CA2323606A1 - Bicyclic compounds having an anti-thrombitic effect - Google Patents

Bicyclic compounds having an anti-thrombitic effect Download PDF

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CA2323606A1
CA2323606A1 CA002323606A CA2323606A CA2323606A1 CA 2323606 A1 CA2323606 A1 CA 2323606A1 CA 002323606 A CA002323606 A CA 002323606A CA 2323606 A CA2323606 A CA 2323606A CA 2323606 A1 CA2323606 A1 CA 2323606A1
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alkyl
carboxy
substituted
amino
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Uwe Ries
Norbert Hauel
Henning Priepke
Herbert Nar
Jean Marie Stassen
Wolfgang Wienen
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Boehringer Ingelheim Pharma GmbH and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention relates to novel 6-membered bicyclic compounds of general formula (I) Ra-Het-A-Ar-Rb, wherein Ra, Rb, A, Ar and Het have the meanings given in claim 1, their tautomers, stereoisomers, mixtures and salts and especially their physiologically compatible salts with inorganic or organic acids or bases, with valuable properties. The compounds of general formula (I) above wherein Rb stands for a cyano group represent valuable intermediate products for producing the other compounds of general formula (I) above and the compounds of general formula (I) above wherein Rb represents one of the following amidino groups and their tautomers and stereoisomers have valuable pharmacological properties, especially an anti-thrombitic effect.

Description

Boehringer Ingelheim Pharma KG Case 5/1234-FL
D-55216 INGELHEIM Ausl,andstext Bicyclic compounds, the preparation thereof and their use as pharmaceutical compositions The present invention relates to bicyclic compounds of general formula Ra - Het - A - Ar - Rb , ( I ) their tautomers, stereoisomers, mixtures thereof 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 Rb deno-tes a cyano group, are useful intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I, wherein Rb denotes one of the follo-wing amidino groups, and the tautomers and stereoisomers thereof, have valuable pharmacological properties, particular-ly an antithrombotic activity.
The present application thus relates to the new compounds of the above general formula I and the preparation thereof, phar-maceutical compositions containing the pharmacologically actve compounds and their use.
In the above general formula A denotes an oxygen or sulphur atom, a difluoromethylene, car-bonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1_3-alkyl group, a methylene group optionally mono- or disubstituted by a carboxy-C1_3-alkyl group, Ar denotes a phenylene or naphthylene group optionally substi-tuted by a fluorine, chlorine or bromine atom, by a trifluoro-methyl, Cl_3-alkyl or Cl_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, py-razinylene or pyridazinylene group optionally substituted in the carbon structure by a C1_3-alkyl group, Het denotes a 1- (C1_3-alkyl) -2-oxo-1, 2-dihydro-thieno [2, 3-b] -pyrazinyl group, a quinolinylene, isoquinolinylene, quinazolinylene, phthalazi-nylene, cinnolinylene or quinoxazolinylene ring, which may be substituted in the aromatic heterocyclic moiety by a C1_3-alkyl, amino, Cl_3-alkyl amino or di- (C1_3-alkyl) amino group, a quinolinylene, isoquinolinylene, quinazolinylene or quinoxa-zolinylene ring, which are di- or tetrahydrogenated in the he-terocyclic moiety, whilst in one of the abovementioned dehy-drogenated rings, which may additionally be substituted by a Cl_3-alkyl group, a methylene group adjacent to a nitrogen atom is replaced by a carbonyl or thiocarbonyl group, or in one of the abovementioned tetrahydrogenated rings, which may additio-nally be substituted by one or two C1_3-alkyl groups, two methy-lene groups adjacent to a nitrogen atom are each replaced by a carbonyl group, and the phenyl moiety of the abovementioned ~bicyclic rings, wherein additionally a methine group may be replaced by a nitrogen atom, is linked to the group Ra, Ra denotes a hydrogen, fluorine, chlorine or bromine atom, a Cl_3-alkyl, C1_3-alkoxy, C2_3-alkenyl or CZ_3-alkynyl group, which may be substituted by a hydroxymethyl or carboxy group, a Cl_3-alkyl group, which is substituted by a Cl_3-alkanoylamino or carboxy-C1_3-alkylcarbonylamino group, a R1-CO-CHZ group which may be substituted in the methylene mo-iety by one or two C1_3-alkyl groups, or a C3_6-cycloalkylene group which is substituted in the 1 posi-tion by an R1-CO group, whilst R1 is a hydroxy, Cl_3-alkoxy, amino, Cl_3-alkyl amino, pyrroli-dino, piperidino, morpholino, piperazino or N-(C1_3-alkyl)-piperazino group, whilst the abovementioned amino, C1_3-al-kylamino, pyrrolidino and piperidino groups may additionally be substituted by a Cl_3-alkyl, carboxy-Cl_3-alkyl, carboxy-C1_3-alkylaminocarbonyl or di- (Cl_3-alkyl) -amino-n-C2_4-alkyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, a phenyl, naphthyl or monocyclic 5 or 6 membered heteroaryl group optionally substituted by a C1_3-alkyl group, whereby a 6 membered heteroaryl group contains one, two or three nitro-gen atoms and a S membered heteroaryl group contains an imino group optionally substituted by a C1_3-alkyl group, an oxygen or sulphur atom group or an imino group optionally substitu-ted by a C1_3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the before mentioned alkyl substi-tuent may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-Cl_3-alkylamino or N- (C1_3-alkyl) -carboxy-Cl_3-alkyl-amino group, a C1_4-alkyl group which is substituted by one or two carboxy groups, a C1_4-alkyl group which is substituted by a C1_3-alkyl-Y1-Cl_3-alkyl, HOOC-Cl_,-alkyl-Y1-C1_3-alkyl, te-trazoly-Cl_3-alkyl-Y2-, RZNR3- or RzNR3-C1_3-alkyl group and by a carboxy, aminocarbonyl, C1_3-alkylaminocarbonyl, di-(C1_3-alkyl) -aminocarbonyl or CS_.,-cycloalkyleniminocarbonyl group, whereby the CS_~-cycloalkylenimino moiety in the before mentioned groups may be substituted by one or two C1_3-alkyl groups and at the same time additionally one alkyl moiety or alkyl substituent of the before mentioned C1_3-alkylaminocar-bonyl, di- (C1_3-alkyl) -aminocarbonyl or CS_~-cycloalkylenimino-carbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of a C1_4-alkyl group may be to-tally or partly replaced by fluorine atoms, wherein RZ denotes a hydrogen atom or a C1_3-alkyl group optionally substituted by a carboxy group and R3 denotes a Cl_3-alkyl-Y1-Cl_3-alkyl-Y2, carboxy-Cl_3-alkyl-Y1-Cl_3-alkyl-Y2, Cl_3-alkyl-Y2 or carboxy-Cl_3-alkyl-Y2 group or R2 and R3 together with the attached nitrogen atom denotes a C3_.,-cycloalkylenimino group optionaylly substituted by a carboxy, Cl_3-alkyl or carboxy-C1_3-alkyl group, wherein Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and YZ denotes a carbon-nitrogen bond or a carbonyl, sulphonyl or -NH-CO- group, whereby the carbonyl group of the -NH-CO-- group is attached to the nitrogen atom of the R2NR3 group, and the imino groups mentioned at the definition of the radi-cals Y1 and YZ may- be additionally substituted by a C1_3-alkyl or carboxy-Cl_3-alkyl group, a nitro group or an amino group optionally substituted by a C1_3-alkanoyl or carboxy-Cl_4-alkyl group, a hydroxyimino-C1_3-alkylene group which may be substituted at the oxygen atom by a carboxy-C1_3-alkyl group, a C3_~-cycloalkyl or CS_6-cycloalkenyl group, a phenyl group which may be substituted by a C1_3-alkyl, C2_3-al-kenyl, carboxy, nitro or amino group, whilst the amino group may additionally be substituted by a C1_3-alkanoyl, carboxy-Cl_3-alkyl, carboxy-Cl_3-alkylcarbonyl or carboxy-C1_3-alkylamino-carbonyl group, a phenyl group which is substituted by a C1_3-alkyl group and by a carboxy or carboxy-C1_3-alkylaminocarbonyl group, a carbonyl group which is substituted by a Cl_6-alkyl, CS_,-cyc-loalkyl, C1_6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1_3-alkyl group and the hydro-gen atom of the abovementioned amino groups is replaced by a carboxy-C1_3-alkyl or tetrazolyl-C1_3-alkyl group, a carboxy-C1_3-alkylsulphonamido, phenylsulphonylamido, naph-thylsulphonylamido, quinolinesulphonamido or isoquinolinesul-phonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C1_3-alkyl, amino-C1_3-alkyl, C1_3-alkyl amino-Cl_3-alkyl or di- (Cl_3-alkyl) -amino-Cl_3-alkyl group, a Cl_6-alkyl amino or C3_.,-cycloalkylamino group, wherein the hy-drogen atom of the amino group is replaced by a carboxy-C1_3-al-kylcarbonyl, carboxy-C1_3-alkylsulphonyl, tetrazolyl-C1_3-alkyl-carbonyl or carboxy-C1_3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 posi-tion is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1_5-alkyl group, an imidazolyl group substituted in the 1 position by a carb-oxy-C1_3-alkyl group, which may additionally be substituted by a Cl_5-alkyl group, a phenylsulphonyl group or a C1_5-alkylsulphonyl group wherein the alkyl moiety may be substituted by an amino, C1_3-alkylamino or di- (C1_3-alkyl) -amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-C1_3-alkyl group, a C3_.,-cycloalkyl group which is substituted in the 1 position by a C4_,-cycloalkylamino or Cl_4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carb-oxy-C1_3-alkylcarbonyl group, and Rb denotes a cyano group or an amidino group.
The carboxy groups mentioned above at the definition of the radicals may be replaced by a group convertable in-vivo into a carboxy group or by a group convertable under physiologically conditions into a negatively charged group or the amino or imino groups groups mentioned above at the defi-nition of the radicals may be substituted by a group which can be splitt off in-vivo.
By a group which can be converted in-vivo into a carboxy group is meant, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcoholic moiety is preferably a Cl_6-alkanol, a phenyl-Cl_3-alkanol, a C3_9-cyclo-alkanol, whereby a CS_8-cycloalkanol may be additionally sub-stituted by one or two Cl_j-alkyl groups, a CS_8-cycloalkanol wherein one methylene group in 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a Cl_3-alkyl, phenyl-C1_3-alkyl, phenyl-Cl_3-alkoxycarbonyl or CZ_6-alkanoyl group and the cycloalkanol moiety may be addi-- 7 _ tionally substituted by one or two C1_3-alkyl groups,/a C4_.,-cycloalkenol, C3_5-alkenol, phenyl-C3_5-alkenol or phenyl-C3_5-alkinol group with the proviso that no bond from a carbon atom to an oxygene atom exists to which carbon atom is atta-ched a double or triple bond, a bicycloalkanol containing a total of 8 to 10 carbon atoms which may be additionally sub-stituted in the bicyloalkyl moiety by one or two C1_3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzfuranyl group or an alcohol of the formula ..- R~CO-O- (RdCRe) -OH, wherein R~ denotes a C1_8-alkyl, CS_~-cycloalkyl, phenyl or phenyl-C1_3-alkyl group, Rd denotes a hydrogen atom, a Cl_3-alkyl, CS_,-cycloalkyl or phe-nyl group and Re denotes a hydrogen atom or a C1_3-alkyl group, by a group convertable under physiologically conditions into a negatively charged group is meant a group such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonyl-aminocarbonyl, C1_6-alkylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C1_6-alkylsulphonylaminocarbonyl, -phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C1_6-alkylsulphonylaminocarbonyl group and by a group which can be cleaved from an imino or amino group in-vivo is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C1_is-al-kanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1_,6-alkoxycarbonyl group such as the methoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, hep-- g _ tyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxy-carbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexade-cyloxycarbonyl group, a phenyl-C1_6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxy-carbonyl group, a Cl_3-alkylsulphonyl-CZ_4-alkoxycarbonyl or Cl_3-alkoxy-C2_4-alkoxycarbonyl group, a steroidal alcohol group bound via a carbonyl group such as the 17-(1,5-dimethyl-hex-yl)-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetra-decahydro-1H-cyclopenta[a]phe-nanthren-3-yl]-oxycarbonyl group or a R~CO-O- (RdCRe) -O-CO group wherein R~ to Re are as hereinbe-fore defined.
Moreover, the saturated alkyl and alkoxy moieties which con-tain more than 2 carbon atoms as mentioned above in the defi-nitions also include the branched isomers thereof, such as, for example, the isopropyl, tert.butyl, isobutyl groups, etc..
