AU763094B2 - Benzimidazoles, production thereof and use thereof as medicaments - Google Patents

Benzimidazoles, production thereof and use thereof as medicaments Download PDF

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AU763094B2
AU763094B2 AU49033/99A AU4903399A AU763094B2 AU 763094 B2 AU763094 B2 AU 763094B2 AU 49033/99 A AU49033/99 A AU 49033/99A AU 4903399 A AU4903399 A AU 4903399A AU 763094 B2 AU763094 B2 AU 763094B2
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group
alkyl
carboxy
substituted
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AU4903399A (en
AU763094C (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
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    • 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
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    • 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

Description

WO 00/01704 1 PCT/EP99/04531 S018842pct.203 Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions The present invention relates to benzimidazoles of general formula Ra A-B -Ar-Rc 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 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 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 R c denotes one of the following amidino groups, as well as 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 their salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, and the 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 use thereof.
In the above general formula Ar denotes a phenylene or naphthylene group optionally 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 substituted in the carbon skeleton by a C_ 3 -alkyl group, A denotes a C_ 3 -alkylene group, B denotes an oxygen or sulphur atom, a methylene, 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, Ra denotes an R 1 -CO-C3- 5 -cycloalkyl group wherein R denotes a C 1 3 -alkoxy, amino, C,_4-alkylamino or di-
(C
1 .4-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by a hydroxy group or by one or two Cl_ 3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, Cl_ 3 -alkoxy, carboxy, carboxy-C_ 3 -alkoxy, carboxy-C 3-alkylamino, N- (C 3 -alkyl) (carboxy-
C_.
3 -alkyl)-amino, carboxy-C_ 3 -alkylaminocarbonyl, iii WO 00/01704 3 PCT/EP99/04531
N-(C
1 _3-alkyl)-N-(carboxy-C 1 3 -alkyl)-aminocarbonyl, carboxy-CI_3-alkylaminocarbonylamino, 1-(C_ 3 -alkyl)- 3-(carboxy-C 1 3 -alkyl)-aminocarbonylamino, 3- (C 13 -alkyl)- 3-(carboxy-C 1 3 -alkyl)-aminocarbonylamino or 1,3-di- (Ci_ 3 -alkyl)-3-(carboxy-C_ 3 -alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, a 5- to 7-membered cycloalkyleneimino group optionally 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, an R 2 -CX-C3-s-cycloalkyl group wherein
R
2 denotes a phenyl, naphthyl or monocyclic 5- or 6-membered heteroaryl group optionally substituted by a
CI_
3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 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 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 .3-alkoxy, carboxy-C 1 -3-alkylamino or N- (C 13 -alkyl)carboxy-C_.3-alkylamino group, and X denotes an oxygen atom, a C-_3-alkylimino,
C_.
3 -alkoxyimino, C 1 3 -alkylhydrazino, di- (C 1 3 -alkyl)hydrazino, C 2 4 -alkanoylhydrazino, N- 3 -alkyl)-
C
2 -4-alkanoylhydrazino or C 13 alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety .i WO 00/01704 4 PCT/EP99/04531 or in the alkyl and alkanoyl moieties by a carboxy group, a C 1 3 -alkyl or C3-,-cycloalkyl group substituted by an 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 C 1 3 -alkyl groups, wherein the substituentp 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) -C 1 3 -alkylamino or di-
(C
1 3 -alkyl)-amino group, and the imidazolone ring may be substituted by a C 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, Cl 1 3 -alkylamino,
N-(C
24 -alkanoyl) -Cl- 3 -alkylamino or di- (Cl 13 -alkyl)-amino group, and 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 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 14 -alkyl group which is substituted by a Cl 1 3 -alkyl-Y,-Cl_ 3 -alkyl, HOOC-Cl-3-alkyl-Yl-Cl 3 -alkyl, tetrazolyl-C, 3 -alkyl-Y,, R3NR4- or R 3
NR
4 -C-3-alkyl group and WO 00/01704 5 PCT/EP99/04531 by an isoxazolidinylcarbonyl group optionally substituted by a C 1 3 -alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-l-ylcarbonyl, carboxy, aminocarbonyl,
C
1 .3-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 two C._3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned
C_
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 Cl_4-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
R
4 denotes a hydrogen atom, a C 1 3 -alkyl- Y,-C1.3-alkyl-Y,, carboxy-C 1 _,-alkyl-Y-C-alkyl-Y,,
C
1 3 -alkyl-Y 2 or carboxy-C 1 3 -alkyl-Y 2 group or R3 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
Y
1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -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 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, a C,_ 3 -alkyl or C 3 _.-cycloalkyl group substituted by a RsNR,group wherein
R
s denotes a hydrogen atom, a C 3 3-alkyl, Cs,-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and
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 Cs,_-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 Rc denotes a cyano group or an amidino group optionally substituted by one or two C 1 3 -alkyl groups.
The carboxy groups mentioned in the definitions of the abovementioned groups may also be replaced by a group 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 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).
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 -alkanol, a phenyl-C 1 3 -alkanol, a C 3 9 _,-cycloalkanol, whilst a C 5 8 -cycloalkanol may additionally be substituted by one or two C 1 3 -alkyl groups, a C 5 ,-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, phenyl-Cl- 3 -alkyl, phenyl-C 1 3 -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,_,-cycloalkenol, a C 3 5 -alkenol, a phenyl-
C
35 alkenol, a C3-,-alkynol or phenyl-C 3 5 -alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a
C
38 -cycloalkyl-C 3 -alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which may additionally be substituted in the bicycloalkyl moiety by one or two C1 3 -alkyl groups, a 1,3-dihydro-3-oxo-l-isobenzofuranol or an alcohol of formula Rd-CO-O- (ReCRf) -OH, wherein Rd denotes a C,_,-alkyl, C 5 _,-cycloalkyl, phenyl or phenyl- C1--alkyl group, Re denotes a hydrogen atom, a C 1 3 -alkyl, C,-cycloalkyl or phenyl group and R, denotes a hydrogen atom or a C 3 -alkyl group, a group which is negatively charged under physiological conditions may be a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluormethylcarbonylaminocarbonyl, alkylsulphonylamino, phenylsulphonylamino, WO 00/01704 PCT/EP99/04531 benzylsulphonylamino, trifluoromethylsulphonylamino, Cl- 6 -alkylsulphonylaminocarbonyl, phenylsuiphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro- Cl- 6 -alkylsulphonylaminocarbonyl group 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 atoms, by C 1 -alky1 or C- 3 -alkoxy groups, wherein the substituents may be identical or different, a pyridinoyl group or a C 116 -alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3trichloropropionyl or allyloxycarbonyl group, a Cl- 16 -alkoxycarbonyl or Cl- -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, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C 16 ,-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by
C-
6 -alkyl or C 37 -cycloalkyl groups and the substituents may be identical or different, a Cl 1 3 -alkylsulphonyl-
C
2 4 -alkoxycarbonyl, C 13 -alkoxy-C 24 ,-alkoxy-
C
24 -alkoxycarbonyl, Rd-CO-O- (RdCRf) Cl-,-alkyl-CO-NH- WO 00/01704 9 PCT/EP99/04531 (RgCRh) -O-CO- or Cl_ 6 -alkyl-CO-O- (RgCRh) (RgCRh) -O-CO- group wherein Rd to R, are as hereinbefore defined, Rg and Rh, which may be identical or different, denote hydrogen atoms or Ci.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, such as, for example, the isopropyl, tert.butyl, isobutyl group etc.
Preferred compounds are those of general formula Ra- Rc (Ia), Rb wherein A denotes a C 13 -alkylene group, B denotes an oxygen or sulphur atom, a methylene, 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, Ra denotes an R 1
-CO-C
3 _s-cycloalkyl group wherein R denotes a C 1 3 -alkoxy, amino, C._4-alkylamino or di-
(C
14 -alkyl)-amino group wherein each alkyl moiety may be 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, 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 3 -alkylamino, N- (C 3 -alkyl)-N-(carboxy-C 1 3 -alkyl)amino, carboxy-C, 3 -alkylaminocarbonyl, N-(C 13 -alkyl)- N-(carboxy-C 1 3 -alkyl)-aminocarbonyl, carboxy- C 3 -alkylaminocarbonylamino, 1- (Cz 3 -alkyl)-3-(carboxy- C, 3 -alkyl) -aminocarbonylamino, 3- (C_ 3 -alkyl)-3-(carboxy-
C,-
3 -alkyl)-aminocarbonylamino or 1,3-di-(C, 1 3 -alkyl)- 3-(carboxy-ql 3 -alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 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 13 -alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-1-yl group, an R,-CX-C 35 ,-cycloalkyl group wherein R, 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 heteroaryl group contains an imino group optionally substituted by a C- 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-
C
1 3 -alkoxy, carboxy-C_-alkylamino or N-(Cl.
3 -alkyl)carboxy-C, 3 -alkylamino group, and WO 00/01704 11 PCT/EP99/04531 X denotes an oxygen atom, a Cl_ 3 -alkylimino,
C
1 3 -alkoxyimino, C 1 3 -alkylhydrazino, di- (C, 3 -alkyl)hydrazino, C 2 4 -alkanoylhydrazino, N- (C 13 -alkyl)
C,
2 4 -alkanoylhydrazino or C 1 3 -alkylidene group each of 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 35 -cycloalkyl group substituted by an 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 C 1 3 -alkyl groups, wherein the 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, C2-4-alkanoylamino, Cl 3 -alkylamino, N- (C 2 ,_-alkanoyl) -C 1 3 -alkylamino or di- (Cl_ 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 amino, C2-4-alkanoylamino, C..
3 -alkylamino, N- (C2- 4 -alkanoyl) -C, 3 -alkylamino or di- (Cl 1 3 -alkyl)-amino group, and 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 substituted by one or two C, 3 -alkyl groups, whilst at the 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-Y,-CI_ 3 -alkyl, HOOC-C 1 3 -alkyl-YI-C 1 3 -alkyl, tetrazolyl-C 1 _3-alkyl-Y 2
R
3
NR
4 or R 3
NR
4 -Ci-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a C 1 3 -alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro-piperidinocarbonyl, pyrroll-yl-carbonyl, carboxy, aminocarbonyl,
C
1 3 -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 two C,_3-alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned Cl.3-alkylaminocarbonyl, di- (C.3-alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may 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_3-alkyl group optionally substituted by a carboxy group and
R
4 denotes a hydrogen atom, a C 1 -3-alkyl- Y, -C 1 3 -alkyl-Y,, carboxy- C, 3 -alkyl-Y,-C 1 3 -alkyl-Y 2
C
1 3 -alkyl-Y 2 or carboxy-C_, 3 -alkyl-Y 2 group or
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
Y
1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-CO- or -NH-CO-NH- group and w~ 00/01704 13 PCT/EP99/04531 (9
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 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,_3-alkyl group, a C_ 3 -alkyl or C 3 ,_-cycloalkyl group substituted by a RsNR,group wherein R, denotes a hydrogen atom, a C 1 3 -alkyl, Cs,-cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and
R
6 denotes a C 1 3 -alkyl, carboxy-C 1 .3-alkyl or carboxy-
C
13 -alkylcarbonyl group, a C 1 .3-alkyl group which is substituted by a C 2 _4-alkanoyl or Cs 57 -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,_ 3 -alkyl group and Re denotes a cyano group or an amidino group which may be substituted by a hydroxy group, by one or two C 1 3 -alkyl groups, or by one or two C_, 8 -alkoxycarbonyl groups, wherein the carboxy, amino and imino groups mentioned in 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.
TWT" n '/7n/I 1 PT/ P9/AC-1 t v v' .L .l U'*rJ L Particularly preferred compounds of the above general formula Ia are those wherein A denotes a C 1 _3-alkylene group, B denotes an oxygen atom, a methylene, imino or N-(Cz.3alkyl)-imino group wherein the alkyl moiety may be substituted by a carboxy group, Ra denotes an C3-s-cycloalkyl group substituted by the R,-CO group in the 1 position wherein R denotes a Cl_ 3 -alkoxy, amino, C, 4 -alkylamino or di- (C_-4-alkyl)-amino group wherein each alkyl moiety may be 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 Cz_ 3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, Cz_-alkoxy, carboxy, carboxy-C 1 3 -alkoxy, carboxy-Cz_ 3 -alkylamino, N- C 3 -alkyl) (carboxy-Cz.
3 -alkyl) -amino, carboxy-
C._
3 -alkylaminocarbonyl, N- (Cz 3 -alkyl) (carboxy-
C,_
3 -alkyl)-aminocarbonyl, carboxy- C_ 3 -alkylaminocarbonylamino, 1- (C_ 3 -alkyl) (carboxy-
C
1 3 -alkyl) -aminocarbonylamino, 3- (Cz 3 -alkyl) (carboxy-
CI.
3 -alkyl) -aminocarbonylamino or 1,3-di-(C 1 z 3 -alkyl)- 3- (carboxy-Ci- 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 is fused via two adjacent carbon atoms, a morpholino, piperazino, N- (C_ 3 -alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, WO 00/01704 15 PCT/EP99/04531 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
C
13 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the heteroaryl group contains an imino group optionally substituted by a C 13 -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- C_3 -alkoxy, carboxy-C, 3 -alkylamino or N-(C 1 .3-alkyl)carboxy- C,3-alkylamino group, and X denotes an oxygen atom, a C_.3-alkylimino,
C
1 .3-alkoxyimino or C 13 -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 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 C-_-alkyl groups, wherein the 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_.3-alkylamino, N-(C 2 _4-alkanoyl) 3 -alkylamino or di-
(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 p WO 00/01704 16 PCT/EP99/04531 amino, C2-4-alkanoylamino, C, 3 -alkylamino, N-(C2-4-alkanoyl) -C, 3 -alkylamino or di- (C 13 -alkyl)-amino group, and 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 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,_ 4 -alkyl group which is substituted in the 1 position by an R 3
NR
4 or R 3 NR-C-alkyl group and by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-l-yl-carbonyl, carboxy, aminocarbonyl, Cl.-alkylaminocarbonyl, di-(C- 3 -alkyl)-aminocarbonyl, isoxazolidin-1-ylcarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C, 3 -alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned CI_3-alkylaminocarbonyl, di- (Cl_ 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 partially replaced by fluorine atoms, wherein
R
3 denotes a hydrogen atom or a C, 3 -alkyl group optionally substituted by a carboxy group and
R
4 denotes a hydrogen atom, a C 13 -alkyl-Y 2 or carboxy-
C,_
3 -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
1 _3-alkyl or carboxy-C 1 3 -alkyl group, wherein
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 substituted by a C 1 3 -alkyl or carboxy-C 1 3 -alkyl group, a C 1 -3-alkyl or C3-s-cycloalkyl group substituted in the 1 position by an RNR 6 group, wherein
R
s denotes a hydrogen atom, a C 1 _3-alkyl, Cs,--cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R, denotes a Cl_ 3 -alkyl, carboxy-C_.
3 -alkyl or carboxy-
C
13 -alkylcarbonyl group, a Cl_ 3 -alkyl group which is substituted by a C2-4-alkanoyl or Cs,-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
R
c denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, C_-,-alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C,_ 3 -alkyl or Cl_3-alkoxy groups and the substituents may be identical or different, WO 00/01704 18 PCT/EP99/04531 the C 13 -alkanol esters, the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of general formula I are those wherein A denotes a methylene group, B denotes an oxygen atom or an imino group, Ra denotes a cyclopropyl group substituted by the R 1
-CO-
group in the 1 position, wherein 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-CI_3-alkoxy, carboxy-C 1 3 -alkylamino or N- (C_ 3 -alkyl) -carboxy-C_3 -alkyl amino group, 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 X denotes an oxygen atom, a C_ 3 -alkoxyimino or Cl_ 3 -alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, a C1-2-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 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 _3-alkylamino, N- (C2-4-alkanoyl) -C 13 -alkylamino or di- (C 13 -alkyl) -amino group, whilst additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole rings via two adjacent carbon atoms, a C1-2-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 substituted by a carboxy group, a methyl or ethyl group which is substituted in the 1 position by an R 3
NR
4 or R 3
NR
4 3 -alkyl group and by a di-(C 1 _-alkyl)-aminocarbonyl group, by an isoxazolidin-l-ylcarbonyl group, by a pyrrolidinocarbonyl 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
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_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 denote a 4- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy group, wherein 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_ 3 -alkyl group, a C 1 -2-alkyl group substituted in the 1 position by an RsNR,- group, wherein
R
s denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and
R
6 denotes a C- 3 -alkyl or carboxy-C_ 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 cyclopentylcarbonyl group, 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
R
e denotes an amidino group which may optionally be substituted by a C,_ 8 -alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, particularly those compounds of general formula Ia wherein A denotes a methylene group, B denotes an imino group, Ra denotes a cyclopropyl group substituted by the R,-COgroup 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-CI_-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 R, denotes a phenyl, pyridyl, pyrazolyl group optionally substituted by a C 1 3 -alkyl group and X denotes an oxygen atom, a C _--alkoxyimino or
C
13 -alkylidene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, a C 1 _.-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 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 position by an R 3
NR
4 or R 3
NR
4
-CH
2 group and by a di-(C 1 3 -alkyl)-aminocarbonyl, by a pyrrolidinocarbonyl 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
R
3 denotes a hydrogen atom or a C 1 _3-alkyl group optionally substituted by a carboxy group and A 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
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
R
e denotes an amidino group which may optionally be substituted by a C_-8-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the abovementioned compounds in which the group Ra is in the 5 position are particularly preferred, the C_3-alkanol esters, the tautomers, stereoisomers and salts thereof.
The following are mentioned as examples of particularly preferred compounds: 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1- (pyrrolidin-1-yl-carbonyl)-cyclopropyl] -benzimidazole, (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5- [1- [(pyridin-2-yl) (carboxymethyloxyimino)methylene] cyclopropyl] -benzimidazole, 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]benzimidazole, WO 00/01704 23 PCT/EP99/04531 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[2-(2carboxyethyl) -pyrrolidin-1-yl-carbonyl] cyclopropyl] benzimidazole, 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2carboxyethyl) 5-dimethyl-imidazol-1-yl-methyl] benzimidazole 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1-(carboxymethylamino) -1-(pyrrolidin-1-yl-carbonyl) -ethyl] benzimidazole and 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1-(N-methyl carboxymethylcarbonylaminomethyl) -1-methyl-i- (pyrrolidin- 1-yl-carbonyl) -ethyl] -benzimidazole and the C 1 3 -alkanol esters, the N-(Cl- 8 -alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl-amidines, the tautomers, stereoisomers and salts thereof.
