCT/EP99/04531 carbonyl)-ethyll-benzimidazole 0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-1 methyl-5-[1-amino-i-(pyrrolidin-1-yl-carbonyl)-ethyl] 5 benzimidazole and 1.65 g ((5.5 mmol) of tert.butyl 2,4 dibromobutyrate are dissolved in 5 ml of ethanol, mixed with 0.2 g (1.86 mmol) of sodium carbonate and stirred under nitrogen for 30 hours at 550C. After cooling, the white precipitate is filtered off and washed with ethanol. 10 The filtrate is concentrated by evaporation, the residue is chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate/ethanol/ammonia (20:1:0.01). The desired fractions are combined and concentrated by evaporation. 15 Yield: 0.44 g (44% of theory) as a mixture of diastereomers,
C
3
,H
3
,N
6 0 3 (542.69) mass spectrum: (M+H)* = 543 20 b. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2 ethoxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl carbonyl)-ethyl]-benzimidazole-hydrochloride (mixture of diastereomers) Prepared analogously to Example ig from 2-(4 25 cyanophenylaminomethyl)-1-methyl-5-[1-(2 tert.butyloxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-yl carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 12 % of theory, 30 C 2 9
H
3
,N
7 0 3 x HCl (531.66/568.12) mass spectrum: (M+H)* = 532 (M+H+HCl) 2 . = 568/70 (Cl) WO 00/01704 - 90 - PCT/EP99/04531 Example 12 (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-3-yl)-ethoxycarbonylmethylidene) 5 methylenecycloporopyll-benzimidazole-hydrochloride a. (E/Z)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1 [(pyridin-3-yl)-ethoxycarbonylmethylidene) methylene]cyclopropyll-benzimidazole 10 897 mg (4.0 mmol) of triethyl phosphonoacetate are dissolved in 30 ml tetrahydrofuran under argon. At -15 0 C 449 mg (4.0 mmol) of potassium tert. butoxide are added. After 30 minutes 815 mg (2.0 mmol) of 2-(4 15 cyanophenylaminomethyl)-1-methyl-5-[1-(pyridin-3-yl carbonyl)cyclopropyl]-benzimidazole are added batchwise and the mixture is stirred overnight at ambient temperature. Then the solution is refluxed for a further 6 hours and concentrated by evaporation. The residue is 20 mixed with sodium chloride solution and extracted 3x with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in dichloromethane and chromatographed on silica gel, eluting with 25 dichloromethane containing 5% ethanol. The desired fractions are concentrated by evaporation, the residue is triturated with ether, suction filtered and dried. Yield: 365 mg (38% of theory). 30 b. ((E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[l [(pyridin-3-yl)-ethoxycarbonylmethylidene) methylenecyclopropyll-benzimidazole-hydrochloride Prepared analogously to Example 1g from (E/Z)-2-(4 35 cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3-yl) ethoxycarbonylmethylidene)-methylene]cyclopropyl]- WO 00/01704 - 91 - PCT/EP99/04531 benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 58 % of theory,
C
29 H3 0
N
6 0 2 x HCl (494.60/531.05) 5 mass spectrum: (M+H)* = 495 The following compound is obtained analogously to Example 12: 10 (1) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-2-yl)-ethoxycarbonylmethylidene)-methylene] cyclopropyl]-benzimidazole-hydrochloride Yield: 72 % of theory,
C
29
H
30
N
6 0 2 x HCl (494.60/531.05) 15 mass spectrum: (M+H)* =495 Example 13 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-(2-carboxy 20 azetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole-hydrochloride (mixture of diastereomers) 200 mg (0.35 mmol) of 2-(4-amidinophenylaminomethyl)-1 methyl-5-[1-(2-ethoxycarbonyl-azetidin-1-yl)-1 25 (pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole hydrochloride are dissolved in 30 ml of 6N hydrochloric acid and stirred for 13 hours at ambient temperature. The reaction mixture is concentrated by evaporation with the addition of toluene, the residue is triturated with 30 acetone/ether, suction filtered, washed with ether and dried. Yield: 200 mg (>100 % of theory, contains ammonium chloride),
C
2 7
H
33
N
7 0 3 x HC1 (503.62/540.07) 35 mass spectrum: (M+H)* = 504 WO 00/01704 - 92 - PCT/EP99/04531 The following compounds are obtained analogously to Example 13: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 5 carboxyethylamino)-1-(dimethylaminocarbonyl)-ethyl] benzimidazole-hydrochloride Yield: 91% of theory, Rf value: 0.75 (Reversed phase; 5% saline solution/methanol = 1:1) 10 C 2
,H
3 1 N,0 3 x HCl, (465.56/502.01) mass spectrum: (M+H)* = 466 (M-H+2HC1) = 537/539 C12) (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy 15 methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole-dihydrochloride Yield: 70 % of theory, RF value: 0.51 (Reversed phase; 5% saline solution/methanol = 3:2) 20 C 2 sH 31
N
7 0 3 x 2 HCl (477.57/550.48) mass spectrum: (M+H)* = 478 (3) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 [(pyridin-2-yl)-carboxymethylidene)-methylene] 25 cyclopropyl]-benzimidazole-hydrochloride Yield: 65 % of theory,
C
27
H
26
N
6 0 2 x HCl (466.55/503.0) mass spectrum: (M+H)* = 467 (M+Cl)* = 501/503 (Cl) 30 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N methyl-carboxymethylcarbonylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole dihydrochloride 35 Yield: 99 % of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5% saline solution = 1:1) WO 00/01704 - 93 - PCT/EP99/04531
C
2
,H
35 N,0 4 x 2 HCl (533.64/606.64) mass spectrum: (M+H)* = 534 (M-H)- = 532 (M-H+HCl)~ = 568/70 (Cl) 5 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 carboxyethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl) ethyl]-benzimidazole-dihydrochloride Yield: 75 % of theory, 10 Rf value: 0.54 (Reversed phase RP 8; methanol/5% saline solution = 1:1)
C
2 sH 33
N
7 0 3 x 2 HCl (479.59/552.59) mass spectrum: (M+H)* = 480 15 Example 14 2-[4-(N-hexyloxycarbonylamidino)-phenylaminomethyl]-1 methyl-5-[1-(2-ethoxycarbonylethylamino)-1 (dimethylaminocarbonyl)-ethyll-benzimidazole 20 1.5 g (2.8 mmol) of 2-(4-amidinophenylaminomethyl)-1 methyl-5-[1-(2-ethoxycarbonylethylamino)-1 (dimethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride are dissolved in 14 ml water and 55 ml tetrahydrofuran, 25 mixed with 2.0 g potassium carbonate and 1.0 ml (6 mmol) of hexyl chloroformate and stirred for 4 hours at ambient temperature. After removal of the solvent in vacuo the residue is mixed with saline solution and extracted 3 x with methylene chloride. The combined organic phases are 30 washed with a little water, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with methylene chloride plus 2 to 7.5% ethanol. The uniform fractions are combined, concentrated by evaporation, dissolved in a 35 little ethyl acetate and mixed with petroleum ether. The solid form is suction filtered, washed with petroleum ether and dried.