Preferred compounds of the abovementioned general formula I
are those, wherein A denotes an oxygen or sulphur atom, a difluoromethylene, car-bonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1_3-alkyl group, a methylene group optionally mono- or disubstituted by a carboxy-C1_3-alkyl or Cl_3-alkoxy-carbonyl-Cl_3-alkyl group, -Ar denotes a phenylene or naphthylene group optionally substi-tuted by a fluorine, chlorine or bromine atom, by a trifluoro-methyl, Cl_3-alkyl or C1_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, py-razinylene or pyridazinylene group optionally substituted in the carbon structure by a C1_3-alkyl group, Het denotes a 1-(C1_3-alkyl)-2-oxo-1,2-dihydro-thieno[2,3-b]-pyrazinyl group, - g _ a quinolinylene, isoquinolinylene, quinazolinylene, phthala-zinylene, cinnolinylene or quinoxazolinylene ring, which may be substituted in the aromatic heterocyclic moiety by a C1_3-alkyl, amino, Cl_3-alkyl amino or di- (C,_3-alkyl) amino group, a quinolinylene, isoquinolinylene, quinazolinylene or quinoxa-zolinylene ring, which are di- or tetrahydrogenated in the he-terocyclic moiety, whilst in one of the abovementioned dehy-drogenated rings, which may additionally be substituted by a C1_3-alkyl group, a methylene group adjacent to a nitrogen atom is replaced by a carbonyl or thiocarbonyl group, or in one of the abovementioned tetrahydrogenated rings, which may additio-nally be substituted by one or two C1_3-alkyl groups, two methy-lene groups adjacent to a nitrogen atom are each replaced by a carbonyl group, and the phenyl moiety of the abovementioned bicyclic rings, wherein additionally a methine group may be replaced by a nitrogen atom, is linked to the group Ra, Ra denotes a hydrogen, fluorine, chlorine or bromine atom, a Cl_3-alkyl, Cl_3-alkoxy, Cz_3-alkenyl or CZ_3-alkynyl group, which may be substituted by a hydroxymethyl, carboxy or Cl_3-alkoxycarbonyl group, a Cl_3-alkyl group, which is substituted by a Cl_3-alkanoylamino, carboxy-C1_3-alkylcarbonylamino or C1_3-alkoxycarbonyl-C1_3-alkyl -carbonylamino group, a C1_4-alkyl group which is substituted by one or two carboxy or C1_3-alkoxycarbonyl groups or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, Cl_3-alkoxycarbonyl, carboxy-Cl_3-alkylamino, Cl_3-alk-oxycarbonyl-Cl_3-alkylamino, N- (Cl_,-alkyl) -carboxy-Cl_3-alkyl-amino or N- (Cl_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moie-ties may be additionally substituted by one or two C1_3-alkyl groups, a nitro group or an amino group optionally substituted by a C1_3-alkanoyl, carboxy-Cl_4-alkyl or Cl_3-alkoxycarbonyl-C1_4-alkyl group, a hydroxyimino-C1_3-alkylene group which may be substituted at the oxygen atom by a carboxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, a C3_,-cycloalkyl or CS_6-cycloalkenyl group, a phenyl group which may be substituted by a Cl_3-alkyl, C2_3-al-kenyl, carboxy, C1_3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a C1_3-alkanoyl, carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylcarbonyl, C1_3-alkoxycarbonyl-Cl_3-alkylcar-bonyl, carboxy-C1_3-alkylaminocarbonyl or C1_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a phenyl group which is substituted by a C1_3-alkyl group and by a carboxy, C1_3-alkoxycarbonyl, carboxy-C1_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a carbonyl group which is substituted by a Cl_6-alkyl, CS_,-cyc--loalkyl, C1_6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1_3-alkyl group and the hydro-gen atom of the abovementioned amino groups is replaced by a carboxy-Cl_3-alkyl, C1_3-alkoxycarbonyl-C1_3-alkyl or tetrazolyl-Cl_3-alkyl group, a carboxy-Cl_3-alkylsulphonamido, C1_3-alkoxycarbonyl-Cl_3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substi-tuted by a carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, amino-Cl_3-alkyl, Cl_3-alkyl amino-Cl_3-alkyl or di- (Cl_3-alkyl) -amino-Cl_3-alkyl group, a Cl_6-alkyl amino or C3_.,-cycloalkylamino group, wherein the hy-drogen atom of the amino group is replaced by a carboxy-C1_3-al-kylcarbonyl, C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl, carboxy-Cl_3-alkylsulphonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylsulphonyl, te-trazolyl-C1_3-alkylcarbonyl, carboxy-C1_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 posi-tion is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1_5-alkyl group, an imidazolyl group substituted in the 1 position by a carb-oxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, which may additionally be substituted by a C1_5-alkyl group, a phenylsulphonyl group or a C1_5-alkylsulphonyl group wherein the alkyl moiety may be substituted by an amino, C1_3-alkylamino or di- (C1_3-alkyl) -amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-Cl_3-alkyl or C1_3-alkoxycarbonyl ~C1_3-alkyl group, a C3_.,-cycloalkyl group which is substituted in the 1 position by a C4_,-cycloalkylamino or Cl_4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carb-oxy-C1_3-alkylcarbonyl or C1_3-alkoxycarbonyl-Cl_3-alkylcarbonyl group, a R1-CO-CHZ group which may be substituted in the methylene mo-iety by one or two C1_3-alkyl groups, or a C3_6-cycloalkylene group which is substituted in the 1 posi-tion by an R1-CO group, whilst R1 is a hydroxy, Cl_3-alkoxy, amino, C1_3-alkyl amino, pyrroli-dino, piperidino, morpholino, piperazino or N-(Cl_3-alkyl)-piperazino group, whilst the abovementioned amino, C1_3-al-kylamino, pyrrolidino and piperidino groups may additionally be substituted by a Cl_3-alkyl, carboxy-Cl_3-alkyl, Cl_3-alk-oxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylaminocarbonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl or di- (Cl_3-alkyl) -.. amino-n-C2_4-alkyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a pyrazolyl group optionally substituted by a C1_3-alkyl group, and Rb denotes a cyano group or an amidino group optionally substituted by a hydroxy, by one or two C1_3-alkyl groups or by a Cl_16-alkoxycarbonyl group, especially those compounds, wherein A denotes an oxygen or sulphur atom, a difluoromethylene, car-bonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1_3-alkyl group, a methylene group optionally -mono- or disubstituted by a carboxy-Cl_3-alkyl or Cl_3-alkoxy-carbonyl-Cl_3-alkyl group, Ar denotes a phenylene or naphthylene group optionally substi-tuted by a fluorine, chlorine or bromine atom, by a trifluoro-methyl, Cl_3-alkyl or Cl_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, py-razinylene or pyridazinylene group optionally substituted in the carbon structure by a C1_3-alkyl group, Het denotes a 1- (Cl_3-alkyl) -2-oxo-1, 2-dihydro-thieno [2, 3-b] -pyrazinyl group, a quinolinylene, isoquinolinylene, quinazolinylene, phthala-zinylene, cinnolinylene or quinoxazolinylene ring, which may be substituted in the aromatic heterocyclic moiety by a C1_3-al-kyl, amino, Cl_3-alkyl amino or di- (C1_3-alkyl) amino group, a quinolinylene, isoquinolinylene, quinazolinylene or quinoxa-zolinylene ring, which are di- or tetrahydrogenated in the he-terocyclic moiety, whilst in one of the abovementioned dehy-drogenated rings, which may additionally be substituted by a C1_3-alkyl group, a methylene group adjacent to a nitrogen atom is replaced by a carbonyl or thiocarbonyl group, or in one of the abovementioned tetrahydrogenated rings, which may additio-nally be substituted by one or two C1_3-alkyl groups, two me-thylene groups adjacent to a nitrogen atom are each replaced by a carbonyl group, and the phenyl moiety of the abovemen-tioned bicyclic rings, wherein additionally a methine group may be replaced by a nitrogen atom, is linked to the group Ra, Ra denotes a hydrogen, fluorine, chlorine or bromine atom, a C1_3-alkyl, CZ_3-alkenyl or C2_3-alkynyl group, which may be substituted by a hydroxymethyl, carboxy or C1_3-alkoxycarbonyl group, a Cl_3-alkyl group, which is substituted by a Cl_3-alkanoylamino, carboxy-C1_3-alkylcarbonylamino or Cl_3-alkoxycarbonyl-C1_3-alkyl-carbonylamino group, a C1_3-alkyl group which is substituted by one or two carboxy or C1_3-alkoxycarbonyl groups or by a pyrrolidinocarbonyl or pipe-ridinocarbonyl group and by a carboxy, C1_3-alkoxycarbonyl, carboxy-Cl_3-alkylcarbonylamino or Cl_3-alkoxycarbonyl-Cl_3-alkyl-carbonylamino group, whilst the abovementioned pyrrolidino and piperidino moieties may additionally be substituted by one or two Cl_3-alkyl groups, a nitro group or an amino group optionally substituted by a C1_3-alkanoyl, carboxy-Cl_4-alkyl or C1_3-alkoxycarbonyl-Cl_4-alkyl group, a hydroxyimino-C1_3-alkylene group which may be substituted at the oxygen atom by a carboxy-Cl_3-alkyl or Cl_3-alkoxy-carbonyl-Cl_3-alkyl group, a C3_,-cycloalkyl or CS_6-cycloalkenyl group, a phenyl group which may be substituted by a Cl_3-alkyl, C2_3-al-kenyl, carboxy, C1_3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a C1_3-alkanoyl, carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylcarbonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylcar-bonyl, carboxy-C1_3-alkylaminocarbonyl or C1_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a phenyl group which is substituted by a C1_3-alkyl group and by a carboxy, C1_3-alkoxycarbonyl, carboxy-C1_3-alkylaminocarbonyl or Cl_3-alkoxyca.rbonyl-Cl_3-alkylaminocarbonyl group, a carbonyl group which is substituted by a Cl_6-alkyl, CS_,-cyc--loalkyl, C1_6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionall-y be substituted by a C1_3-alkyl group and the hy-drogen atom of the abovementioned amino groups is replaced by a carboxy-C1_3-alkyl, C1_3-alkoxycarbonyl-C1_3-alkyl or tetrazo-lyl-Cl_3-alkyl group, a carboxy-Cl_3-alkylsulphonamido, Cl_3-alkoxycarbonyl-C1_3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substi-tuted by a carboxy-Cl_3-alkyl, C1_3-alkoxycarbonyl-Cl_3-alkyl, amino-Cl_3-alkyl, Cl_3-alkyl amino-Cl_3-alkyl or di- (Cl_3-alkyl) -amino-Cl_3-alkyl group, a Cl_6-alkyl amino or C3_~-cycloalkylamino group, wherein the hy-drogen atom of the amino group is replaced by a carboxy-C1_3-al-kylcarbonyl, C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl, tetrazolyl-C1_3-alkylcarbonyl, carboxy-Cl_3-alkylaminocarbonyl or Cl_3-alk-oxycarbonyl-C1_3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 posi-tion is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1_5-alkyl group, an imidazolyl group substituted in the 1 position by a carb-oxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, which may additionally be substituted by a C1_5-alkyl group, a phenylsulphonyl group or a C1_5-alkylsulphonyl group wherein the alkyl moiety may be substituted by an amino, C1_3-alkylamino or di- (C1_3-alkyl) -amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, a C3_.,-cycloalkyl group which is substituted in the 1 position by a C4_.,-cycloalkylamino or Cl_4-alkyl amino group, .wherein the hydrogen atom of the amino moiety may be replaced by a carb-oxy-Cl_3-alkylcarbonyl or C1_j-alkoxycarbonyl-Cl_3-alkyl carbonyl group, a R1-CO-CHZ group which is substituted in the methylene moiety by two Cl_3-alkyl groups, or a C3_6-cycloalkylene group which is substituted in the 1 position by an R1-CO group, whilst Rl is a hydroxy, Cl_3-alkoxy, amino, Cl_3-alkylamino, pyrro-lidino, piperidino, morpholino, piperazino or N-(C1_3-alkyl)-piperazino group, whilst the abovementioned amino, C1_3-al-kylamino, pyrrolidino and piperidino groups may additionally be substituted by a Cl_3-alkyl, carboxy-Cl_3-alkyl, Cl_3-alkoxy-carbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylaminocarbonyl- or Cl_3-alkoxycarbonyl-C1_3-alkyl-aminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, and Rb 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 a Cl_ls-alkoxycarbonyl group, whereby Het denotes preferably a 1,3-dioxo-3,4-dihydro-1H-iso-quinolin-2-yl, 1-oxo-1,2-dihydro-1H-isoquinolin-2-yl, quino-lin-2-yl, 1,4-dihydro-2H-quinazolin-2,4-dion-3-yl, 4H-quina-zolin-4-on-3-yl, 4-oxo-3,4-dihydro-quinazolin-2-yl, 2-oxo-1,2-dihydro-quinoxalin-3-yl, 2-thio-1,2-dihydro-quinoxalin-3-yl, 1,8-naphthyridin-2-yl, 3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-2-yl or 2-oxo-1,2-dihydro-pyrido[2,3-b]pyrazin-3-yl-group, the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of general formula I are those wherein A denotes an oxygen atom, a methylene or imino group, Ar denotes a phenylene or naphthylene group optionally substi-tuted by a fluorine, chlorine or bromine atom, by a trifluoro-methyl, Cl_3-alkyl or C1_3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, py-razinylene or pyridazinylene group optionally substituted in the carbon structure by a C1_3-alkyl group, Het denotes a 4,4-di-(C1_3-alkyl)-1,3-dioxo-3,4-dihydro-1H-iso-quinolinyl-2-yl, 4-(C1_3-alkyl)-1-oxo-1,2-dihydro-1H-isoquino-linyl-2-yl, 4-(C1_3-alkyl)-quinolinyl-2-yl, 4-amino-quinazolin-2-yl, 4- (C1_3-alkyl amino) -quinazolin-2-yl, 4- [di- (C1_3-alkyl) -amino]-quinazolin-2-yl, 4-(Cl_3-alkyl)-quinazolin-2-yl, 3- (Cl_3-alkyl) -4H-quinazolin-4-on-2-yl, 3- (C1_3-alkyl) -4-oxo-3,4-dihydro-quinazolin-2-yl, 1-(Cl_3-alkyl)-2-oxo-1,2-dihydro-quinazolin-3-yl, 1-(C1_3-alkyl)-2-thio-1,2-dihydro-quinazolin-3-yl-, 1-(Cl_3-alkyl)-1,8-naphthyridin-2-yl, 3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-2-yl or 2-oxo-1,2-dihydro-pyrido[2,3-b]-pyrazin-3-yl group each attached via the phenyl moiety with the radical Ra, Ra denotes a hydrogen, chlorine or bromine atom, a Cl_3-alkyl, Cz_3-alkenyl or Cz_3-alkynyl group, which may be substituted by a hydroxymethyl, carboxy or C1_3-alkoxycarbonyl group, a Cl_3-alkyl group, which is substituted by a Cl_3-alkanoylamino, carboxy-Cl_3-alkylcarbonylamino or Cl_3-alkoxycarbonyl-Cl_3-alkyl-carbonylamino group, a Cl_4-alkyl group which is substituted by a carboxy or Cl_3-alk-oxycarbonyl group or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, Cl_3-alkoxycarbonyl, carboxy-C1_3-alkyl amino, Cl_3-alk-oxycarbonyl-C1_3-alkylamino, N- (C1_3-alkyl) -carboxy-Cl_3-alkyl-amino or N- (C1_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moie-ties may be additionally substituted by one or two C1_3-alkyl groups, a nitro group or an amino group optionally substituted by a C1_3-alkanoyl, carboxy-C1_4-alkyl or Cl_3-alkoxycarbonyl-Cl_4-alkyl group, a hydroxyimino-C1_3-alkylene group which may be substituted at the oxygen atom by a carboxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, a C3_,-cycloalkyl or CS_6-cycloalkenyl group, a phenyl group which may be substituted by a C1_3-alkyl, CZ_3-al-kenyl, carboxy, C1_3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a Cl_3-alkanoyl, carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylcarbonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylcar-bonyl, carboxy-C1_3-alkylaminocarbonyl or C1_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl group, a phenyl group which is substituted by a C1_3-alkyl group and by a carboxy, C1_3-alkoxycarbonyl, carboxy-C1_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a carbonyl group which is substituted by a Cl_6-alkyl, CS_.,-cyc-loalkyl group, C1_6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl mo-iety may additionally be substituted by a C1_3-alkyl group and -the hydrogen atom of the abovementioned amino groups is re-placed by a carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl or _tetrazolyl-C1_3-alkyl group, a