According to the invention, the compounds of general formula I are prepared by methods known per se, for example by the following methods: a) In order to prepare a compound of general formula I wherein Rc denotes a cyano group: cyclising a compound of general formula a,,NH-CAB -Ar
-CN
Ra I WO 00/01704 24 PCT/EP99/04531 optionally formed in the reaction mixture, wherein Rb, Ar, A and B are as hereinbefore defined,
Z
i 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 Z 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 alkylenedithiQ 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, 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 example at temperatures between 0 and 250 0 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 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 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 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 reaction mixture.
b) In order to prepare a compound of general formula I wherein Ra denotes an R 2
-CX'-C
35 -cycloalkylene group, wherein R 2 is as hereinbefore defined and X' denotes one of the imino groups mentioned for X hereinbefore: reacting a compound of general formula Ra'- -A-B-Ar--R (IV),
N
I
Rb wherein Rb, Ar, A and B are as hereinbefore defined and Ra' denotes an R 2 -CO-C3-,-cycloalkylene group, where
R
2 is as hereinbefore defined, with an amine of general formula
H
2 X' wherein X' denotes one of the imino groups mentioned for X hereinbefore.
The reaction is preferably carried out in a solvent such 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 wherein Radenotes an R 2 -CX"-C3-.-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 Ra' -A-B-Ar-Re
(IV),
Rb wherein Rb, Ar, A and B are as hereinbefore defined and Ra' denotes an R 2 -CO-C3-s-cycloalkylene group, where
R
2 is as hereinbefore defined, with a phosphone of general formula
Z
3 -HX" (VI), wherein X" denotes one of the alkylidene groups mentioned for X hereinbefore and
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 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 -150 and ambient temperature.
d) In order to prepare a compound of general formula I wherein R e denotes an amidino group which may be substituted by one or two C 1 3 -alkyl groups: reacting a compound of general formula Ra -A-B-Ar-C= (NH) Z 4
(VII),
N
Rb optionally formed in the reaction mixture wherein Ra, Rb, Ar, A and B are as hereinbefore defined and
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 H R 7
NR
8
,(VIII)
wherein R, and which may be identical or different, each 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 dioxane at temperatures between 0 and 150 0 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 by reacting a corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 0 C, but preferably at 200C, or a corresponding nitrile with hydrogen sulphide expediently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequently alkylating the thioamide formed with a corresponding alkyl or aralkyl halide.
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 13 -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or C 1 3 -alkoxycarbonyl group: cyclising a compound of general formula Ra" -A-B -Ar CN
(IX),
N
Rb optionally formed in the reaction mixture 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 C,3-alkoxycarbonyl-CI 3 -alkyl group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at temperatures between 0 and 50 0 C, but preferably at 0
C.
f) In order to prepare a compound of general formula I wherein Rc denotes a hydroxyamidino group: reacting a nitrile of general formula
R
a CN
N
15 Rb wherein Ra, Rb, Ar, A and B are as hereinbefore defined, with hydroxylamine or the salts thereof.
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.
g) In order to prepare a compound of general formula I wherein Ra contains a carboxy group and R c is as hereinbefore defined or Ra is as hereinbefore defined and
R
e denotes an amidino group optionally substituted by a hydroxy group or by one or two C 1 3 -alkyl groups: converting a compound of general formula WO 00/01704 30 PCT/EP99/04531 Ra' R (XI), Rb wherein Rb, Ar, A and B are as hereinbefore defined and R' and have the meanings given for Ra and R e 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 R c is as hereinbefore defined or Rc 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 C 13 -alkyl groups and Ra is as hereinbefore defined, 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
R
e is as hereinbefore defined or Ra is as hereinbefore defined and R e denotes an amidino group optionally substituted by a hydroxy group or by one or two C 1 3 -alkyl 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 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, 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 0) 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.
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 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 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 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 as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 1200C, e.g. at temperatures between 0 and 60 0 C, or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, 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 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 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.
h) In order to prepare a compound of general formula I wherein R e denotes an amidino group which is substituted by one or two C 1 .,-alkoxycarbonyl groups or by a group which can be cleaved in vivo: reacting a compound of general formula I Ra -A-B-Ar- Rc" (XII),
-~N
Rb wherein Ra, Rb, Ar, A and B are as hereinbefore defined and Re" denotes an amidino group, with a compound of general formula Zs R 9
(XIII),
wherein
R
9 denotes a C 1 8 -alkoxycarbonyl group or the acyl group of one of the groups which can be cleaved in vivo mentioned hereinbefore and
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 optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 0 C and the boiling temperature of the solvent used.
With a compound of general formula XIII wherein Z, denotes 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 carbonate, potassium tert. butoxide or N-ethyldiisopropylamine at temperatures between 0 and 60 0
C.
If according to the invention a compound of general formula I is obtained which contains a (R 3
NR
4
)-C
13 -alkyl 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 if a compound of general formula I is obtained which contains an NH 2 -CI-3-alkyl group, this may subsequently be converted with a corresponding acrylic acid ester into a corresponding 2- (C_ 3 -alkoxycarbonyl)-ethyl compound of general formula I and/or if a compound of general formula I is obtained which contains an (R 3
NR
4 13 -alkyl group wherein R 3 and R4 each denote a hydrogen atom, this may subsequently be 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 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 R c 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 if a compound of general formula I is obtained wherein R e denotes a hydroxyamidino group, this may subsequently be converted into a corresponding amidino compound by catalytic hydrogenation and/or 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.
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 as triethylamine at temperatures between 0 and 50 0
C,
preferably at ambient temperature,.
The subsequent preparation of a corresponding 2-(C 1 3 -alkoxy-carbonyl) -ethyl-compound is carried out with 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.
The subsequent preparation of a corresponding 4- to 7membered 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 100 0
C,
preferably at the boiling temperature of the reaction mixture.
The subsequent alkylation is expediently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously act as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 0 C, but preferably at temperatures between -10 and 80 0
C.
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 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 described at temperatures between -10 and 1200C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The subsequent esterification is carried out with a corresponding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, 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 chloroformate, thionyl chloride, trimethylchlorosilane, sulphuric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine expediently at temperatures between 0 and 1500C, preferably at temperatures between 0 and 800C, or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, 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-ethyldiisopropylamine 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 0 C, but preferably at temperatures between -10 and 800C.
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 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, 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 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.
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 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 1000C, preferably at temperatures between 10 and 50 0
C.
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, 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 500C, but preferably at ambient temperature, and at a hydrogen 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 500C, but preferably at ambient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl pr 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.
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 0
C.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 0 C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between and 70 0
C.
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 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- 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 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 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 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 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 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.
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 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 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, dio-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or 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 (-)-menthyloxycarbonyl.
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, 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 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, ethanolamine, diethanolamine and triethanolamine.
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 R e denotes a cyano group are valuable intermediate products for preparing the other compounds of general formula I, and the compounds of general formula I wherein Re denotes one of the abovementioned amidino groups, and the tautomers, stereoisomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an activity which influences thrombin or factor Xa, for example on a thrombininhibiting or factor Xa-inhibiting activity, on an activity which extends the aPTT time and on an inhibiting effect on related serine proteases such as, for example, trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.
For example, the compounds A 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (pyrrolidin-l-yl-carbonyl)cyclopropyl]-benzimidazolehydrochloride, B (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1- [(pyridin-2-yl)-(carboxymethyloxyimino)methylene]cyclopropyl]-benzimidazole-hydrochloride, C 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2carboxyethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]benzimidazole-hydrochloride, WO 00/01704 42 PCT/EP99/04531 D 2-(4-amidinophenylaminomethyl)-1-methyl-5-Il-[2-(2carboxyethyl)-pyrrolidin-1-yl-carbonyl]cyclopropyl]benzimidazole-hydrochloride, E 2-(4-amidinophenylaminomethyl )-1-methyl-5- (2carboxyethyl)-4,5-dimethyl-imidazol-1-yl-methyl]benzimidazole-hydrochloride, F 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamio)-l-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole-hydrochioride and G 2- (4-amidinophenylaminomethyl) methyl-5- (N-methyl carboxymethylcarbonylaminomethyl)-1-methyl-l-(pyrrolidin- 1-yl-carbonyl)-ethyl] -benzimidazole-dihydrochloride were investigated for their effect on extending the aPTT time as follows: Materials: Plasma, from human citrated blood, PTT reagent, Boehringer Mannheim (524298), calcium solution (0.025 Mol/1), Behring Werke, Marburg (ORH 056/57), diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61), -Biomatic B10 coagulometer, Desaga, Wiesloch.
Method: The aPTT time was determined using a Biomatic made by Messrs. Desaga.
The test substance was added to the test vessels 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 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 curve.
The following Table contains the values found: substance APTT time
(ED
2 0 0 in AM) A 0.12 B 0.42 C 0.31 D 0.29 E 0.29 F 0.20 G 0.17 The compounds prepared according to the invention are well tolerated, since no toxic side effects could be detected at therapeutic doses.
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 treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty 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 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 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 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.
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, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples which follow are intended to illustrate the invention: WO 00/01704 45 PCT/EP99/04531 Example 1 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidin- 1-vl-carbonyl)cyclopropyl]-benzimidazole-hydrochloride a. 1-(4-chloro-3-nitro-phenyl)-1-cyclopropanecarboxylic acid To 350 ml of fuming nitric acid are added, in batches, at 0 C, 50.0 g (0.21 mol) of 1-(4-chlorophenyl)-1cyclopropanecarboxylic acid. The solution is stirred for 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), Rf value: 0.45 (silica gel; methylene chloride/methanol 9.5:0.5) b. 1-(4-methylamino-3-nitro-phenyl)-1cyclopropanecarboxylic acid 20.0 g (0.083 mol) of 1-(4-chloro-3-nitro-phenyl)-1cyclopropanecarboxylic acid and 100 ml of methylamine solution (40% in H 2 0) 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 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) c. 4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-nitro-Nmethyl-aniline 2.4 g (0.01 mol) of 1-(4-methylamino-3-nitro-phenyl)-lcyclopropanecarboxylic acid are dissolved in 50 ml dimethylformamide and after the addition of 3.2 g (0.01 mol) of O-(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 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) d. 4-[l-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-amino-Nmethyl-aniline 1.8 g (6.2 mmol) of 4-[l-(pyrrolidin-1-ylcarbonyl)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 hydrogenated for 4 hours at ambient temperature. Then the catalyst is filtered off and the residue is concentrated by evaporation.
Yield: 1.6 g (100 of theory), Rf value: 0.26 (silica gel; methylene chloride/methanol 9:1) e. 4-[l-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-(4cyanophenyl)aminomethylcarbonylamino-N-methyl-aniline Prepared analogously to Example Ic from 4-[l-(pyrrolidinl-yl-carbonyl)cyclopropyl]-2-amino-N-methyl-aniline, 0- (benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 66 of theory, Rf value: 0.51 (silica gel; methylene chloride/methanol 9:1) f. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidinl-yl-carbonyl)cyclopropyl]-benzimidazole t. WO 00/01704 47 PCT/EP99/04531 1.7 g (0.004 mol) of 4-[l-(pyrrolidin-l-ylcarbonyl)cyclopropyl]-2-(4-cyanophenyl)aminomethylcarbonylamino-N-methyl-aniline are refluxed in 7 ml of glacial acetic acid for 2 hours. The solvent is 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.
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- (pyrrolidin-l-yl-carbonyl)cyclopropyl]-benzimidazolehydrochloride g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methylare dissolved in 50 ml saturated ethanolic hydrochloric 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 chromatographed on silica gel, eluting with methylene chloride/methanol Yield: 700 mg (62 of theory), R, value: 0.61 (silica gel; methylene chloride/methanol 4:1)
C
24
H
28
N
6 0 x HC1 (416.54/453.0) mass spectrum: 417 The following compounds are obtained analogously to Example 1: WO 00/01704 48 WO 0/oi74 8 -PCT/EP99/04531 2- (4-amidinophenylaminomethyl) -1-methyl-5- methyl-piperidin-1-yl-carbonyl) cyclopropyl] -benzimidazolehydrochloride Yield: 45 of theory, Rf value: 0.25 (silica gel; methylene chloride/methanol 4:1)
C
2
,H
32
N
6 0 x HCl (444.59/481.05) mass spectrum: 445 2- (4-amidjinophenylaminomethyl) -l-methyl-5- [1- (piperidin-1-yl-carbonyl) cyclopropyll -benzimidazolehydrochloride Yield: 57 of theory, Rf value: 0.23 (silica gel; methylene chloride/methanol 4:1)
C
25
H-
3 0
N
6 0 x HCl (430.56/467.93) mass spectrum: 431 2- (4-amidinophenylaminomethyl) -l-methyl-5- methyl-piperazin--l-yl-carbonyl) cyclopropyl] -benzimidazolehydrochloride Yield: 32 of theory, Rf value: 0.26 (silica gel; methylene chloride/methanol!ammonia 2:1:0.25)
C
2
,H
3
,N
7 0 x HCl (445.58/482.04) mass spectrum: 4 446 2-(4-amidinophenylaminomethyl)-l-methyl-5-[l-(2,3dihydroindolin-1-yl-carbonyl) cyclopropyl] -benzimidazolehydrochloride Yield: 60 of theory, Rf value: 0.34 (silica gel; methylene chloride/methanol 4:1)
C
2
,H
2 NO x HCl (464.58/501.04) mass spectrum: 465 r' WO 00/01704 49 PCT/EP99/04531 2-(4-amidinophenylaminomethyl)-1-methyl-5-(1-((2ethoxycarbonylethyl) -piperidin-1-yl-carbonyl) cyclopropyl] benzimidazole -hydrochloride Yield: 85 of theory, Rf value: 0.57 (silica gel; methylene chloride/methanol= 4:1)
C
30
H
3 8
N
6 0 3 x HCl (530.67/567.13) mass spectrum: 531 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-((2ethoxycarbonylethyl) -pyrrolidin-1-ylcarbonyl) cyclopropyl] -benzimidazole-hydrochloride Yield: 60 of theory,
C
2 9
H
3 6
N
6 0 3 x HCl (516.64/553.10) mass spectrum: 517 259 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2ethoxycarbonylethyl) -N-methyl-aminomethyl) -pyrrolidin-1yl-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: 560 280.6 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-[(2ethoxycarbonylmethyloxymethyl) -pyrrol idin- 1-yl carbonyl] cyclopropyl] -benzimidazole-hydrochloride Yield: 61 of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol= 8:2 1 0- glacial acetic acid)
C
29
H
3
,N
6 0 4 x HCl (532.66/569.11) mass spectrum: 533 267 WO 00/01704 50 PCT/EP99/04531 Example 2 2-(4-amidinophenylaminomethyl)-l-methyl-5-(1cyclopentylcarbonyl-3-chloro-n-propyl)-benzimidazolehydrochloride a. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-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, 14.9 g (0.1 mol) 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 l-(4-chlorophenyl)-lcyclopropanecarbonitrile 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 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) b. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-2-nitrochlorobenzene Prepared analogously to Example la from 4-[1- (cyclopentylcarbonyl)cyclopropyl]-chlorobenzene and fuming nitric acid.
Yield: 87 of theory, R, value: 0.60 (silica gel; petroleum ether/ethyl acetate 9:1) WO 00/01704 51 PCT/EP99/04531 c. 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-nitro-Nmethyl-aniline Prepared analogously to Example lb from 4-[1- (cyclopentylcarbonyl)cyclopropyl]-2-nitro-chlorobenzene and aqueous methylamine solution.
Yield: 18 of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol 19:1) d. 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-amino-Nmethyl-aniline 2.3 g (7.9 mmol) of 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 125 ml ethyl acetate and 25 ml ethanol and after the addition 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 19:1) e. 4-[l-(cyclopentylcarbonyl)cyclopropyl]-2-(4cyanophenyl-aminomethylcarbonylamino)-N-methyl-aniline Prepared analogously to Example Ic from 4-[1- (cyclopentylcarbonyl)cyclopropyl]-2-amino-N-methylaniline, O-(benzotriazol-1-yl)-N,N,N',N'tetramethyluroniumtetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 96 of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol 19:1) f. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[l- (cyclopentylcarbonyl)-cyclopropyll-benzimidazole 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 19:1) g. 2-(4-amidinophenylaminomethyl)-1-methyl-5-(1cyclopentyl-carbonyl-3-chloro-n-propyl)-benzimidazole hydrochloride Prepared analogously to Example Ig from 2-(4- 3-chloro-n-propyl)-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 61 of theory,
C
25
H
30
CN
5 0O x HC1 (452.00/488.56) mass spectrum: 452/4 (Cl)) Example 3 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[l- [(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino)methylene]cyclopropyl]-benzimidazole-hydrochloride a. 1-[(pyridin-3-yl)-carbonyl]cyclopropyl-benzene A solution of 21.4 g (0.135 mol) of 3-bromopyridine in 125 ml of ether is added dropwise at -40 to -500C to 100 ml of butyllithium (1.6 M in hexane) and then stirred for minutes at -400C. The mixture is then cooled to -600C and a solution of 20.1 g (0.14 mol) of 1-phenyl-cyclopropanecarbonitrile 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 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 Yield: 14.0 g (46 of theory), Rf value: 0.27 (aluminium oxide; petroleum ether/ethyl acetate 9:1) b. 4-[1-[(pvridin-3-yl)-carbonyl]cyclopropyl]-nitrobenzene Prepared analogously to Example la from l-[(pyridin-3-yl)carbonyl]cyclopropyl-benzene and fuming nitric acid.
Yield: 53.7 of theory, R, value: 0.29 (aluminium oxide; petroleum ether/ethyl acetate 4:1) c. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyll-aniline Prepared analogously to Example 2d from 4-[l-[(pyridin-3yl)-carbonyl]cyclopropyl]-nitrobenzene and Raney nickel in ethyl acetate/ethanol.
Yield: 94 of theory, R, value: 0.51 (silica gel; methylene chloride/ethanol 19:1) d. 4-[l-[(pyridin-3-yl)-carbonyl]cyclopropyl]trifluoroacetylaniline 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 stirred with petroleum ether/ether suction filtered and dried.
Yield: 10.0 g (88 of theory), R, value: 0.54 (silica gel; methylene chloride/ethanol 19:1) WO 00/01704 54 PCT/EP99/04531 e. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitrotrifluoroacetylaniline 1.7 g (5 mmol) of 4-[l-[(pyridin-3-yl)carbonyl]cyclopropyl]-trifluoroacetylaniline are added batchwise to 13 ml of conc. sulphuric acid and 16 ml of nitric acid at -50C. 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 dried and congentrated 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.
Yield: 1.2 g (75 of theory), Rf value: 0.70 (silica gel; methylene chloride/ethanol 19:1) f. 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-Ntrifluoroacetyl-N-methvl-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 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).
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-Nmethyl-aniline 7.4 g (18.8 mmol) of 4-[l-[(pyridin-3-yl)carbonyl]cyclopropyl]-2-nitro-N-trifluoroacetyl-N-methylaniline 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 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 1:1) h. 4-[l-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-amino-Nmethyl-aniline Prepared analogously to Example 2d from 4-[l-[(pyridin-3yl)-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 19:1) i. 4-[l-[(pyridin-3-yl)-carbonyl]cyclopropyll-2-(4-cyanophenvl)-aminomethylcarbonylamino-N-methyl-aniline Prepared analogously to Example Ic from 4-[l-[(pyridin-3yl)-carbonyl]cyclopropyl]-2-amino-N-methyl-aniline, 0- (benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide.