WO 00/01704 - 94 - PCT/EP99/04531 Yield: 0.8 g (43 % of theory),
C
33
H
47
N
7 0 5 (621.79) Rf value: 0.50 (silica gel; methylene chloride/ethanol = 19:1) 5 mass spectrum: (M+H)* = 622 (M+Na)* = 644 Example 15 10 2-(4-amidinopenylaminomethyl)-1-methyl-5-[1-(N ethoxycarbonylmethylcarbonyl-methylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 15 a. Methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl propionate 35 ml of a 1.6 molar solution of n-butyllithium in hexane (61 mmol) are added dropwise to a solution of 8.1 ml of 20 diisopropylamine (85 mmol) in 20 ml tetrahydrofuran at -78*C. Then a solution of 10.0 g (50 mmol) of methyl 2-(4 chloro-phenyl)-propionate in 30 ml tetrahydrofuran is added dropwise at -780C. Formaldehyde gas is then piped into the reaction mixture at -20*C for 30 minutes. After 25 the addition of 5% citric acid and glacial acetic acid the mixture is extracted with ethyl acetate. The organic phases are washed with 1N sulphuric acid, water, saturated sodium bicarbonate solution and saline solution and dried over magnesium sulphate. The crude product is purified on 30 silica gel, eluting with cyclohexane/ethyl acetate (19:1; 9:1; 4:1; 1:1 and 0:1). The uniform fractions are combined and concentrated by evaporation. Yield: 9.7 g (84% of theory) yellow oil, R, value: 0.25 (silica gel; petroleum ether/ethyl acetate 35 4:1) WO 00/01704 - 95 - PCT/EP99/04531 b. 2- (4-chloro-phenyl) -3-hydroxy-2-methyl-propionic acid Prepared analogously to Example 4 from methyl 2-(4-chloro phenyl) -3-hydroxy-2-methyl-propionate and sodium hydroxide solution in ethanol. 5 Yield: 83% of theory, RF value: 0.55 (silica gel; ethyl acetate/cyclohexane 2:1 + glacial acetic acid) c. 2- (4-chloro-3-nitro-phenyl) -2-methyl-3-nitroxy 10 propionic acid Prepared analogously to Example la from 2-(4-chloro phenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid. Yield: 90% of theory, melting point: 129-1324C 15 C 1
OH
9 ClN 2 0, (304.64) d. 2- (4-chloro-3-nitro-phenyl) -2-methyl-3-hydroxy propionic acid Prepared analogously to Example 6 from 2-(4-chloro-3 20 nitro-phenyl)-3-nitrooxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxane. Yield: 98% of theory, CIOHOClNO 5 (259.65) mass spectrum: (M-H) = 258/60 (Cl) 25 (2M-H) = 517/9 (C12) e. 2- [4- (N-benzyl-methylamino) -3-nitro-phenyl] -2-methyl-3 hydroxy-propionic acid 30 Prepared analogously to Example lb from 2-(4-chloro-3 nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and N methyl-benzylamine. Yield: 81% of theory,
C
18
H
20 ClN 2 0, (344.37) 35 mass spectrum: M* = 344 WO 00/01704 - 96 - PCT/EP99/04531 f. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3 hydroxy-1-pyrrolidin-1-vl-propan-1-one Prepared analogously to Example 1c from 2-[4-(N-benzyl 5 methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine. Yield: 96% of theory,
C
22
H
27
N
3 0 4 (397.48) mass spectrum: M* = 398 10 (M+Na)* = 420 g. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3 methanesulphonyloxv-1-pyrrolidin-1-vl-propan-l-one 15 A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1 pyrrolidin-1-yl-propan-1-one in 20 ml tetrahydrofuran is mixed at ambient temperature with 1.3 ml (9.3 mmol) of triethylamine. Then 0.27 ml (3.5 mmol) of methanesulphonyl 20 chloride are added dropwise at 2-5 0 C. After 2 hours at ambient temperature the precipitate formed is suction filtered and the filtrate is concentrated by evaporation. The crude product is further reacted without being purified. 25 Yield: 1.4 g (98% of theory) h. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3 methylamino-i-pyrrolidin-1-yl-prop~an-1-one 30 A solution of 1.4 g (2.9 mmol) of 2-[4-(N-benzyl methylamino)-3-nitro-phenyl)-2-methyl-3 methanesulphonyloxy-1-pyrrolidin-1-yl-propan-l-one in 10 ml dimethylformamide is combined with 20 ml of a 40% aqueous methylamine solution and heated to 100 0 C for 70 35 minutes. After cooling the reaction mixture is combined with ice water and extracted with ethyl acetate. The organic phases are washed with water and with saline WO 00/01704 - 97 - PCT/EP99/04531 solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with ethyl acetate/ethanol (10:1, 9:1, 4:1 + 1% conc. ammonia). The uniform fractions are combined and 5 concentrated by evaporation. Yield: 740 mg (61% of theory), RF value: 0.45 (silica gel; methylene chloride/ethanol 9:1 + 1% conc. ammonia) 10 i. 2-[4-(benzyl-methylamino)-3-nitro-phenyl]-2-methyl 3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1 pyrrolidin-1-vl-propan-1-one Prepared analogously to Example 7d from 2-[4-(N-benzyl 15 methylamino)-3-nitro-phenyl]-2-methyl-3- methylamino-1 pyrrolidin-1-yl-propan-l-one and methyl malonate chloride. Yield: 84% of theory, RF value: 0.65 (silica gel; ethyl acetate/ethanol 9:1 + ammonia) 20 C 27
H
34
N
4 0, (510 . 60) mass spectrum: (M-H)~ = 509 (M+Na)* = 533 j. 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(N 25 methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-l yl-propan-1-one Prepared analogously to Example 1d from 2-[4-(N-benzyl methylamino)-3-nitro-phenyl]-2-methyl-3-(N 30 methoxycarbonylmethylcarbonyl-methylamino)-l-pyrrolidin-l yl-propan-1-one and hydrogen/palladium on activated charcoal. Yield: 100% of theory, RF value: 0.40 (silica gel; ethyl acetate/ethanol 9:1 +1% 35 conc. ammonia)
C
20
H
30 NI0 4 (390.49) mass spectrum: M* = 390 WO 00/01704 - 98 - PCT/EP99/04531 k. 4-[2-(3-(N-methoxycarbonylmethylcarbonyl-methylamino)) 2-methyl-l-pyrrolidin-1-yl-propan-l-on-2-yl]-2-(4-cyano phenyl)-aminomethvlcarbonylamino-N-methyl-aniline 5 Prepared analogously to Example le from 2-(4-methylamino 3-amino-phenyl)-2-methyl-3-(N methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-l yl-propan-1-one and 0-(benzotriazol-1-yl)-N,N,N'N' 10 tetramethylurynium tetrafluoroborate, 4-cyano phenylglycine and triethylamine in dimethylformamide. Yield: 95% of theory, RF value: 0.35 (silica gel; ethyl acetate/ethanol 9:1 + 1% conc. ammonia) 15 1. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N ethoxycarbonylmethylcarbonyl-methylamino)-2 (pyrrolidinocarbonyl)-prop-2-vll-benzimidazole 20 Prepared analogously to Example if from 4-[2-(3-(N methoxycarbonylmethylcarbonyl-methylamino))-2-methyl-1 pyrrolidin-1-yl-propan-l-on-2-yl]-2-(4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid. 25 Yield: 47 % of theory, Rf value: 0.20 (silica gel; ethyl acetate/ethanol = 9:1)
C
29
H
3
,N
6 0 4 (530.63) mass spectrum: (M+H)* = 531 (M+Na)* = 553 30 m. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N ethoxycarbonylmethylcarbonyl-methylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 35 Prepared analogously to Example lg from 2-(4 cyanophenylaminomethyl)-1-methyl-5-[1-(N ethoxycarbonylmethylcarbonyl-methylamino)-2- WO 00/01704 - 99 - PCT/EP99/04531 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 65 % of theory, Rf value: 0.30 (silica gel; methylene chloride/methanol = 5 4:1 + glacial acetic acid)
C
30
H
39
N
7 0 4 x HC1 (561.69/598.19) mass spectrum: (M+H)* = 562 (M+Cl)~ = 596/8 (Cl) 10 The following compounds are obtained analogously to Example 15: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (N-methoxycarbonylmethyl-methylamino)-2 15 (pyrrolidinocarbonyl)-prop-2-yl)-benzimidazole hydrochloride Yield: 89 % of theory, Rf value: 0.35 (Reversed phase RP 8; methanol/5% saline solution = 3:2) 20 C 2
,H
37
N
7 0 3 x HCl (519.66/556.11) mass spectrum: (M+H)* = 520 (M-H+HCl)- = 554/6 (Cl) (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N 25 ethoxycarbonylmethylcarbonylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-acetate Yield: 45% of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % ethyl acetate) 30 C 29
H
37
N
7 0 4 x CH 3 COOH (547.66/607.71) mass spectrum: (M+H)* = 548 (M-H)- = 546
(M-H+CH
3 COOH)- = 606 35 (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(N-methyl ethylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride WO 00/01704 - 100 - PCT/EP99/04531 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (N-ethoxycarbonylmethyl-methylamino)-2-(N-methyl-N ethylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride 5 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l (N-ethoxycarbonylmethylcarbonyl-methylamino)-2 (piperidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 10 (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (N-ethoxycarbonylmethylsulphonyl-methylamino)-2 (piperidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 15 (7) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N methoxycarbonylmethylcarbonyl-methylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-acetate Yield: 72% of theory, 20 Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2 + 1 % glacial acetic acid)
C
29
H
3 ,N,0 4 x CH 3 COOH (547.66/607.71) mass spectrum: (M+H)* = 548 (M-H) = 546 25 (8) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 ethoxycarbonyl-ethylcarbonylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 30 (9) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylsulphonylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 35 Yield: 14% of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 8:2) WO 00/01704 - 101 - PCT/EP99/04531
C
2
,H
37
N
7 0 5 S x HC1 (583.65/620.17) mass spectrum: (M+H)* = 584 (M+Na)* = 606 5 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H tetrazol-5-yl)-methylcarbonylamino)-2 (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole hydrochloride 10 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-2-(pyrrolidinocarbonyl)-prop 2-yl]-benzimidazole-dihydrochloride Yield: 40% of theory, 15 C 2
,H
37
N