carboxy-Cl_3-alkylsulphonamido, C1_3-alkoxycarbonyl-Cl_3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substitu-ted by a carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-C1_3-alkyl, amino-Cl_3-alkyl, Cl_3-alkyl amino-Cl_3-alkyl or di- (C1_3-alkyl) -amino-C1_3-alkyl group, a Cl_6-alkyl amino or C3_~-cycloalkylamino group, wherein the hy-drogen atom of the amino group is replaced by a carboxy-C1_3-alkylcarbonyl, C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl, carboxy-Cl_3-alkylsulphonyl, Cl_3-alkoxycarbonyl-Cl_3-alkylsulphonyl, tetrazolyl-C1_3-alkylcarbonyl, carboxy-C1_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 posi-tion is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a Cl_5-alkyl group, an imidazolyl group substituted in the 1 position by a carb-oxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, which may additionally be substituted by a Cl_5-alkyl group, a phenylsulphonyl group or a C1_5-alkylsulphonyl group wherein the alkyl moiety may be substituted by a di-(C1_3-alkyl)-amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, a C3_.,-cycloalkyl group which is substituted in the 1 position ~by a CS_,-cycloalkylamino or C1_4-alkylamino group, wherein the hydrogen atom of the amino moiety may be replaced by a carb-oxy-Cl_3-alkylcarbonyl or Cl_3-alkoxycarbonyl-C1_3-alkylcarbonyl group, a R1-CO-CH2 group which is substituted in the methylene moiety by one or two Cl_3-alkyl groups, or a C3_6-cycloalkylene group which is substituted in the 1 posi-tion by an R1-CO group, whilst Rl is a hydroxy, Cl_3-alkoxy, amino, Cl_3-alkyl amino, pyrroli-dino, piperidino, morpholino, piperazino or N-(Cl_3-alkyl)-piperazino group, whilst the abovementioned amino, C1_3-alkyl-amino, pyrrolidino and piperidino groups may additionally be substituted by a Cl_3-alkyl, carboxy-Cl_3-alkyl, C1_3-alkoxy-carbonyl-C1_3-alkyl, carboxy-Cl_3-alkylaminocarbonyl or C1_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a pyrazolyl group optionally substituted by a C1_3-alkyl group, and Rb denotes a cyano group or an amidino group optionally substituted by a hydroxy, C1_ls-alkoxycarbonyl or 17-(1,5-di-methyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,-16,17-tetradecahydro-1H-cyclopenta[a]phe-nanthren-3-yl]-oxy-carbonyl group, the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of general formula I are those wherein A denotes an oxygen atom, a methylene or imino group, Ar denotes a phenylene group, preferably a 1,4-phenylene group, Het denotes a 4- (C1_3-alkyl) -quinolinyl-2-yl or 1- (C1_3-alkyl) -2-oxo-1,2-dihydro-quinazolin-3-yl group each attached via the phenyl moiety with the radical Ra, Ra denotes a hydrogen, chlorine or bromine atom, a Cl_3-alkyl group which is substituted by a Cl_3-alkanoylamino, carboxy-C1_3-alkylcarbonylamino or Cl_3-alkoxycarbonyl-Cl_3-alkyl-carbonylamino group, a Cl_4-alkyl group which is substituted by a carboxy or C1_3-alk-oxycarbonyl group or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, Cl_3-alkoxycarbonyl, carboxy-Cl_3-alkyl amino, Cl_3-alk-oxycarbonyl-Cl_3-alkylamino, N- (Cl_3-alkyl) -carboxy-C1_3-alkyl-amino or N- (Cl_3-alkyl) -C1_3-alkoxycarbonyl-Cl_3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moie-ties may be additionally substituted by one or two C1_3-alkyl groups, a R1-CO-CH2 group which is substituted in the methylene moiety by one or two Cl_3-alkyl groups, or a C3_6-cycloalkylene group which is substituted in the 1 posi-tion by an R1-CO group, whilst R1 is a hydroxy, Cl_3-alkoxy, amino, C1_3-alkyl amino, pyrroli-dino, piperidino, piperazino or N-(Cl_3-alkyl)-piperazino group, whilst the abovementioned amino, C1_3-alkylamino, pyrrolidino and piperidino groups may additionally be sub-stituted by a Cl_3-alkyl, carboxy-C1_3-alkyl, C1_3-alkoxycar-bonyl-Cl_3-alkyl, carboxy-Cl_3-alkylaminocarbonyl or Cl_3-alk-oxycarbonyl-C1_3-alkylaminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a pyrazolyl group optionally substituted by a C1_3-alkyl group, a hydroxyimino-C1_3-alkylene group which may be substituted at the oxygen atom by a carboxy-Cl_3-alkyl or C1_3-alkoxycarbonyl-C1_3-alkyl group, a phenyl group which may be substituted by a Cl_3-alkyl, C2_3-al-kenyl, carboxy, C1_3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a Cl_3-alkanoyl, carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-C1_3-alkyl-aminocarbonyl group, a phenyl group which is substituted by a C1_3-alkyl group and by a carboxy, Cl_3-alkoxycarbonyl, carboxy-Cl_3-alkylaminocarbonyl .,. or Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a carbonyl group which is substituted by a Cl_6-alkyl, CS_.,-cyc-loalkyl group, C1_6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl mo-iety may additionally be substituted by a C1_3-alkyl group and the hydrogen atom of the abovementioned amino groups is re-placed by a carboxy-C1_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl or tetrazolyl-Cl_3-alkyl group, a carboxy-Cl_3-alkylsulphonamido, Cl_3-alkoxycarbonyl-Cl_3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substi-tuted by a carboxy-C1_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl or di- (Cl_3-alkyl) -amino-C1_3-alkyl group, a Cl_6-alkyl amino or C3_.,-cycloalkylamino group, wherein the hy-drogen atom of the amino group is replaced by a carboxy-C1_3-al-kylcarbonyl, C1_3-alkoxycarbonyl-Cl_3-alkylcarbonyl, carboxy-Cl_3-alkylsulphonyl, C1_3-alkoxycarbonyl-C1_3-alkylsulphonyl, tetra-zolyl-C1_3-alkylcarbonyl, carboxy-C1_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a tetrazolyl group optionally substituted by a C1_5-alkyl group, an imidazolyl group substituted in the 1 position by a carb-oxy-C1_3-alkyl or Cl_3-alkoxycarbonyl-C1_3-alkyl group, which may additionally be substituted by a C1_5-alkyl group, a C3_.,-cycloalkyl group which is substituted in the 1 position by a CS_.,-cycloalkylamino or C1_4-alkylamino group, wherein the hydrogen atom of the amino moiety may be replaced by a carb-oxy-Cl_3-alkylcarbonyl or Cl_3-alkoxycarbonyl-C1_3-alkylcarbonyl group, and Rb denotes an amidino group optionally substituted by a hydroxy, C1_ls-alkoxycarbonyl or 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phe-nanthren-3-yl]-oxycarbonyl group, particulary the compounds wherein A denotes an oxygen atom, a methylene or imino group, Ar denotes a 1,4-phenylene group, Het denotes a 4-methyl-quinolinyl-2-yl or 1-methyl-2-oxo-1,2-dihydro-quinazolin-3-yl group each attached via the phenyl moiety with the radical Ra, Ra denotes a hydrogen atom, a C1_3-alkyl group which is substituted by a Cl_3-alkanoylamino, carboxy-C1_3-alkylcarbonylamino or C1_3-alkoxycarbonyl-C1_3-alkyl-carbonylamino group, a C1_4-alkyl group which is substituted by a carboxy or C1_3-alk-oxycarbonyl group or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, C1_3-alkoxycarbonyl, carboxy-C1_3-alkyl amino, C1_3-alk-oxycarbonyl-Cl_3-alkylamino, N- (C1_,-alkyl) -carboxy-C1_3-alkyl-amino or N- (C1_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moie-ties may be additionally substituted by one or two methyl groups, a R1-CO-CHz group which is substituted in the methylene moiety by one or two Cl_3-alkyl groups, or a C3_6-cycloalkylene group which is substituted in the 1 posi-tion by an R1-CO group, whilst R1 is a hydroxy, Cl_3-alkoxy, amino, Cl_3-alkylamino, pyrroli-dino, piperidino or N-(Cl_3-alkyl)-piperazino group, whilst the abovementioned amino, C1_3-alkylamino, pyrrolidino and piperidino groups may additionally be substituted by a C1_3-alkyl, carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkylaminocarbonyl or Cl_3-alkoxycarbonyl-Cl_3-al-kylaminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moie-ties via two adjacent carbon atoms, or a 1- (C1_3-alkyl) -pyrazol-5-yl group, a hydroxyimino-C1_3-alkylene group which may be substituted at the oxygen atom by a carboxy-Cl_3-alkyl or Cl_3-alkoxycarbonyl-Cl_3-alkyl group, a phenyl group which may be substituted by a Cl_3-alkyl, CZ_3-al-kenyl, carboxy, C1_3-alkoxycarbonyl or amino group, whilst the amino group may additionally be substituted by a carboxy-Cl_3-alkyl, C1_3-alkoxycarbonyl-Cl_3-alkyl, carboxy-Cl_3-alkyl-aminocarbonyl or C1_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl group, a phenyl group which is substituted by a methyl group and by a carboxy, C1_3-alkoxycarbonyl, carboxy-C1_3-alkylaminocarbonyl or C1_3-alkoxycarbonyl-C1_3-alkylaminocarbonyl group, a carbonyl group which is substituted by a Cl_6-alkyl, CS_~-cyc-loalkyl group, C1_6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl mo-iety may additionally be substituted by a C1_3-alkyl group and the hydrogen atom of the abovementioned amino groups is repla-ced by a carboxy-Cl_3-alkyl, Cl_3-alkoxycarbonyl-C1_3-alkyl or tetrazolyl-Cl_3-alkyl group, a carboxy-Cl_3-alkylsulphonamido, Cl_3-alkoxycarbonyl-C1_3-alkyl-_ sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substi-tuted by a carboxy-Cl_3-alkyl, C1_3-alkoxycarbonyl-Cl_3-alkyl or di- (Cl_3-alkyl) -amino-Cl_3-alkyl group, a Cl_6-alkyl amino or C3_.,-cycloalkylamino group, wherein the hy-drogen atom of the amino group is replaced by a carboxy-C1_3-al-kylcarbonyl, C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl, carboxy-Cl_3-alkylsulphonyl, C1_3-alkoxycarbonyl-C1_3-alkylsulphonyl, tetrazolyl-C1_3-alkylcarbonyl, carboxy-C1_3-alkylaminocarbonyl or C1_3-alkoxycarbonyl-Cl_3-alkylaminocarbonyl group, a tetrazolyl group optionally substituted by a C1_5-alkyl group, an imidazolyl group substituted in the 1 position by a carb -oxy-C1_3-alkyl or C1_3-alkoxycarbonyl-C1_3-alkyl group, which may additionally be substituted by a C1_5-alkyl group, a C3_,-cycloalkyl group which is substituted in the 1 position by a CS_~-cycloalkylamino or C1_4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carb-oxy-Cl_3-alkylcarbonyl or C1_3-alkoxycarbonyl-C1_3-alkylcarbonyl group, and Rb denotes an amidino group optionally substituted by a hydroxy, C1_ls-alkoxycarbonyl or 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phe-nanthren-3-yl]-oxycarbonyl group, the tautomers, stereoisomers and salts thereof.
The following are examples of particularly preferred com-pounds:
(a) 4-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine, (b) 4-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyclo-propyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine, (c) 4-{[7-(N-carboxymethylaminocarbonyl-ethylamino)-4-methyl-quinolin-2-yl]-oxo}-benzamidine, (d) 4-{ [7- (N- (pyridin-2-yl) -N- (2-carboxyethyl) -aminocarbonyl) -4-methyl-quinolin-2-yl]-oxo}-benzamidine, (e) 4-{[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine, (f) 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-_2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine, (g),4-{[6-(1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquin-oxalin-3-yl]-methyl}-benzamidine and the salts thereof.
According to the invention the compounds of general formula I
are obtained by known methods, e.g. by the following proces-ses:

a) In order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 1,4-dihydro-2H-qui-nazolin-2,4-dion-3-yl group and Rb denotes a cyano group:
cyclising a compound of general formula NHz Ra / , (II) CO-NH-CHZ -Ar-CN
wherein Ar and Ra are as hereinbefore defined, in the presence of a carbonic acid diester derivative.
The cyclisation is conveniently carried out in a solvent or mixture of solvents such as glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, pyridine, diethyleneglycol dimethyl ether, sulpholane, dimethylformamide or tetralin in the presence of a carbonic acid diester derivative such as phosgene or triphosgene at temperatures between 0 and 250°C, but preferably at the boi-ling temperature of the reaction mixture.
b) In order to prepare a compound of general formula I wherein -A denotes a methylene group, Het denotes a 4-oxo-3,4-dihydro-quinazolin-2-yl group and Rb denotes a cyano group:
cyclising a compound of general formula Ra / , (III) CO-NH-CH2 -Ar-CN
wherein Ar and Ra are as hereinbefore defined and Z1 denotes a leaving group such as a halogen atom, an alkoxy, phenylalkoxy or phenoxy group, e.g. a methoxy or ethoxy group, in the presence of an ammonium salt.
The reaction is preferably carried out in the presence of an ammonium salt such as ammonium chloride and in the presence of a condensing agent such as phosphorus pentoxide and in the presence of a tertiary organic base such as N,N-dimethylcyclo-hexylamine at elevated temperatures, e.g. at temperatures bet-ween 150 and 250°C, preferably at 190°C.
c) In order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 2-oxo-1,2-dihydro-quinoxalin-3-yl group and Rb denotes a cyano group:
reacting a diamine of general formula NHRS
Ra , ( IV) NHZ
wherein Ra is as hereinbefore defined and RS denotes a hydrogen atom or a C1_3-alkyl group, with a ketone -of general formula HOCO-CO-CHZ-Ar-CN , (V) wherein Ar is as hereinbefore defined, or the reactive derivatives thereof .
The reaction is preferably carried out with a reactive deri-vative of the ketone of formula V such as the ethyl or phenyl-ester, conveniently in a solvent such as ethanol at elevated temperatures, e.g. at the boiling temperature of the solvent used.
d) In order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 4-oxo-3,4-dihydro-quinazolin-2-yl group and Rb denotes a cyano group:
cyclising a compound of general formula CONHZ
Ra / , (VI) NH- CO-CHz -Ar- CN
wherein Ar and Ra are as hereinbefore defined, in the presence of a ba-sic condensing agent.
The cyclisation is carried out in the presence of a basic con-densing agent such as an alkoxide, e.g. sodium ethoxide, pre-ferably in a solvent such as ethanol at elevated temperatures, preferably at the boiling temperature of the solvent used.
e) In order to prepare a compound of general formula I wherein Het is linked to A via a nitrogen atom and A denotes a methy-lene group and Rb denotes a cyano group:
reacting a compound of general formula Ra - Het - H , (VII) wherein Ra is as hereinbefore defined and Het contains a hydrogen atom bound to a cyclic nitrogen atom, with a compound of general formula ZZ-A-Ar-CN , (VI I I ) wherein A and Ar are as hereinbefore defined and Zz denotes a leaving group such as a halogen atom, e.g. a chlo-rine, bromine or iodine atom.
The reaction is conveniently carried out in a solvent or mix-ture of solvents such as water, methylene chloride, chloro-form, ether, tetrahydrofuran, dioxan or dimethylformamide op-tionally in the presence of an inorganic or organic base, such as sodium hydroxide, potassium carbonate, triethylamine or py-ridine, whilst the last two may simultaneously act as solvent, at temperatures between -25 and 100°C, but preferably at tem-peratures between -10 and 80°C.
f) In order to prepare a compound of general formula I wherein Het is linked to A via a C1_3-alkylimino group, an oxygen, sul-phur or nitrogen atom and A denotes a methylene group and Rb denotes a cyano group:
reacting a compound of general formula Ra - Het - Z3 , (IX) wherein Ra and Het are as hereinbefore defined, with the proviso that -Z3 is linked to a carbon atom of the Het group and denotes a leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, with a compound of general formula H-A'-Ar-CN ,(X) wherein Ar is as hereinbefore defined and A' denotes an imino or C1_3-alkylimino group, an oxygen or sul-phur atom.