Yield: 97 of theory, R, value: 0.48 (silica gel; methylene chloride/ethanol 19:1) WO 00/01704 56 PCT/EP99/04531 k. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1-[(pyridin-3yl)-carbonyl]cyclopropyl]-benzimidazole Prepared analogously to Example If from 4-(pyridin-3-ylcarbonyl)cyclopropyl-2-(4-cyanophenyl)aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.
Yield: 76 of theory, Rf value: 0.52 (silica gel; methylene chloride/ethanol 19:1) 1. (E/Z)-2-(4-cyanophenylaminomethyl)-l-methyl-5-[1- [(pyridin-3-yl)-(carboxymethyloxyimino)methylene]cyclopropyl]benzimidazole 1.6 g (4.0 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl- 5-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-benzimidazole, g (12 mmol) of carboxy-methoxylamine-hemihydrate, 0.84 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 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), Rf value: 0.34 (silica gel; methylene chloride/ethanol/glacial acetic acid 8:2:0.2) m. (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [(pyridin-3-yl)-(ethoxycarbonylmethyloxyimino)methylene]cyclopropyl]-benzimidazole-hydrochloride Prepared analogously to Example Ig from cyanophenylaminomethyl)-l-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, Rf value: 0.28 (silica gel; methylene chloride/ethanol/glacial acetic acid 8:2:0.2)
C
29
H
3 1
N
7 3 x HC1 (525.62/562.09) mass spectrum: 526 The following compounds are obtained analogously to Example 3: (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [(pyridine-2-yl)-(ethoxycarbonylmethyloxyimino)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
29
H
31 N,0 3 x HC1 (525.62/562.09) mass spectrum: (M+H) 526 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [phenyl-(ethoxycarbonylmethyloxyimino)-methylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 18 of theory,
C
30
H
32
N
6 0 3 x HC1 (524.63/561.09) mass spectrum: 525 (M-H+HC1)- 559/61 (Cl) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-(lhydrochloride Yield: 10 of theory,
C
24
H
25 NO x HC1 (427.51/ 463.97) mass spectrum: (M+H) 428 (M+H+HC1)- 464/6 (Cl) WO 00/01704 58 PCT/EP99/04531 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[lmethylene]cyclopropyl]-benzimidazole-hydrochloride Yield: 80 of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol 8:2 1 glacial acetic acid)
C
28
H
32 NO0 3 x HC1 (528.63/565.08) mass spectrum: 529 (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1- [phenyl-(3-ethoxycarbonyl-n-propyloxyimino)methylene]cyclopropyll-benzimidazole-dihydrochloride Yield: 47 of theory, Rf value: 0.06 (silica gel; methylene chloride/methanol 9:1)
C
32
HN
6 0 3 x 2 HC1 (552.69/625.60) mass spectrum: 553 Example 4 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [(pyridine-2-yl)-(carboxymethyloxyimino)methylene]cyclopropyl]-benzimidazole-hydrochloride 150 mg (E/Z)-2-(4-amidinophenylaminomethyl)-1-methyl- 5-[1-[(pyridin-2-yl-(ethoxycarbonylmethyloxyimino)methylene]cyclopropyl]-benzimidazole-hydrochloride and ml of 2N sodium hydroxide solution are stirred in 10 ml ethanol for 5 hours at ambient temperature. The alcohol is 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, R, value: 0.10 (silica gel; methylene chloride/ethanol/glacial acetic acid 8:2:0.1)
C
27
H
27 N7O 3 x HC1 (497.58/534.05) WO 00/01704 59 PCT/EP99/04531 mass spectrum: 498 520 The following compounds are obtained analogously to Example 4: 2-(4-amidinophenylaminomethyl)-l-methyl-5-[l-[2-(2carboxyethyl)-piperidin-l-yl-carbonyl]cyclopropyl]benzimidazole-hydrochloride Yield: 94 of theory, Rf value: 0.57 (Reversed phase RP 18; methanol/5% sodium chloride solution 3:2)
C
2
,H
34
N
6 0 3 x HC1 (502.62/539.08) mass spectrum: 503 (M+Na) 525 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2carboxyethylamino)-l-(pyrrolidin-l-yl-carbonyl)-ethyl]benzimidazole-hydrochloride Yield: 98 of theory, Rf value: 0.73 (Reversed phase RP 8; methanol/5% sodium chloride solution 1:2)
C
26
H
33 N,0 3 x HC1 (491.60/564.54) mass spectrum: (M+H) =0492 (M+2H) 247 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (3carboxypropionylamino)-l-(ethoxycarbonyl)-ethyl]benzimidazole-hydrochloride Yield: 98 of theory, Rf value: 0.70 (RP 8; methanol/5% sodium chloride solution 1 :2)
C
25
H
30
N
6 0 5 x HC1 (494.55/531.05) mass spectrum: (M+H) 495 989 WO 00/01704 60 PCT/EP99/04531 2- (4-amidinophenylamiriomethyl) -l-methyl-5- [1- (carboxymethylamino) -1-(pyrrolidin-l-yl-carbonyl) -methyl] benzimidazole -hydrochloride Yield: 87 0- of theory,
C
2 4
H
2 9
N
7 0 3 x HCl (463.54/500.04) mass spectrum: 464 232.6 2-(4-amidinophenylaminomethyl) -l-methyl-5-[l-[2-(2carboxyethyl) 7 pyrrolidin-l-yl-carbonyl] cyclopropyl] benz imidazole hydrochloride Yield: 94 of theory,
C
2 7
H
3 2
N
6 0 3 x HCl (488.59/525.05) mass spectrum: 489 511 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (carboxymethylcarbonylamino) -1-(pyrrolidin-l-yl-carbonyl) methyl] -benzimidazole-hydrochloride Yield: 49 of theory,
C
2 5
H
2 9
N
7 0 4 x HCl (491.'55/528.01) mass spectrum: 492 257.7 2- (4-amidinophenylaminomethyl) -l-methyl-5- Il- (carboxymethylcarbonylamino) -1-(pyrrolidin-l-yl-carbonyl) ethyl] -benzimidazole-hydrochloride Yield: 92 of theory,
C
26
H
3 1
N
7 0 4 x HCl (505.58/542.04) mass spectrum: 506 (M+HiNa)++ 264.7 2- (4-amidinophenylaminomethyl) -l-methyl-5- (5-methyl-3carboxymethyl-imidazolin-2,4-dion-5-yl) -benzimidazolehydrochloride Yield: 88 of theory,
C
2 2
H
2 3 N7O 4 x HCl (449.47/485.94) WO 00/01704 61 PCT/EP99/04531 mass spectrum: 450 247.7 (4-amidinophenylaminomethyl) -1-methyl-5- [1- [(pyridin-3-yl) -(carboxymethyloxyimino)methylene] cyclopropyl] -benzimidazole-hydrochloride Yield: 54 of theory,
C
2
,H
2
,N
7 0 3 x HCi (497.56/534.09) mass spectrum: 498 520 2- (4-amidinophenylaminomethyl) -1-methyl-5- (N- (2-carboxyethyl) -N-methyl-aminomethyl) -pyrrolidin-1-ylcarbontyl] cyclopropyl] -benzimidazole-hydrochloride Yield: 100 0- of theory,
C
2 9
H
3 ,N,0 3 x HCl (531.66/568.12) mass spectrum: 532 (M-HY- 530 (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2carboxyethyl) (2-pyridyl) -aminomethyl] -benz imidazolehydrochloride Yield: 91 01 of theory,
C
2 5 11 2 7
N
7 0 2 x HCl (457.54/493.96) mass spectrum: 458 (12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (Nbenzenesulphonyl carboxymethyl -aminomethyl) benzimidazole -hydrochloride Yield: 84 %1 of theory,
C
2
,H
2 6
N
6 0 4 S x HCl (506.59/543.06) mass spectrum: 507 (13) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2carboxy-ethyl) -benzimidazole-1-yl -methyl] -benzimidazolehydrochloride Yield: 76% of theory, WO 00/01704 62 PCT/EP99/04531
C
27
H
2 7
N
7 0 2 x HCl (481.56/518.05) mass spectrum: 482 (M+2H 2 242 504 (M+H+Na 2 253 (M-H+2Na)+ 526 (M+2Na 2 264 (14) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2-methyl- 4-carboxy-imi(.azo1-1-y1-methy1) -benzimidazolehydrochloride.
Yield: 61%1 of theory,
C
2 2
H
2 3
N
7 0 2 x Rd1 (417.47/453.92) mass spectrum: 418 2- (4-amidinophenylaminomethyl) -1-methyl-5- (3carboxy-n-propyl) -benzimidazol-2-on-l-yl-methyl] benzimidazole-hydrochloride Yield: 86*1 of theory,
C
2
,H
2 9
N
7 0 3 x HCl (511.59/548.04) mass spectrum: 512 534 (M+H+Na 2 267.7 (M+2Na 2 278.8 (16) 2- (4-amidinophenylaminomethyl) -1-methyl--5- (2carboxy-ethyl) -imidazo pyridin-2-on-1-yl-methyl] benz imidazole -hydrochloride Yield: 83% of theory,
C
2
,H
2 6 N.0 3 x HC1 (498.55/535) mass spectrum: 499 521 (M-HV- 497 (2M-HV 995 WO 00/01704 63 PCT/EP99/04531 (17) 2-(4-amidinophenylaminomethyl)-1-methyl-5- carboxyethyl) -4,5-dimethyl-imidazol-l-yl-methyl] benz imidazole -hydrochloride Yield: 68% of theory, Rf value: 0.70 (Reversed phase RP 8; methanol/5% sodium chloride solution 6:4)
C
2
,H
2 9
N
7 0 2 x HCl (459.56/496.01) mass spectrum: 460 482 (M+H+Na 2 241 (18) (4-amidinophenylaminomethyl) -l-methyl-5- [1- [phenyl- (carboxymethyloxyimino) methylene] cyclopropyl] benz imidazole -dihydrochloride Yield: 70%6 of theory,
C
2 ,H2,NO0 x 2C(496.57/569.5) mass spectrum: 49 7 (M-HY- 495 (19) (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5- [1- [(pyridin-3-yl) -(carboxymethylidene) methylene] cyclopropyl] -benz imidazole-hydrochloride Yield: 37% of theory Rf value: 0.45 (Reversed phase RP 8; methanol/5% sodium chloride solution 6:4)
C
2 7
H
2 6
N
6 0 2 x HCl (466.55/503.0) mass spectrum: 467 (4-amidinophenylaminomethyl) -l-methyl-5- [1- [(l-methyl-pyrazol-5-yl) -(carboxymethyloxyimino) methylene] cyclopropyl] -benz imidazole-hydrochloride Yield: 30% of theory, Rf value: 0.25 (Reversed phase RP 8; saline solution/methanol 1:1)
C
26 11 28 ,N,0 x HCl (500.58/537.03) WO 00/01704 64 PCT/EP99/04531 mass spectrum: 501 499 (M+C1) 535/537 (Cl) (21) (E/Z)-2-(4-amidinophenylaminomethyl)-l-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 solution/methanol 3:2)
C
30
H
32
N
6 0 3 x 2 HC1 (524.64/597.55) mass spectrum: 525 Example 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(pyrrolidinl-yl-carbonvl)-aminomethyl]-benzimidazole-hydrochloride a. 5-(4-chlorophenyl)-imidazolidin-2,4-dione 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 550 C. The solvent is distilled off, the residue dissolved in water and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation.
Yield: 8.6 g (38 of theory), melting point: 2150C b. 5-(4-chloro-3-nitro-phenvl)-imidazolidin-2.4-dione Prepared analogously to Example la from 5-(4chlorophenyl)-imidazolidin-2,4-dione and fuming nitric acid.
Yield: 52 of theory, Rf value: 0.63 (silica gel; methylene chloride/methanol 9:1) WO 00/01704 65 PCT/EP99/04531 c. 4-chloro-3-nitro-phenvlalanine-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 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.
Yield: 380 mg (65 of theory), melting point: 186 0
C
d. 4-chloro-3-nitro-N-tert.butvloxycarbonyl-phenylalanine 5.7 g (17.8 mmol) of 4-chloro-3-nitro-phenylalanine-hydrochloride 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.butyldicarbonate, stirred for 18 hours at ambient temperature.
Then the mixture is diluted with 0.5 M potassium hydrogen 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 9:1) e. 2-(4-chloro-3-nitro-phenyl)-2tert.butvloxycarbonylamino-l-(pyrrolidin-1-yl)-ethanone Prepared analogously to Example Ic from 4-chloro-3-nitro- N-tert.butyloxycarbonyl-phenylalanine, O-(benzotriazol-lyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, pyrrolidine and N-ethyl-diisopropylamine in tetrahydrofuran.
Yield: 68 of theory, melting point: 203°C WO 00/01704 66 WO 0/0174 6 -PCT/EP99/0453l f. 2- (4-methylamino-3-nitro-phenyl) -2tert .butvloxvcarbonvlamino-l- (Pvrrolidin-l-vl) -ethanone Prepared analogously to Example lb from 2-(4-chloro-3nitro-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 1:1) g. 2- (4-methylamino-3-amino-phenyl) -2tert .butyloxvcarbonvlamino-l-pvrrolidin-l-vl-ethanone Prepared analogously to Example ld from 2-(4-methylamino- 3-nitro-phenyl) -2-tert .butyloxycarbonylamino-1- (pyrrolidin-l-yl)-ethanone and palladium on activated charcoal in methylene chloride/ethanol.
Yield: 100 1; of theory, Rf value: 0.12 (silica gel; cyclohexane/ethyl acetate 1:1) h. 2- [4-methylamino-3- (4cyanophenylaminomethylcarbonylamino) -phenyl] -2tert .butyloxvcarbonylamino-l- (Pvrrolidin-l-vl) -ethanone Prepared analogously to Example ic from 2-(4-methylamino- 3-aminophenyl) -2-tert .butyloxycarbonylamino-l- (pyrrolidinl-yl)-ethanone, O-(benzotriazol-l-yl)-N,N,N',N'tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in tetrahydrofuran.
Yield: 100 of theory, Rf value: 0.50 (silica gel; methylene chloride/methanol= 9:1) WO 00/01704 67 PCT/EP99/04531 i. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(pyrrolidin- 1-vl-carbonvl)-aminomethyll-benzimidazole Prepared analogously to Example if from 2-[4-methylamino- 3- (4-cyanophenylaminomethylcarbonylamino) -phenyl] -2tert.butyloxycarbonylamino-l-(pyrrolidin-1-yl)-ethanone in glacial acetic acid.
Yield: 30 *1 of theory, R. value: 0.19 (silica gel; methylene chloride/methanol 9.5:0.5) k. 2-(4-amidinophenylaminomethyl)-l-methyl-5- (pyrrolidin-l-yl-carbonyl)-aminomethyl]-benzimidazolehydrochloride Prepared analogously to Example Ig from 2-(4cyanophenylaminomethyl)-l-methyl-5-[l-(pyrrolidin-1-ylcarbonyl)-aminomethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 27 of theory,
C
22
H
27
N
7 0 x HCl (405.50/441.96) mass spectrum: 406 The following compounds are obtained analogously to Example 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (pyrrolidin-1-yl-carbonyl)-N-acetyl-aminomethyl]benzimidazole-hydrochloride Yield: 29 of theory,
C
24
H
29
N
7 0 2 x HCl (447.54/484.54) mass spectrum: 448 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1- (pyrrolidin-1-yl-carbonyl)-N-(2-ethoxycarbonylethyl)-Nmethyl-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: 520 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (pyrrolidin-1-yl-carboiyl) (ethoxycarbonylmethyl) aminomethyl] -benzimidazole-hydrochloride Yield: 76 01 of theory,
C
2
,H
33
N
7 0 3 x HCl (491.59/528.05) mass spectrum: 492 246.7 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (pyrrolidin-1-yl-carbonyl) -N,N-di- (ethoxycarbonylmethyl) aminomethyl] -benzimidazole-hydrochloride Yield: 51 of theory,
C
3 0
H
3 9
N
7 0 5 x HC1 (577.68/614.14) mass spectrum: 578 600 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (pyrrolidin-l-yl-carbonyl) -N- (ethoxycarbonylmethylcarbonyl) -aminomethyll-benzimidazolehydrochloride Yield: 29 of theory,
C
2 7
H
33
N
7 0 4 x HCi (519.60/556.06) mass spectrum: 520 (M+2 260.7 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (pyrrolidin-1-yl-carbonyl) (2-ethoxycarbonylethyl) aminomethyl] -benzimidazole-hydrochloride Yield: 84 of theory,
C
2 7
H
3 5 7 3 x I-Cl (505.62/542.62) mass spectrum: 506 253.7 WO 00/01704 69 PCT/EP99/04531 Example 6 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N-(2-ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)-ethyl]benzimidazole-hydrochloride a. 5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidin-2,4dione To 50 ml of fuming nitric acid are added batchwise at -250C to -350C 10.0 g (4.45 mmol) of 5-(4-chloro-phenyl)- 5-methyl-imidazolidin-2,4-dione. After 45 minutes at to -20 0 C the reaction mixture is poured onto ice water.
The crystalline product is suction filtered, washed with water and dried.
Yield: 10.5 g (100 of theory), melting point: 173-1780C Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate 1:1) b. 2-amino-2-(4-chloro-3-nitro-phenyl)-propionic acid 10.5 g (0.044 mol) of 5-(4-chloro-3-nitro-phenyl)-5methyl-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 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), Rf value: 0.24 (Reversed phase RP8, 5% saline solution/methanol 1:1) c. 2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitrophenyl)-propionic acid Prepared analogously to Example 5d from 2-amino-2-(4chloro-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 01 of theory), Rf value: 0.31 (Reversed phase RPB, saline solution/methanol 1:2) d. 2- (4-chloro-3-nitro-phenyl) -2tert .butvloxvcarbonvlamino-l- (Pvrrolidin-l-vl) -prop~anone Prepared analogously to Example lc from 2tert .butyloxyqarbonylamino-2- (4-chloro-3-nitro-phenyl) propionic acid, 0- (benzotriazol-1-yl) tetramethyluronium tetrafluoroborate, pyrrolidine and Nmethylmorpholine in dimethylformamide.
Yield: 94 of theory, Rf value: 0.11 (silica gel; cyclohexane/ethyl acetate 1:1) e. 2- (4-methylamino-3-nitro-phenyl) -2tert .butyloxvcarbonylamino-l- (Pvrrolidin-l-vl) -prolpanone Prepared analogously to Example lb from 2-(4-chloro-3nitro-phenyl) -2-tert .butyloxycarbonylamino-l- (pyrrolidinl-yl)-propanone and methylamine solution in dimethylformamide at 160 0
C.
Rf value: 0.79 (silica gel; ethyl acetate/ethanol 9:1) f. 2- (4-methylamino-3-amino-phenyl) -2tert .butvloxvcarbonvlamino-l-pvrrolidin-l-vl--proipanone Prepared analogously to Example id from 2-(4-methylamino- 3-nitro-phenyl) -2-tert .butyloxycarbonylamino-l- (pyrrolidin-l-yl)-propanone and palladium on activated charcoal/hydrogen in methanol.