7 0 3 x 2 HCl (519.65/592.56) mass spectrum: (M+H)* = 520 (M+Na)* = 542 (M+HCOO)- = 564 (M+Cl)- = 554 20 Example 16 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 25 (carboxymethylamino)-1-(isoxazolidin-1-yl-carbonyl) ethyll-benzimidazole-hydrochloride Prepared by hydrolysis of 2-(4-amidinophenylaminomethyl) 1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(isoxazolidin 30 1-yl-carbonyl)-ethyl]-benzimidazole-hydrochloride with sodium hydroxide solution in ethanol. Yield: 90 % of theory, R. value: 0.65 (Reversed phase RP 8; methanol/5% saline solution = 3:2) 35 C 24
H
29 N,0 4 x HCl (479.54/515.99) mass spectrum: (M+H)* = 480 WO 00/01704 - 102 - PCT/EP99/04531 The following compounds are prepared analogously to Example 16: (1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 5 carboxyethylamino)-1-(isoxazolidin-1-yl-carbonyl)-ethyl] benzimidazole-hydrochloride (2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[I (carboxymethylamino)-1-(N-methyl-N-ethylaminocarbonyl) 10 ethyl]-benzimidazole-hydrochloride Yield: 93% of theory, Rf value: 0.40 (Reversed phase RP 8; methanol/5% saline solution = 1:1)
C
24
H
31
N
7 0 3 x HCl (465.57/502.02) 15 mass spectrum: (M+H)* = 466 (M+Cl-H)~ = 500/2 (Cl) (3) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N carboxymethyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2 20 yl]-benzimidazole-dihydrochloride Yield: 89% of theory, Rf value: 0.57 (Reversed phase RP 8; methanol/5% saline solution = 4:3)
C
2
,H
3
,N
7 0 3 x 2 HCl (505.63/578.54) 25 mass spectrum: (M+H)* = 506 (M+2H)** = 253 (M+H+Na)** = 264.5 (4) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 30 (carboxymethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop 2-yl]-benzimidazole-hydrochloride Yield: 90% of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5% saline solution = 4:6) 35 C 2 7
,H
33 N, x HCl (519.61/556.06) mass spectrum: (M+H)* = 520 (M-H) - = 518 WO 00/01704 - 103 - PCT/EP99/04531 (5) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (N-carboxymethyl-methylamino) -2- (N-ethyl methylaminocarbonyl)-prop-2-yl]-benzimidazole 5 hydrochloride (6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (N-carboxymethylcarbonyl-methylamino) -2- (N-ethyl methylaminocarbonyl)-prop-2-yl]-benzimidazole 10 hydrochloride (7) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 (N-carboxymethylcarbonyl-methylamino) -2 (piperidinocarbonyl)-prop-2-yl]-benzimidazole 15 hydrochloride (8) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 (N-carboxymethylsulphonyl -methylamino) -2 (piperidinocarbonyl)-prop-2-yl]-benzimidazole 20 hydrochloride (9) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 (carboxymethylamino) -1- (piperidinocarbonyl) -ethyl] benzimidazole-hydrochloride 25 Yield: 81% of theory, Rf value: 0.40 (Reversed phase RP 8; methanol/5% saline solution = 1:1)
C
2 6
H
3 3
N
7 0 3 (491.60/528.05) mass spectrum: (M+H)* = 492 30 (M-H)^ = 490 (10) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-( 2 carboxyethylcarbonylamino)-2-(pyrrolidinocarbonyl)-prop-2 yl]-benzimidazole-hydrochloride 35 WO 00/01704 - 104 - PCT/EP99/04531 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylsulphonylamino)-2-(pyrrolidinocarbonyl) prop-2-yl]-benzimidazole-hydrochloride 5 (12) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylamino)-1-(diethylaminocarbonyl)-ethyl] benzimidazole-hydrochloride Yield: 70% of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/5% saline 10 solution = 1:1)
C
25
H
33 N,0 3 (479.59/516.05) mass spectrum: (M+H)* = 480 (M-H) = 478 (M-H+HCl) = 514/516 (Cl) 15 (13) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] benzimidazole-dihydrochloride 20 Yield: 22 % of theory, Rf value: 0.50 (Reversed phase RP 8; 5% saline solution/ methanol = 1:1)
C
2
,H
33 N,0 3 x 2 HCl (491.60/564.51) mass spectrum: (M+H)* = 492 25 (M-H)~ = 490 (14) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carb oxymethyl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl] 30 benzimidazole-dihydrochloride Rf value: 0.48 (Reversed phase RP 8; 5% saline solution/ methanol = 3:2)
C
2
,H
33 N,0 3 x 2 HCl (491.60/564.51) mass spectrum: (M+H)* = 492 35 (M-H)~ = 490 WO 00/01704 - 105 - PCT/EP99/04531 (15) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(3 carboxy-propylamino)-1-(pyrrolidinocarbonyl)-ethyl] benzimidazole-dihydrochloride 5 Yield: 82 % of theory, Rf value: 0.73 (Reversed phase; 5% sodium chloride solution/ methanol = 1:1)
C
27
H
3
,N
7 0 3 x 2 HCl (505.63/578.54) mass spectrum: (M+H)* = 506 10 Example 17 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1 methyl-5-[1-(ethoxycarbonylmethylamino)-1 15 (pyrrolidinocarbonyl)-ethyll-benzimidazole A suspension of 1.4 g (2.4 mmol) of 2-(4 amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) 20 ethyl]-benzimidazole-dihydrochloride in 5 ml of N-ethyl diisopropylamine and 2 ml dimethylformamide is combined with 1.5 g (6 mmol) of 4-nitrophenyl benzoate, whilst a clear solution is formed by heating. After 2 hours at 1200C the solution is concentrated by evaporation in 25 vacuo, after cooling the residue is dissolved in dichloromethane and purified on silica gel, eluting first with dichloromethane, later with dichloromethane/ethanol (50:1, 25:1, 18:1). The uniform fractions are combined, concentrated by evaporation, triturated with water, 30 suction filtered and dried. Yield: 0.7 g (49% of theory), Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1)
C
34 H3 9
N
7 0 4 (609.73) 35 mass spectrum: (M+H)* = 610 (M+Na)* = 632 WO 00/01704 - 106 - PCT/EP99/04531 (M-H)~ = 608 The following compounds are obtained analogously to Examples 14 and 17: 5 (1) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(ethoxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 53% of theory, 10 Rf value: 0.35 (silica gel; methylene chloride/ethanol = 9:1)
C
34
H
4 ,N,0 5 (633.79) mass spectrum: (M+Na)* = 656 (M-H) = 632 15 (2) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(ethoxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 46% of theory, 20 Rf value: 0.43 (silica gel; methylene chloride/ethanol = 9:1)
C
36 H,,N,0 5 (661.84) mass spectrum: (M+Na)* = 684 (M-H) = 660 25 (3) 2-[4-(N-n-hexyloxycarbonyl-amidino) phenylaminomethyl)-1-methyl-5-[1 (methoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole 30 (4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(methoxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)ethyl]-benzimidazole Yield: 32% of theory, 35 Rf value: 0.27 (silica gel; methylene chloride/ethanol = 9:1) WO 00/01704 - 107 - PCT/EP99/04531
C
35
H
49
N
7 0, (647.82) mass spectrum: (M+Na)* = 670 (M-H) = 646 5 (5) 2- [4- (N-n-hexyloxycarbonylamidino) -phenylaminomethyl] 1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] benzimidazole Yield: 52% of theory, 10 Rf value: 0.60, (silica gel; methylene chloride/ethanol = 9:1)
C
3
,H
51 N,0 6 (689.85) mass spectrum: (M+H)* = 690 (M-H) = 688) 15 (M+Na)* = 712 (M+HCl-H)- = 724/26 (Cl) (6) 2-[4-(N-n-octyloxycarbonyl-amidino) phenylaminomethyl) -1-methyl-5- [1 20 (N-ethoxycarbonylmethylcarbonyl-methylamino) 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole (7) 2- [4- (N-n-hexyloxycarbonylamidino) -phenylaminomethyl] 1-methyl-5- [1- (N-methoxycarbonylmethylcarbonyl 25 methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] benzimidazole Yield: 21% of theory, Rf value: 0.55 (silica gel; methylene chloride/ethanol = 9:1) 30 C 36
H
49
N
7 0 6 (675.83) mass spectrum: (M+H)* = 676 (M+Na)* = 698 (M+HCl-H)~ = 724/26 (Cl) 35 (8) 2-[4-(N-n-octyloxycarbonyl-amidino) phenylaminomethyl) -1-methyl-5- [1- (N- WO 00/01704 - 108 - PCT/EP99/04531 methoxycarbonylmethylcarbonyl-methylamino) 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole (9) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1 5 methyl-5-[1-(methoxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 34% of theory. R, value: 0.55 (silica gel; methylene chloride/ethanol = 9:1 + 1 % ammonia) 10 C 33
H
37 N,0 4 (595. 70) mass spectrum: (M-H) = 594 (M+Na)* = 618 (10) 2-[4-(N-isopropyloxycarbonylamidino) 15 phenylaminomethyl]-1-methyl-5-[1-(N ethoxycarbonylmethylcarbonyl-methylamino) 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 66% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 20 9:1)
C
34
H
45
N
7 0 6 (647.77) mass spectrum: (M+H)* = 648 (M-H)~ = 646 (M+Na)* = 670 25 (11) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1 methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl-methylamino) 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 23% of theory, 30 Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)
C
37
H
43
N
7 0, (665.79) mass spectrum: (M+H)* = 666 (M-H)~ = 664 35 (M+Na)* = 688 (M+H+Cl)* = 700/2 (Cl) WO 00/01704 - 109 - PCT/EP99/04531 (12) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] 5 benzimidazole Yield: 67% of theory, Rf value: 0.60 (silica gel; methylene chloride/ethanol = 9:1)
C
36
H
41
N
7 0, (651.76) 10 mass spectrum (M+H)* = 652 (M-H) = 650 (M+Na)* = 674 (13) 2-[4-(N-n-butyloxycarbonylamidino) 15 phenylaminomethyl]-l-methyl-5-[1-(N methoxycarbonylmethylcarbonyl-methylamino) 2-(pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole Yield: 45% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 20 9:1)
C
34
H
45
N
7 0 6 (647.77) mass spectrum: (M+H)* = 648 (M-H)- = 646 (M+Na)* = 670 25 (M-H+HCl)~ = 682/4 (Cl) (14) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(N-ethoxycarbonylmethylcarbonyl methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] 30 benzimidazole Yield: 54% of theory, Rf value: 0.40 (silica gel; methylene chloride/ethanol = 9:1)
C
33
H
4 3
N
7 01 (633.75) 35 mass spectrum: (M+H)* = 634 (M-H)- = 632 (M+Na)* = 656 WO 00/01704 - 110 - PCT/EP99/04531 (15) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(N-methoxycarbonylmethylcarbonyl methylamino)-2-(pyrrolidinocarbonyl)-prop-2-yl] 5 benzimidazole Yield: 53% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 9:1)