The reaction is conveniently carried out in a solvent or mix-ture of solvents such as water, methylene chloride, chloro-form, ether, tetrahydrofuran, dioxan or dimethylformamide op-tionally in the presence of an inorganic or organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the last two may simultaneously act as sol-vent, at temperatures between -25 and 100°C, but preferably at temperatures between -10 and 80°C.
g) In order to prepare a compound of general formula I wherein Ra denotes one of the optionally substituted -CONH- and -SOZNH-groups mentioned for Ra hereinbefore which is linked to the Het group either via the nitrogen atom or via the carbonyl or sul-phonyl group:
reacting a compound of general formula U-Het-A-Ar-CN ,(XI) with a compound of general formula V - Ra' , (XII) wherein A, Ar and Het are as hereinbefore defined, one of the groups U or V denotes an HOCO- or HOSOZ group or the reactive derivatives thereof and the other one of the groups U or V denotes one of the optio-nally substituted amino groups mentioned for Ra hereinbefore, which is linked to the Het group either via the nitrogen atom or via the carbonyl or sulphonyl group.
The reaction of an acid with an amine is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan or in an excess of the amine used conveniently in the presence of a dehydrating agent, e.g. in the presence of isobutyl chlorofor-mate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodi-imide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotria-zol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hy-droxy-benzotriazole, N,N'-carbonyldiimidazole or triphenyl-phosphine/carbon tetrachloride, and optionally with the addi-tion of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, conveniently at tem-peratures between 0 and 150°C, preferably at temperatures between 0 and 100°C.
The reaction of a corresponding reactive compound of general formula X or XI such as the esters, imidazolides or halides thereof with a corresponding amine is preferably carried out in a corresponding amine as the solvent, optionally in the presence of another solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.
In order to prepare a compound of general formula I wherein Ra denotes one of the optionally substituted phenyl and alkenyl 'groups mentioned for Ra hereinbefore and Rb denotes a cyano group:
reacting a compound of general formula Z4-Het-A-Ar-CN ,(XIII) wherein A, Ar and Het are as hereinbefore defined and Z4 denotes a trifluoromethanesulphonyloxy group, a bromine or iodine atom, with a compound of general formula R6 - ZS , (XIV) wherein R6 denotes on of the optionally substituted phenyl and alkenyl groups mentioned for Ra hereinbefore and ZS denotes a boric acid group or a tri-(C1_4-alkyl)-tin group.
The reaction is preferably carried out in a solvent such as toluene/water, dimethoxyethane or dimethylformamide in the presence of a metal catalyst such as bis(triphenylphosphine)-palladium-(II)chloride or tetrakis-(triphenylphosphine)-palla-dium(0) in the presence of a base such as sodium carbonate or caesium carbonate at temperatures between 20 and 100°C, pre-ferably at temperatures between 40 and 80°C.
i) In order to prepare a compound of general formula I wherein Rb denotes an amidino group, which may be substituted by a hy-droxy group, by one or two C1_3-alkyl groups:
reacting a compound of general formula H
Ra-Het-A-Ar C ~ , (XV) 'Z
optionally formed in the reaction mixture wherein A, Ar, Het and Ra are as hereinbefore defined and Z6 denotes an alkoxy group such as the methoxy, ethoxy, n-prop-oxy, isopropoxy or benzyloxy group or an alkylthio or aralkyl-thio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula R6NH - R, , (XVI ) wherein R6 denotes a hydrogen atom, a C1_3-alkyl or a hydroxy group and R., denotes a hydrogen atom or a Cl_3-alkyl group .
The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahy-drofuran or dioxan at temperatures between 0 and 150°C, prefe-rably at temperatures between 20 and 120°C, with a compound of general formula XVI or with a corresponding acid addition salt such as for example ammonium carbonate.
A compound of general formula XV is obtained for example by reacting a corresponding cyano compound of general formula I
with a corresponding alcohol such as methanol, ethanol, n-pro-panol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at 20°C, or a corresponding nitrile with hydrogen sulphide, conveniently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide for-med with a corresponding alkyl or aralkylhalide.
A hydroxyamidino compound thus obtained may subsequently, if desired, be converted into the corresponding amidino compound by means of reduction, preferably by means of catalytic hydro-genation with hydrogen in the presence of a catalyst such as palladium/charcoal or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/-acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hy-drogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
j) In order to prepare a compound of general formula I wherein Rb denotes an amidino group substituted by a prodrug group:

reacting a compound of general formula NH
Ra-Het-A-Ar C ~ , (XVII ) NHz wherein A, Ar, Het and Ra are as hereinbefore defined, with a compound of general formula Z., - Rg , ( XV I I I ) wherein R8 denotes one of the abovementioned prodrug groups and Z., denotes a leaving group such as a halogen atom, e.g. a chlo-rine or bromine atom, or a p-nitrophenyl group.
The reaction is conveniently carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform, dimethylform-amide, water or mixtures of these solvents, optionally in the presence of a base such as sodium carbonate, potassium carbo-nate or sodium hydroxide solution or in the presence of an or-ganic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine, which may simultaneously serve as solvent, at temperatures between -30 and 100°C, but -preferably at temperatures between -10 and 60°C.
If according to the invention a compound of general formula I
is obtained which contains an esterified carboxy group, this may be converted by hydrolysis into a corresponding carboxy compound or if a compound of general formula I is obtained which contains a nitro group, this may be converted by reduction into a cor-responding amino compound or if a compound of general formula I is obtained which contains an imino group in the Het moiety, this may be converted by al-kylation into a corresponding alkylated compound or if a compound of general formula I is obtained which contains a primary or secondary amino group, this may be converted by alkylation or reductive alkylation into a corresponding alkyl or dialkyl compound or if a compound of general formula I is obtained which contains .,._ a primary or secondary amino group, this may be converted by acylation into a corresponding acyl compound or if a compound of general formula I is obtained which contains a carbonyl group in the Het moiety, this may be converted by means of a sulphurising agent into a corresponding thiocarbo-nyl compound or if a compound of general formula I is obtained which contains a carbonyl group in the Het moiety, this may be converted by means of a halogen-introducing agent and subsequent reaction with an amine into a corresponding amino compound, or if a compound of general formula I is obtained which contains an alkenyl or alkynyl function, this may be converted by cata-lytic hydrogenation into a corresponding saturated compound or if a compound of general formula I is obtained which contains an alkenyl function, this may be converted by oxidation into a corresponding carboxylic acid or if a compound of general formula I is obtained which contains an enolether group, this may be converted by hydrolysis into a corresponding carbonyl compound or if a compound of general formula I is obtained which contains an aliphatic carbonyl group, this may be converted by reaction with a hydroxylamine into a corresponding oxime.
The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphu-ric 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 potas-sium hydroxide in a suitable solvent such as water, water/me-thanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxan at temperatures between -10 and 120°C, e.g. at temperatures between ambient tempera-ture and the boiling temperature of the reaction mixture.
The subsequent reduction of a nitro group is preferably car-ried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, con-veniently with hydrogen in the presence of a hydrogenation ca-talyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(II)sulphate, tin(II)chloride, sodium sulphide, sodium hydrogen sulphite or sodium dithi-onite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 80°C, but preferably at tempera-tures between 20 and 40°C.
The subsequent alkylation is conveniently 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 po-tassium 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°C, but preferably at temperatures between -10 and 80°C.
The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol/water, metha-nol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activa-ted hydrogen, e.g. hydrogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or li-thium aluminium hydride at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.
The subsequent acylation is conveniently carried out with an acid halide or anhydride in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetra-hydrofuran, dioxane or dimethylformamide optionally in the presence of an inorganic or organic base, such as sodium hy-droxide, potassium carbonate, triethylamine or pyridine, whilst the last two may simultaneously act as solvent, at temperatures between -25 and 100°C, but preferably at tempe-ratures between -10 and 80°C. However, with a corresponding acid, this is preferably carried out in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionylchloride, phosphorus -trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbo-diimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole or tri-phenylphosphine/carbon tetrachloride, and optionally in the presence of an inorganic base such as sodium carbonate or an organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures between -25°C
and 150°C, but preferably at temperatures between -10°C and the boiling temperature of the solvent used.

The subsequent conversion of a carbonyl group into the corres-ponding thiocarbonyl group is carried out with a sulphurising agent such as phosphorus pentasulphide or 2,4-bis(4-methoxy-phenyl)-1,3-di-thia-2,4-diphosphetan-2,4-disulphide, conven-iently in a solvent such as toluene or xylene at temperatures between 50 and 150°C, e.g. at the boiling temperature of the reaction mixture.
The subsequent conversion of a carbonyl group into a halome-thyl group in the Het moiety is preferably carried out with a halogen-introducing agent such as a phosphorus oxyhalide or a phosphorus pentahalide at elevated temperatures, e.g. at the boiling temperature of the phosphorus oxychloride used, and the subsequent reaction with a corresponding amine is carried out in a solvent such as ethanol or isopropanol at tempera-tures between 0 and 50°C.
The subsequent catalytic hydrogenation is carried out with hy-drogen in the presence of a catalyst such as palladium/char-coal or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or gla-cial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
-The subsequent conversion of an alkenyl compound into a cor-responding carboxylic acid is conveniently carried out with an oxidising agent such as sodium periodate in the presence of a catalyst such as ruthenium trichloride in a solvent such as methylene chloride, acetonitrile or methylene chloride/ace-tonitrile hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature.
The subsequent oxime formation is preferably carried out in a solvent such as methanol, toluene or methanol/toluene optio-nally in the presence of a tertiary organic base such as tri-ethylamine and in the presence of a water-eliminating agent, e.g. in the presence of a molecular sieve, at elevated tem-peratures, but preferably at the boiling temperature of the solvent used.
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.
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 wa-ter, isopropanol/water, tetrahydrofuran/water or dioxane/-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 bet-ween 0 and 100°C, preferably at temperatures between 10 and 50°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, dimethyl-formamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or aceto-nitrile/water at temperatures between 0 and 50°C, but pre-ferably at ambient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as me-thylene chloride, dioxan or ether.
A phthalyl group is preferably cleaved in the presence of hy-drazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopro-panol, toluene/water or dioxane at temperatures between 20 and 50°C.
An allyloxycarbonyl group is cleaved by treating with a cata-lytic amount of tetrakis-(triphenylphosphine)-palladium(O) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100°C, preferably at ambient temperature and under inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rho-dium(I)chloride in a solvent such as aqueous ethanol and op-tionally in the presence of a base such as 1,4-diazabicyclo-[2.2.2)octane at temperatures between 20 and 70°C.
The compounds of general formulae II to XVII used as starting materials, some of which are known from the literature, are obtained by methods known from the literature, moreover their preparation is described in the Examples.
The preparation of a compound of general formula II is descri-bed for example in J. Org. Chem. $, 168-171 (1943), a compound .. of general formula III in Arzneim. Forsch. 2F~, 516-517 (1976) and a compound of general formula V in Liebigs Ann. Chem.
1980, 611-621.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.
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 Stereo-chemistry", Vol. 6, Wiley Interscience, 1971) into their opti-cal antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diaste-reomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or _fractional crystallisation, and, if these compounds are ob-tained 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 sub-stance 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 diastereo-meric salts or derivatives by the action of suitable agents.
Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-to-lyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optical-ly active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl group.
.. 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, phosphoric acid, fumaric acid, succinic acid, lactic acid, ci-tric acid, tartaric acid or malefic 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, particu-larly for pharmaceutical use into the physiologically accep-table salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine.
-As already mentioned, the new compounds of general formula I
and the salts thereof have valuable properties. Thus, the com-pounds of general formula I wherein Rb 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 Rb denotes one of the abovementioned amidino groups and the tautomers, the stereoisomers and the physiolo-gically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity which is preferably based on a thrombin- or factor Xa-influencing ef-fect, e.g. a thrombin-inhibiting or factor Xa-inhibiting ef-fect, an effect of prolonging the aPTT time and an inhibitory effect on related serine proteases such as e.g. trypsin, uro-kinase factor VIIa, factor IX, factor XI and factor XII.
For example, the following compounds:
A = 4-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hy-drochloride, B = 4-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyclo-propyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride, C = 4-~[7-(N-carboxymethylaminocarbonyl-ethylamino)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride, D = 4-{[7-(N-(pyridin-2-yl)-N-(2-carboxyethyl)-aminocarbonyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride, E = 4-{[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochloride, F = 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydro--chloride and G = 4-{[6-(1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquin-oxalin-3-yl]-methyl}-benzamidine-hydrochloride were investigated as follows for their effect on prolonging the aPTT time:
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 Koagulometer, Desaga, Wiesloch.
Method:
The aPTT time was determined using a Biomatic B10 coagulometer made by Messrs. Desaga.
The test substance was placed in the test vessels prescribed by the manufacturer with 0.1 ml of human citrated plasma and 0.1 ml of PTT reagent. The mixture was incubated for three mi-nutes at 37°C. The clotting reaction was started by the addi-tion of 0.1 ml of calcium solution. The time is measured using the apparatus from the addition of the calcium solution up to the clotting of the mixture. Mixtures to which 0.1 ml of DBA
buffer were added were used as the controls.
According to the definition, a dosage-activity curve was used to determine the effective concentration of the substance, i.e. the concentration at which the aPTT time is double compa-red with the control.
The Table which follows contains the results found:
Substance aPTT-time (EDzoa in ~,M) A 0.950 B 0.470 C 0.550 D 0.370 0.160 F 0.095 G 0.170 The compounds are well tolerated as no toxic side effects were observed 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 throm-botic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass ope-rations or angioplasty (PT(C)A), and occlusion in peripheral _ arterial diseases such as pulmonary embolism, disseminated in-travascular 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 pro-cesses.
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 car-riers and/or diluents, e.g. with corn starch, lactose, glu-cose, microcrystalline cellulose, magnesium stearate, polyvi-nylpyrrolidone, citric acid, tartaric acid, water, water/etha-nol, 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 in-vention:
4-[(7-benzolsulphonylamino-4,4-dimethyl-1,3-dioxo-3,4-dihydro-a. 4 . 4-di m hurl - .H-'~ 4-di h~rdrn-i ~pwino i n 1 , 3 di nna To 100 ml of glacial acetic acid are added, batchwise, 38.5 g (0.4 mol) ammonium carbonate and then 38 g (0.2 mol) dimethyl-homophthalic acid anhydride. Then the mixture is heated for 3 minutes to 130oC and for 2 hours to 180oC. After cooling the reaction solution is poured onto ice, the product precipitated is suction filtered and dried.
Yield: 31.5 g (83.5 0 of theory), Rf value: 0,17 (silica gel; methylene chloride) To 60 ml of fuming nitric acid are added at l5oC batchwise 18.9 g (0.1 mol) of 4,4-dimethyl-2H-3,4-dihydro-isoquinolin-1,3-dione. The solution is stirred for 60 minutes at l5oC and .. poured onto ice water. The product precipitated is suction filtered and dried.