Yield: 100 of theory, Rf value: 0.63 (silica gel; ethyl acetate/ethanol 9:1) WO 00/01704 71 PCT/EP99/04531 q. 2-[4-methvlamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butvloxvcarbonylamino-1- (pyrrolidin-1-yl)-propanone Prepared analogously to Example Ic from 2-(4-methylamino- 3-amino-phenyl)-2-tert.butyloxycarbonylamino-l- (pyrrolidin-1-yl)-propanone, O-(benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and N-methylmorpholine in dimethylformamide.
Yield: 37 of theory, R, value: 0.47 (silica gel; ethyl acetate) h. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[1- (N-tert.butyloxycarbonylamino)-1-(pyrrolidin-1-ylcarbonyl)-ethyl]-benzimidazole Prepared analogously to Example if from 2-[4-methylamino- 3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2tert.butyloxycarbonylamino-l-(pyrrolidin-1-yl)-propanone and glacial acetic acid.
Yield: 60 of theory, R, value: 0.37 (silica gel; ethyl acetate) i. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[l-amino-l- (pyrrolidin-l-yl-carbonyl)-ethyl]-benzimidazole 1.3 g (2.3 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl- 5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidin-1-ylcarbonyl)-ethyl]-benzimidazole are dissolved in 20 ml 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 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-(2ethoxycarbonylethyl)-amino]-l-(pyrrolidin-1-yl-carbonyl)ethyl]-benzimidazole 0.4 g (1.04 mmol) of 2-(4-cyanophenylaminomethyl)-lmethyl-5-[l-amino-l-(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 for 24 hours at 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), R, value: 0.26 (silica gel; ethyl acetate/ethanol 9:1) 1. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[N-(2ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)ethyl]-benzimidazole-hydrochloride Prepared analogously to Example Ig from 2-(4cyanophenylaminomethyl)-l-methyl-5-[1-[N-(2ethoxycarbonylethyl)-amino]-1-(pyrrolidin-1-yl-carbonyl)ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 96 of theory,
C,
8
H
3
,NO
3 x HC1 (519.65/556.11) mass spectrum: 520 (M+Na) 542 The following compounds are obtained analogously to Example 6: 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3ethoxycarbonylpropionylamino)-1-ethoxycarbonyl-ethyl]benzimidazole-hydrochloride Yield: 69 of theory,
C
27
H
34
N
6 ,O x HC1 (522.62/555.08) WO 00/01704 -73 PCT/EP99/04531 mass spectrum: 523 273 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylcarbonylamino) -1-(pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole-hydrochloride Yield: 95 '1 of theory,
C
2
,H
3 ,N',0 4 x HCl (533.64/570.10) mass spectrum: 534 556 2- (4-amidinophenylaminomethyl) -l-methyl-5- ethoxycarbonylpropionylamino) (pyrrolidin-l-ylcarbonyl) -ethyl] -benz imidazole -hydrochloride Yield: 20 of theory,
C
2 9
H
37
N
7 0 4 x H1-i (547.66/584.12) mass spectrum: 548 285.7 2- (4-amidinophenyl-N- (2-ethoxycarbonylethyl) aminomethyl] -1-methyl-5- [1-dimethylamino-1- (pyrrolidin-lyl-carbonyl) -ethyl] -benzimidazole-hydrochloride Yield: 91 of theory,
C
3 0
H
4
,N
7 0 3 x HCl (547.71/584.17) mass spectrum: 548 546 2- (4-amidinophenylaminomethyl) -1-methyl-5- ethoxycarbonylethylamino) -1-(dimethylaminocarbonyl) ethyl] -benzimidazole-hydrochloride Yield: 40 of theory, Rf value: 0.60 (Reversed phase RP 8; 5% saline solution/methanol 1/1)
C
2 6
H
3 5
N
7 0 3 x I-Id (493.63/530.08) mass spectrum: 494 (M-H+2HClV- 564/566/568 (C1 2 WO 00/01704 74 PCT/EP99/04531 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidin-1-yl-carbonyl)ethyl]-benzimidazole-hydrochloride Yield: 77 of theory, 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 2-(4-amidinophenylaminomethyl)-1-methyl-5-[l-(2ethoxycarbonylethyl-amino)-1-(N-ethyl-Nmethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride Yield: 85 of theory, RF value: 0.44 (silica gel; methylene chloride/ethanol 9:1)
C
27
H
37
N
7 0 3 x HC1 (507.64/544.14) mass spectrum: 508 (M+C1) 542/4 (Cl) 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 4:1 1 glacial acetic acid)
C
26
H
33
N
7 0 3 x HC1 (491.60/528.05) mass spectrum: 492 (M-H+HC1)- 526/8 (Cl) (M-H+2HC1)- 562/4/8 (C1 2 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(N,Nbis(ethoxycarbonylmethyl)amino)-1-(pyrrolidinocarbonyl)ethyl]-benzimidazole-hydrochloride Yield: 65 of theory, Rf value: 0.35 (silica gel; methylene chloride/methanol 4:1 1 glacial acetic acid)
C
3
H
41 N/)s x HC1 (591.72/628.17) WO 00/01704 75 Wa 0/0174 5 -PCT/EP99/0453.
mass spectrum: 592 (M-H+HCl)- 626/8 (Cl) (M-H+2HClY- 662/4/6 (C1 2 (10) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1-(isoxazolidin-1-ylcarbonyl) -ethyl] -benzimidazole-hydrochloride Yield: 99k of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/591 saline solution 3:2)
C
2
,H
33
N
7 0 4 x HC1 (507.60/544.05) mass spectrum: 508 (11) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2ethoxycarbonyl-ethylamino) -1-(isoxazolidin-1-yl-carbonyl) ethyl] -benzimidazole-hydrochloride (12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1-(N-methyl-Nethylaminocarbonyl) -ethyl] -benzimidazole-dihydrochloride Yield: 58% of theory, Rf value: 0.70 (Reversed phase RP 8; methanol/5% saline solution 3:2)
C
2 6
H
3 ,N.,0 3 x 2 Htl (493.62/566.52) mass spectrum: 494 (M+HC1-H)- 528/30 (Cl) (13) 2- (4-amidinophenylaminomethyl) -l-methyl-5- di- (ethoxycarbonylmethyl) -amino) -1-(N-methyl-Nethylaminocarbonyl) -ethyl] -benzimidazole-dihydrochloride Yield: 309s of theory, Rf value: 0.40 (Reversed phase RP 8; methanol/5% saline solution 3:2)
C
3 0 11 4 1
N
7 0 5 x 2 HCl (579.71/652.62) mass spectrum: 580 578 WO 00/01704 76 PCT/EP99/04531 (14) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1-(piperidinocarbonyl) -ethyl] benzimidazole-dihydrochloride Yield: 820- of theory, Rf value: 0.60 (Reversed phase RP 8; methanol/5%- saline solution 3:2)
C
2
,H
3 7
N
7 0 3 x 2 HCl (519.65/592.75) mass spectrum: 520 (M-H+HClV- 534/6 (Cl) (M-H+2HClV- 590/2/4 (C12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1-(diethylaminocarbonyl) 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) Mass spectrum: 508 (M-H+2HClV- 578/580/582 (Cl 2 (16) 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (ethoxycarbonylmethyl-methylamino) -1-(pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole-dihydrochloride Yield: 46 of theory, Rf value: 0.43 (silica gel; methylene chloride/methanol= 4:1 1% glacial acetic acid)
C
2 8 1 37 3 x 2 HCl (519.65/592.56) mass spectrum: 520 (M+Cl)V 554/6 (Cl) (17) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol -5 -yl-methylamino) -1-(pyrrolidin-l-yl -carbonyl) ethyl] -benzimidazole-dihydrochloride WO 00/01704 77 PCT/EP99/04531 (18) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3ethoxycarbonyl-propylamino)-l-(pyrrolidin-1-yl-carbonyl)ethyl]-benzimidazole-dihydrochloride Yield: 95 of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/5% saline solution 1:1)
C
29
H
39
N
7 0 3 x 2 HC1 (533.68/606.58) mass spectrum: 534 Example 7 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-[Ncyclopentyl-N-(3-ethoxycarbonylpropionyl)amino]cyclopropyl]-benzimidazole-hydrochloride a. 4-((l-tert.butyloxycarbonylamino)cyclopropyl)-2-nitro- N-methyl-aniline 15.0 g (63.5 mmol) of 4-((1-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°C. After one hour at ambient temperature 0.75 g tetrabutylammonium 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 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), 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-anilinehydrochloride 15.5 g (0.05 mol) of 4-[(l-tert.butyloxycarbonylamino)cyclopropyl]-2-nitro-N-methyl-aniline are dissolved in 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.
Yield: 98 of theory, R, value: 0.44 (silica gel; methylene chloride/methanol 9.5:0.5) c. 4-[N-(l-cyclopentylamino)cyclopropyl]-2-nitro-N-methylaniline 12.0 g (0.05 mol) of 4-[(1-amino)cyclopropyl]-2-nitro-Nmethyl-aniline-hydrochloride are dissolved in 500 ml of tetrahydrofuran and after the addition of 4.1 g (0.05 mol) 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 acetate. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with ethyl acetate/cyclohexane Yield: 10.8 g (80 of theory) R, value: 0.56 (silica gel; methylene chloride/methanol 9.5:0.5) d. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentylamino)cyclopropyl]-2-nitro-N-methyl-aniline 1.0 g (3.6 mmol) of 4-[(l-cyclopentylamino)cyclopropyl]-2nitro-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 solution, the organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/cyclohexane Yield: 1.3 g (90 of theory), Rf value: 0.46 (silica gel; ethyl acetate/cyclohexane 1:1) e. 4-[l-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentylamino)cyclopropyl]-2-amino-N-methyl-aniline Prepared analogously to Example Id ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]- 2-nitro-N-methyl-aniline and palladium on activated charcoal/hydrogen in methylene chloride/ethanol.
Yield: 100 of theory, Rf value: 0.18 (silica gel; ethyl acetate/cyclohexane 1:1) f. 4-[l-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentylamino)cyclopropyl]-2-(4-cyanophenyl)aminomethylcarbonylamino-N-methyl-aniline Prepared analogously to Example Ic ethoxycarbonylpropionyl)-N-cyclopentyl-amino)cyclopropyl]- 2-amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N',N'tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine and triethylamine in dimethylformamide.
Yield: 96 of theory, Rf value: 0.54 (silica gel; methylene chloride/methanol 9.5:0.5) WO 00/01704 80 PCT/EP99/04531 g. 2- (4-cyanophenylaminomethyl) -1-methyl-5- cyclopentyl-N- (3 -ethoxycarbonylpropionyl) -amino] cycloproloyll -benzimidazole Prepared analogously to Example if from ethoxycarbonylpropionyl) -N-cyclopentyl-amino) cyclopropyl] 2- (4-cyanophenyl) -aminomethylcarbonylamino-N-methylaniline in glacial acetic acid.
Yield: 52 0- of theory, Rf value: 0.82, (silica gel; methylene chloride/methanol= 9:1) h. 2- (4-amidinophenylaminomethyl) -l-methyl-5- 1- [Ncyclopentyl-N- (3-ethoxycarbonyipropionyl) amino] cyclopropyl] -benzimidazole-hvdrochloride Prepared analogously to Example ig from 2-(4cyanophenylaminomethyl) -1-methyl-5- [1-[N-cyclopentyl-N- (3ethoxycarbonyipropionyl) -amino] cyclopropyl] -benz imidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 36 *1 of theory,
C
3 0
H
3 8
N
6 0 3 x HCl (530.68/567.14) mass spectrum: (M+H) 4 531 Example 8 2- (4-amidinophenylaminomethyl) -1-methyl-5- (5-methyl-3ethoxycarbonylmethyl -imidazolin- 2,4 -dion- -vl) benzimidazole-hvdrochloride a. 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylaminocarbonylamino) -1-(pyrrolidin-1vl-carbonyl) -ethyl] -benz imidazole 1.0 g (2.5 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl- [1-amino-i- (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 residue is chromatographed on silica gel, eluting with methylene chloride/ethanol/ammonia (20:1:0.01 and 10:1:0.01).
R, value: 0.77 (silica gel; methylene chloride/ethanol/ammonia 9:1:0.01) b. 2-(4-amidinophenylaminomethyl)-l-methyl-5-(5-methyl-3ethoxycarbonylmethyl-imidazolin-2,4-dion-5-yl)benzimidazole-hydrochloride Prepared analogously to Example Ig from 2-(4cyanophenylaminomethyl)-l-methyl-5-[1- (ethoxycarbonylmethylaminocarbonylamino)-1-(pyrrolidin-lyl-carbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 68 of theory,
C
24
H
27
N
7 0 4 x HC1 (477.52/513.99) mass spectrum: 478 Example 9 2-(4-amidinophenylaminomethyl)-l-methyl-5-[N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazolehydrochloride 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.butyloxycarbonylethylaminopyridine are stirred in 80 ml of N-ethyl-diisopropylamine for 3 hours at 900C. 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 8:2) b. 4-(2-tert.butyloxycarbonylethyl)-2- (pyridylaminomethyl)-2-nitro-N-methyl-aniline Prepared analqgously to Example lb from 4-(2tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2nitro-chlorobenzene and methylamine solution.
Yield: 20 of theory, Rf value: 0.65 (silica gel; methylene chloride/ethanol 9:1) c. 4-(2-tert.butyloxycarbonylethyl)-2- (pyridylaminomethyl)-2-amino-N-methyl-aniline 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 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 9:1) d. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)-aminomethyl]-benzimidazole Prepared analogously to Example ic from 4-(2tert.butyloxycarbonylethyl)-2-(pyridylaminomethyl)-2amino-N-methyl-aniline, O-(benzotriazol-l-yl)-N,N,N',N'- WO 00/01704 83 PCT/EP99/04531 tetramethyluronium tetrafluoroborate, 4-cyanophenylglycine in tetrahydrofuran and glacial acetic acid.
Yield: 72 of theory, R, value: 0.36 (silica gel; methylene chloride/ethanol 9:1) e. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[N-(2pyridyl)-N-(2-ethoxycarbonylethyl)-aminomethyl]benzimidazole-hydrochloride Prepared analogously to Example Ig from tert.butyloxycarbonylethyl)-2-pyridylaminomethyl-1-methylbenzimidazole-2-yl)-methylamino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 59 of theory,
C
27
H
31
N
7 0 2 x HC1 (485.59/522.1) mass spectrum: 486 The following compounds are obtained analogously to Example 9: 2-(4-amidinophenylaminomethyl)-l-methyl-5- [N-(ethoxycarbonylmethyl)-benzenesulphonylaminomethyl]benzimidazole-hydrochloride Yield: 53 of theory,
C
27 Ho 3
N
6 0 4 S x HC1 (534.64/571.1) mass spectrum: 535 2-(4-amidinophenylaminomethyl)-l-methyl-5-(N-methylphenylcarbonylaminomethyl)]-benzimidazole-hydrochloride Yield: 42 of theory,
C
2
,H
26
N
6 0 x HC1 (426.53/462.96) mass spectrum: (M+H) 427 WO 00/01704 84 PCT/EP99/04531 Example 2- (4-amidinophenylaminomethyl) -l-methyl-5- [(2-methylbenzimidazol-l-yl) methyl] -benzimidazole-hvdrochloride a. 1- (4-chloro-3-nitrobenzyl) -2-methvl-benzimidazole Prepared analogously to Example 9a from 2-methylbenzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulphoxide.
Yield: 78% of,theory,
C
15 H1 12 ClN 3 0 2 (301.7) mass spectrum: M' 301/303 b. 1- (4-methylamino-3-nitrobenzvl) -2-methyl-benzimidazole Prepared analogously to Example lb from l-(4-chloro-3nitrobenzyl) -2-methyl-benzimidazole and methylamine.
Yield: 96% of theory, Rf value: 0.56 (silica gel; methylene chloride/ethanol= 19:1) c. 1- (4-methylamino-3-aminobenzyl) -2-methvl-benzimidazole Prepared analogously to Example lc from 1-(4-methylamino- 3-nitrobenzyl) -2-methyl-benzimidazole and hydrogen/Raney nickel.
Yield: 100% of theory, R, value: 0.34 (silica gel; methylene chloride/ethanol= 19:1) d. 2- (4-cyanophenylaminomethyl) -l-methyl-5- [(2-methylbenzimidazol-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 ref luxed in 80 ml of absolute tetrahydrofuran for minutes. After the addition of 2.7 g (10.46 mmol) of 1-(4methylamino-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 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), R, value: 0.30 (silica gel; methylene chloride/ethanol 19:1)
C
25
H
22
N
6 (406.5) mass spectrum: M' 406 e. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[(2-methylbenzimidazol-l-yl)methyl]-benzimidazole-hydrochloride Prepared analogously to Example Ig from 2-(4cyanophenylaminomethyl)-1-methyl-5-[(2-methylbenzimidazol-1-yl)methyl]-benzimidazole hydrochloric acid/ammonium carbonate.