C
32
H
41
N
7 0 6 (619. 72) 10 mass spectrum: (M+H)* = 620 (M-H) - = 618 (M+Na)* = 642 (16) 2-[4-(N-pyridin-3-yl-carbonylamidino) 15 phenylaminomethyll-1-methyl-5-[1-(N ethoxycarbonylmethylcarbonyl-methylamino) 2-(pyrrolidinocarbonyl)-prop-2-yll-benzimidazole Yield: 16% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 20 9:1)
C
36
H
4 2
N
8 0, (666.78) mass spectrum: (M-H)~ = 665 (M+Na)* = 689 25 (17) 2-[4-(N-n-butyloxycarbonylamidino) phenylaminomethyl]-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole Yield: 52% of theory, 30 Rf value: 0.42 (silica gel; methylene chloride/ethanol = 9:1)
C
3 2
H
4 3
N
7 0, (605.74) mass spectrum: (M+H)* = 606 (M+Na)* = 628 35 (M-H)- = 604 WO 00/01704 - 111 - PCT/EP99/04531 (18) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(ethoxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 30% of theory, 5 Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1)
C
30
H
39
N
7 0, (577.68) mass spectrum: (M+H)* = 578 (M+Na)* = 600 10 (M-H)- = 576 (19) 2-[4-(N-benzyloxycarbonylamidino)-phenylaminomethyl] 1-methyl-5-[1-(ethoxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole 15 Yield: 51% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1)
C
35
H
41
N
7 0 5 (639.75) mass spectrum: (M+Na)* = 662 20 (M-H)- = 638 (20) 2-[4-(N-pyridin-3-yl-carbonylamidino) phenylaminomethyl]-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) 25 ethyl]-benzimidazole Yield: 84% of theory, Rf value: 0.20 (silica gel; ethyl acetate/ethanol = 4:1)
C
33
H
3 8 NB0 4 (610.72) mass spectrum: (M+H)* = 611 30 (M-H)~ = 609 (M-HCOO)' = 611 (21) 2-[4-(N-acetoxymethyloxycarbonylamidino) phenylaminomethyl]-1-methyl-5-[1 35 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole Yield: 42% of theory, WO 00/01704 - 112 - PCT/EP99/04531 Rf value: 0.44 (silica gel; methylene chloride/ethanol = 9:1)
C
31
H
39
N
7 07, (621.09) mass spectrum: (M+Na)* = 644 5 (M-H) - = 620 (22) 2- [4- (N- (2,2,2-trichloroethyloxycarbonyl) -amidino) phenylaminomethyll-1-methyl-5-[1 (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) 10 ethyl]-benzimidazole Yield: 73% of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol = 9:1)
C
3 0
H
36 Cl 3
N
7 01 (681) 15 mass spectrum: M* = 679/81/3 (Cl 3 ) (M+Na)* = 702/4/6 (Cl 3 ) (M-H)- = 678/80/2 (Cl 3 ) Example 18 20 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-1 methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) ethyl]-benzimidazole 25 A solution of 0.2 g (0.3 mmol) of 2-[4-(N-n octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[l (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole in 3 ml tetrahydrofuran and 2.5 ml ethanol is mixed with 1.1 ml of 1N sodium hydroxide 30 solution and stirred for 4 hours at ambient temperature. The reaction mixture is concentrated by evaporation and combined with 1 ml of 1N hydrochloric acid. After 12 hours at ambient temperature (pH 4) 2 drops of ammonia (33%) are added, whereupon a bright yellow precipitate is formed. 35 After the solid formed has been suction filtered the filtrate is combined with 1 ml of 1 N hydrochloric acid and concentrated by evaporation with the addition of WO 00/01704 - 113 - PCT/EP99/04531 toluene. The residue is triturated with acetone, suction filtered, washed with diethylether and dried. Yield: 0.1 g (50% of theory), Rf value: 0.35 (Reversed phase RP 8; methanol/5% saline 5 solution = 2:1)
C
3 4
H
47
N
7 0, (633.79) mass spectrum: (M+H)* = 634 (M+H+Na)** = 328.5 10 Example 19 2-[4-(N-hydroxyamidino)-phenylaminomethyl]-l-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole 15 A suspension of 0.6 g (1.2 mmol) of 2-(4 cyanophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole in 50 ml ethanol is mixed with 0.47 g 20 (7.8 mmol) of hydroxylamine hydrochloride and 0.35 g (3.5 mmol) of sodium carbonate and refluxed for 17 hours. After cooling, the residue is filtered off, the filtrate is concentrated by evaporation and taken up in water. After extracting twice with dichloromethane, the combined 25 organic phases are dried and concentrated by evaporation. The crude product is purified on silica gel, eluting with dichloromethane/ethanol (19/1 and 7/1). The uniform fractions are combined, concentrated by evaporation, triturated with diisopropylether and dried. 30 Yield: 0.025 g (4% of theory), Rf value: 0.68 (silica gel; methylene chloride/ethanol = 4:1)
C
27
H
35
N
7 0 4 (521.62) mass spectrum: (M-H)~ = 520 35 (M+Na)* = 544 WO 00/01704 - 114 - PCT/EP99/04531 Example 20 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1 methyl-5-[1-(isopropyloxycarbonylmethylamino)-1 5 (pyrrolidinocarbonyl)-ethyll-benzimidazole a. Ethyl 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino acetate 10 Prepared analogously to Example 9a from 4-(5-methyl-1,2,4 oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl diisopropylamine. Yield: 78% of theory, Rf value: 0.60 (silica gel; ethyl acetate/petroleum ether 15 = 1:1) b. 4-(5-methyl-1,2,4-oxadiazol-3-vl)-phenylamino-acetic acid Prepared analogously to Example 4 from ethyl 4-(5-methyl 20 1,2,4-oxadiazol-3-yl)-phenylamino-acetate and sodium hydroxide solution in ethanol. Yield: 75% of theory, Rf value: 0.15 (silica gel; methylene chloride/ethanol = 9:1) 25 c. 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl) phenylaminomethyll-1-methyl-5-[1-amino-(pyrrolidin-1-yl carbonyl)-ethyll-benzimidazole 30 Prepared analogously to Example le/f from 2-(4 methylamino-3-amino-phenyl)-2-tert.butyloxycarbonyl-amino 1-pyrrolidin-1-yl-propanone, 4-(5-methyl-1,2,4-oxadiazol 3-yl)-phenylamino-acetic acid and carbonyldiimidazole in tetrahydrofuran and subsequent treatment with glacial 35 acetic acid. Yield: 34% of theory, WO 00/01704 - 115 - PCT/EP99/04531 Rf value: 0.10 (silica gel; methylene chloride/ethanol = 9:1) d. 2-[4-(5-methyl-1,2,4-oxadiazol-3-yl) 5 phenylaminomethyl]-1-methyl-5-[l (isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole Prepared analogously to Example 11 from 2-[4-(5-methyl 1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1 10 amino-i-(pyrrolidinocarbonyl)-ethyl]-benzimidazole, isopropyl bromoacetate and potassium carbonate in isopropanol/methylene chloride. Yield: 42% of theory, Rf value: 0.60 (silica gel; methylene chloride/ethanol = 15 9:1) e. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l (isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole-acetate 20 Prepared analogously to Example ld from 2-[4-(5-methyl 1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1 (isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole and hydrogen/palladium (10% on 25 activated charcoal) in ethanol/glacial acetic acid. Yield: 69% of theory, Rf value: 0.30 (silica gel; methylene chloride/ethanol = 7:3) 30 f. 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1 methyl-5-[1-(isopropyloxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyll-benzimidazole Prepared analogously to Example 17 from 2-(4 35 amidinophenylaminomethyl)-1-methyl-5-[1 (isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)- WO 00/01704 - 116 - PCT/EP99/04531 ethyl]-benzimidazole-acetate and 4-nitrophenyl benzoate in N-ethyl-diisopropylamine/dimethylformamide. Yield: 26% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 5 9:1)
C
35
H
41
N
7 0 4 (623.75) mass spectrum: (M+Na)* = 646 (M-H)- = 622 10 The following compounds are prepared analogously to Example 20: (1) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyll-1 methyl-5-[1-(n-butyloxycarbonylmethylamino)-1 15 (pyrrolidinocarbonyl)-ethyl]-benzimidazole (2) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1 methyl-5-[1-(2-phenylethyloxycarbonylmethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole 20 (3) 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyll 1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrro lidinocarbonyl)-ethyl]-benzimidazole Yield: 40 % of theory, 25 Rf value: 0.45 (silica gel: methylene chloride/ethanol = 9:1)
C
35
H
49
N
7 0, (647.82) mass spectrum: (M+H)* = 648 (M-H)~ = 646 30 (M+Na)* = 670 (4) 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyll 1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrro lidinocarbonyl)-ethyl]-benzimidazole 35 Yield: 31% of theory, Rf value: 0.48 (silica gel: methylene chloride/ethanol = 9:1) WO 00/01704 - 117 - PCT/EP99/04531
C
37
H
53
N
7 0, (675.88) mass spectrum: (M+H)* = 674 (M+Na)* = 698 5 (5) 2- [4- (N- (2,2,2-trichloroethyloxycarbonyl) -amidino) phenylaminomethyl]-1-methyl-5-[l-(isopropyloxycarbonyl methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 43% of theory, Rf value: 0.50 (silica gel: methylene chloride/ethanol = 10 9:1)
C
31
H
38 Cl 3
N
7 0 5 (695.05) mass spectrum: (M-H) = 692/694/696/698 (C1 3 ) (6) 2-[4-(N-phenylcarbonylamidino)- phenylaminomethyll 15 1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrro lidinocarbonyl) -ethyl] -benzimidazole Yield: 79% of theory Rf value: 0.35 (silica gel; ethyl acetate/ethanol = 9:1)
C
35
H
4 1
N
7 0 4 (623.76) 20 mass spectrum: (M+H)* = 624 (M-H)- = 622 (M+HCOO)~ = 668 (7) 2-[4-(N-n-octyloxycarbonylamidino) 25 phenylaminomethyl] -1-methyl-5- [- (n-propyloxycarbonyl methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 53% of theory Rf value: 0.39 (silica gel; ethyl acetate/ethanol = 9:1)
C
37
H
5 3
N