Yield: 22.1 g (95.4 % of theory), _Rf value: 0.35 (silica gel; methylene chloride/ethanol = 19:1) c. 4-[(4,4-dimethyl-7-nitro-1,3-dioxo-3,4-dihydro-1H-isoquino-4.7 g (0,02 mol) of 4,4-dimethyl-7-nitro-2H-3,4-dihydro-iso-quinolin-1,3-dione are dissolved in 40 ml dimethylsulphoxide and after the addition of 2.2 g (0,02 mol) of potassium-tert.
butoxide stirred for 15 minutes at ambient temperature. After the addition of 4.3 g (0.022 mol) of 4-bromomethylbenzonitrile the reaction mixture is stirred for 60 minutes, subsequently poured onto water. The product precipitated is suction filte-red, the residue is dissolved in ethyl acetate, dried and fil-tered through activated charcoal. After evaporation of the solvent the product is digested with ether, suction filtered and dried.
Yield: 6.0 g (86 0 of theory), Rf value: 0.62 (silica gel; methylene chloride/ethanol - 50:1) melting point: 172-174oC
d. 4-[(7-amino-4,4-dimethyl-1,3-dioxo-3,4-dihydro-1H-isoquino-1 i n- .-yl ) -meth~rl 1 -bc~n~nni tri 1 a 3.5 g (0.01 mol) of 4-[(4,4-dimethyl-7-nitro-1,3-dioxo-3,4-di-hydro-1H-isoquinolin-2-yl)-methyl]-benzonitrile are suspended in 100 ml methanol and 100 ml ethanol and after the addition of 1.0 g palladium on activated charcoal the mixture is hydro-genated with hydrogen. The catalyst is filtered off and the filtrate is evaporated down.
Yield: 1.7 g (54.7 0 of theory), Rf value: 0.37 (silica gel; methylene chloride/ethanol - 50:1) e. 4-[(7-benzenesulphonylamino-4,4-dimethyl-1,3-dioxo-3,4-di-638 mg (2 mmol) of 4-[(7-amino-4,4-dimethyl-1,3-dioxo-3,4-di-hydro-1H-isoquinolin-2-yl)-methyl]-benzonitrile are dissolved in 30 ml pyridine and after the addition of 0.26 ml (2 mmol) of benzenesulphonic acid chloride the mixture is heated over a steam bath for 30 minutes. Then the mixture is distilled off in vacuo, the residue chromatographed on silica gel and eluted with methylene chloride/ethanol (99:1). The desired fractions are evaporated down, triturated with ether and acetone, suc-tion filtered and dried.
Yield: 610 mg (66.5 0 of theory), Rf value: 0.11 (silica gel; methylene chloride) f.-4-[(7-benzenesulphonylamino-4,4-dimethyl-1,3-dioxo-3,4-di-550 mg (1.2 mmol) of 4-[(7-benzenesulphonylamino-4,4-dimethyl-1,3-di-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-methyl]-benzoni-trile are dissolved in 50 ml of saturated ethanolic hydrochlo-ric acid and stirred for 18 hours at ambient temperature. The solvent is distilled off, the residue is dissolved in 60 ml of absolute ethanol and mixed with 1.0 g (12 mmol) of ammonium carbonate. After 60 hours at ambient temperature the mixture is evaporated to dryness. The residue is chromatographed on silica gel and eluted with methylene chloride/methanol (90:10 and 85:15). The desired fractions are concentrated by evapo-ration, triturated with ether and suction filtered.
Yield: 500 mg (81.5 % of theory), C25H24N404S x HC1 (476.57/513.03) mass spectrum: (M+H)+ = 477 The following compound is prepared analogously:
(1) 4-f[7-(naphthalin-1-yl-sulphonylamino)-4,4-dimethyl-1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl]-methyl}-benzamidine-hy-drochloride Yield: 69 % of theory, C29H26N404S x HC1 (526.63/563.09) mass spectrum: (M+H)+ = 527 4-[(7-benzenesulphonylamino-4-methyl-1-oxo-1,2-dihydro-1H-iso-N-al 1 girl -?-brnmn ni trn b n~ami r3a To a solution of 2.5 g (0.01 mol) of 2-bromo-5-nitro-benzoic acid in 70 ml tetrahydrofuran are added dropwise 3.2 g (0.01 mol) of O-(benzotriazol-1-yl)-N,N,N~N~-tetramethyluronium-tetrafluoroborate, 5 ml triethylamine and a solution of 570 mg (0.01 mol) of allylamine in 5 ml tetrahydrofuran. After 60 mi-nutes at ambient temperature the mixture is poured onto ice water, the product precipitated is suction filtered, washed with water and dried.
Yield: 1.6 g (54.4 0 of theory), Rf value: 0.57 (silica gel; ethyl acetate/petroleum ether) b_ 4-m - hurl -7-ni rn~i ~ot~i~innl in 1 onP
1.4 g (5 mmol) of N-allyl-2-bromo-5-nitro-benzamide are heated to 110oC with 160 mg palladium(II)-acetate, 160 mg triphenyl-phosphine and 1.2 ml triethylamine in 2.5 ml dimethylformamide under a nitrogen atmosphere for 2 hours. Then the mixture is stirred into ice water and adjusted to pH 5 with glacial ace-tic acid. The crystalline product with the catalyst is suction filtered and dried. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol 50:1 and 25:1.
The desired fractions are combined and evaporated down.
Yield: 95 mg (9.3 % of theory), 4-methyl-7-nitro-2H-isoquino-lin-1-one.
Rf value: 0.46 (silica gel; methylene chloride/ethanol - 19:1) c. 4-[(7-nitro-4-methyl-1-oxo-1,2-dihydro-1H-isoquinolin-505 mg (2.5 mmol) of 4-methyl-7-nitro-2H-isoquinolin-1-one are dissolved in 50 ml dimethylsulphoxide and after the addition of 1 g potassium carbonate stirred for 15 minutes under a ni-trogen atmosphere. After the addition of 588 mg (3 mmol) of 4-(bromomethyl)-benzonitrile the reaction mixture is stirred for 2 hours at ambient temperature and subsequently stirred into ice water. The product precipitated is suction filtered, washed with water and dried.
Yield: 505 mg (63.6 % of theory), Rf value: 0.63 (silica gel; methylene chloride/ethanol = 19:1) d. 4-[(7-amino-4-methyl-1-oxo-1,2-dihydro-1H-isoquinolin 500 mg (1.5 mmol) of 4-[(7-vitro-4-methyl-1-oxo-1,2-dihydro-1H-isoquinolin-2-yl)-methyl]-benzonitrile are dissolved in 20 ml methylene chloride and 80 ml ethanol and after the addi-tion of 0.5 g palladium on activated charcoal (l00) hydrogena-ted with hydrogen for 1 hour. Then the mixture is filtered off from the catalyst and evaporated down. The residue is tritura-ted with ether, suction filtered and dried.
Yield: 395 mg (91 % of theory), Rf value: 0.26 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[(7-benzenesulphonylamino-4-methyl-1-oxo-1,2-dihydro-1H-375 mg (1.3 mmol) of 4-[(7-amino-4-methyl-1-oxo-1,2-dihydro-1H-isoquinolin-2-yl)-methyl]-benzonitrile, 264 mg (1.5 mmol) of benzenesulphonic acid chloride and 50 mg dimethylaminopyri-dine are stirred in 25 ml pyridine under a nitrogen atmosphere for 18 hours at ambient temperature. Then the mixture is pou-red onto ice water and adjusted to pH 4 with acetic acid. The precipitate formed is suction filtered, washed with water and dried.
Yield: 360 mg (64.9 % of theory), Rf value: 0.54 (silica gel; methylene chloride/ethanol - 19:1) f. 4-[(7-benzenesulphonylamino-4-methyl-1-oxo-1,2-dihydro-1H-Prepared analogously to Example if from 4-[(7-benzenesulpho-nylamino-4-methyl-1-oxo-1,2-dihydro-1H-isoquinolin-2-yl)-me-thyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 57.4 % of theory, C24H23N4~3S x HC1 (446.5/492.97) mass spectrum: (M+H)+ = 447 4-[(7-benzenesulphonylamino-1-n-propyl-1,4-dihydro-2H-quina-zoli_n-2; 4-di on-~-girl ) -~m ~h~rl ] -bPn~=m;,a; no bydr~rrl Sri rlP
a_ ~-ami no-N- (4- Drano-~~rl ) -4-ni firo b n ami ~3P
31.7 g (0.17 mol) of 4-nitro-anthranilic acid are dissolved in 350 ml dimethylformamide and after the addition of 45.4 g (0.28 mol) of N,N'-carbonyldiimidazole stirred for 30 minutes at 50oC. Then a solution of 23 g (0.17 mol) of 4-aminomethyl benzonitrile in 100 ml dimethylformamide is added dropwise and stirred for 2 hours at 50oC. The solution is evaporated down, dissolved in ethyl acetate and extracted with sodium hydrogen carbonate solution. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (97:3).
Yield: 33.8 g (66 0 of theory), Rf value: 0.65 (silica gel; petroleum ether/ethyl acetate =
1:1) b. 4-[(7-nitro-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-me-t11y11 -hPnzoni t-ri l 33.5 g (0.11 mol) of 2-amino-N-(4-cyano-benzyl)-4-nitro-benz-amide are dissolved in 275 ml pyridine and 33.6 g (0.11 mol) of triphosgene are added batchwise whilst the temperature ri-ses to 50oC. After for 2 hours at 70oC the pyridine is distil-led off in vacuo, the residue is triturated with water, suc-tion filtered and dried.
Yield: 35.8 g (98 0 of theory), Rf value: 0.5 (silica gel; methylene chloride/acetone = 9:1) c. 4-[(7-nitro-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3 ~ l ) -~m ~h~rl 1 -bPnzoni t-ri 1 P
Prepared analogously to Example lc from 4-[(7-nitro-1,4-di-hydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzonitrile, pro-pyl iodide and potassium carbonate in dimethyl sulphoxide.

Yield: 86 % of theory, Rf value: 0.76 (silica gel; petroleum ether/ethyl acetate =
2:1) d. 4-[(7-amino-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion 5.0 g (0.014 mol) of 4-[(7-nitro-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzonitrile are dissolved in 150 ml methanol and 150 ml methylene chloride and after the addition of 4 g Raney nickel hydrogenated for 7 hours with hy-drogen. The catalyst is filtered off, the solvent is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride/ethyl acetate/ammonia (97:3:0.3). The desired fractions are combined and evaporated down.
Yield: 1.9 g (40 % of theory), Rf value: 0.5 (silica gel; methylene chloride/ethyl acetate/-ammonia - 9:1:0.1) e. 4-[(7-benzenesulphonylamino-1-n-propyl-1,4-dihydro-2H-qui-Prepared analogously to Example le from 4-[(7-amino-1-n-pro-pyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzo-nitrile, benzenesulphonic acid chloride and dimethylamino-pyridine in pyridine.
Yield: 89 % of theory, Rf value: 0.88 (silica gel; ethyl acetate/ethanol - 9:1) f. 4-[(7-benzenesulphonylamino-1-n-propyl-1,4-dihydro-2H-qui-Prepared analogously to Example if from 4-[(7-benzenesulpho-nylamino-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 50 % of theory, C25H25N5~4S x HC1 (491,57/528,03) mass spectrum: (M+H)+ = 492 The following compounds are prepared analogously:
(1) 4-([7-(quinolin-8-yl-sulphonylamino)-1-n-propyl-1,4-dihy-dro-2H-quinazolin-2,4-dion-3-yl]-methyl}-benzamidine-hydro-chloride Yield: 66 % of theory, C2gH27N604S x HCl (542,63/579,10) mass spectrum: (M+H)+ - 543 (M+Na)+ - 565 (M+2Na)++ = 294 (2) 4-f[7-(naphthalin-1-yl-sulphonylamino)-1-n-propyl-1,4-di-hydro-2H-quinazolin-2,4-dion-3-yl]-methyl -benzamidine-hydro-chloride Yield: 80 % of theory, C2gH27N504S x HCl (541.64/578.11) mass spectrum: (M+H)+ - 542 (M+Na)+ = 564 (3) 4-f[7-(naphthalin-2-yl-sulphonylamino)-1-n-propyl-1,4-di-hydro-2H-quinazolin-2,4-dion-3-yl]-methyl}-benzamidine-hydro-chloride Yield: 98 % of theory, C2gH27N504S x HC1 (541.64/578.11) mass spectrum: (M+H)+ = 542 (4) 4-[(7-benzenesulphonylamino-1-ethoxycarbonylmethyl-1,4-di-hydro-2H-quinazolin-2,4-dion-3-yl)-methyl]-benzamidine-hydro-chloride Yield: 59 % of theory, C26H25N5~6S x HC1 (535.59/572.06) mass spectrum: (M+H)+ = 536 4-{[7-(N-(2-dimethylaminoethyl)-quinolin-8-yl-sulphonylamino)-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)methyl}-benzami di nP-di h~rdrn~h~ err; ~ao a. 4-{[7-(N-(2-dimethylaminoethyl)-quinolin-8-ylsulphonyl-amino)-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl]-m hvl3benzoni ril 800 mg (1.52 mmol) of 4-{[7-(quinolin-8-yl-sulphonylamino)-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl]-methyl~-benzonitrile, 260 mg (1.8 mmol) of dimethylaminoethylchloride, 350 mg (2.3 mmol) of 1,8-diazabicyclo[5.4.0]under-7-ene and 1.5 g potassium carbonate are refluxed in 120 ml acetone for 30 hours. The solvent is distilled off and mixed with water.
The crystalline product is suction filtered and washed with water. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (97.5 . 2.5).
Yield: 500 mg (55 0 of theory), Rf value: 0.21 (silica gel; methylene chloride/ethanol -9.5:0.5) b. 4-{[7-(N-(2-dimethylaminoethyl)-quinolin-8-yl-sulphonyl-amino)-1-n-propyl-1,4-dihydro-2H-quinazolin-2,4-dion-3-yl)-Prepared analogously to Example if from 4-{[7-(N-(2-dimethyl--aminoethyl)-quinolin-8-yl-sulphonylamino)-1-n-propyl-1,4-di-hydro-2H-quinazolin-2,4-dion-3-yl)-methyl-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 92 % of theory, C32F";35N7C4S x 2 HCl (613, 75/686, 67) mass spectrum: (M+H)+ - 614 (M+2 H)++ = 307.6 4-[(7-benzenesulphonylamino-2-methyl-4H-quinazolin-4-on-3-yl)-me_thvl1 -hPnzami ~i na-h~~dro hl on d a. -m hyl -7-ni r -'~H-qmi na~~~ ; r-4 on 18.2 g (0.1 mol) of 2-amino-4-nitro-benzoic acid are dissolved in 100 ml ethyleneglycol monoethyl ether and after the addi-tion of 18.6 g (0.15 mol) of ethyl acetimidate and 24 ml (0.17 mol) of triethylamine refluxed for 9 hours. After coo-ling the precipitate is suction filtered, the residue is chro-matographed on silica gel and eluted with methylene chloride/-ethanol (97:3).