Yield: 59% of theory,
C
25
H
25
N
7 x HC1 (423.5/459.9) mass spectrum: 424 (M+2H) 2 217.7 The following compounds are obtained analogously to Example 2-(4-amidinophenyloxymethyl)-1-methyl-5-[(imidazol-1yl)-methyl]-benzimidazole-hydrochloride Yield: 30% of theory,
C
20
H
2 0NO x HC1 (360.4/396.9) mass spectrum: (M+H) 361 (M+2H) 2 181 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1- (imidazol-1-yl)-ethyl]-benzimidazole-hydrochloride WO 00/01704 86 WO 0/0174 6 -PCT/EP99/04531 Yield: 700% of theory,
C
21
H
2 3 N, x HCl (373.46/410) mass spectrum: 374 (M+2H 2 187.6 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1-(2-ethyl- 4-methyl-imidazol-1-yl) -ethyl] -benzimidazoledihydrochioride Yield: 18% of theory,
C
2 4
H
2 9
N
7 x 2HC,(415. 55/488 .46) mass spectrum: 416 (M+2H 2 208.7 2- (4-amidinophenylaminomethyl) -1-methyl-5- [(2-ethyl-4methyl-imidazol-1-yl) -methyl] -benzimidazoledihydrochioride Yield: 36% of theory,
C
23
H
2 7
N
7 x 2HC1 (401.52/437.97) mass spectrum: 402 (M+2H 2 201.7 2- (4-amidinophenylaminomethyl) -l-methyl-5- (pyridin- 2-yl) -N-methyl-aminomethyl] -benzimidazole-dihydrochloride Yield: 78% of theory,
C
2 3
H
2 5 N. x 2HC1 (399.5/435.95) mass spectrum: (M+H) 4 400 (M+2H 2 200.6 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2ethoxycarbonyl-ethyl) -benzimidazol-l-yl) -methyl] benzimidazole -dihydrochioride Yield: 61% of theory,
C
2 9
H
3 1
N
7 OIx HCl (509.62/546.07) mass spectrum: 510 (M+2H 2 255.7 (M+H+Na 2 266.7 01 WO 00/01704 87 PCT/EP99/04531 2- (4-amidinophenylaminomethyl) -1-methyl-5- [(imidazoll-yl) -methyl] -benzimidazole-hydrochloride Yield: 35*- of theory,
C
20
H
2 x HCl (359.44/395.89) mass spectrum: 360 (M+2H 2 180.6 2-(4-amidinophenylaminomethyl)-1-methyl-5-[(2-(2acetylamino-ethyl) -4,5-dimethyl-imidazol-1-yl) -methyl] benzimidazole-dihydrochloride Yield: 4211 of theory,
C
2 6
H
3 2 N.0 x 2HCl (472.6/545.51) mass spectrum: 473 (M+2H 2 237 (M+H+Na 2+ 248 2-(4-amidinophenylaminomethyl)-1-methyl-5- aminocarbonyl-ethyl) -41 5-dimethyl-imidazol-l-yl) -methyl] benzimidazole -dihydrochloride Yield: 681; of theory,
C
2
,H
3 0
N
8 0 x 2HC1 (458.6/531.51) mass spectrum: 459 (M+2H 2 230 (10) 2- (4-amidinophenylaminomethyl) -l-methyl-5- [(2-methyl- 4-ethoxycarbonyl-imidazol-l-yl) -methyl] -benzimidazolehydrochloride Yield: 34%- of theory,
C
2 4
H
2 7 7 2 x HCl (445.53/481.98) mass spectrum: 446 (M+2H) 2 223.5 (M+H+Na 2 234.5 (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (3ethoxycarbonyl-n-propyl) -benzimidazol-2-on-1-yl) -methyl] benzimidazole -hydrochloride Yield: 58% of theory, WO 00/01704 88 PCT/EP99/04 531
C
30
H
3 3
N
7 0 3 x HC1 (539.64/576.09) mass spectrum: 540 (M+H+Na 2 281.7 (12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- (2ethoxycarbonyl-ethyl) -imidazo 5-b] pyridin-2-on-l-yl) methyl] -benzimidazole-hydrochloride Yield: 29% of theory,
C
2
,H
30 N,0 3 x HC1 (526.6/563.05) mass spectrum; 527 (M+2H 2 264 (M+H+Na 2 275 (13) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [(2-phenylimidazol-1-yl) -methyl] -benzimidazole-hydrochloride Yield: 58% of theory,
C
2 6
H
2
,N
7 x HCl (435.54/472) mass spectrum: 436 218.6 (14) 2- (4-amidinophenylaminomethyl) -l-methyl-5- dimethyl-2- (2-ethoxycarbonylethyl) -imidazol-l-yl) -methyl] benz imidazole -dihydrochloride Yield: 52%; of theory,
C
2 7
H
3 3 N.0 2 x 2HCl (487.61/560.52) mass spectrum: 488 (M+2 2 244.6 Example 11 2- (4-amidinophenylaminomethyl) -l-methyl-5- ethoxycarbonyl-azetidin-l-yl) (pyrrolidin-1-ylcarbonyl) -ethyl] -benzimidazole-hydrochloride a. 2-(4-cyanophenylaminomethyl)-l-methyl-5-[l-(2tert .butyloxycarbonyl-azetidin-1-yl) -1-(pyrrolidin-l-yl- WO 00/01704 89 PCT/EP99/04531 carbonyl)-ethyl]-benzimidazole 0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-lmethyl-5-[1-amino-l-(pyrrolidin-l-yl-carbonyl)-ethyl]benzimidazole and 1.65 g mmol) of tert.butyl 2,4dibromobutyrate 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 55 0 C. After cooling, the white precipitate is filtered off and washed with ethanol.
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.
Yield: 0.44 g (44% of theory) as a mixture of diastereomers,
C
31
H
38
N
6 0 3 (542.69) mass spectrum: 543 b. 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(2ethoxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-ylcarbonyl)-ethyl]-benzimidazole-hydrochloride (mixture of diastereomers) Prepared analogously to Example Ig from 2-(4cyanophenylaminomethyl)-l-methyl-5-[1-(2tert.butyloxycarbonyl-azetidin-1-yl)-1-(pyrrolidin-1-ylcarbonyl)-ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 12 of theory,
C
2
,H
3 ,N,0 3 x HC1 (531.66/568.12) mass spectrum: 532 (M+H+HC1) 2 568/70 (Cl) WO 00/01704 90 PCT/EP99/04531 Example 12 (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [(pyridin-3-yl)-ethoxycarbonylmethylidene)methylene]cyclopropyl]-benzimidazole-hydrochloride a. (E/Z)-2-(4-cyanophenylaminomethyl)-l-methyl-5-[1- [(pyridin-3-yl)-ethoxycarbonylmethylidene)methylene]cyclopropvl]-benzimidazole 897 mg (4.0 mmol) of triethyl phosphonoacetate are dissolved in 30 ml tetrahydrofuran under argon. At 449 mg (4.0 mmol) of potassium tert. butoxide are added.
After 30 minutes 815 mg (2.0 mmol) of 2-(4cyanophenylaminomethyl)-l-methyl-5- [1-(pyridin-3-ylcarbonyl)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 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 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).
b. ((E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- [(pyridin-3-yl)-ethoxycarbonylmethylidene)methylene]cyclopropyl]-benzimidazole-hydrochloride Prepared analogously to Example Ig from 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
H
30
N
6 0 2 x HC1 (494.60/531.05) mass spectrum: 495 The following compound is obtained analogously to Example 12: (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 HC1 (494.60/531.05) mass spectrum: =495 Example 13 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2-carboxyazetidin-1-yl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]benzimidazole-hvdrochloride (mixture of diastereomers) 200 mg (0.35 mmol) of 2-(4-amidinophenylaminomethyl)-1methyl-5-[l-(2-ethoxycarbonyl-azetidin-l-yl)-1- (pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazolehydrochloride 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 acetone/ether, suction filtered, washed with ether and dried.
Yield: 200 mg (>100 of theory, contains ammonium chloride),
C
27
H
33 NO0 3 x HC1 (503.62/540.07) mass spectrum: 504 WO 00/01704 92 PCT/EP99/04531 The following compounds are obtained analogously to Example 13: 2- (4-amidinophenylaminomethyl) -1-methyl-5- carboxyethylamino) -1-(dimethylaminocarbonyl) -ethyl] benz imidazole -hydrochloride Yield: 91*- of theory, Rf value: 0.75 (Reversed phase; saline solution/methanol 1:1)
C
24
H
31 N0 x HCl1 (465.56/502.01) mass spectrum: (M+H) 4 466 (M-H+2HC1lV 537/539 C12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1-(carboxymethylamino) -1-(pyrrolidin-1-yl-carbonyl) -ethyl] benzimidazole-dihydrochloride Yield: 70 of theory, RF value: 0.51 (Reversed phase; 5% saline solution/methanol 3:2)
C
25
H
3
,N
7 ,0 3 x 2 HCl (477.57/550.48) mass spectrum: 478 (4-amidinophenylaminomethyl) -1-methyl-5- [1- [(pyridin-2-yl) -carboxymethylidene) -methylene] cyclopropyl] -benzimidazole-hydrochloride Yield: 65 of theory,
C
2 7 11 26
N
6 0 2 x HCl (466.55/503.0) mass spectrum: 467 501/503 (Cl) 2- (4-amidinophenylaminomethyl) -1-methyl-5- methyl-carboxymethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazoledihydrochloride Yield: 99 of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5% saline solution 1:1)
SI
WO 00/01704 93 PCT/EP99/04531
C
28
H
35
N
7 0 4 x 2 HC1 (533.64/606.64) mass spectrum: 534 532 (M-H+HC1)- 568/70 (Cl) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2carboxyethyl-amino)-1-(N-ethyl-N-methylaminocarbonyl)ethyl]-benzimidazole-dihydrochloride Yield: 75 of theory, Rf value: 0.54 (Reversed phase RP 8; methanol/5% saline solution 1:1)
C
25
H
33
N
7 0 3 x 2 HC1 (479.59/552.59) mass spectrum: (M+H) 480 Example 14 2-[4-(N-hexyloxycarbonylamidino)-phenylaminomethyl]-1methyl-5-[1-(2-ethoxycarbonylethylamino)-1- (dimethylaminocarbonvl)-ethyl]-benzimidazole g (2.8 mmol) of 2-(4-amidinophenylaminomethyl)-1methyl-5-[1-(2-ethoxycarbonylethylamino)-1- (dimethylaminocarbonyl)-ethyl]-benzimidazole-hydrochloride are dissolved in 14 ml water and 55 ml tetrahydrofuran, 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 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 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) mass spectrum: (M+H) 622 (M+Na) 644 Example 2-(4-amidinophenylaminomethyl)-l-methyl-5-[l- (Nethoxycarbonylmethylcarbonyl-methylamino)-2- (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazolehydrochloride a. Methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methylpropionate 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 diisopropylamine (85 mmol) in 20 ml tetrahydrofuran at -780C. Then a solution of 10.0 g (50 mmol) of methyl 2-(4chloro-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 the addition of 5% citric acid and glacial acetic acid the mixture is extracted with ethyl acetate. The organic phases are washed with lN sulphuric acid, water, saturated sodium bicarbonate solution and saline solution and dried over magnesium sulphate. The crude product is purified on silica gel, eluting with cyclohexane/ethyl acetate (19:1; 9:1; 4:1; 1:1 and 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 4:1) WO 00/01704 95 Wa 0/0174 5 -PCT/EP99/04531 b. 2- (4-chioro-iphenvi) -3-hydroxy-2-methvl--proipionic acid Prepared analogously to Example 4 from methyl 2-(4-chlorophenyl) -3 -hydroxy-2-methyl-propionate and sodium hydroxide solution in ethanol.
Yield: 83%6 of theory, R. value: 0.55 (silica gel; ethyl acetate/cyclohexane 2:1 glacial acetic acid) c. 2- (4-chloro-3-nitro-phenvl) -2-methyl-3-nitroxvprolpionic acid Prepared analogously to Example la from 2-(4-chlorophenyl) -3-hydroxy-2-methyl-propionic acid and nitric acid.
Yield: 90% of theory, melting point: 129-132 0
C
C
10 1- 9 C1N 2 0, (304.64) d. 2- (4-chloro-3-nitro-phenvl) -2-methyl-3-hvdroxv- -provionic acid Prepared analogously to Example 6 from 2-(4-chloro-3nitro-phenyl)-3-nitrooxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxane.
Yield: 98% of theory,
C
10
H
10 C1N0 5 (259. mass spectrum: (M-HV- 258/60 (Cl) 517/9 (C12) e. 2- (N-benzyl-methylamino) -3--nitro-phenyl] -2-methyl-3hydroxy-poropionic acid Prepared analogously to Example lb from 2-(4-chloro-3nitro-phenyl) -3-hydroxy-2-methyl-propionic acid and Nmethyl -benzyl amine.
Yield: 81% of theory,
C
18
H
2 0 ClN 2 0, (344.37) mass spectrum: M' 344
W;
WO 00/01704 96 PCT/EP99/04531 f. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3hydroxy-l-pyrrolidin-l-vl-propan-1-one Prepared analogously to Example Ic from 2-[4-(N-benzylmethylamino)-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' 398 420 g. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3methanesulphonyloxy-l-pyrrolidin-l-vl-propan-1-one A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzylmethylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-lpyrrolidin-1-yl-propan-l-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 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.
Yield: 1.4 g (98% of theory) h. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3methylamino-1-pyrrolidin-l-yl-propan-l-one A solution of 1.4 g (2.9 mmol) of 2-[4-(N-benzylmethylamino)-3-nitro-phenyl]-2-methyl-3methanesulphonyloxy-1-pyrrolidin-1-yl-propan-l-one in ml dimethylformamide is combined with 20 ml of a aqueous methylamine solution and heated to 100 0 C for 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 concentrated by evaporation.
Yield: 740 mg (61% of theory), RF value: 0.45 (silica gel; methylene chloride/ethanol 9:1 1% conc. ammonia) i. 2-[4-(benzyl-methylamino)-3-nitro-phenyl]-2-methyl- 3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1pyrrolidin-l-vl-propan-1-one Prepared analogously to Example 7d from 2-[4-(N-benzylmethylamino)-3-nitro-phenyl]-2-methyl-3- methylamino-lpyrrolidin-l-yl-propan-l-one and methyl malonate chloride.
Yield: 84% of theory, RF value: 0.65 (silica gel; ethyl acetate/ethanol 9:1 ammonia)
C
27
H
34
N
4 0, (510.60) mass spectrum: 509 533 j. 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(Nmethoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-lyl-propan-l-one Prepared analogously to Example id from 2-[4-(N-benzylmethylamino)-3-nitro-phenyl]-2-methyl-3-(Nmethoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-lyl-propan-l-one and hydrogen/palladium on activated charcoal.
Yield: 100% of theory, RF value: 0.40 (silica gel; ethyl acetate/ethanol 9:1 +1% conc. ammonia)
C
20
H,
3
N
4 0 4 (390.49) mass spectrum: M' 390 WO 00/01704 98 PCT/EP99/04531 k. 4- (N-methoxycarbonylmethylcarbonyl-methylamino)) 2 -methyl-l-pyrrolidin-1-yl-propan-l-on-2 -yl] (4 -cyanophenyl) -aminomethvlcarbonvlamino-N-methvl-aniline Prepared analogously to Example le from 2-(4-methylamino- 3-amino-phenyl) -2-methyl-3- (Nmethoxycarbonylmethylcarbonyl-methylamino) -l-pyrrolidin-lyl-propan-l-one and 0- (benzotriazol-l-yl) tetramethylurQnium tetrafluoroborate, 4-cyanophenyiglycine and triethylamine in dimethylformamide.
Yield: 95*- of theory, RF value: 0.35 (silica gel; ethyl acetate/ethanol 9:1 1% conc. ammonia) 1. 2- (4-cyanophenylaminomethyl) -1-methyl-5-(1- (Nethoxycarbonylmethylcarbonyl -methylamino) -2- (pyrrolidinocarbonyl) -prop-2-vl] -benzimidazole Prepared analogously to Example if from methoxycarbonylmethylcarbonyl-methylamino) )-2-methyl-lpyrrolidin-l--yl-propan-l-on-2-yl] (4-cyanophenyl) aminomethylcarbonylamino-N-methyl-aniline in glacial acetic acid.
Yield: 47 of theory, Rf value: 0.20 (silica gel; ethyl acetate/ethanol 9:1)
C
2
,H
3 4
N
6 0 4 (530.63) mass spectrum: 531 553 m. 2- (4-amidinophenylaminomethyl) -l-methyl-5- ethoxycarbonylmethylcarbonyl -methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride Prepared analogously to Example 1g from 2-(4cyanophenylaminomethyl) -l-methyl-5- 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 4:1 glacial acetic acid)
C
30
H
39
N
7 0 4 x HC1 (561.69/598.19) mass spectrum: (M+H) 562 596/8 (Cl) The following compounds are obtained analogously to Example 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (N-methoxycarbonylmethyl-methylamino)-2- (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazolehydrochloride Yield: 89 of theory, Rf value: 0.35 (Reversed phase RP 8; methanol/5% saline solution 3:2)
C
28
H,
37
NO
3 x HC1 (519.66/556.11) mass spectrum: 520 (M-H+HC1)- 554/6 (Cl) 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(Nethoxycarbonylmethylcarbonylamino)-2- (pyrrolidinocarbonyl)-prop-2-yl]-benzimidazole-acetate Yield: 45% of theory, R, value: 0.20 (silica gel; methylene chloride/ethanol 8:2 1 ethyl acetate)
C
29
H,
3 N,,0 x CH 3 COOH (547.66/607.71) mass spectrum: 548 546
(M-H+CH
3 COOH)- 606 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1- (N-ethoxycarbonylmethylcarbonyl-methylamino)-2-(N-methylethylaminocarbonyl)-prop-2-yl]-benzimidazole-hydrochloride WO 00/01704 100 PCT/EP99/04531 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethyl-methylamino) (N-methyl-Nethylaminocarbonyl) -prop-2-yl] -benzimidazole-hydrochloride 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl -methylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -1-rethyl-5- [1- (N-ethoxycarbonylmethylsulphonyl-methylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -1-methyl-5- methoxycarbonylmethylcarbonyl -methylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole-acetate Yield: 721 of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol 8:2 1 11 glacial acetic acid)
C
2 9
H
3 7
N
7 0 4 X CH 3 COOH (547.66/607.71) mass spectrum: 548 546 2- (4-amidinophenylaminomethyl) -l-methyl-5- ethoxycarbonyl -ethylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylsuiphonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride Yield: 14%- of theory, Rf value: 0.20 (silica gel; methylene chloride/ethanol 8:2) WO 00/01704 101 WO 0/0174 01 -PCT/EP99/04531
C
2 8
H
3 7
N
7 0 5 S x HCl (583.65/620.17) mass spectrum: 584 606 2- (4-amidinophenylaminomethyl) -l-methyl-5- (H- -methylcarbonylamino) -2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) (pyrrolidinocarbonyl) -prop- 2-yl] -benz imidazole-dihydrochioride Yield: 40*1 of theory,
C
2 8
H
3 7
N
7 0 3 x 2 HCl (519.65/592.56) mass spectrum: 520 542 (M+HCOOY- 564 554 Example 16 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1-(isoxazolidin-1-yl-carbonyl) ethyl] -benzimidazole-hvdrochloride Prepared by hydrolysis of 2-(4-amidinophenylaminomethyl)- [1-(ethoxycarbonylmethylamino) -1-(isoxazolidinl-yl-carbonyl) -ethyl] -benzimidazole-hydrochloride with sodium hydroxide solution in ethanol.