7 0, (675.88) 30 mass spectrum: (M+H)* = 676 (M+Na)* = 698 (M-H)- = 674 WO 00/01704 - 118 - PCT/EP99/04531 Example 21 (R)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyll 5 benzimidazole hydrochloride a. Ethyl 2-amino-2-(4-chloro-3-nitrophenyl)-propionate A mixture of 28 g (0.11 mol) of 2-amin-2-(4-chloro-3 nitrophenyl)-propionic acid in 200 ml of 5.6 N ethanolic 10 hydrochloric acid is refluxed for 36 hours. After the solvent has been evaporated off the residue is suspended in 300 ml of ethyl acetate and combined with 300 ml of saturated sodium hydrogen carbonate solution. The organic phase is washed twice with saturated sodium hydrogen 15 carbonate solution and once with water, dried over sodium sulphate and evaporated down. Yield: 21.1 g (68% of theory) of light brown oil. b. ethyl (R)-(+)-2-amino-2-(4-chloro-3-nitrophenyl) 20 propionate 17.33 g (63.6 mmol) of ethyl 2-amino-2-(4-chloro-3 nitrophenyl)-propionate are dissolved in 247 ml of isopropanol and 207 ml of methanol and mixed with 9.54 g 25 (63.6 mmol) of L-(+)-tartaric acid. The reaction mixture is heated to 100*C, whereupon a clear solution is formed. The solution is cooled to 27*C within 3 hours, the precipitate formed is suction filtered, washed with ethanol and dried. Then the solid formed (21.5 g) is 30 suspended in 400 ml of ethyl acetate and combined with 400 ml of saturated sodium hydrogen carbonate solution. After extraction and phase separation, the organic phase is washed with water, dried and evaporated down. Yield: 7.68 g (44.4% of theory) of light yellow oil, 35 [a] 20 = +4.380 (ethyl acetate) HPLC analysis: ee value > 98.6% WO 00/01704 - 119 - PCT/EP99/04531 c. (R)-(-)-2-amino-2-(4-chloro-3-nitrophenyl)-propionic acid 5 Prepared analogously to Example 4 from ethyl (R)-(+)-2 amino-2-(4-chloro-3-nitrophenyl)-propionate and sodium hydroxide solution in tetrahydrofuran. Yield: 63% of theory, [a] 20 = -59.60 (methanol/water 1:1) 10 d. (R)- 2-t~rt.butyloxvcarbonylamino-2-(4-chloro-3 nitrophenyl) -propionic acid Prepared analogously to Example 5d from (R)-(-)-2-amino-2 15 (4-chloro-3-nitrophenyl)-propionic acid and pyrocarbonic acid di-tert.butyldicarbonate and triethylamine in dioxan. Yield: 100% of theory. e. (R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3 20 nitrophenvl)-propionic acid Prepared analogously to Example lb from (R)-2 tert.butyloxycarbonylamino-2-(4-chloro-3-nitrophenyl) propionic acid and methylamine. 25 Yield: 69% of theory. f. (R)-2-(4-methylamino-3-nitrophenvl)-2 tert.butyloxvcarbonylamino-l-pyrrolidino-propanone 30 Prepared analogously to Example 1c from (R)-2 tert.butyloxycarbonylamino-2-(4-methylamino-3 nitrophenyl)-propionic acid, pyrrolidine and carbonyldiimidazole in tetrahydrofuran. Yield: 96% of theory. 35 WO 00/01704 - 120 - PCT/EP99/04531 q. (R)-2-(4-methylamino-3-aminophenyl)-2 tert.butyloxvcarbonylamino-l-pyrrolidino-propanone Prepared analogously to Example ic from (R)-2-(4 5 methylamino-3-nitrophenyl)-2-tert.butyloxycarbonylamino-l pyrrolidino-propanone and hydrogen/palladium on activated charcoal in methanol. Yield: 99% of theory. 10 h. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[l-(N tert.butyloxvcarbonylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole Prepared analogously to Example 1c/1f from (R)-2-(4 15 methylamino-3-aminophenyl)-2-tert.butyloxycarbonylamino-l pyrrolidino-propanone, 4-cyanophenylglycine, carbonyldiimidazole in tetrahydrofuran and subsequent cyclisation in glacial acetic acid. Yield: 100% of theory. 20 i. (R)-2-(4-cyanophenylaminomethyl)-1-methvl-5-[1-amino 1-(pyrrolidinocarbonyl)-ethyll-benzimidazole Prepared analogously to Example 6i from (R)-2-(4 25 cyanophenylaminomethyl)-1-methyl-5-[l-(N tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole and 6N hydrochloric acid in dioxan. Yield: 76% of theory. 30 k. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[l (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) ethyl]-benzimidazole Prepared analogously to Example 6k from (R)-2-(4 35 cyanophenylaminomethyl)-1-methyl-5-[l-amino-l (pyrrolidino-carbonyl)-ethyl]-benzimidazole and ethyl iodoacetate/potassium carbonate in acetone.
WO 00/01704 - 121 - PCT/EP99/04531 Yield: 75% of theory. 1. (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl) 5 ethyl]-benzimidazole hydrochloride Prepared analogously to Example lg from (R)-2-(4 cyanophenylaminomethyl)-1-methyl-5-[l (ethoxycarbonylmethylamino)-1-(pyrrolidino-carbonyl) 10 ethyl]-benzimdazole and hydrochloric acid/ammonium carbonate in ethanol. Yield: 95% of theory. m. (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 15 (carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyll benzimidazole hydrochloride Prepared analogously to Example 4 from (R)-2-(4 amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonyl 20 methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and sodium hydroxide solution in ethanol. Yield: 100% of theory,
C
25
H
31
N
7 0 3 x 2HCl (477.57/550.5) Mass spectrum: (M+H)* = 478 25 (M-H+HCl)~ = 512/514 (Cl) (M-H+2HCl) = 448/550/552 (Cl 2 ) Example 22 30 Dry ampoule containing 75 mg of active substance per 10 ml Composition: Active substance 75.0 mg 35 Mannitol 50.0 mg water for injections ad 10.0 ml WO 00/01704 - 122 - PCT/EP99/04531 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 5 water for injections. Example 23 Dry ampoule containing 35 mg of active substance per 2 ml 10 Composition: Active substance 35.0 mg Mannitol 100.0 mg 15 water for injections ad 2.0 ml Preparation: Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. 20 To produce the solution ready for use, the product is dissolved in water for injections. Example 24 25 Tablet containing 50 mg of active substance Composition: 30 (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 35 215.0 mg WO 00/01704 - 123 - PCT/EP99/04531 Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried 5 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. 10 Example 25 Tablet containing 350 mg of active substance 15 Preparation: (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 mg 600.0 mg (1), (2) and (3) are mixed together and granulated with an 25 aqueous solution of (4). (5) 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. 30 WO 00/01704 - 124 - PCT/EP99/04531 Example 26 Capsules containing 50 mg of active substance 5 Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg 10 (4) Magnesium stearate 2.0 mg 160.0 mg Preparation: (1) is triturated with (3). This trituration is added to 15 the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine. 20 Example 27 Capsules containing 350 mg of active substance Composition: 25 (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 30 430.0 mg Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. 35 WO 00/01704 - 125 - PCT/EP99/04531 This powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine. Example 28 5 Suppositories containing 100 mg of active substance 1 suppository contains: 10 Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg 15 Method: The polyethyleneglycol is melted together with polyethylene sorbitan monostearate. At 40 0 C the ground active substance is homogeneously dispersed in the melt. 20 It is cooled to 38 0 C and poured into slightly chilled suppository moulds.

Claims (11)

1. Benzimidazoles of general formula 5 N Ra A-B -Ar- R, (I), aR Rb wherein Ar denotes a phenylene or naphthylene group optionally 10 substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 1 3 -alkyl or C 1 3 -alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally 15 substituted in the carbon skeleton by a C 1 - 3 -alkyl group, A denotes a C 1 3 -alkylene group, B denotes an oxygen or sulphur atom, a methylene, 20 carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C 13 -alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, 25 Ra denotes an R 1 -CO-C 3 _ 5 -cycloalkyl group wherein R denotes a C 1 3 -alkoxy, amino, C 1 ,-alkylamino or di (C- 4 -alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, 30 a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two C- 3 -alkyl groups, whilst WO 00/01704 - 127 - PCT/EP99/04531 an alkyl substituent may simultaneously be substituted by a hydroxy, C,-,-alkoxy, carboxy, carboxy-C 1 3 -alkoxy, carboxy-C 1 3 -alkylamino, N- (C, 3 -alkyl) -N- (carboxy C 1 3 -alkyl) -amino, carboxy-C 1 3 -alkylaminocarbonyl, 5 N- (C 1 3 -alkyl) -N- (carboxy-C 1 3 -alkyl) -aminocarbonyl, carboxy-C 1 3 -alkylaminocarbonylamino, 1-(C 1 3 -alkyl)
3- (carboxy-C 1 3 -alkyl) -aminocarbonylamino, 3-(C 1 3 -alkyl) 3- (carboxy-C, -alkyl) -aminocarbonylamino or 1,3-di (C 1 3 -alkyl)-3-(carboxy-C 1 3 -alkyl)-aminocarbonylamino 10 group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 15 a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C 13 -alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C 1 3 -alkyl) -piperazino, 20 pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R 2 -CX-C 35 -cycloalkyl group wherein R 2 denotes a phenyl, naphthyl or monocyclic 5- or 25 6-membered heteroaryl group optionally substituted by a Cs 3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the