Yield: 7.3 g (35.8 % of theory), Rf value: 0.62 (silica gel; methylene chloride/ethanol - 9:1) b. 4-[(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-methyl]-8.0 g (0.04 mol) of 2-methyl-7-nitro-3H-quinazolin-4-one are stirred in 100 ml acetone and after the addition of 5.5 g (0.04 mol) of potassium carbonate and 7.8 g (0.04 mol) of p-cyanobenzylbromide stirred for 4 hours at ambient tempe-rature and 4 hours at 50oC. After filtration the mother liquor is evaporated down and the residue is chromatographed on si-lica gel eluting with methylene chloride/ethanol (99:1 and 98:2). The desired fractions are combined and evaporated down.
-Yield: 4.2 g (34 % of theory), Rf value: 0.53 (silica gel; methylene chloride/ethanol =
9,5:0.5) c. [4-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-methyl]-Prepared analogously to Example 3d from 4-[(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-methyl]-benzonitrile and Raney nickel/hydrogen in methylene chloride/methanol.
Yield: 72 0 of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol =
9.5:0.5) d. 4-[(7-benzenesulphonylamino-2-methyl-4H-quinazolin-4-on-Prepared analogously to Example le from 4-[(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-methyl]-benzonitrile, benzenesul-phonic acid chloride and dimethylaminopyridine in pyridine.
Yield: 90 % of theory, Rf value: 0.58 (silica gel; methylene chloride/ethanol = 9:1) e. 4-[(7-benzenesulphonylamino-2-methyl-4H-quinazolin-4-on-Prepared analogously to Example if from 4-[(7-benzenesulpho-nylamino-2-methyl-4H-quinazolin-4-on-3-yl)-methyl]-benzoni-trile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 91 % of theory, C23H21N503S x HC1 (447,53/484,00) mass spectrum: (M+H)+ = 448 The following compounds are prepared analogously:
(1) 4-~[7-(N-(2-dimethylaminoethyl)-benzenesulphonylamino)-2-methyl-4H-quinazolin-4-on-3-yl)-methyl]-benzamidine-dihy-drochloride _Yield: 65 0 of theory, C27H30N603S x HC1 (518.65/555,12) mass spectrum: (M+H)+ - 519 (M+2H)++ = 260 (2) 4-[(6-benzenesulphonylamino-2-methyl-4H-quinazolin-4-on-3-yl)-methyl]-benzamidine-hydrochloride Yield: 100 0 of theory, C23H21N5~3S x HC1 (447.53/484.00) mass spectrum: (M+H)+ = 448 _ 58 _ (3) 4-{[6-(N-(2-dimethylaminoethyl)-benzenesulphonylamino)-2-methyl-4H-quinazolin-4-on-3-yl]-methyl -benzamidine-dihydro-chloride Yield: 93 % of theory, C27H3pN603S x HCl (518.65/555,12) mass spectrum: (M+H)+ - 519 (M+2H)++ = 260 4-[(6-benzenesulphonylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-me-th~rl 1 -bP~~3i nP-h~rdrorhl nri c~P
Meth~rl (~~rano-~~r~ ) -ar-ArarA
30.0 g (0.15 mol) of 4-bromomethyl-benzonitrile, 2.0 ml (0.12 mol) of iron pentacarbonyl, 29.0 g potassium carbonate, 10.0 ml mesitylene and 250 ml absolute methanol are placed in a pressure vessel and about 3.5 1 carbon monoxide gas is in-troduced. The reaction mixture is shaken for 16 hours at am-bient temperature, mixed with water, neutralised with hydro-chloric acid and extracted with ethyl acetate. The combined organic extracts are washed with sodium hydrogen carbonate solution, dried and evaporated down. The residue is chroma-tographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1, 8:2 and 7:3). The desired fractions are combined and evaporated down.
Yield: 18.3 g (69.4 % of theory), ClpHgN02 (175.2) mass spectrum: M+ = 175 b.. (4-c~rano-~h~n~rl 1 -a t i r~ a i d 14.2 g (0.081 mol) of methyl(4-cyano-phenyl)-acetate are dis-solved in 100 ml ethanol and after the addition of 20 ml 2N
sodium hydroxide solution stirred for 1 hour at ambient tempe-rature. The solvent is distilled off, the residue is mixed with ice water and glacial acetic acid. The substance preci-pitated is suction filtered and dried.
Yield: 10.3 g (78 % of theory).
4.8 g (3 mmol) of (4-cyano-phenyl)-acetic acid are suspended in 25 ml of methylene chloride and refluxed for 15 minutes after the addition of 5 ml thionyl chloride. The solvent is distilled off, the residue dissolved in 100 ml chlorobenzene and after the addition of 4.9 g (2.5 mmol) of methyl 2-amino-5-nitro-benzoate refluxed for 2 hours. Three-quarters of the volume of chlorobenzene is distilled off and the residue is combined with ether/petroleum ether. The crystalline product is suction filtered and dried.
Yield: 5.7 g (69.4 0 of theory).
d. 4-[(6-nitro-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-1. 6 g (5 mmol) of methyl 2- [2- (4-cyano-phenyl) -acetyl amino] -5-nitro-benzoate, 1.1 g (20 mmol) of ammonium chloride, 3.0 g (21 mmol) of phosphorus pentoxide and 2.5 g (20 mmol) of N,N-dimethylcyclohexylamine are stirred at 190oC for 30 minu-tes. Then the mixture is cooled to 100oC, adjusted to pH 8 with 2N sodium hydroxide solution and stirred for 1 hour at 80oC. The precipitate formed is suction filtered, washed with water and dried. The residue is chromatographed on silica gel and eluted initially with petroleum ether/ethyl acetate (1:1) and then with ethyl acetate/ethanol (9:1). The desired frac-tions are combined and evaporated down.
Yield: 365 mg (23.8 % of theory), Rf value: 0.63 (silica gel; methylene chloride/ethanol - 19:1) e. 4-[(6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-b~nzoni t-ri l a Prepared analogously to Example ld from 4-[(6-nitro-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-benzonitrile and pal-ladium on activated charcoal/hydrogen in methylene chloride/-ethanol.
Yield: 71 % of theory, Rf value: 0.26 (silica gel; methylene chloride/ethanol = 19:1) f. 4-[(6-benzenesulphonylamino-4-oxo-3,4-dihydroquinazolin-2-s l~rl 1 -han~nni t-ri 1 a Prepared analogously to Example le from 4-[(6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-benzonitrile, benzene-sulphonic acid chloride and dimethylaminopyridine in pyridine.
Yield: 80.5 % of theory, melting point: 235-237oC
g. 4-[(6-benzenesulphonylamino-4-oxo-3,4-dihydroquinazolin-Prepared analogously to Example if from 4-[(6-benzenesulpho-nylamino-4-oxo-3,4-dihydroquinazolin-2-yl)-methyl]-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 48.3 % of theory, C22H19N5~3S x HC1 (433.49/469.95) mass spectrum: (M+H)+ = 434 The following compounds are prepared analogously:
(1) 4-[(6-(quinolin-8-yl-sulphonylamino)-4-oxo-3,4-dihydro--quinazolin-2-yl)-methyl]-benzamidine-hydrochloride Yield: 28.7 % of theory, C25H20N6~3S x HC1 (484.54/521,00) mass spectrum: (M+H)+ = 485 (2) 4-[(6-benzenesulphonylamino-3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-benzamidine-hydrochloride Yield: 20.9 % of theory, C23H21N5~3S x HC1 (447.51/483.97) mass spectrum: (M+H)+ = 448 4-[(6-benzenesulphonylamino-1-methyl-2-oxo-1,2-dihydroquin-oxal i n-'~-girl ) -~m ~h~rl 1 -b n ami ~7i nP-hy~rorr~ err; ~~
a _ 2-meth_~rl_ami no- -ni ro-ani 1 i na 3.3 g (20 mmol) of 2-fluoro-5-nitro-aniline are dissolved in 50 ml of methylamine solution (400) and stirred for 3 days at ambient temperature. The precipitate is suction filtered and dried.
Yield: 3.3 g (98.8 0 of theory), Rf value: 0.65 (silica gel; ethyl acetate) b _ Di Pth~l .-ac t~rl ami no- - (4~~rann-bPn girl ) -mal onatP
3.0 g sodium are dissolved in 100 ml ethanol and subsequently combined with a solution of 27.7 g (0.127 mol) of diethyl acetamidomalonate and 6.4 g (0.04 mol) of potassium iodide in 200 ml dioxane. Then a solution of 25 g (0.127 mol) of 4-cya-nobenzylbromide in 200 ml dioxane is added dropwise and the reaction mixture is refluxed for 3 hours. After 12 hours at ambient temperature the mixture is filtered, the filtrate is evaporated down, the residue is crystallised with petroleum ether and suction filtered.
Yield: 41.1 g (970 of theory), Rf value: 0.62 (silica gel; methylethylketone/xylene = 1:1) melting point: 177-78oC
c _ 2-ami no-'~- (4-c~rano-~h~n~rl ) -p ror~i oni c a i d 40 g (0.12 mol) of diethyl 2-acetylamino-2-(4-cyano-benzyl)-malonate are dissolved in 110 ml glacial acetic acid, 50 ml concentrated hydrochloric acid and 135 ml water and refluxed for 8 hours. The solution is evaporated down in vacuo, the residue is crystallised with isopropanol/ether, suction filte-red and dried.
Yield: 18.6 g (68% of theory), Rf value: 0.37 (silica gel; methylethylketone/xylene = 1:1) d. 4-[(5-oxo-2-trifluoromethyl-4,5-dihydro-oxazol-4-yl)-me-5.7 g (2.5 mmol) of 2-amino-3-(4-cyano-phenyl)-propionic acid are dissolved in 26.3 g (12.5 mmol) of trifluoroacetic acid anhydride and refluxed for 24 hours. Then the solution is eva-porated down in vacuo, the residue is chromatographed on sili-ca gel and eluted with methylene chloride. The desired frac-tions are combined and evaporated down.
Yield: 3.6 g (53 % of theory), Rf value: 0.71 (silica gel; methylethylketone/xylene = 1:1) e_ 3- (4-r_~rano-phenyl ) -2-oxo-~ ror i nni ~ ar~; r~
3.5 g (0.013 mol) of 4-(5-oxo-2-trifluoromethyl-4,5-dihydro-oxazol-4-yl)-methyl-benzonitrile are dissolved in 20 ml of 70 % trifluoroacetic acid and stirred for 24 hours at ambient temperature. The solid formed is suction filtered, washed with water and dried.
Yield: 1.8 g (75 % of theory), Rf value: 0.2 (silica gel; methylene chloride/ethanol = 9:1) f. 4-[(6-nitro-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-me-th~ 11 -bPn .oni ri 1 1.0 g (6.3 mmol) of 2-methylamino-5-nitro-aniline and 1.2 g (6.3 mmol) of 3-(4-cyano-phenyl)-2-oxo-propionic acid are re--fluxed for 15 hours in 15 ml ethanol. Then the mixture is coo-led, the precipitate formed is suction filtered and dried.
Yield: 1.3 g (64.3 0 of theory), Rf value: 0.76 (silica gel; ethyl acetate) g. 4-[(6-amino-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-me-Prepared analogously to Example 3d from 4-[(6-nitro-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzonitrile and palladium on activated charcoal/hydrogen in methylene chlo-ride/methanol.
Yield: 100 % of theory, Rf value: 0.3 (silica gel; ethyl acetate) h. 4-[(6-benzenesulphonylamino-1-methyl-2-oxo-1,2-dihydroquin-Prepared analogously to Example le from 4-[(6-amino-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzonitrile and benzenesulphonic acid chloride in pyridine.
Yield: 90.9 % of theory, Rf value: 0.71 (silica gel; ethyl acetate) i. 4-[(6-benzenesulphonylamino-1-methyl-2-oxo-1,2-dihydroquin-c~xal i n- -yl ) -mPth~rl 1 -bPn ami r3i nr~ h~rdrnnhl nri rlA
Prepared analogously to Example if from 4-[(6-benzenesulpho-nylamino-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 49.5 % of theory, C23H21N5~3S x HC1 (447.51/483.97) mass spectrum: (M+H)+ = 448 The following compounds are prepared analogously:
(1) 4-[(6-(quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 47.7 % of theory, -C26H22N6~3S x HCl (498.56/535.02) mass spectrum: (M+H)+ = 499 (2) 4-[(6-tert.butylcarbonyl-1-methyl-2-oxo-1,2-dihydroquin-oxalin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 37 % of theory, C22H24N4~2 x HC1 (376.5/412.9) mass spectrum: (M+H)+ = 377 (3) 4-[(6-(1-methyl-cyclopentan-1-yl-carbonyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 47 % of theory, C24H26N4~2 x HC1 (402.5/439.0) mass spectrum: (M+H)+ = 403 (4) 4-[(6-bromo-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-me- ' thyl]-benzamidine-hydrochloride Yield: 80 % of theory, C17H15BrN40 x HCl (371.26/407.72) mass spectrum: M+ = 370/2 (Br) (5) 4-[(6-(2-methyl-propionyl)-1-methyl-2-oxo-1,2-dihydro-quinoxalin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 74.9 0 of theory, C21H22N402 x HCl (362.44/398.9) mass spectrum: (M+H)+ = 363 (6) 4-[(6-(1-ethoxycarbonylmethyloxyimino-ethylidene)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 98 % of theory, C23H25N5~4 x HC1 (435.49/471.96) mass spectrum: (M+H)+ = 436 (7) 4-[(6-propionyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 100 % of theory, C20H20N4~2 x HC1 (348.40/384.88) mass spectrum: M+ = 348 4-{[6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochlnrirla a. 4-~[6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benzo-nitrilP
2.0 g (4.15 mmol) of 4-~[6-(quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzo-nitrile are dissolved in 150 ml tetrahydrofuran and after the addition of 0.2 g (4.15 mmol) of sodium hydride (50o in oil) stirred for 2 hours at ambient temperature. After the addition of 0.47 ml (4.15 mmol) of ethyl bromoacetate the reaction mix-ture was stirred for 5 hours. The precipitate is suction fil-tered, the mother liquor is evaporated down and chromatogra-phed on silica gel, eluting initially with petroleum ether and then with petroleum ether/ethyl acetate (55:45). The desired fractions are combined and evaporated down.
Yield: 1.7 g (59.1 0 of theory), Rf value: 0.4 (silica gel; ethyl acetate/petroleum ether =
3:1) b. 4-([6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benz-Prepared analogously to Example if from 4-{[6-(N-methoxycar-bonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 62.5 0 of theory, C29H26N6~5S x HC1 (570.61/607,08) mass spectrum: (M+H)+ = 571 4-{[6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino]-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N'-ethoxy-~arbonvl-b n.amidine 450 mg (0.74 mmol) of 4-{[6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~benzamidine-hydrochloride are dissolved in 30 ml tetrahydrofuran and 5 ml water and after the addition of 0.3 g (2.2 mmol) of potassium carbonate, stirred for 10 minutes at ambient temperature. Then 0.07 ml (0.74 mmol) of ethyl chloro-formate are added and stirred for a further 1 hour. The aque-ous phase is separated off, the organic phase is dried and evaporated down.