Yield: 90 of theory, Rf value: 0.65 (Reversed phase RP 8; methanol/5t saline solution 3:2)
C
24 11 29
N
7 0 4 x HCl (479.54/515.99) mass spectrum: 480 WO 00/01704 102 PCT/EP99/04531 The following compounds are prepared analogously to Example 16: 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(2carboxyethylamino) (isoxazolidin-l-yl-carbonyl) -ethyl] benzimidazole-hydrochloride 2-(4-amidinophenylaminomethyl)-l-methyl-5-[l- (carboxymethylamino)-l-(N-methyl-N-ethylaminocarbonyl)ethyl]-benzimjdazole-hydrochloride Yield: 93% of theory, R. value: 0.40 (Reversed phase RP 8; methanol/5% saline solution 1:1)
C
24
H
3 1 70 3 x HCl (465.57/502.02) mass spectrum: 466 500/2 (Cl) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(Ncarboxymethyl-methylamino)-2-(pyrrolidinocarbonyl)-prop-2yl] -benzimidazole-dihydrochloride Yield: 89% of theory, Rf value: 0.57 (Reversed phase RP 8; methanol/5% saline solution 4:3)
C
27
H
3 5N 7
O
3 x 2 HCl (505.63/578.54) mass spectrum: 506 253 264.5 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (carboxymethylcarbonylamino) (pyrrolidinocarbonyl) -prop- 2-yl]-benzimidazole-hydrochloride Yield: 90% of theory, Rf value: 0.55 (Reversed phase RP 8; methanol/5% saline solution 4:6)
C
27
H
33 N704 x HCl (519.61/556.06) mass spectrum: 520 518 WO 00/01704 103 WO 0/0174 03 -PCT/EP99/04531 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethyl-methylamino) (N-ethylmethylaminocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (N-carboxyinethylcarbonyl-methylamilo) (N-ethylmethylaminocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (N-carboxymethylcarbonyl-methylamilo) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1- (N-carboxymethylsulphonyl-methylamino) -2- (piperidinocarbonyl) -prop-2-yl] -benzimidazolehydrochloride 2- (4-amidinophenylaminomethyl) -l-methyl-5- El- (carboxymethylamino) -1-(piperidinocarbonyl) -ethyl] benzimidazole -hydrochloride 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: 492 490 2- (4-amidinophenylaminomethyl) -1-methyl-5- carboxyethylcarbonylamino) (pyrrolidinocarbonyl) -prop-2yl] -benzimidazole-hydrochloride WO 00/01704 -14PTE9/43 104 PCT/EP99/04531 (11) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylsuiphonylamino) (pyrrolidinocarbonyl) prop-2-yl] -benzimidazole-hydrochloride (12) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1-(diethylaminocarbonyl) -ethyl] benzimidazole -hydrochloride Yield: 7011 of theory, Rf value: 0.50 (Reversed phase RP 8; methanol/5*i saline solution 1:1)
C
2 5
H
3 3
N
7 10 3 (479.59/516.05) mass spectrum: 480 (M-HY- 478 (M-H+HClY- 514/516 (Cl) (13) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole -dihydrochloride Yield: 22 of theory, Rf value: 0.50 (Reversed phase RP 8; saline solution/ methanol 1:1)
C
2 6
H
3 3
N
7 0 3 x 2 HCl (491.60/564.51) mass spectrum: 492 (M-HY- 490 (14) 2- (4-amidi nophenylaminomethyl) -1-methyl-5- [1-(N-carboxymethyl-methylamino) -1-(pyrrolidinocarbonyl) -ethyl] benzimidazole-dihydrochloride Rf value: 0.48 (Reversed phase RP 8; 511 saline solution/ methanol 3:2)
C
2 6
H
3 3
N.,O
3 x 2 HCl (491.60/5G4.51) mass spectrum: 492 490 WO 00/01704 105 PCT/EP99/04531 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1-(3carboxy-propylamino)-l-(pyrrolidinocarbonyl)-ethyl]benzimidazole-dihydrochloride Yield: 82 of theory, Rf value: 0.73 (Reversed phase; 5% sodium chloride solution/ methanol 1:1)
C
27
H
35 ,N0 3 x 2 HC1 (505.63/578.54) mass spectrum: 506 Example 17 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1methyl-5-[1-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole A suspension of 1.4 g (2.4 mmol) of 2-(4amidinophenylaminomethyl)-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-benzimidazole-dihydrochloride in 5 ml of N-ethyldiisopropylamine 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 120°C the solution is concentrated by evaporation in 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, suction filtered and dried.
Yield: 0.7 g (49% of theory), R, value: 0.40 (silica gel; methylene chloride/ethanol 19:1)
C
34
H
39 N,0 (609.73) mass spectrum: (M+H) 610 (M+Na) 632 WO 00/01704 106 PCT/EP99/04531 608 The following compounds are obtained analogously to Examples 14 and 17: 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]l-methyl-5-El-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 53% of theory, Rf value: 0.35 (silica gel; methylene chloride/ethanol 9:1)
C
34
H
47
N
7 0 5 (633.79) mass spectrum: 656 632 (N-n-octyloxycarbonylamidino) -phenylaminomethyl] l-methyl-5-[l-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 46% of theory, Rf value: 0.43 (silica gel; methylene chloride/ethanol 9:1)
C
36
H
51
N
7 0 5 (661.84) mass spectrum: 684 660 2-[4-(N-n-hexyloxycarbonyl-amidino)- (methoxycarbonylmethylamino)-l-(pyrrolidinocarbonyl)ethyl] -benzimidazole 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]l-methyl-5-l-(methoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)ethyl]-benzimidazole Yield: 32% of theory, Rf value: 0.27 (silica gel; methylene chloride/ethanol 9:1) WO 00/01704 107 WO 0/0174 07 -PCT/EP99/04 531
C
35
H
49 N,0 5 (647.82) mass spectrum: 670 646 2- (N-n-hexyloxycarbonylamidino) -phenylaminomethyl] [1-(N-ethoxycarbonylmethylcarbonylmethylamino) (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole Yield: 52% of theory, Rf value: 0.60, (silica gel; methylene chloride/ethanol= 9:1)
C
3 7
H
51
N
7 0 6 (689.85) mass spectrum: 690 (M-HY- 688) 712 (M+HC1-H)- 724/26 (Cl) 2- (N-n-octyloxycarbonyl-amidino) phenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylcarbonyl -methylamino) 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole 2- (N-n-hexyloxycarbonylamidino) -phenylaminomethyl] [1-(N-methoxycarbonylmethylcarbonylmethylamino) (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole Yield: 210- of theory, Rf value: 0.55 (silica gel; methylene chloride/ethanol= 9:1)
C
3 6
H
4 9
N
7 0 6 (675.83) mass spectrum: 676 698 (M+HCl-H)- 724/26 (Cl) 2- (N-n-octyloxycarbonyl-amidino) phenylaminomethyl) -1-methyl-5- WO 00/01704 108 PCT/EP99/0453 methoxycarbonylmethylcarbonyl -methylamino) 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole 2- (N-phenylcarbonylamidino) -phenylaminomethyl] -1methyl-5- [1-(methoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) -ethyl] -benz imidazole Yield: 34% of theory.
Rf value: 0.55 (silica gel; methylene chloride/ethanol 9:1 1 ammonia)
C
3 3
H
3 7
N
7 0, (595.70) mass spectrum: 594 618 2- isopropyloxycarbonylamidino) phenylaminomethyl] -1-methyl-5- ethoxycarbonylmethylcarbonyl -methylamino) 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 66% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol= 9:1)
C
3 4
H
4 5
N
7 0 6 (647. 77) mass spectrum: 648 646 (M+Na) 4 670 (11) 2- (N-phenylcarbonylamidino) -phenylaminomethyl] -1- [1-(N-ethoxycarbonylmethylcarbonyl-methylamino) 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 23% of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol= 9:1)
C
37
H
43
N
7 0 5 (665.79) mass spectrum: (M+H) 4 666 664 688 700/2 (Cl) 1 WO 00/01704 109 PCT/EP99/04531 (12) 2- (N-phenylcarbonylamidino) -phenylaminomethyl] [1-(N-methoxycarbonylmethylcarbonylmethylamino) (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole Yield: 6711 of theory, Rf value: 0.60 (silica gel; methylene chloride/ethanol= 9:1)
C
3 6
H
4 1
N
7 0, (651.76) mass spectrumi 652 650 674 (13) 2- (N-n-butyloxycarbonylamidino) phenylaminomethyl] -l-methyl-5- methoxycarbonylmethylcarbonyl -methylamino) 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 45*% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol= 9:1)
C
3 4
H
4 5
N
7 0 6 (647.77) mass spectrum: 648 (M-HV- 646 670 (M-H+HClV- 682/4 (Cl) (14) 2- (N-ethyloxycarbonylamidino) -phenylaminomethyl] [1-(N-ethoxycarbonylmethylcarbonylmethylamino) (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole Yield: 54*% of theory, Rf value: 0.40 (silica gel; methylene chloride/ethanol= 9:1)
C
33
H
43
N
7 0 6 (633.75) mass spectrum: 634 (M-HV- 632 656 WO 00/01704 110 WO 0/0174 10 -PCT/EP99/0453l 2- (N-ethyloxycarbonylamidino) -phenylaminomethyl] [1-(N-methoxycarbonylmethylcarbonylmethylamino) (pyrrolidinocarbonyl) -prop-2-yl] benzimidazole Yield: 53%. of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol 9:1)
C
32
H
41 N,0 6 (619.72) mass spectrum: 620 CM-H) 618 642 (16) 2- (N-pyridin-3-yl-carbonylamidino) phenylaminomethyl] -1-methyl-5- ethoxycarbonylmethylcarbonyl -methylamino) 2- (pyrrolidinocarbonyl) -prop-2-yl] -benzimidazole Yield: 16%1 of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol= 9:1)
C
3 6
H
4 2
N
8 0 5 (666.78) mass spectrum: (M-HY- 665 689 (17) 2- (N-n-butyloxycarbonylamidino) phenylaminomethyl] -l-methyl-5- [1- (ethoxycarbonylmethylamino) -1-(pyrrolidinocarbonyl) ethyl] -benzimidazole Yield: 52% of theory, Rf value: 0.42 (silica gel; methylene chloride/ethanol 9:1)
C
32
H
4 3
N
7 0, (605.74) mass spectrum: 606 628 604 WO 00/01704 111 PCT/EP99/04531 (18) 2-[4-(N-ethyloxycarbonylamidino)-phenylaminorethyll- 1-methyl-5-[l-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 30% of theory, Rf value: 0.44 (silica gel; methylene chloride/ethanol 9:1)
C
30
H
39
N
7 01 (577.68).
mass spectrum: 578 600 (M-HV- 576 (19) 2-[4-(N-benzyloxycarbonylamidino)-phenylaminomethyl]- 1-methyl-5-[l-(ethoxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 51% of theory, Rf value: 0.50 (silica gel; methylene chloride/ethanol 9:1)
C
35
H
41 N,0 5 (639.75) mass spectrum: 662 (M-HV- 638 2-4-(N-pyridin-3-yl-carbonylamidino)- (ethoxycarbonylmethylamino)-l-(pyrrolidinocarbonyl)ethyl]-benz imidazole Yield: 84% of theory, Rf value: 0.20 (silica gel; ethyl acetate/ethanol 4:1)
C
33
H
38
N
8 0 4 (610.72) mass spectrum: 611 (M-HV- 609 (M-HCOO)Y 611 (21) 2-[4-(N-acetoxymethyloxycarbonylamidino)- (ethoxycarbonylmethylamino)-l-(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,07 s (621.09) mass spectrum: (M+Na) 644 620 (22) 2-[4-(N-(2,2,2-trichloroethyloxycarbonyl)-amidino)- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-benzimidazole Yield: 73% of theory, Rf value: 0.54 (silica gel; methylene chloride/ethanol 9:1)
C
30
H
36 C13NO (681) mass spectrum: M' 679/81/3 (C1 3 (M+Na) 702/4/6 (C1 3 678/80/2 (C1 3 Example 18 2-[4-(N-n-octyloxycarbonylamidino)-phenylaminomethyl]-lethyl]-benzimidazole A solution of 0.2 g (0.3 mmol) of octyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-benzimidazole in 3 ml tetrahydrofuran and 2.5 ml ethanol is mixed with 1.1 ml of IN sodium hydroxide solution and stirred for 4 hours at ambient temperature.
The reaction mixture is concentrated by evaporation and combined with 1 ml of IN hydrochloric acid. After 12 hours at ambient temperature (pH 4) 2 drops of ammonia are added, whereupon a bright yellow precipitate is formed.
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), R, value: 0.35 (Reversed phase RP 8; methanol/5% saline solution 2:1)
C
34
H
4 ,N,Os (633.79) mass spectrum: 634 328.5 Example 19 2-[4-(N-hydroxyamidino)-phenylaminomethyl] methyl-5- [1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyll-benzimidazole A suspension of 0.6 g (1.2 mmol) of 2-(4cyanophenylaminomethyl)-l-methyl-5-[1- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-benzimidazole in 50 ml ethanol is mixed with 0.47 g (7.8 mmol) of hydroxylamine hydrochloride and 0.35 g 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 organic phases are dried and concentrated by evaporation.
The crude product is purified on silica gel, eluting with dichloromethane/ethanol (19/1 and The uniform fractions are combined, concentrated by evaporation, triturated with diisopropylether and dried.
Yield: 0.025 g of theory), R, value: 0.68 (silica gel; methylene chloride/ethanol 4:1)
C
27
H
35 sN,0 (521.62) mass spectrum: 520 544 WO 00/01704 114 PCT/EP99/0431 Example 2-4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1methyl-5-[l-(isopropyloxycarbonylmethylamino)-1- (pyrrolidinocarbonyl) -ethyl] -benz imidazole a. Ethyl 4-(5-methyl-l,2,4-oxadiazol-3-yl)-phenylaminoacetate Prepared analogously to Example 9a from 4-(5-methyl-l,2,4oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyldiisopropylamine.
Yield: 78% of theory, Rf value: 0.60 (silica gel; ethyl acetate/petroleum ether 1:1) b. 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-acetic acid Prepared analogously to Example 4 from ethyl l,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) c. 2-[4-(5-methyl-l,2,4-oxadiazol-3-yl)carbonyl)-ethyl]-benzimidazole Prepared analogously to Example le/f from 2-(4methylamino-3-amino-phenyl)-2-tert.butyloxycarbonyl-aminol-pyrrolidin-l-yl-propanone, 4-(5-methyl-l,2,4-oxadiazol- 3-yl)-phenylamino-acetic acid and carbonyldiimidazole in tetrahydrofuran and subsequent treatment with glacial 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)phenylaminomethyl]-1-methyl-5- [1- (isopropyloxycarbonylmethylamino)-l-(pyrrolidinocarbonyl)ethyl]-benzimidazole Prepared analogously to Example 11 from 2-[4-(5-methyl- 1,2,4-oxadiazol-3-yl)-phenylaminomethyl] 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 9:1) e. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[1- (isopropyloxycarbonylmethylamino)-l-(pyrrolidinocarbonyl)ethyl]-benzimidazole-acetate Prepared analogously to Example id from 2-[4-(5-methyll,2,4-oxadiazol-3-yl)-phenylaminomethyl]-l-methyl-5-11- (isopropyloxycarbonylmethylamino)-l-(pyrrolidinocarbonyl)ethyl]-benzimidazole and hydrogen/palladium (10% on activated charcoal) in ethanol/glacial acetic acid.
Yield: 69% of theory, Rf value: 0.30 (silica gel; methylene chloride/ethanol 7:3) f. (N-phenylcarbonylamidino) -phenylaminomethyl] -1methyl-5-[l-(isopropyloxycarbonylmethylamino)-1- (pyrrolidinocarbonyl) -ethyl] -benz imidazole Prepared analogously to Example 17 from 2-(4- (isopropyloxycarbonylmethylamino)-l-(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 9:1)
C
35
H
41
N
7 0 4 (623.75) mass spectrum: 646 622 The following compounds are prepared analogously to Example 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1methyl-5-[l-(n-butyloxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1methyl-5-[l-(2-phenylethyloxycarbonylmethylamino)-1- (pyrrolidinocarbonyl)-ethyl]-benzimidazole 2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]l-methyl-5-[l-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 40 of theory, Rf value: 0.45 (silica gel: methylene chloride/ethanol 9:1)
C
35
H
49
N
7 0, (647.82) mass spectrum: 648 (M-HV- 646 670 (N-n-octyloxycarbonylamidino) -phenylaminomethyl] 1-methyl-5-[l-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Yield: 31% of theory, Rf value: 0.48 (silica gel: methylene chloride/ethanol 9:1) WO 00/01704 117 WO 0/0174 17 -PCT/EP99/04531
C
37
H
5 3
N
7 0, (675.88) mass spectrum: 674 698 2- (2,2,2-trichloroethyloxycarbonyl) -amidino) phenylaminomethyl] -1-methyl-5- [1-(isopropyloxycarbonylmethylamino) -1-(pyrrolidinocarbonyl) -ethyl] -benzimidazole Yield: 43% of theory, Rf value: 0.50 (silica gel: methylene chloride/ethanol 9:1)
C
3 1
H
38 C1 3
N
7 0 5 (6-95 mass spectrum: (M-HV 692/694/696/698 (Cl 3 2- (N-phenylcarbonylamidino) phenylaminomethyll 1-methyl-5- [1-(n-propyloxycarbonylmethylamino) -1-(pyrrolidinocarbonyl) -ethyl] -benzimidazole Yield: 791 of theory Rf value: 0.35 (silica gel; ethyl acetate/ethanol 9:1)
C
35
H
4 1 N7O 4 (623 .76) mass spectrum: 624 622 (M+HCOOV- 668 2- (N-n-octyloxycarbonylamidino) phenylaminomethyl] -l-methyl-5- [1-(n-propyloxycarbonylmethylamino) -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 5 (675.88) mass spectrum: 676 698 (M-HY- 674 WO 00/01704 118 PCT/EP99/04531 Example 21 (R)-2-(4-Amidinophenylaminomethyl)-l-methyl-5-[1- (carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyllbenzimidazole 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-3nitrophenyl)-propionic acid in 200 ml of 5.6 N ethanolic 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 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)propionate 17.33 g (63.6 mmol) of ethyl 2-amino-2-(4-chloro-3nitrophenyl)-propionate are dissolved in 247 ml of isopropanol and 207 ml of methanol and mixed with 9.54 g (63.6 mmol) of L-(+)-tartaric acid. The reaction mixture is heated to 100 0 C, whereupon a clear solution is formed.
The solution is cooled to 27 0 C within 3 hours, the precipitate formed is suction filtered, washed with ethanol and dried. Then the solid formed (21.5 g) is 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, [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-nitrophenvl)-propionic acid Prepared analogously to Example 4 from ethyl amino-2- (4-chloro-3-nitrophenyl) -propionate and sodium hydroxide solution in tetrahydrofuran.
Yield: 63*% of theory, 20 -59.60 (methanol/water 1:1) d. 2-t~rt.butvloxvcarbonvlamino-2- (4-chloro-3nitrophenyl) -propionic acid Prepared analogously to Example 5d from (4-chloro-3-nitrophenyl) -propionic acid and pyrocarbonic acid di-tert.butyldicarbonate and triethylamine in dioxan.
Yield: 100*% of theory.
e. -2-tert.butvloxvcarbonvlamino-2- (4-methylamino-3nitrophenvl)-propionic acid Prepared analogously to Example lb from tert .butyloxycarbonylamino-2- (4-chloro-3-nitrophenyl) propionic acid and methylamine.
Yield: 69% of theory.
f. (4-methylamino-3-nitrophenvl) -2tert .butvloxvcarbonvlamino-l-pvrrolidino-propanone Prepared analogously to Example 1c from tert .butyloxycarbonylamino-2- (4-methylamino-3nitrophenyl)-propionic acid, pyrrolidine and carbonyldiimidazole in tetrahydrofuran.
Yield: 96% of theory.
WO 00/01704 120 PCT/EP99/04531 g. (4-methylamino-3-aminophenyl) -2tert .butyloxycarbonylamino- 1-pyrrolidino-propanone Prepared analogously to Example ic from methylamino-3-nitrophenyl) -2-tert .butyloxycarbonylamino-lpyrrolidino-propanone and hydrogen/palladium on activated charcoal in methanol.