5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen 30 or sulphur atom or an imino group optionally substituted by a Cs -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy C 1 3 -alkoxy, carboxy-C- 3 -alkylamino or N- (C 1 3 -alkyl) 35 carboxy-C. 3 -alkylamino group, and WO 00/01704 - 128 - PCT/EP99/04531 X denotes an oxygen atom, a C- 3 -alkylimino, Cl- -alkoxyimino, Cl 3 -alkylhydrazino, di- (Cl, 3 -alkyl) hydrazino, C 2 - 4 -alkanoylhydrazino, N-(C, 3 -alkyl) C 2 - 4 -alkanoylhydrazino or C, 3 -alkylidene group each of 5 which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a CI- 3 -alkyl or C3-1cycloalkyl group substituted by an 10 imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C ,-alkyl groups or by one, two or three C, 3 -alkyl groups, wherein the 15 substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C 2 4 -alkanoylamino, Cl- 3 -alkylamino, N- (C 2 4 -alkanoyl) -C1 3 -alkylamino or di 20 (C, 3 -alkyl)-amino group, and the imidazolone ring may be substituted by a C1-3-alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an 25 amino, C 2 4 -alkanoylamino, C- 3 -alkylamino, N- (C 2 4 -alkanoyl) -C, 3 -alkylamino or di-(C,-,-alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to 30 the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C, 3 -alkyl groups, whilst at the 35 same time an alkyl substituent may be substituted by a carboxy group, WO 00/01704 - 129 - PCT/EP99/04531 a C 1 4 -alkyl group which is substituted by a C 1 3 -alkyl-YI-CI--alkyl, HOOC-C 1 3 -alkyl-YI-C 1 3 -alkyl, tetrazolyl-C 3 -alkyl-Y 2 , R 3 NR 4 - or R 3 NR 4 -C 1 3 -alkyl group 5 and by an isoxazolidinylcarbonyl group optionally substituted by a C 1 3 -alkyl group, by a pyrrolino carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-1-yl 10 carbonyl, carboxy, aminocarbonyl, C 1 3 -alkylaminocarbonyl, di-(C 13 -alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or 15 two Cl -alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C 1 3 -alkylaminocarbonyl, di-(C- 3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the 20 C 1 4 -alkyl group may be wholly or partially replaced by fluorine atoms wherein R 3 denotes a hydrogen atom or a C 1 3 -alkyl group optionally substituted by a carboxy group and 25 R 4 denotes a hydrogen atom, a Cl - alkyl Y 1 -C 1 3 - alkyl-Y 2 , carboxy-C 3 -alkyl-Yl-C 3 -alkyl-Y 2 , C 1 3 -alkyl-Y 2 or carboxy-C 1 3 -alkyl-Y 2 group or 30 R 3 and R 4 together with the nitrogen atom between them denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C 1 3 -alkyl or carboxy-C 1 3 -alkyl group wherein 35 Y 1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and WO 00/01704 - 130 - PCT/EP99/04531 Y 2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO- group, wherein the carbonylgroup of the -NH-CO- group is linked to the 5 nitrogen atom of the R 3 NR- group, and the imino groups occurring in the definition of the groups Yj and Y 2 may each additionally be substituted by a C,- alkyl or carboxy-C 1 3 -alkyl group, 10 a C 1 3 -alkyl or C 3 - 5 -cycloalkyl group substituted by a RNR, group wherein R 5 denotes a hydrogen atom, a C 1 3 -alkyl, C 5 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 15 R 6 denotes a C 1 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy C 1 3 -alkylcarbonyl group, a C 1 3 -alkyl group which is substituted by a C 2 4 -alkanoyl 20 or C 5 7 -cycloalkanoyl group and by a C 13 -alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C 1 - 3 -alkyl group and 25 Re denotes a cyano group or an amidino group optionally substituted by one or two C 1 3 -alkyl groups, the tautomers. stereoisomers, mixtures thereof, the prodrugs thereof, the derivatives thereof which contain, 30 instead of a carboxy group, a group which is negatively charged under physiological conditions, and the salts thereof. WO 00/01704 - 131 - PCT/EP99/04531 2. Benzimidazoles of general formula N Ra A-B RC (Ia), -():N Rb wherein 5 A denotes a C 13 -alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group 10 optionally substituted by a C 1 3 -alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, Ra denotes an Ri-CO-C 3 - 5 -cycloalkyl group wherein 15 R denotes a C, -alkoxy, amino, C 1 4 -alkylamino or di (C 1 4 -alkyl) -amino group wherein each alkyl moiety may be substituted by a carboxy group, 20 a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by one or two C 1 3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C 13 -alkoxy, carboxy, carboxy-C 13 -alkoxy, carboxy 25 C 1 3 -alkylamino, N- (C 1 3 -alkyl) -N- (carboxy-C 1 3 -alkyl) amino, carboxy-C 1 3 -alkylaminocarbonyl, N- (C 13 -alkyl) N- (carboxy-C 1 3 -alkyl) -aminocarbonyl, carboxy C 1 3 -alkylaminocarbonylamino, 1- (C 1 3 -alkyl) -3- (carboxy Cl- 3 -alkyl) -aminocarbonylamino, 3- (Cl 13 -alkyl) -3- (carboxy 30 C 1 3 -alkyl) -aminocarbonylamino or 1, 3-di- (Cl 13 -alkyl) 3- (carboxy-C 1 3 ,-alkyl) -aminocarbonylamino group, WO 00/01704 - 132 - PCT/EP99/04531 a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally 5 substituted by a C -3-alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C. 3 -alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, 10 an R 2 -CX-C 3 _.-cycloalkyl group wherein R 2 denotes a phenyl, naphthyl or monocyclic 5- or
6-membered heteroaryl group optionally substituted by a 15 C, 3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1 3 -alkyl group, an oxygen or sulphur atom or an imino group optionally substituted 20 by a C, 3 -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy C, 3 -alkoxy, carboxy-C 1 3 -alkylamino or N-(C, 3 -alkyl) carboxy-C 1 3 -alkylamino group, and 25 X denotes an oxygen atom, a C, 3 -alkylimino, C 1 3 -alkoxyimino, Cl 1 3 -alkylhydrazino, di- (C,- 3 -alkyl) hydrazino, C 24 -alkanoylhydrazino, N-(C 13 -alkyl) C 2 4 -alkanoylhydrazino or C 1 3 -alkylidene group each of 30 which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C, 3 -alkyl or C 3 -- cycloalkyl group substituted by an 35 imidazole or imidazolone group wherein WO 00/01704 - 133 - PCT/EP99/04531 the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C 1 3 -alkyl groups or by one, two or three C 1 3 -alkyl groups, wherein the substituents may be identical or different and one of 5 the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C 2 4 -alkanoylamino, C 1 3 -alkylamino, N- (C 2 -- alkanoyl) -C 1 3 -alkylamino or di (C 1 3 -alkyl)-amino group, and 10 the imidazolone ring may be substituted by a C 1 3 -alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an amino, C 2 4 -alkanoylamino, C 1 3 -alkylamino, 15 N-(C 2 4 -alkanoyl)-C 1 3 -alkylamino or di- (C 1 3 -alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via 20 two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two Ca -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a 25 carboxy group, a Cl- 4 -alkyl group which is substituted by a CI- alkyl-YI-Cs -alkyl, HOOC-C 1 3 -alkyl-Y 1 -C 1 3 -alkyl, 30 tetrazolyl-C 3 -alkyl-Y 2 , R 3 NR 4 - or R 3 NR 4 -C 1 3 -alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a CI--alkyl group, by a pyrro 35 linocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol 1-yl-carbonyl, carboxy, aminocarbonyl, C 1 3 -alkylaminocarbonyl, di-(CI 3 -alkyl)-aminocarbonyl or WO 00/01704 - 134 - PCT/EP99/04531 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C 1 3 -alkyl groups and at the same time each alkyl 5 moiety or alkyl substituent in the abovementioned C,--alkylaminocarbonyl, di-(C 1 3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the CI- 4 -alkyl group may be wholly or partially replaced by 10 fluorine atoms wherein R 3 denotes a hydrogen atom or a C 1 3 -alkyl group optionally substituted by a carboxy group and 15 R 4 denotes a hydrogen atom, a C 1 3 -alkyl Yi-C,- alkyl-Y, carboxy-C 1 3 -alkyl-YI-C -- alkyl-Y2, C 1 - 3 -alkyl-Y 2 or carboxy-C 1 3 -alkyl-Y 2 group or R 3 and R 4 together with the nitrogen atom between them 20 denote an 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy, C 1 3 -alkyl or carboxy-C 1 3 -alkyl group wherein Y 1 denotes a carbon-carbon bond, an oxygen atom, a 25 sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and Y 2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl, imino or -NH-CO- group, wherein the carbonyl 30 group of the -NH-CO- group is linked to the nitrogen atom of the R 3 NR 4 - group, and the imino groups occurring in the definition of the groups Y, and Y 2 may each additionally be substituted by a C 1 3 -alkyl or carboxy C 1 3 -alkyl group, 35 a C 1 3 -alkyl or C 3 -- cycloalkyl group substituted by a RNR, group wherein WO 00/01704 - 135 - PCT/EP99/04531 R 5 denotes a hydrogen atom, a C 1 - 3 -alkyl, C 5 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and 5 R 6 denotes a C 1 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy Cl_ 3 -alkylcarbonyl group, a C 1 3 -alkyl group which is substituted by a C 2 4 -alkanoyl or C- 7 -cycloalkanoyl group and by a C 1 3 -alkyl group 10 substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C 1 - 3 -alkyl group and Re denotes a cyano group or an amidino group which may be 15 substituted by a hydroxy group, by one or two C 1 3 -alkyl groups, or by one or two C 1 8 -alkoxycarbonyl groups, wherein the carboxy, amino and imino groups mentioned in the definition of the abovementioned groups may also be 20 substituted by a group which can be cleaved in vivo, the tautomers, stereoisomers and salts thereof. 