Yield: 430 mg (89.6 % of theory), C32H30N6~5S (642.68) mass spectrum: (M+H)+ - 643 (M+Na) + = 665 The following compounds are prepared analogously:
(1) 4-{[6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-N'-cyclohexyloxycarbonyl-benzamidine Yield: 63.7 % of theory, _C36H36N607S (696.78) mass spectrum: (M+H)+ = 697 (2) 4-{[6-(N-ethoxycarbonylmethylquinolin-8-yl-sulphonyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N'-methoxycarbonyl-benzamidine Yield: 23.2 % of theory, C32H30N6~7S x HC1 (642.69) mass spectrum: (M+H)+ = 643 (3) 4-{[6-(N-ethoxycarbonylmethylquinolin-8-yl-sulphonyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N'-benzyloxycarbonyl-benzamidine Yield: 20.7 % of theory, C38H34N6~7S (718.78) mass spectrum: (M+H)+ - 719 (M+Na) + = 741 (4) 4-{[6-(N-ethoxycarbonylmethylquinolin-8-yl-sulphonyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N'-[17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,-16,17-tetradecahydro-1H-cyclopenta[a)phenanthren-3-yl]-oxycarbonyl-benzamidine Yield: 31 % of theory, C58H72N6~7S (997,32) mass spectrum: (M+H)+ - 997 (M+Na)+ = 1019 (5) 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N'-n-octyloxycarbonyl-benzamidine Yield: 81.8 0 of theory, C39H44N6~7S (740.78) mass spectrum: (M+H)+ - 741 _ (M+2H)++ = 371 (6) 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N-(n-hexyloxycarbonyl)-benzamidine Yield: 73.4 % of theory, C37H40N6~7S (712.82) mass spectrum: (M+H)+ = 713 (7) 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N-(n-heptyloxycarbonyl)-benzamidine Yield: 72 0 of theory, C38H42N607S (726.85) mass spectrum: (M+H)+ = 727 (8) 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N-(n-hexadecyloxycarbonyl)-benzamidine Yield: 87.4 % of theory, C47H6pN607S (853.10) mass spectrum: (M+H)+ - 853 ( M+Na ) + = 8 7 5 (9) 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N-(2-methoxyethyloxycarbonyl)-benzamidine Yield: 68.5 % of theory, C34H34N6~8S (686.75) mass spectrum: (M+H)+ = 687 4-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-~-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydro-~hlorid 300 mg (0.49 mmol) of 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride are dissolved in 5 ml ethanol and, after the addition of 4.9 ml 1N sodium hydroxide solution, stirred for 1 hour at ambient temperature. The sol-vent is distilled off, the residue is acidified with hydro-chloric acid and stirred for 5 hours. Then the mixture is eva-porated down, mixed with water and stirred overnight. The pre-cipitate is suction filtered and dried.

Yield: 220 mg (75.9 % of theory), C2gH24N605S x HCl (556.60/593,06) mass spectrum: (M+H)+ - 557 (M+Na)+ = 579 The following compounds are prepared analogously:
(1) 4-{[6-(N-(2-carboxyethyl)-N-isobutyl-aminocarbonyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzamidine-hy-drochloride Yield: 43 0 of theory, C25H29N504 x HC1 (463.5/500.0) mass spectrum: (M+H)+ = 464 (2) 4-{[6-(N-(2-carboxyethyl)-N-phenyl-aminocarbonyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzamidine-hydrochloride Yield: 44 % of theory, C27H25N504 x HC1 (483.54/520.01) mass spectrum: (M+H)+ - 484 (M+Na)+ = 506 (3) 4-{[6-(1-carboxymethyl-4-isobutyl-imidazol-5-yl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzamidine-hydro-chloride Yield: 51 0 of theory, C26H28N603 x HC1 (472.56/509.02) mass spectrum: (M+H) + - 473 (M+2H)++ = 237 (4) 4-~[6-(N-cyclopentyl-carboxymethylsulphonylamino)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 28.8 % of theory, C24H27N505S x HCl (497.59/534.05) mass spectrum: (M+H)+ - 498 (M+Na)+ = 520 (5) 4-{[6-(1-carboxymethylaminocarbonyl-1-methyl-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hy-drochloride Yield: 69.8 % of theory, C23H25N5~4 x HCl (435.9/472.36) mass spectrum: (M+H)+ = 436 (6) 4-{[6-(1-carboxymethylaminocarbonyl-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydro-chloride Yield: 65.7 % of theory, C23H23N504 x HCl (433.48/469.94) mass spectrum: (M+H)+ = 434 (7) 4-{[6-(1-carboxymethylcarbonylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 97 % of theory, C27H36N605 x HCl (518.58/555.05) mass spectrum: (M+H)+ - 519 (M+Na)+ = 541 (8) 4-{[6-(1-(N-methyl-carboxymethylaminocarbonyl)-1-methyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 58 0 of theory, C24H27N5~4 x HC1 (449.52/485.99) mass spectrum: (M+H)+ = 450 (9) 4-{[6-(1-carboxymethyloxyimino-ethylidene)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 56 % of theory, C21H21N5~4 x HCl (407.44/443.9) mass spectrum: (M+H)+ = 408 (10) 4-{[6-(1-(N-methyl-N-(2-carboxy-ethyl)-aminocarbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thyl}-benzamidine-hydrochloride Yield: 95 % of theory, C25H27N504 x HCl (461.53/498.0) mass spectrum: (M+H)+ - 462 (M+Na)+ = 484 (11) 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-2-carboxymethyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-benzamidine-hydrochloride Yield: 65.2 % of theory, C25H27N504 x HC1 (461.50/497.99) mass spectrum: (M+H)+ - 462 (M+Na)+ = 484 (12) 4-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 54 0 of theory, C28H31N504 x HC1 (501.59/538.06) _mass spectrum: (M+H)+ - 502 (M+Na)+ = 524 (13) 4-{[7-(2-carboxyethyl-phenyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 79 % of theory, C26H23N3~3 x HC1 (425.49/461.95) mass spectrum: (M+H)+ - 426 (M+Na)+ = 448 (14) 4-~[7-(2-(E)-carboxyethenyl-phenyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 33 0 of theory, C26H21N3~3 x HC1 (423.47/459.94) mass spectrum: (M+H)+ - 424 (M+Na) + = 446 (15) 4-[7-(3-carboxymethylamino-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 79 % of theory, C25H22N4C3 x HC1 (426.48/462.94) mass spectrum: (M+H)+ - 427 (M+Na)+ - 449 (M+2Na)++ = 236 (16) 4-{[7-(2-carboxy-2-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 96 0 of theory, C21H21N3~3 x HC1 (363.42/399.88) mass spectrum: (M+H)+ - 364 (M+Na)+ = 386 (17) 4-{[7-(4-carboxymethylaminocarbonyl-phenyl)-4-methyl-qui-nolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 92 % of theory, C26~"I22N4C4 x HC1 (454.49/490.96) mass spectrum: (M+H)+ = 455 (18) 4-[(7-carboxymethyl-4-methyl-quinolin-2-yl)-oxo]-benzami-dine-hydrochloride Yield: 75 % of theory, C19H17N303 x HC1 (335.37/371.83) mass spectrum: (M+H)+ - 336 ( M+Na ) + = 3 5 8 (19) 4-{[7-(2-methyl-5-carboxymethylaminocarbonyl-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 66 0 of theory, C27H24N404 x HC1 (468.57/505.03) mass spectrum: (M+H)+ - 469 (M+Na)+ = 491 (20) 4-~[7-((E)-2-carboxy-1-methyl-ethenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 75 0 of theory, C21H1gN303 x HC1 (361.41/397.87) mass spectrum: (M+H)+ = 362 (21) 4-([7-(2-carboxy-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 59 % of theory, C21H21N3~3 x HC1 (363.42/399.88) mass spectrum: (M+H)+ - 364 (M+Na) + = 386 (22) 4-{[(7-(2-carboxymethylaminocarbonyl-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 91 % of theory, C23H24N4~4 x HCl (420.48/456.94) _mass spectrum: (M+H)+ - 421 (M+Na)+ = 443 (23) 4-{[7-(1-carboxymethylaminocarbonyl-1-methyl-ethyl)-4-me-thyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 96 % of theory, C23H24N4~4 x HCl (420.47/456.94) mass spectrum: (M+H) + - 421 (M+Na)+ = 443 (24) 4-{(7-(3-carboxymethyl-4,5-dihydroimidazol-2-on-1-yl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 52.7 % of theory, C22H21N5~4 x HC1 (419.4/479.5) mass spectrum: (M+H)+ - 420 (M+Na)+ = 442 (25) 4-{[7-(N-ethyl-carboxymethylcarbonylamino)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 11.3 % of theory, C22H22N4C4 x HC1 (406.4/442.87) mass spectrum: (M+H)+ - 407 (M+Na) + = 429 (26) 4-{[7-(N-carboxymethylaminocarbonyl-ethylamino)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 39.6 % of theory, C22H23N5~4 x HCl (421.5/461.6) mass spectrum: (M+H)+ - 422 (M+Na)+ = 444 (27) 4-{[7-(N-(pyridin-2-yl)-N-(2-carboxy-ethyl)-aminocarbo-nyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 79 0 of theory, C26H23N5~4 x HCl (469.51/505.98) mass spectrum: (M+H)+ - 470 (M+Na)+ - 492 (M-H+2Na)+ = 514 (28) 4-{[7-(1-carboxymethyloxyimino-ethylidene)-4-methyl-qui-nolin-2-yl]-amino}-benzamidine-hydrochloride Yield: 98 0 of theory, C21H21N5~3 x HC1 (391.44/427.9) mass spectrum: (M+H)+ - 392 (M+Na)+ = 414 (M-H) - - 390 (29) 4-[(6-carboxymethyloxy-4-methyl-quinolin-2-yl)-oxo]-benz-amidine-hydrochloride Yield: 59 % of theory, C1gH17N304 x HCl (351.37/387.83) mass spectrum: (M+H)+ - 352 (M+Na) + = 374 (30) 4-~[7-(1-(2-carboxyethyl)-carbonylamino)-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 85 0 of theory, C24H26N4~4 x HCl (434.5/470.97) mass spectrum: (M+H)+ - 435 (M+Na)+ = 457 (M+K) + - 473 (31) 4-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-difluoromethyl}-benzamidine-hydrochloride (32) 2-~[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiophen-5-yl-amidine-hydrochloride (33) 2-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiazol-5-yl-amidine-hydrochloride (34) 5-~[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-pyridin-2-yl-amidine-hydrochloride (35) 2-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-pyridin-5-yl-amidine-hydrochloride (36) 4-{ [6- (N- (2-carboxyethyl) -N- (2-pyridyl) -aminocarbonyl) -1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benz-amidine-hydrochloride (37) 4-{[6-(1-(2-carboxyethyl)-4-isobutyl-imidazol-5-yl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hy-drochloride (38) 4-{[6-(N-cyclopentyl-2-carboxyethylsulphonylamino)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hy-drochloride (39) 4-{[6-(1-(2-carboxyethylamino)-1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride (40) 4-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-difluoro-methyl}-benzamidine-hydrochloride (41) 2-{[(6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}--thiophen-5-yl-amidine-hydrochloride (42) 2-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiazol-5-yl-amidine-hydrochloride (43) 5-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-pyridin-2-yl-amidine-hydrochloride _ 77 -(44) 2-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-pyridin-5-yl-amidine-hydrochloride (45) 5-{[6-(1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquin-oxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 87 % of theory, C2gH34N605 x HC1 (546.63/583.09) mass spectrum: (M+H)+ - 547 (M-H)+ - 545 (M+Na)' - 569 (46) 5-{ [6- (1- (carboxymethylamino) -1- (pyrrolidin-1-yl-carbo-nyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thyl}-benzamidine-hydrochloride Yield: 90 % of theory, C26H30N6~4 x HC1 (490.57/527.02) mass spectrum: (M+H)+ - 491 4-{[6-(2-dimethylaminoethylsulphonyl)-1-methyl-2-oxo-1,2-dihy--a~ f2- (4-rhl t~rnhan~ona~"~ ~~rl~~rll di m~yl ami nP
50 ml of dimethylamine are placed in a pressure vessel at -50oC and 23 g (0.1 mol) of 2-chloroethyl-(4-chlorophenyl)-sulphone are added batchwise. After 5 hours at 80oC the re-action mixture is cooled to ambient temperature, taken up in methylene chloride, washed with water, dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (99:1 and 98:1). The desired fractions are combined and evaporated down.
Yield: 17 g (71.5 % of theory), Rf value: 0.46 (silica gel; methylene chloride/ethanol - 19:1) _ 78 -b. [4-(2-dimethylamino-ethansulphonyl)-2-nitro-phenyl]-methyl-16 ml conc. sulphuric acid are added to 8.0 g (32.4 mmol) of [2-(4-chloro-benzenesulphonyl)-ethyl]-dimethyl-amine, the re-action being strongly exothermic. Then the mixture is cooled to ambient temperature, and 6 ml conc. nitric acid are added dropwise. The reaction mixture is heated to 53oC for 5 hours and 105oC for 3 hours and subsequently poured onto ice water.
After the addition of 150 ml methylamine solution with cooling the reaction mixture is stirred over a weekend at ambient tem-perature. The crystalline product is suction filtered and dried. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (99:1). The desired fractions are combined and evaporated down.
Yield: 3.5 g (37.6 0 of theory), Rf value: 0.28 (silica gel; methylene chloride/ethanol - 19:1) c. [4-(2-dimethylamino-ethanesulphonyl)-2-amino-phenyl]-m~thvl-amine Prepared analogously to Example 1d from [4-(2-dimethylamino-ethanesulphonyl)-2-nitro-phenyl]-methyl-amine and palladium on activated charcoal/hydrogen in methylene chloride/methanol.
Yield: 92.5 0 of theory, Rf value: 0.1 (silica gel; methylene chloride/ethanol = 19:1) d. 4-([6-(2-dimethylaminoethylsulphonyl)-1-methyl-2-oxo-Prepared analogously to Example 7f from [4-(2-dimethylamino-ethane-sulphonyl)-2-amino-phenyl]-methyl-amine and 4-(2-oxo-propionic acid)-benzonitrile in ethanol.
Yield: 52 % of theory, Rf value: 0.65 (silica gel; methylene chloride/ethanol - 19:1) e. 4-{[6-(2-dimethylaminoethylsulphonyl)-1-methyl-2-oxo Prepared analogously to Example if from 4-{[6-(2-dimethyl-aminoethylsulphonyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 39 % of theory, C21H25N5~3S x HC1 (427,54/500.47) mass spectrum: (M+H) + - 428 (M+2H) + = 214 . 6 The following compound is prepared analogously:
(1) 4-[(6-benzenesulphonyl-1-methyl-2-oxo-1,2-dihydroquinoxa-lin-3-yl)-methyl]-benzamidine-hydrochloride Yield: 89.8 0 of theory, C23H20N4~3S x HCl (432.50/468.96) mass spectrum: (M+H)+ = 433 4-{[6-(2-oxo-piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquin-oxal i n- -girl 1 -m~t,h~~rl ~ -b~mi chi na h~rdrnrhl nri rla ~ 4-fl »nro- -ni trn-N- (5-bromh»t~rlc~x~r) ani 1 i nP
~'o a solution of 3.7 g (0.024 mol) of 4-fluoro-3-nitro-aniline in 100 ml tetrahydrofuran, 4.8 g (0.024 mol) of 5-bromovaleric acid chloride are added dropwise after the addition of 3 ml triethylamine at ambient temperature. Then the mixture is stirred for two hours at ambient temperature and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride. The desired fractions are combined and concentrated by evaporation.