Yield: 99*1 of theory.
h. -2-(4-cyanoiphenvlaminomethyl)-l-methyl-5- rl- (Ntert .butyloxycarbonylamino) (prrolidinocarbonyl) ethyl] -benzimidazole Prepared analogously to Example lc/lf from methylamino-3-aminophenyl) -2-tert .butyloxycarbonylamino-lpyrrolidino-propanone, 4 -cyanophenylglycine, carbonyldiimidazole in tetrahydrofuran and subsequent cyclisation in glacial acetic acid.
Yield: 100% of theory.
i. (4-cyanophenylaminomethyl) -1-methyl-S-[l -amino- 1- (pyrrolidinocarbonyvl) -ethyl] -benzimidazole Prepared analogously to Example 6i from cyanophenylaminomethyl) -1-methyl-5- El- (Ntert .butyloxycarbonylamino) -1-(pyrrolidinocarbonyl) ethyl] -benzimidazole and 6N hydrochloric acid in dioxan.
Yield: 76% of theory.
k. (4-cyanophenylaminomethyl) -l-methvl-5- [1- (ethoxycarbonylmethylamino) -1-(pyrrolidinocarbonyl) ethyvl]-benzimidazole Prepared analogously to Example 6k from cyanophenylaminomethyl) (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)-l-methyl-5- l- (ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)ethyl]-benzimidazole hydrochloride Prepared analogously to Example Ig from (ethoxycarbonylmethylamino)-1-(pyrrolidino-carbonyl)ethyl]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 95% of theory.
m. (R)-2-(4-amidinophenylaminomethyl)-l-methyl-5-fl- (carbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]benzimidazole hydrochloride Prepared analogously to Example 4 from methylamino)-1-(pyrrolidinocarbonyl)-ethyl] -benzimidazole and sodium hydroxide solution in ethanol.
Yield: 100% of theory,
C
25
H
31 N,0 3 x 2HC1 (477.57/550.5) Mass spectrum: 478 (M-H+HC1)- 512/514 (Cl) (M-H+2HC1)- 448/550/552 (C1 2 Example 22 Dry ampoule containing 75 mg of active substance per 10 ml Composition: Active substance 75.0 mg 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 water for injections.
Example 23 Dry ampoule containing 35 mg of active substance per 2 ml Composition: Active substance Mannitol water for injections 35.0 mg 100.0 mg ad 2.0 ml Preparation: Active substance and mannitol are dissolved in water.
After packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is dissolved in water for injections.
Example 24 Tablet containing 50 mg of active substance Composition: Active substance Lactose Maize starch Polyvinylpyrrolidone Magnesium stearate 50.0 mg 98.0 mg 50.0 mg 15.0 mg 2.0 mg 215.0 mg WO 00/01704 123 PCT/EP99/04531 Preparation: and are mixed together and granulated with an aqueous solution of is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Example Tablet containing 350 mg of active substance Preparation: Active substance Lactose Maize starch Polyvinylpyrrolidone Magnesium stearate 350.0 mg 136.0 mg 80.0 mg 30.0 mg 4.0 mq 600.0 mg and are mixed together and granulated with an aqueous solution of 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.
WO 00/01704 124 PCT/EP99/04531 Example 26 Capsules containing 50 mg of active substance Composition: Active substance Dried maize starch Powdered lactose Magnesium stearate 50.0 mg 58.0 mg 50.0 mg 2.0 mc 160.0 mg Preparation: is triturated with This trituration is added to the mixture of and with vigorous mixing.
This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.
Example 27 Capsules containing 350 mg of active substance Composition: Active substance Dried maize starch Powdered lactose Magnesium stearate 350.0 mg 46.0 mg 30.0 mg 4.0 mq 430.0 mg Preparation: is triturated with This trituration is added to the mixture of and with vigorous mixing.
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 Suppositories containing 100 mg of active substance 1 suppository contains: Active substance 100.0 mg Polyethyleneglycol 1500) 600.0 mg Polyethyleneglycol 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mq 2,000.0 mg Method: The polyethyleneglycol is melted together with polyethylene sorbitan monostearate. At 40 0 C the ground active substance is homogeneously dispersed in the melt.
It is cooled to 38 0 C and poured into slightly chilled suppository moulds.
P:\OPERLgc\49033-99 claims.doc-20/5/03 125A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form or suggestion that that prior art forms part of the common general knowledge in Australia.
*o *e *ee

Claims (8)

1. Benzimidazoles of general formula -N RaC I A-B-Ar--R c -/N Rb wherein Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C, 3-alkyl or C 1 3 -alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C 1 3 -alkyl group, A denotes a C .3-alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a Cl-3-alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, 2R, denotes an R,-CO-C3 5 -cycloalkyl group wherein R denotes a Cl- 3 -alkoxy, amino, C 4-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 1 3 -alkyl groups, whilst WO 00/01704 127 PCT/EP99/04531 an alkyl substituent may simultaneously be substituted by a hydroxy, C,_ 3 -alkoxy, carboxy, carboxy-C 1 -,-alkoxy, carboxy-C- 3 -alkylamino, N- (C, 3 -alkyl) (carboxy- Cl_ 3 -alkyl)-amino, carboxy-C 1 3 -alkylaminocarbonyl, N- (C 1 3 -alkyl) (carboxy-C 3 -alkyl) -aminocarbonyl, carboxy-C,3-alkylaminocarbonylamino, 1-(C, 3 -alkyl)-
3-(carboxy-C. 3 -alkyl)-aminocarbonylamino, 3-(C, 3 -alkyl)- 3-(carboxy-C. 3 -alkyl)-aminocarbonylamino or 1,3-di- (Cl -alkyl)-3-(carboxy-Cl 1 3 -alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 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, 3 -alkyl) -piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, an R 2 -CX-C 3 5 cycloalkyl group wherein 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 heteroaryl group contains an imino group optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted 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, 1 3 -alkoxy, carboxy- C 1 3 -alkylamino or N-(Cl_ 3 -alkyl)- carboxy-C 1 3-alkylamino group, and WO 00/01704 128 PCT/EP99/04531 X denotes an oxygen atom, a C 1 _3-alkylimino, C 1 _3-alkoxyimino, C 1 3 -alkylhydrazino, di- (C 1 3 -alkyl)- hydrazino, C2- 4 -alkanoylhydrazino, N-(C_ 3 -alkyl) C 2 _4-alkanoylhydrazino or C_ 3-alkylidene group each of 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 5 -cycloalkyl group substituted by an 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,_--alkyl groups, wherein the 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, C 1 3 -alkylamino, N-(C2- 4 -alkanoyl) -C 1 3 -alkylamino or di- (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 amino, C2- 4 -alkanoylamino, C 1 3 -alkylamino, N- (C 2 4 -alkanoyl) -Cl- -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 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 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_3-alkyl, HOOC-C 1 3 -alkyl-Yi-CI 3 -alkyl, tetrazolyl-C 1 3 -alkyl-Y2, R3NR or R3NR4-C,-3-alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a CI.3-alkyl group, by a pyrrolino- carbonyl, 3,4-dehydro-piperidinocarbonyl, pyrrol-l-yl- carbonyl, carboxy, aminocarbonyl, Cl_ 3 -alkylaminocarbonyl, di-(CI 3 -alkyl)-aminocarbonyl or 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 moiety or alkyl substituent in the abovementioned C 1 .3-alkylaminocarbonyl, di-(Cl_ 3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the Cl. 4 -alkyl group may be wholly or partially replaced by fluorine atoms wherein R 3 denotes a hydrogen atom or a C_.3-alkyl group optionally substituted by a carboxy group and R 4 denotes a hydrogen atom, a C_.3-alkyl- Y,-C 1 3 -alkyl-Y 2 carboxy-C_ 3 -alkyl-YI-Ci 3 -alkyl-Y 2 C 1 _--alkyl-Y 2 or carboxy-C,, 3 -alkyl-Y 2 group or 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-_3-alkyl or carboxy-C_ 3 -alkyl group wherein Y 1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-CO- or -NH-CO-NH- group and P:\OPERLgcU49033-99 caims.doc-21/05/)3 -130- 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 nitrogen atom of the R 3 NR 4 group, and the imino groups occurring in the definition of the groups Yi and Y 2 may each additionally be substituted by a C1- 3 -alkyl or carboxy-C 1 -3-alkyl group, a C1- 3 -alkyl or C3-5-cycloalkyl group substituted by a R 5 NR 6 group wherein R 5 denotes a hydrogen atom, a C 1 -3-alkyl, C5- 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R 6 denotes a Ci- 3 -alkyl, carboxy-C 1 -3-alkyl or carboxy- C1- 3 -alkylcarbonyl group, a Ci- 3 -alkyl group which is substituted by a C2-4-alkanoyl or C 5 7 -cycloalkanoyl group and by a C1- 3 -alkyl group 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 optionally substituted by one or two C1- 3 -alkyl groups, wherein, the carboxy groups mentioned in the definitions of the abovementioned groups may also be replaced by a group which 30 can be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions, or P:\OPERUgc\49033-99 laims.doc-20/0A03 -131- the amino and imino groups mentioned in the definitions of the abovementioned groups may also be substituted by a group which can be cleaved in vivo, wherein a group which can be converted in vivo into a carboxy group denotes a hydroxmethyl group or a carboxy group esterified with an alcohol, wherein the alcoholic moiety is a C 1 -6-alkanol, a phenyl-C 1 3 -alkanol, a C3- 9 -cycloalkanol, whilst a Cs- 8 -cycloalkanol may additionally be substituted by one or two C1- 3 -alkyl groups, a C 5 s--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 Ci- 3 -alkyl, phenyl-C1- 3 -alkyl, phenyl-C-3-alkoxycarbonyl or C2- 6 -alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C 1 3 -alkyl groups, a C 4 7 -cycloalkenol, a C 3 -5-alkenol, a phenyl-C 3 -5-alkenol, a C3- 5 -alkynol or phenyl-C 3 -5-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3- 8 -cycloalkyl- S. 20 C1- 3 -alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which may additionally be substituted in the bicycloalkyl moiety by one or two C 1 3 -alkyl groups, a 1,3- dihydro-3-oxo-l-isobenzofuranol or an alcohol of formula Rd-CO-O- (ReCRf) -OH, wherein Rd denotes a C1-8-alkyl, C5- 7 -cycloalkyl, phenyl or phenyl- C 1 3 -alkyl group, 30 Re denotes a hydrogen atom, a C1- 3 -alkyl, Cs- 7 -cycloalkyl or phenyl group and P:\OPERUgc 9033-99 claims.doc-20/053
132- Rf denotes a hydrogen atom or a C1- 3 -alkyl group, a group which is negatively charged under physiological conditions denotes a tetrazol-5-yl, phenylcarbonylamino-car- bonyl, trifluormethylcarbonylaminocarbonyl, C 1 -6-alkylsulpho- nylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C 1 -6-alkylsulphonylaminocarbonyl, phenylsulphonylamino- carbonyl, benzylsulphonylaminocarbonyl or perfluoro- C 1 -6-alkylsulphonylaminocarbonyl group and a group which can be cleaved in vivo from an imino or amino group denotes a hydroxy group or an acyl group selected from a benzoyl group, optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1- 3 -alkyl or C 1 3 -alkoxy groups, wherein the substituents may be identical or different, a pyridinoyl group or a C1- 1 6 -alkanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C 1 16 -alkoxycarbonyl or 20 C 1 16 -alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, a phenyl-C 1 -6-alkoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C 1 -6-alkyl or C 3 -7-cycloalkyl groups and the substituents may be identical or different, a Cl- 3 -alkylsulphonyl- C 2 -4-alkoxycarbonyl, C 1 -3-alkoxy-C 2 -4-alkoxy- C 2 -4-alkoxycarbonyl, Rd-CO-O- (RdCRf) C 1 -6-alkyl-CO-NH- (RCRh)-O-CO- or Ci-6-alkyl-CO-O-(RgCRh)-(RgCRh)-O-CO- group ~wherein Rd to Rf are as hereinbefore defined, and R9 and Rhr 30 which may be identical or different, denote hydrogen atoms or C1- 3 -alkyl groups, P:\OPER\gc\9033-99 claimsdoc-20/05/03 -133- the tautomers, stereoisomers, mixtures and salts thereof. 2. Benzimidazoles of general formula Ra N -R c (Ia), Rb wherein A denotes a C1- 3 -alkylene group, B denotes an oxygen or sulphur atom, a methylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1- 3 -alkyl group wherein the alkyl moiety may be mono- or disubstituted by a carboxy group, Ra denotes an R 1 -CO-C3-5-cycloalkyl group wherein R i denotes a C 1 -3-alkoxy, amino, C 1 -4-alkylamino or di- S"(C 1 -4-alkyl)-amino group wherein each alkyl moiety may be substituted by a carboxy group, a 4- to 7-membered cycloalkyleneimino or cycloalkenyleneimino group which may be substituted by one or two C1- 3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C1- 3 -alkoxy, C carboxy, carboxy-C 1 3 -alkoxy, carboxy-C 1 3 -alkylamino, N-(C 1 3 -alkyl)-N-(carboxy-C 1 3 -alkyl)-amino, carboxy- Cl- 3 -alkylaminocarbonyl, N-(C-1 3 -alkyl)-N-(carboxy- C 1 3 -alkyl)-aminocarbonyl, carboxy- Ci- 3 -alkylaminocarbonylamino, 1-(Ci-3-alkyl)-3-(carboxy- C- 1-(CC P:\OPERUgcl49033-99 claim.dc-20/03 -134- C 1 -3-alkyl)-aminocarbonylamino, 3-(C 1 3 -alkyl)-3-(carboxy- C 1 3 -alkyl)-aminocarbonylamino or 1,3-di-(C 1 3 -alkyl)- 3-(carboxy-C 1 3 -alkyl)-aminocarbonylamino group, a 4- to 7-membered cycloalkenyleneimino group substituted by a hydroxy group, 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, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, an R 2 -CX-C 3 -5-cycloalkyl group wherein 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 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 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 3 -alkoxy, carboxy-C1- 3 -alkylamino or N-(C1- 3 -alkyl)- carboxy-C1- 3 -alkylamino group, and 30 X denotes an oxygen atom, a C1- 3 -alkylimino, C 1 3 -alkoxyimino, C1- 3 -alkylhydrazino, di-(C1- 3 -alkyl)- hydrazino, C 2 4 -alkanoylhydrazino, N-(C 1 -3-alkyl)- P:\OPERUgc\49033-99 dclims.doc-20/05/I 3 -135- C 2 4 -alkanoylhydrazino or Ci- 3 -alkylidene group each of which may be substituted in the alkyl or alkanoyl moiety or in the alkyl and alkanoyl moieties by a carboxy group, a C1- 3 -alkyl or C3- 5 -cycloalkyl group substituted by an imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1- 3 -alkyl groups or by one, two or three C1- 3 -alkyl groups, wherein the 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, C1- 3 -alkylamino, N-(C 2 4 -alkanoyl)-C1- 3 -alkylamino or di- (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 amino, C 2 4 -alkanoylamino, C1- 3 -alkylamino, N-(C 2 4 -alkanoyl)- C 1 3 -alkylamino or di-(C1_ 3 -alkyl)-amino group, and o additionally a phenyl or pyridine ring may be fused to the abovementioned imidazole or imidazolone rings via two adjacent carbon atoms, e 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, P:\OPERUgc\49033-99 claims.doc-20A/503 -136- a C1- 4 -alkyl group which is substituted by a C 1 3 -alkyl-Y 1 -C 1 3 -alkyl, HOOC-C1- 3 -alkyl-Y 1 -C 1 3 -alkyl, tetrazolyl-C 1 3 -alkyl-Y 2 R 3 NR 4 or R 3 NR 4 -C1- 3 -alkyl group and by an isoxazolidinylcarbonyl group optionally substituted by a C1- 3 -alkyl group, by a pyrrolinocarbonyl, 3,4-dehydro- piperidinocarbonyl, pyrrol-1-yl-carbonyl, carboxy, aminocarbonyl, C 1 l 3 -alkylaminocarbonyl, di-(C 13 -alkyl) aminocarbonyl or 4- to 7-membered cyclo- alkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C1- 3 -alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C 1 3 -alkylaminocarbonyl, di-(C 13 -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 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 R 4 denotes a hydrogen atom, a C1- 3 -alkyl-Y 1 -C 1 I 3 -alkyl-Y 2 carboxy-C 1 3 -alkyl-Yi-C 1 3 -alkyl-Y 2 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 denote an 4- to 7-membered cycloalkyleneimino group 30 optionally substituted by a carboxy, C 1 3 -alkyl or carboxy-C 1 3 -alkyl group wherein P:\OPERUgcW'933-99 claims.doc-20/15O03 -137- Yi denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -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 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 Yi and Y 2 may each additionally be substituted by a C 1 3 -alkyl or carboxy-C 1 3 -alkyl group, a C1- 3 -alkyl or C 3 -5-cycloalkyl group substituted by a R 5 NR 6 group wherein Rs denotes a hydrogen atom, a C 1 3 -alkyl, C 5 7 -cycloalkyl, 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, a Ci- 3 -alkyl group which is substituted by a C 2 4 -alkanoyl or 7 -cycloalkanoyl group and by a Ci- 3 -alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a hydrogen atom or a C1- 3 -alkyl group and R denotes a cyano group or an amidino group which may be substituted by a hydroxy group, by one or two C1- 3 -alkyl groups, or by one or two C 1 -s-alkoxycarbonyl groups, wherein the carboxy, amino and imino groups mentioned in the definition of the abovementioned groups may also be P:\OPER\gc64)933-99 claims.do-20/05/03 -138- substituted by a group as defined in claim 1 which can be converted in vivo into a carboxy group or cleaved in vivo from an amino or imino group, the tautomers, stereoisomers and salts thereof. 3. Benzimidazoles of general formula Ia according to claim 2, wherein A denotes a Ci- 3 -alkylene group, B denotes an oxygen atom, a methylene, imino or N-(C1- 3 alkyl)-imino group wherein the alkyl moiety may be substituted by a carboxy group, Ra denotes an C3-5-cycloalkyl group substituted by the Ri-CO group in the 1 position wherein R denotes a C1- 3 -alkoxy, amino, C1- 4 -alkylamino or di- S 20 (C1- 4 -alkyl)-amino group wherein each alkyl moiety may be 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 C1- 3 -alkyl groups, whilst an alkyl substituent may simultaneously be substituted by a hydroxy, C 1 3 -alkoxy, carboxy, carboxy- C- 3 -alkoxy, carboxy-C 1 -3-alkylamino, N-(C1- 3 -alkyl)-N-(carb- oxy-C 1 3 -alkyl) -amino, carboxy-C 1 _3-alkylaminocarbonyl, N-(Ci- 3 -alkyl)-N-(carboxy-C1- 3 -alkyl) -aminocarbonyl, carboxy-C 1 -3-alkylaminocarbonylamino, 1-(Cl-3-alkyl)- 3-(carboxy-C1- 3 -alkyl)-aminocarbonylamino, 3-(Ci- 3 -alkyl) 9. P:\OPERUgcW9033-99 claima.doc-20/05/03 -139- 3-(carboxy-C1-3-alkyl)-aminocarbonylamino or 1,3-di- (Ci- 3 -alkyl)-3-(carboxy-C1- 3 -alkyl)-aminocarbonylamino group, a 5- to 7-membered cycloalkyleneimino group optionally substituted by a C1- 3 -alkyl group, to which a phenyl ring is fused via two adjacent carbon atoms, a morpholino, piperazino, N-(C1- 3 -alkyl)-piperazino, pyrrolino, 3,4-dehydro-piperidino or pyrrol-l-yl group, a C3- 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 C 1 3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the heteroaryl group contains an imino group 20 optionally substituted by a C1- 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- C1- 3 -alkoxy, carboxy-C 1 3 -alkylamino or N-(C 1 3 -alkyl)- carboxy-Ci- 3 -alkylamino group, and e X denotes an oxygen atom, a Ci- 3 -alkylimino, Cl-3-alkoxyimino or C 1 -3-alkylidene group, each of which may 30 be substituted in the alkyl or alkanoyl moiety by a carboxy group, P:\OPERUgc\49033-99 claims.doc-20/D5/03