3. Benzimidazoles of general formula Ia according to claim 25 2, wherein A denotes a C 1 3 -alkylene group, B denotes an oxygen atom, a methylene, imino or N-(CI 30 alkyl)-imino group wherein the alkyl moiety may be substituted by a carboxy group, Ra denotes an C 3 _ 5 -cycloalkyl group substituted by the R 1 -CO group in the 1 position wherein 35 WO 00/01704 - 136 - PCT/EP99/04531 R denotes a C 1 3 -alkoxy, amino, Cl 4 -alkylamino or di (C 1 4 -alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, 5 a 4- to 7-membered cycloalkyleneimino group which may be substituted by a hydroxy group or by one or two C 1 3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C 1 3 -alkoxy, carboxy, carboxy-C 1 3 -alkoxy, carboxy-C 1 3 -alkylamino, 10 N- (C 1 3 -alkyl) -N- (carboxy-C 1 3 -alkyl) -amino, carboxy C 1 3 -alkylaminocarbonyl, N- (C 1 3 -alkyl) -N- (carboxy C 13 -alkyl)-aminocarbonyl, carboxy C 1 3 -alkylaminocarbonylamino, 1- (Cl 3 -alkyl) -3- (carboxy C 1 3 -alkyl) -aminocarbonylamino, 3-(C 1 3 -alkyl)-3-(carboxy 15 C 1 3 -alkyl)-aminocarbonylamino or 1,3-di-(C 13 -alkyl) 3-(carboxy-C 1 3 -alkyl)-aminocarbonylamino group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C 1 3 -alkyl group, to which a phenyl ring 20 is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C 1 3 -alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, 25 a C 3 5 -cycloalkyl group substituted in the 1 position by the R 2 -CX- group, wherein R 2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a 30 C 1 3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1 3 -alkyl group, an oxygen or sulphur atom or an imino group optionally substituted 35 by a C 3 -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the abovementioned alkyl substituent may be substituted by a carboxy, carboxy- WO 00/01704 - 137 - PCT/EP99/04531 C 1 3 -alkoxy, carboxy-C- 3 -alkylamino or N- (C 1 3 -alkyl) carboxy-C 1 3 -alkylamino group, and X denotes an oxygen atom, a C 1 3 -alkylimino, 5 C 1 3 -alkoxyimino or C 1 3 -alkylidene group, each of which may be substituted in the alkyl or alkanoyl moiety by a carboxy group, a C 1 3 -alkyl group substituted in the 1 position by an 10 imidazole or midazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C 1 3 -alkyl groups or by one, two or three C 1 3 -alkyl groups, wherein the 15 substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a carboxy group or may be substituted in the 2 or 3 position by an amino, C 2 --alkanoylamino, Cl- 3 -alkylamino, N- (C 2 - 4 -alkanoyl) -C 1 3 -alkylamino or di 20 (C- 3 -alkyl)-amino group, and the imidazolone ring may be substituted by a C 1 3 -alkyl group, whilst the alkyl substituent may be substituted by a carboxy group or in the 2 or 3 position by an 25 amino, C 2 -4-alkanoylamino, C 1 3 -alkylamino, N- (C 2 4 -alkanoyl) -C 1 3 -alkylamino or di- (C 1 3 -alkyl) -amino group, and additionally a phenyl or pyridine ring may be fused to 30 the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, an imidazolidine-2,4-dion-5-yl group which may be substituted by one or two C 1 - 3 -alkyl groups, whilst at the 35 same time an alkyl substituent may be substituted by a carboxy group, WO 00/01704 - 138 - PCT/EP99/04531 a C, 4 -alkyl group which is substituted in the 1 position by an R 3 NR 4 - or R3NR4-C,--alkyl group and 5 by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-1-yl-carbonyl, carboxy, aminocarbonyl, C, 3 -alkylaminocarbonyl, di-(C, 3 -alkyl)-aminocarbonyl, isoxazolidin-1-ylcarbonyl or 4- to 7-membered cyclo alkyleneiminocarbonyl group, whilst in the 10 abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C,--alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C, 3 -alkylaminocarbonyl, di-(C, 3 -alkyl) aminocarbonyl or cycloalkyleneiminocarbonyl groups may 15 be substituted by a carboxy group, and the remaining hydrogen atoms of the C, 4 -alkyl group may be wholly or partially replaced by fluorine atoms, wherein R 3 denotes a hydrogen atom or a C 1 3 -alkyl group 20 optionally substituted by a carboxy group and R 4 denotes a hydrogen atom, a C, 3 -alkyl-Y 2 or carboxy C- 3 -alkyl-Y 2 group or 25 R 3 and R 4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted in the 1 position by a carboxy, C 1 - 3 -alkyl or carboxy-C, 3 -alkyl group, wherein 30 Y 2 denotes a carbon-nitrogen bond or a carbonyl, imino or -NH-CO- group, wherein the carbonyl group of the -NH-CO- group is linked to the nitrogen atom of the R 3 NR 4 - group, and the imino group occurring in the definition of the groups Y 2 may additionally be 35 substituted by a C 1 3 -alkyl or carboxy-C, 3 -alkyl group, WO 00/01704 - 139 - PCT/EP99/04531 a C 1 3 -alkyl or C 3 -- cycloalkyl group substituted in the 1 position by an RNR,- group, wherein R 5 denotes a hydrogen atom, a C 1 - 3 -alkyl, C 5 7 -cycloalkyl, 5 phenylcarbonyl, phenylsulphonyl or pyridinyl group and R 6 denotes a C 1 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy C 1 3 -alkylcarbonyl group, 10 a C 1 3 -alkyl group which is substituted by a C 2 4 -alkanoyl or C 57 -cycloalkanoyl group and by a C 1 3 -alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a C 1 3 -alkyl group and 15 Re denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, C1-8-alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the benzoyl 20 moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1 - 3 -alkyl or C1- alkoxy groups and the substituents may be identical or different, 25 the C 1 3 -alkanol esters, the tautomers, stereoisomers and salts thereof. 4. Benzimidazoles of general formula Ia according to claim 2, wherein 30 A denotes a methylene group, B denotes an oxygen atom or an imino group, 35 Ra denotes a cyclopropyl group substituted by the R 1 -CO group in the 1 position, wherein WO 00/01704 - 140 - PCT/EP99/04531 R denotes a pyrrolidino or piperidino group optionally substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, 5 carboxy-C 1 3 -alkoxy, carboxy-C 1 3 -alkylamino or N- (C 1 3 -alkyl) -carboxy-C 1 3 -alkylamino group, a cyclopropyl group substituted in the 1 position by the R 2 -CX- group, wherein 10 R 2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C 1 3 -alkyl group and X denotes an oxygen atom, a C 13 -alkoxyimino or 15 C 1 3 -alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, a C 1 2 -alkyl group substituted in the 1 position by an imidazole group wherein the imidazole ring may be 20 substituted by a phenyl or carboxy group and by one or two C 1 3 -alkyl groups or by one, two or three CI 3 -alkyl groups, wherein the substituents may be identical or different and one of the abovementioned alkyl substituents may simultaneously be substituted by a 25 carboxy group or may be substituted in the 2 or 3 position by an amino, C,, -alkanoylamino, C 1 3 -alkylamino, N-(C 2 4 -alkanoyl)-C 1 3 -alkylamino or di-(C 1 3 -alkyl) -amino group, whilst additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole rings via two 30 adjacent carbon atoms, a C 1 2 -alkyl substituted in the 1 position by a benzimidazolon-1-yl group, whilst the imidazolone ring may be substituted by a methyl or ethyl group optionally 35 substituted by a carboxy group, WO 00/01704 - 141 - PCT/EP99/04531 a methyl or ethyl group which is substituted in the 1 position by an R 3 NR 4 or R 3 NR 4 -C 1 _ 3 -alkyl group and 5 by a di-(C 13 -alkyl)-aminocarbonyl group, by a isoxazolidin-1-ylcarbonyl group, by a pyrrolidino carbonyl or piperidinocarbonyl group substituted by a C 1 3 -alkyl group, whilst in the abovementioned groups 10 each alkyl ngoiety or alkyl substituent in the abovementioned groups may be substituted by a carboxy group, wherein R 3 denotes a hydrogen atom or a CI- 3 -alkyl group 15 optionally substituted by a carboxy group and R 4 denotes a hydrogen atom, a C 1 3 -alkyl-Y 2 or carboxy C 1 3 -alkyl-Y 2 group or 20 R 3 and R 4 together with the nitrogen atom between them denote a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy group, wherein Y 2 denotes a carbon-nitrogen bond, a carbonyl group or 25 an imino group optionally substituted by a C 13 -alkyl group, a C 1 2 -alkyl group substituted in the 1 position by an R 5 NR 6 - group, wherein 30 R 5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and R 6 denotes a Cl_ 3 -alkyl or carboxy-C 1 3 -alkyl group, 35 WO 00/01704 - 142 - PCT/EP99/04531 an n-propyl group substituted in the 3 position by a chlorine atom, which is substituted in the 1 position by a cyclopentylcarbonyl group, 5 a cyclopropyl group substituted in the 1 position by a cyclopentylamino group, which is substituted at the nitrogen atom by a carboxy-C 1 3 -alkylcarbonyl group, Rb denotes a methyl group and 10 Re denotes an amidino group which may optionally be substituted by a C 18 -alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, 15 the C 1 3 -alkanol esters thereof, the tautomers, stereoisomers and salts thereof. 5. Benzimidazoles of general formula Ia according to claim 20 2, wherein A denotes a methylene group, B denotes an imino group, 25 Ra denotes a cyclopropyl group substituted by the R,-CO group in the 1 position, wherein R denotes a pyrrolidino or piperidino group optionally 30 substituted by a methyl or ethyl group wherein each methyl or ethyl moiety may be substituted by a carboxy, carboxy-C 1 3 -alkoxy, carboxy-C 1 3 -alkylamino or N- (C 1 3 -alkyl) -carboxy-C 1 3 -alkylamino group, 35 a cyclopropyl group substituted in the 1 position by the R 2 -CX group, wherein WO 00/01704 - 143 - PCT/EP99/04531 R 2 denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C1-3-alkyl group and 5 X denotes an oxygen atom, a C 1 3 -alkoxyimino or C 1 3 -alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, a C 1 2 -alkyl group substituted in the 1 position by an 10 imidazole gioup wherein the imidazole ring may be substituted'by one to three methyl groups or by two methyl groups and an ethyl group, whilst additionally one of the abovementioned methyl or ethyl substituents may simultaneously be substituted by a carboxy group, 15 a methyl or ethyl group which is substituted in the 1 position by an R 3 NR 4 - or R 3 NR 4 -CH 2 - group and 20 by a di-(C 1 3 -alkyl)-aminocarbonyl, by a pyrro lidinocarbonyl or piperidinocarbonyl group optionally substituted by a C--alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl 25 substituent may be substituted by a carboxy group, wherein R 3 denotes a hydrogen atom or a C 1 3 -alkyl group optionally substituted by a carboxy group and 30 R 4 denotes a C 1 3 -alkyl-Y 2 or carboxy- C 1 3 -alkyl-Y 2 group wherein Y 2 denotes a carbon-nitrogen bond, a carbonyl group or 35 an imino group optionally substituted by a C 1 3 -alkyl group, WO 00/01704 - 144 - PCT/EP99/04531 Rb denotes a methyl group and Re denotes an amidino group which may optionally be substituted by a C1-8-alkoxycarbonyl, 5 acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, the C 1 - 3 -alkanol esters thereof, the tautomers, stereoisomers and salts thereof. 10 6. Benzimidazoles of general formula I according to at least one of claims 1 to 5 wherein the group Ra is in the 5 position, 15 the tautomers, stereoisomers and salts thereof.
7. The following compounds of general formula Ia: (a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l 20 (pyrrolidin-1-yl-carbonyl)cyclopropyl]-benzimidazole, (b) (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[l [(pyridin-2-yl)-(carboxymethyloxyimino)methylene] cyclopropyl]-benzimidazole, 25 (c) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2 carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] benzimidazole, 30 (d) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-[2-(2 carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl] benzimidazole, (e) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[2-(2 35 carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl] benzimidazole WO 00/01704 - 145 - PCT/EP99/04531 (f) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxy methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimi dazole and 5 (g) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-methyl carboxymethylcarbonylaminomethyl)-1-methyl-i-(pyrrolidin 1-yl-carbonyl)-ethyl]-benzimidazole and the C 3 -alkanolesters, the N-(C 18 -alkoxycarbonyl), 10 N-benzyloxycalbonyl and N-benzoyl-amidines thereof, the tautomers, stereoisomers and salts thereof.
8. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 (carboxymethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl] 15 benzimidazole, the C 1 3 -alkanolesters thereof, and their N-(C,-,-alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl amidines, tautomers, stereoisomers and salts.
9. Physiologically acceptable salts of the compounds 20 according to claims 1 to 8 wherein Re denotes one of the amidino groups mentioned in claims 1 to 8.
10. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 8 wherein Re 25 denotes one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, optionally together with one or more inert carriers and/or diluents.
11. Use of a compound according to at least one of claims 30 1 to 8 wherein Re denotes one of the amidino groups mentioned in claims 1 to 8, or a salt according to claim 9, for preparing a pharmaceutical composition with a thrombin time prolonging effect, a thrombin-inhibiting effect and an inhibiting effect on related serine 35 proteases. WO 00/01704 - 146 - PCT/EP99/04531
12. Process for preparing a pharmaceutical composition according to claim 10, characterised in that a compound according to at least one of claims 1 to 8 wherein Re denotes one of the amidino groups mentioned in claims 1 to 5 8, or a salt according to claim 9, is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
13. Process for preparing the compounds according to 10 claims 1 to 9, characterised in that a) in order to prepare a compound of general formula I wherein Rc denotes a cyano group: 15 a compound of general formula zi Z 2 NH-C -A-B -Ar -CN NH Rb optionally formed in the reaction mixture, 20 wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 8, Zi and Z 2 , which may be identical or different, denote amino, hydroxy or mercapto groups optionally substituted by alkyl groups with 1 to 6 carbon atoms or 25 Zi and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms, is cyclised, or 30 b) in order to prepare a compound of general formula I wherein Ra denotes an R2-CX'-C 3 _-cycloalkylene group, WO 00/01704 - 147 - PCT/EP99/04531 wherein R 2 is defined as in claims 1 to 8 and X' denotes one of the imino groups mentioned for X in claims 1 to 8: a compound of general formula 5 N R AB-Ar -R (IV), N Rb wherein Rb, Ar, A and B are defined as in claims 1 to 8 and Ra' denotes an R 2 -CO-C 3 _ -cycloalkylene group, where 10 R 2 is defined as in claims 1 to 8, is reacted with an amine of general formula 15 H 2 X' (V) wherein X' denotes one of the imino groups mentioned for X in claims 1 to 8, or 20 c) in order to prepare a compound of general formula I wherein Ra denotes an R 2 -CX"-C 3 _ 5 -cycloalkylene group, wherein R 2 is defined as in claims 1 to 8 and X" denotes one of the alkylidene groups mentioned for X in claims 1 25 to 8, a compound of general formula N Ra A-B-Ar--R (IV), N Rb wherein Rb, Ar, A and B are defined as in claims 1 to 8 and WO 00/01704 - 148 - PCT/EP99/04531 Ra' denotes an R 2 -CO-C 3 _ 5 -cycloalkylene group, where R 2 is defined as in claims 1 to 8, 5 is reacted with a phosphone of general formula Z 3 -HX" (VI), wherein 10 X" denotes one of the alkylidene groups mentioned for X in claims 1 to 8 and Z 3 denotes a triphenylphosphono or di (Cl- 3 -alkoxy)phosphono group, or 15 d) in order to prepare a compound of general formula I wherein Re denotes an amidino group which may be substituted by one or two C 1 - 3 -alkyl groups: a compound of general formula Ra A-B-Ar- C= (NH) Z 4 (VII), N 20 Rb optionally formed in the reaction mixture wherein 25 Ra, Rb, Ar, A and B are defined as in claims 1 to 8 and Z 4 denotes an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with an amine of general formula H - R 7 NR 8 , (VIII) 30 wherein WO 00/01704 - 149 - PCT/EP99/04531 R 7 and R., which may be identical or different, each denote a hydrogen atom or a C 1 - 3 -alkyl group, or with the salts thereof, or 5 e) in order to prepare a compound of general formula I wherein Ra denotes an imidazolidin-2,4-dion-5-yl group which may be substituted by one or two C 1 _ 3 -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or C 1 3 -alkoxycarbonyl group: 10 a compound of general formula N Ra"--[a A-B-Ar - CN (IX), CII Rb 15 optionally formed in the reaction mixture wherein Rb, Ar, A and B are defined as in claims 1 to 8 and Ra" denotes an aminocarbonylamino group, substituted in 20 the 3 position by a CI- alkoxycarbonyl-C 1 3 -alkyl group, is cyclised, or f) in order to prepare a compound of general formula I wherein Re denotes a hydroxyamidino group: 25 a nitrile of general formula N Ra " A-- B-Ar - CN (X), N Rb wherein WO 00/01704 - 150 - PCT/EP99/04531 Ra, Rb, Ar, A and B are defined as in claims 1 to 8, is reacted with hydroxylamine or the salts thereof, or g) in order to prepare a compound of general formula I 5 wherein Ra contains a carboxy group and R, is defined as in claims 1 to 8 or Ra is defined as in claims 1 to 8 and R, denotes an amidino group optionally substituted by a hydroxy group or by one or two C,--alkyl groups: 10 a compound of general formula N Ra'I" A-B--Ar - Re (XI), Rb wherein Rb, Ar, A and B are defined as in claims 1 to 8 and 15 Ra'" and R,' have the meanings given for Ra and Rc in claims 1 to 8, with the proviso that Ra contains a group which may be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and Re is defined as in claims 1 to 8 or R, 20 denotes a group which may optionally be converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into an amidino group substituted by a hydroxy group or by one or two Cl-,-alkyl groups and Ra is defined as in claims 1 to 8, 25 is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I wherein Ra contains a carboxy group and Rc is defined as in claims 1 to 8 or Ra is defined as in 30 claims 1 to 8 and R. denotes an amidino group optionally substituted by a hydroxy group or by one or two C 13 -alkyl groups, or WO 00/01704 - 151 - PCT/EP99/04531 h) in order to prepare a compound of general formula I wherein Rc denotes an amidino group which is substituted by one or two C 1 8 -alkoxycarbonyl groups or by a group which can be cleaved in vivo: 5 a compound of general formula I N Ra I " A-B-Ar- Re (XII), N Rb wherein 10 Ra, Rb, Ar, A and B are defined as in claims 1 to 8 and Rc" denotes an amidino group, is reacted with a compound of general formula Z5 - R 9 (XIII), 15 wherein R 9 denotes a C 18 -alkoxycarbonyl group or the acyl group of one of the groups which can be cleaved in vivo mentioned hereinbefore and 20 Z 5 denotes a nucleofugic leaving group, and subsequently if desired a compound of general formula I thus obtained which contains an (R 3 NR 4 ) -C 1 3 -alkyl group in which at least one of the groups R 3 or R 4 denotes a 25 hydrogen atom, is converted with a corresponding isocyanate or carbamoyl halide into a corresponding urea compound of general formula I, and/or a compound of general formula I thus obtained which 30 contains a NH 2 -C 1 3 -alkyl group is converted with a corresponding acrylic acid ester into a corresponding WO 00/01704 - 152 - PCT/EP99/04531 2-(C 1 3 -alkoxycarbonyl)-ethyl compound of general formula I and/or a compound of general formula I thus obtained which 5 contains an (R 3 NR 4 )-C 1 3 -alkyl group in which R, and R 4 each denote a hydrogen atom is converted with a corresponding dihaloalkane into a corresponding compound of general formula I wherein R 3 and R 4 together with the nitrogen atom between them denote a corresponding 4- to 7-membered 10 cycloalkyleneimino group and/or a compound of general formula I thus obtained wherein Re denotes an amidino group is converted with a haloacetic acid derivative and subsequent hydrolysis and 15 decarboxylation into a corresponding amidino compound substituted by one or two methyl groups and/or a compound of general formula I thus obtained wherein Re denotes a hydroxyamidino group is converted by catalytic 20 hydrogenation into a corresponding amidino compound and/or a compound of general formula I thus obtained wherein Ra contains a carboxy group is converted by esterification into a corresponding ester and/or 25 a protecting group used to protect reactive groups during the reactions is cleaved and/or a compound of general formula I thus obtained is resolved 30 into its stereoisomers and/or a compound of general formula I thus obtained is converted into the salts thereof, more particularly for pharmaceutical use into the physiologically acceptable 35 salts thereof with an inorganic or organic acid or base.
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DE1998129964 DE19829964A1 (en) 1998-07-04 1998-07-04 New benzimidazolyl amidine or nitrile compounds, used as thrombin inhibitors, antithrombotic agents or intermediates
DE1998157202 DE19857202A1 (en) 1998-12-11 1998-12-11 New benzimidazolyl amidine or nitrile compounds, useful as thrombin inhibitors or antithrombotic agents, for treating deep leg vein thrombosis
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