140- a Ci- 3 -alkyl group substituted in the 1 position by an imidazole or imidazolone group wherein the imidazole ring may be substituted by a phenyl or carboxy group and by one or two C1- 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 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, C2- 4 -alkanoylamino, C 1 3 -alkylamino, N-(C2- 4 -alkanoyl)-Cl- 3 -alkylamino or di- (C1- 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 amino, C 2 4 -alkanoylamino, C 1 3 -alkylamino, N-(C2-4-alkanoyl)- C 1 3 -alkylamino or di-(C1- 3 -alkyl)-amino group, and 20 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 substituted by one or two C1- 3 -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy group, a C1- 4 -alkyl group which is substituted in the 1 position by an R 3 NR 4 or R 3 NR 4 -Ci- 3 -alkyl group and P:\OPERUgc\49033-99 claims.doc-20/05/03 -141- by a pyrrolinocarbonyl, 2,3-dehydro-piperidinocarbonyl, imidazol-l-yl-carbonyl, carboxy, aminocarbonyl, C 1 3 -alkylaminocarbonyl, di- (C- 3 -alkyl)-aminocarbonyl, isoxazolidin-l-ylcarbonyl or 4- to 7-membered cyclo- alkyleneiminocarbonyl group, whilst in the abovementioned groups the cycloalkyleneimino moiety may be substituted by one or two C1- 3 -alkyl groups and at the same time each alkyl moiety or alkyl substituent in the abovementioned C 1 3 -alkylaminocarbonyl, di-(C1- 3 -alkyl)-aminocarbonyl or cycloalkyleneiminocarbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of the C 1 i 4 -alkyl group may be wholly or partially replaced by fluorine atoms, wherein R 3 denotes a hydrogen atom or a C1- 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- C 1 3 -alkyl-Y 2 group or G* 5.5.5 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-C1- 3 -alkyl group, wherein 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 49 30 groups Y 2 may additionally be substituted by a Ci- 3 -alkyl or carboxy-C1- 3 -alkyl group, P:\OPERUgc49033-99 claim.doc-20/05A03 -142- a Ci- 3 -alkyl or C3- 5 -cycloalkyl group substituted in the 1 position by an R 5 NR 6 group, wherein R 5 denotes a hydrogen atom, a C 1 3 -alkyl, Cs- 7 -cycloalkyl, phenylcarbonyl, phenylsulphonyl or pyridinyl group and R 6 denotes a C1- 3 -alkyl, carboxy-C 1 3 -alkyl or carboxy- C 1 3 -alkylcarbonyl group, a C1- 3 -alkyl group which is substituted by a C 2 4 -alkanoyl or C 5 -7-cycloalkanoyl group and by a C1- 3 -alkyl group substituted by a chlorine, bromine or iodine atom, Rb denotes a C1- 3 -alkyl group and Rc denotes an amidino group which may optionally be substituted by a 2,2,2-trichloroethoxycarbonyl, C 1 -8-alkoxycarbonyl, acetoxymethyloxycarbonyl, benzyloxycarbonyl or benzoyl group, whilst the benzoyl moiety may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1 3 -alkyl or Ci- 3 -alkoxy groups and the substituents may be identical or different, the C1- 3 -alkanol esters, the tautomers, stereoisomers and S 25 salts thereof. 4. Benzimidazoles of general formula Ia according to claim 2, wherein 30 A denotes a methylene group, *d B denotes an oxygen atom or an imino group, P:\OPERUgc\19033-99 claims.doc20/05/03 -143- Ra denotes a cyclopropyl group substituted by the R 1 -CO- group in the 1 position, wherein R i 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 N-(C- 3 -alkyl) carboxy-C1_ 3 -alkylamino group, 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 C1- 3 -alkyl group and X denotes an oxygen atom, a C1- 3 -alkoxyimino or C 1 -3-alkyli- dene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, a C1- 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 1 3 -alkyl groups or by one, two or three C1- 3 -alkyl groups, wherein the 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)- 30 C1- 3 -alkylamino or di-(C1- 3 -alkyl)-amino group, whilst additionally a phenyl or pyridine ring may be fused to the *SSS ooo ooO P:\OPERUgc49033-99 claims.doc-205/03
144- abovementioned imidazole rings via two adjacent carbon atoms, a C1- 2 -alkyl substituted in the 1 position by a benzimidazolon-l-yl group, whilst the imidazolone ring may 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 by an R 3 NR 4 or R 3 NR 4 -C- 3 -alkyl group and by a di-(C1- 3 -alkyl)-aminocarbonyl group, by a isoxazolidin-l-ylcarbonyl group, by a pyrrolidino-carbonyl or piperidinocarbonyl group substituted by a C1- 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 9 9 999 R 3 denotes a hydrogen atom or a Ci- 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- 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 Y 2 denotes a carbon-nitrogen bond, a carbonyl group or an imino group optionally substituted by a C1- 3 -alkyl group, P:\OPERUgc\4)33-99 claimsdoc-20/05/053
145- a C1- 2 -alkyl group substituted in the 1 position by an RsNR 6 group, wherein R 5 denotes a pyridinyl, phenylcarbonyl or phenylsulphonyl group and 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 cyclopentylcarbonyl group, 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 Rc denotes an amidino group which may optionally be substituted by a C 1 -s-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or benzoyl group, the C1- 3 -alkanol esters thereof, the tautomers, stereoisomers and salts thereof. 3 oo** o o* Benzimidazoles of general formula Ia according to claim 2, wherein A denotes a methylene group, P:\OPER\Jgc)4933-99 claim.do-20/05/03 -146- B denotes an imino group, Ra denotes a cyclopropyl group substituted by the Ri-CO- group in the 1 position, wherein 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 N-(C- 3 -alkyl)- carboxy-Ci- 3 -alkylamino group, 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 C1- 3 -alkyl group and X denotes an oxygen atom, a C 1 3 -alkoxyimino or C1- 3 -alkyli- dene group, each of which is substituted in the alkyl or alkoxy moiety by a carboxy group, *9 .I a C1- 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 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. a methyl or ethyl group which is substituted in the 1 30 position 9 P:\OPERUgc\49033-99 caims.doc-20/5/)3 -147- by an R 3 NR 4 or R 3 NR 4 -CH 2 group and by a di-(C 1 -3-alkyl)-aminocarbonyl, by a pyrro- lidinocarbonyl or piperidinocarbonyl group optionally substituted by a C1- 3 -alkyl group, whilst in the abovementioned groups each alkyl moiety or alkyl substituent may be substituted by a carboxy group, wherein R 3 denotes a hydrogen atom or a C1- 3 -alkyl group optionally substituted by a carboxy group and R 4 denotes a Ci- 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 an imino group optionally substituted by a C1- 3 -alkyl group, Rb denotes a methyl group and Rc denotes an amidino group which may optionally be substituted by a C 1 -8-alkoxycarbonyl, acetoxymethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, S* "benzyloxycarbonyl or benzoyl group, 25 the C1_ 3 -alkanol esters thereof, the tautomers, stereoisomers and salts thereof. 6. Benzimidazoles of general formula I according to any one of claims 1 to 5 wherein the group Ra is in the 30 position, the tautomers, stereoisomers and salts thereof. S* S. P:\OPER\Jgc\49%)33-99 cbii.dc-2A)SA) 148 7. The following compounds of general formula Ia: 2- (4-amidinophenylaminomethyl) -l-methyl-5-[1- (pyrrolidin-1-yl-carbonyl) cyclopropyl] -benzimiclazole, (E/Z)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[l- [(pyridin-2-yl) -(carboxymethyloxyimino)methylenel cyclopropyl] -benzimidazole, 2- (4-amidinophenylaminomethyl) -1-methyl-5-[1- (2- carboxyethylamino) -1-(pyrrolidin-l-yl-carbonyl) -ethyl] benzimidazole, 2-(4-amidinophenylaminomethyl) -1-methyl-5-[l-[2-(2- carboxyethyl) -pyrrolidin-l-yl-carbonyl] cyclopropyl] benzimidazole, 2- (4-amidinophenylaminomethyl) -1-methyl-5-[2- (2- carboxyethyl) 5-dimethyl-imidazol-1-yl-methyl] benzimidazole 2- (4-amidinophenylaminomethyl) -l-methyl-5- [1-(carboxy- methylamino) -1-(pyrrolidin-l-yl-carbonyl) -ethyl] -benzimi- dazole and 2- (4-amidinophenylaminomethyl) -l-methyl-5-[1- (N-methyl carboxymethylcarbonylaminomethyl) -1-methyl-l- (pyrrolidin-
301-yl-carbonyl) -ethyl] -benzimidazole P:\OPERUgc49033-99 claims.doc-20/05/03 -149- and the C 1 3 -alkanolesters, the N-(C 1 -8-alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl-amidines thereof, the tautomers, stereoisomers and salts thereof. 8. 2-(4-amidinophenylaminomethyl)-l-methyl-5-[l- (carboxymethylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl]- benzimidazole, the C 1 3 -alkanolesters thereof, and their N-(Cl-8-alkoxycarbonyl), N-benzyloxycarbonyl and N-benzoyl- amidines, tautomers, stereoisomers and salts. 9. (R)-2-(4-amidinophenylaminomethyl)-l-methyl-5-[l- (carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]- benzimidazole, the C 1 3 -alkanolesters thereof, and their N- (C 1 -8-alkoxycarbonyl), N-benzyloxy-carbonyl and N- benzylamidines, tautomers, stereoisomers and salts. Physiologically acceptable salts of the compounds according to any one of claims 1 to 9 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9. 11. Pharmaceutical compositions containing a compound according to any one of claims 1 to 9 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9, or a salt according to claim 10, optionally together with one or more 25 inert carriers and/or diluents. 12. Use of a compound according to any one of claims 1 to 9 wherein Re denotes one of the amidino groups mentioned in claims 1 to 9, or a salt according to claim 10, for 30 preparing a pharmaceutical composition with a thrombin time prolonging effect, a thrombin-inhibiting effect and an inhibiting effect on related serine proteases. 6eoo P:\OPERUgc\4)933-99 clains.doc-20A5/03 -150- 13. Process for preparing a pharmaceutical composition according to claim 11, wherein a compound according to at least one of claims 1 to 9 wherein Rc denotes one of the amidino groups mentioned in claims 1 to 9, or a salt according to claim 10, is incorporated in one or more inert carriers and/or diluents by a non-chemical method. 14. Process for preparing the compounds according to claims 1 to 10, wherein a) in order to prepare a compound of general formula I wherein Rc denotes a cyano group: a compound of general formula Z z 2 NH- C -A-B-Ar-CN R NH aNH (II). 20 optionally formed in the reaction mixture, wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 9, Z 1 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 Z 1 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 in a solvent or mixture of solvents in an excess of the acylating agent used a S. P:\OPERJgc49033-99 claims.doc-20/05/03 -151- to prepare the compound of general formula II, at temperatures between 0 and 250°C, to form a benzimidazole of general formula I wherein Rc denotes a cyano group, or b) in order to prepare a compound of general formula I wherein Ra denotes an R 2 -CX'-C3- 5 -cycloalkylene group, wherein R 2 is defined as in claims 1 to 9 and X' denotes one of the imino groups mentioned for X in claims 1 to 9: a compound of general formula Ra' A-B-Ar--R c (IV), N Rb wherein Rb, Ar, A and B are defined as in claims 1 to 9 and Ra' denotes an R 2 -CO-C3-5-cycloalkylene group, where R 2 is defined as in claims 1 to 9, is reacted with an amine of general formula H 2 X' 20 wherein X' denotes one of the imino groups mentioned for X in claims 1 to 9, or 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 9 and X" denotes one of the alkylidene groups mentioned for X in claims 1 to 9, a .u compound of general formula a P:\OPER\Jgc49033-99 claims.doc-20/05/03 -152- Ra'- I -A-B-Ar--R (IV). Rb wherein Rb, Ar, A and B are defined as in claims 1 to 9 and Ra' denotes an R 2 -CO-C 3 5 -cycloalkylene group, where R 2 is defined as in claims 1 to 9, is reacted with a phosphone of general formula Z 3 -X"H (VI), wherein X" denotes one of the alkylidene groups mentioned for X in claims 1 to 9 and Z 3 denotes a triphenylphosphono or di-(Cl-3-alkoxy)phosphono group, or d) in order to prepare a compound of general formula I wherein Rc denotes an amidino group which may be substituted by one or two C 1 -3-alkyl groups: 20 a compound of general formula Ra- A-B-Ar--C=(NH)Z 4 (VII), Rb optionally formed in the reaction mixture wherein 2*A 25 Ra, Rb, Ar, A and B are defined as in claims 1 to 9 and P:\OPER\Jgc\4W)33-99 claims.doc-20/05/03 -153- Z 4 denotes an alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with an amine of general formula H R 7 NR 8 (VIII), wherein R 7 and R 8 which may be identical or different, each denote a hydrogen atom or a C1- 3 -alkyl group, or with the salts thereof, or 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 C1- 3 -alkyl groups, whilst at the same time an alkyl substituent may be substituted by a carboxy or Cl-3-alkoxycarbonyl group: a compound of general formula Ra -A-B-Ar--CN (IX), N Rb optionally formed in the reaction mixture wherein 20 Rb, Ar, A and B are defined as in claims 1 to 9 and Ra" denotes an aminocarbonylamino group, substituted in the 3 position by a C 1 3 -alkoxycarbonyl-C1- 3 -alkyl group, is cyclised in a solvent in the presence of an acid at temperatures between 0 and 50°C to form said imidazolidin- 2,4-dion-5-yl compound, or S. f) in order to prepare a compound of general formula I wherein Rc denotes a hydroxyamidino group: P:\OPERigcWX133-99 claims.doc-20/05)3 -154- a nitrile of general formula -,N Ra A-B-Ar -CN N Rb wherein Ra, Rb, Ar, A and B are defined as in claims 1 to 9, is reacted with hydroxylamine or the salts thereof, or g) in order to prepare a compound of general formula I wherein Ra contains a carboxy group and Rc is defined as in claims 1 to 9 or Ra is defined as in claims 1 to 9 and Rc denotes an amidino group optionally substituted by a hydroxy group or by one or two C1- 3 -alkyl groups: a compound of general formula Ra" >A-B-Ar--Rc' (XI), N Rb wherein Rb, Ar, A and B are defined as in claims 1 to 9 and Ra"' and Rc' have the meanings given for Ra and Rc respectively in claims 1 to 9, 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 Rc is defined as in claims 1 to 9 or Rc denotes a group which may optionally be converted by hydrolysis, treatment with an acid or base, thermolysis or 9. P:\OPERUgc49033-99 claims.doc-2005/0) 3 155- hydrogenolysis into an amidino group substituted by a hydroxy group or by one or two C1- 3 -alkyl groups and Ra is defined as in claims 1 to 9, 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 9 or Ra is defined as in claims 1 to 9 and Rc denotes an amidino group optionally substituted by a hydroxy group or by one or two C1- 3 -alkyl groups, or 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: a compound of general formula I Ra (XII). Rb wherein 20 Ra, Rb, Ar, A and B are defined as in claims 1 to 9 and Re" denotes an amidino group, is reacted with a compound of general formula R 9 (XIII), wherein R 9 denotes a C 1 8 -alkoxycarbonyl group or an acyl group ~selected from a benzoyl group, optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1- 3 -alkyl or C1- 3 -alkoxy groups, wherein the P:\OPERUgceU9033-99 caims.doc-20A5/03 -156- substituents may be identical or different, a pyridinoyl group or a C1- 16 -alkanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C 1 16 -alkoxycarbonyl or C1-1 6 -alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, a phenyl-C 1 -6-alkoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C 1 -6-alkyl or C 3 7 -cycloalkyl groups and the substituents may be identical or different, a C 1 3 -alkylsulphonyl- C 2 4 -alkoxycarbonyl, C 1 3 -alkoxy-C2-4-alkoxy- C2- 4 -alkoxycarbonyl, Rd-CO-O- (RdCRf) Ci-6-alkyl-CO-NH- (RgCRh) -O-CO- or Ci- 6 -alkyl-CO-O- (RgCRh) (RgCRh) -O-CO- group wherein Rd to Rf are as hereinbefore defined, and Rg and Rh, which may be identical or different, denote hydrogen atoms or C1- 3 -alkyl groups which can be cleaved in vivo, and 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 13 -alkyl group in which at least one of the groups R 3 or R 4 denotes a hydrogen atom, is converted with a corresponding isocyanate or carbamoyl halide into a corresponding urea compound of general formula I, and/or 25 a compound of general formula I thus obtained which contains a NH 2 -C 1 3 -alkyl group is converted with a corresponding acrylic acid ester into a corresponding 2-(C 1 3 -alkoxycarbonyl)-ethyl compound of general formula I and/or a compound of general formula I thus obtained which contains an (R 3 NR 4 )-C1- 3 -alkyl group in which R 3 and R 4 each denote a .00. 0* P:\OPERUgcU\9033-99 claim.doc-20A5/03 -157- 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 cycloalkyleneimino group and/or a compound of general formula I thus obtained wherein Rc denotes an amidino group is converted with a haloacetic acid derivative and subsequent hydrolysis and decarboxylation into a corresponding amidino compound substituted by one or two methyl groups and/or a compound of general formula I thus obtained wherein Rc denotes a hydroxyamidino group is converted by catalytic 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 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 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 salts thereof with 30 an inorganic or organic acid or base. P:\OPER\gc4)9033-99 claims.doc-20/05/03 -158- Benzimidazoles of claim 1 substantially as hereinbefore described with reference to the Examples. 16. Benzimidazoles of claim 2 substantially as hereinbefore described with reference to the Examples. DATED this 2 0 th day of May, 2003 Boehringer Ingelheim Pharma KG by DAVIES COLLISON CAVE Patent Attorneys for the Applicant *e
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BG105111A (en) 2001-12-29
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MY123310A (en) 2006-05-31
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