Yield: 7.0 g (92 0 of theory), Rf value: 0.6 (silica gel; petroleum ether/ethyl acetate =
3:7) b. 4- (2-oxo-~i_C7 .rir7in-'I -girl ) -7-ni 1-r fl ~ornhan~ona To a suspension of 1.0 g (21.9 mmol) of sodium hydride (50o in oil) in 200 ml tetrahydrofuran, a solution of 7.0 g (21.9 mmol) of 4-fluoro-3-nitro-N-(5-brombutyloxy)-aniline in 50 ml tetrahydrofuran is added dropwise at ambient tempera-ture. After 30 minutes the mixture is poured onto ice water, the tetrahydrofuran is distilled off and the aqueous phase is extracted with methylene chloride. The combined organic ex-tracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (7:3).
Yield: 4.1 g (79 % of theory), Rf value: 0.4 (silica gel; petroleum ether/ethyl acetate =
3:7) 4- (~-oxo-~i ~ ri ~7i n-1 -girl ) -~-ni ro-N-m hurl ani 1 i nP
4.1 g (0.017 mol) of 4-(2-oxo-piperidin-1-yl)-2-nitro-fluoro-benzene are stirred in 50 ml methylamine solution (40% in H20) in a sealed vessel for 1 hour at ambient temperature. Then the mixture is diluted with water, suction filtered and dried.
Yield: 3.9 g (92 0 of theory), Rf value: 0.35 (silica gel; petroleum ether/ethyl acetate =
1:9) d. 4- f 2-oxo-~i_p Pri chi n-'I -yl ) -2-ami no-N-mP hurl ani 1 i na -Prepared analogously to Example ld from 4-(2-oxo-piperidin-1-yl)-2-nitro-N-methyl-aniline and palladium on activated charcoal/hydrogen in methanol.
Yield: 97 % of theory, Rf value: 0.25 (silica gel; methylene chloride/ethanol - 19:1) e. 4-~[6-(2-oxo-piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-Prepared analogously to Example 7f from 4-(2-oxo-piperidin-1-yl)-2-amino-N-methyl-aniline and 4-(2-oxo-propionic acid)-benzonitrile in ethanol.
Yield: 50 0 of theory, Rf value: 0.28 (silica gel; methylene chloride/ethanol - 19:1) f. 4-{[6-(2-oxo-piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-~uinoxal i n-'~-girl 1 -meth~rl ~ -b n ami chi nP-h~rdroc~hl Sri ~7P
Prepared analogously to Example if from 4-(6-(2-oxo-piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl-benzo-nitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 60 0 of theory, C22H23N5~2 x HCl (389.5/425.9) mass spectrum: (M+H)+ = 390 The following compound is prepared analogously:
(1) 4-{[6-(n-butanesultam-2-yl)-1-methyl-2-oxo-1,2-dihydro-quinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 46 0 of theory, C21F";23N5C3S x HC1 (425.5/462.0) mass spectrum: (M+H)+ = 426 4-{[6-(1-isobutyl-tetrazol-5-yl)-1-methyl-2-oxo-1,2-dihydro-quinoxal i n-~ -girl 1 -~m ~h~rl ~, -b n ami di nP-h~rdroc~hl nri c~P
a. 4- hl oro-'~-ni ro-bc~n .oi r ac~i d-i ~obut~rl ami c3a 6 ml (0.06 mol) of isobutylamine in 60 ml tetrahydrofuran are added dropwise to a solution of 13.2 g (0.06 mol) of 4-chloro-3-nitro-benzoylchloride and 6 g (0.06 mol) of triethylamine in 150 ml tetrahydrofuran and the mixture is stirred for 1 hour.
The solution is evaporated down, dissolved in methylene chlo-ride and washed with water. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (98:2).
The desired fractions are combined and evaporated down.
Yield: 13.5 g (88 0 of theory), b. 4- f (5- (7 -i ~obm girl - tra .ol -5-girl ) -2-ni ro- hl orob n c~nP
10.3 g (0.04 mol) of 4-chloro-3-nitro-benzoic acid-isobutyl-amide are dissolved in 200 ml methylene chloride and mixed with 2.6 g (0.04 mol) of sodium azide. Then at OoC 6.7 ml (0.04 mol) of trifluoromethanesulphonic acid anhydride are added dropwise. Then the reaction mixture is stirred for 40 hours at ambient temperature and combined with 5% sodium car-bonate solution. The organic phase is separated off, dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride + 0-1% ethanol.
The desired fractions are combined and concentrated by evaporation.
Yield: 3.6 g (32 0 of theory), C11H12C1N502 (281.7) mass spectrum: M+ = 281 c. 4- I[ (5-('I -i ~obu ~rl_- ra .ol -S-girl) - -ni ro-N-m~~h~rl -ani 1 in Prepared analogously to Example 12c from 4-[(5-(1-isobutyl-tetrazol-5-yl)-2-nitro-chlorobenzene and methylamine solution.
Yield: 100 % of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol = 50:1) d. 4 - f ( 5 - ( ~ - i yob ~ -yl - ra .ol - -girl ) -? -ami no-N-methyl -ani 1 i n Prepared analogously to Example ld from 4-[(5-(1-isobutyl-te-trazol-5-yl)-2-nitro-N-methyl-aniline and palladium on activa-ted charcoal/hydrogen in methanol.
Yield: 100 % of theory, Rf value: 0.3 (silica gel; methylene chloride/ethanol - 19:1) e. 4-{[6-(1-isobutyl-tetrazol-5-yl)-1-methyl-2-oxo-1,2-dihy-Prepared analogously to Example 7f from 4-[(5-(1-isobutyl-te-trazol-5-yl)-2-amino-N-methyl-aniline and 4-(2-oxo-propionic acid)-benzonitrile in ethanol.
Yield: 31 0 of theory, Rf value: 0.53 (silica gel; methylene chloride/ethanol - 19:1) f. 4-{[6-(1-isobutyl-tetrazol-5-yl)-1-methyl-2-oxo-1,2-dihy-dro- = ii nnxal i n~~l 1 -mPth~rl ~~ -b n ami ~i nP h~rdr~~hl nri ~P
Prepared analogously to Example if from 4-~[6-(1-isobutyl-tetrazol-5-yl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 24 % of theory, C22H24N80 x HCl (416.5/452.96) mass spectrum: (M+H)+ = 417 4-[(6-phenyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-me-thyl1-ben2ami di na-h~rdrnrhl nri ~3a a~ ~-ni t'ro-4- hip girl -N-mPi-h~rl -a t-ani l i r3P
3.0 g (11.7 mmol) of 2-nitro-4-phenylacetanilide are dissolved in 70 ml dimethylformamide and at ambient temperature combined batchwise with 576 mg (12 mmol) of sodium hydride (50o in oil). After 30 minutes at 65oC the reaction mixture is cooled to ambient temperature, combined with 3 ml methyl iodide and stirred for 30 minutes. The reaction mixture is stirred into saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried and concentrated by evaporation. The residue is chroma-tographed on silica gel and eluted with methylene chloride +
0-5% ethanol. The desired fractions are combined and concen-trated by evaporation.

Yield: 3.2 g (100 0 of theory), Rf value: 0.43 (silica gel; methylene chloride/ethanol = 19:1) b _ 2-ni ro-4-= hPn~rl -N-m hurl -ani l i na 3.2 g (11.7 mmol) of 2-nitro-4-phenyl-N-methyl-acetanilide are refluxed in 99 ml semiconcentrated hydrochloric acid for 7 hours. The solution is cooled and extracted with methylene chloride. The organic phase is washed with water and sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride. The desired fractions are combined and concentrated by evaporation.
Yield: 2.0 g (75 0 of theory), Rf value: 0.8 (silica gel; methylene chloride) 2-ami no-4-~h -n~rl -N-mPt-h~rl -ani 1 i nP
Prepared analogously to Example ld from 2-nitro-4-phenyl-N-me-thyl-aniline and palladium on activated charcoal/hydrogen in methanol.
Yield: 91 0 of theory, Rf value: 0.4 (silica gel; methylene chloride/ethanol = 19:1) d. 4-[(6-phenyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-me-Prepared analogously to Example 7f from 2-amino-4-phenyl-N
methyl-aniline and 4-(2-oxo-propionic acid)-benzonitrile in Jethanol.
Yield: 44 % of theory, Rf value: 0.76 (silica gel; methylene chloride/ethanol = 19:1) e. 4-((6-phenyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-Prepared analogously to Example if from 4-[(6-phenyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl]-benzonitrile and hy-drochloric acid/ammonium carbonate in ethanol.
Yield: 63 0 of theory, C23H20N40 x HCl (368.4/404.9) mass spectrum: (M+H)+ = 369 The following compound is prepared analogously:
(1) 4-{[6-(2-methyl-phenyl)-1-methyl-2-oxo-1,2-dihydroquinoxa-lin-3-yl]-methyl-benzamidine-hydrochloride Yield: 80 % of theory, C24H22N4~ x HC1 (382.47/418.94) mass spectrum: (M+H)+ = 383 4-{[6-(N-(2-ethoxycarbonylethyl)-N-isobutyl-aminocarbonyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzami-di_ne-hydrnr~hl nri rla a _ ,t-h~rl'3-i Sohmt~rl ami nn- roni nnat-a 7.7 g (0.05 mol) of f3-alanine ethylester-hydrochloride, 3.6 g (0.05 mol) of isobutyraldehyde, 5.1 g (0.05 mol) of triethyl-amine and 3 g palladium on activated charcoal are dissolved in 200 ml ethanol and hydrogenated under hydrogen pressure. The ._ catalyst is suction filtered and the filtrate evaporated down.
The residue is digested with ether, suction filtered and dried.
Yield: 9.3 g (100 % of theory) contaminated with triethyl-ami-ne-hydrochloride.
Ethyl 3-N-[isobutyl-(4-methylamino-3-nitro-benzoyl)-amino]-4.5 g (25.9 mmol) of ethyl 3-isobutylamino-propionate are sus-pended in 100 ml tetrahydrofuran and 5 ml triethylamine and after the addition of 3.3 g (15.3 mmol) of 4-amino-3-nitro-benzoylchloride stirred overnight at ambient temperature. The tetrahydrofuran is distilled off in vacuo, the residue dissol-ved in methylene chloride and extracted with water. The orga-nic phase is dried and evaporated down. The residue is chroma-tographed on silica gel and eluted with methylene chloride +
1-5% ethanol.
Yield: 4.7 g (87 % of theory), Rf value: 0.32 (silica gel; methylene chloride/ethanol = 50:1) c. Ethyl 3-N-[isobutyl-(4-methylamino-3-amino-benzoyl)-amino]-Prepared analogously to Example ld from ethyl 3-N-[isobutyl-(4-methylamino-3-nitro-benzoyl)-amino]-propionate and palla-.. dium on activated charcoal/hydrogen in ethanol/methylene chlo-ride.
Yield: 100 % of theory, Rf value: 0.78 (silica gel; methylene chloride/ethanol - 19:1) d. 4-{[6-(N-(2-ethoxycarbonylethyl)-N-isobutyl-aminocarbonyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzoni-tril Prepared analogously to Example 7f from ethyl-3-[isobutyl-(4-methylamino-3-amino-benzoyl)-amino]-propionate and 4-(2-oxo-propionic acid)-benzonitrile in ethanol.
Yield: 34 % of theory, e. 4-{[6-(N-(2-ethoxycarbonylethyl)-N-isobutyl-aminocarbonyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dinP-hydrnr~hl nr; r~P
Prepared analogously to Example if from 4-(6-(N-2-ethoxycar-bonyl-ethyl-N-isobutyl)aminocarbonyl-1-methyl-2-oxo-1,2-di-hydroquinoxalin-3-yl)-methyl-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 71 % of theory, C27H35N504 x HC1 (491.6/528.07) mass spectrum: (M+H)+ - 492 (M+H+Na)+ = 257.7 The following compounds are prepared analogously:
(1) 4-{[6-(N-(2-ethoxycarbonylethyl)-N-phenyl-aminocarbonyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochloride Yield: 85 0 of theory, C2gH2gN504 x HC1 (511.59/548.06) mass spectrum: (M+H)+ - 512 ( M+H+Na ) ++ = 2 6 7 . 8 (2) 4-{[6-(N-(2-(1H-tetrazol-5-yl)ethyl)-N-phenyl-aminocarbo-nyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benz-amidine-hydrochloride Yield: 37 % of theory, C27H25N902 x HC1 (507.6/544.0) mass spectrum: (M+H)+ = 508 (3) 4-~[6-(N-ethoxycarbonylmethyl-N-(pyridin-2-yl)-aminocarbo-nyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benz-amidine-hydrochloride Yield: 84 0 of theory, C27H26N604 x HCl (498.55/535.02) mass spectrum: (M+H)+ = 499 (4) 4-~[6-(N-(2-ethoxycarbonylethyl)-N-(pyridin-2-yl)-amino -carbonyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}
benzamidine-hydrochloride Yield: 50 0 of theory, C28H28N604 x HC1 (512.58/549.04) mass spectrum: (M+H)+ = 513 _ 88 _ 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-N'-(2-me-thy l~nhon~rl -~th~rl ox~rc-ar on~r-Z) -ben~ami chi nP
0.5 g (0.77 mmol) of 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride, 0.32 g (2.3 mmol) of potassium carbonate and 0.39 g (1.4 mmol) of 2-(methylsulpho-nyl)-ethyl-4-nitrophenyl carbonate are stirred in 40 ml te-trahydrofuran for 54 hours at ambient temperature. The solvent is distilled off and the residue is taken up in methylene chloride and sodium hydrogen carbonate solution. The combined organic extracts are dried and evaporated down. The residue is chromatographed on aluminium oxide and eluted with methylene chloride + 1-5o ethanol.
Yield: 180 mg (31.8 0 of theory), C34H34N6~9S2 (734.80) mass spectrum: (M+H)+ - 735 (M+Na) + = 757 4-{[6-(N-cyclopentyl-3-carboxypropionylamino)-1-methyl-2-oxo-400 mg (0.74 mmol) of 4-{[6-(N-cyclopentyl-3-ethoxycarbonyl-propionylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thyl~-benzamidine-hydrochloride are stirred for 6 hours at am-bient temperature in 15 ml of semiconcentrated hydrochloric acid. Then the mixture is evaporated down in vacuo and dried over phosphorus pentoxide in a high vacuum.
Yield: 400 mg (98.5 % of theory), C26H2gN504 x HC1 (475.56/512.02) mass spectrum: (M+H)+ - 476 (M+Na)+ = 498 _ 89 -The following compounds are prepared analogously:
(1) 4-{[6-(1-(2-carboxy-piperidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochloride Yield: 70.2 % of theory, C27H2gN504 x HC1 (487.56/524.03) mass spectrum: (M+H)+ = 488 (M+Na)+ = 510 (2) 4-{[6-(1-(N-cyclopentyl-3-carboxypropionylamino)-cyclopro-pyl-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benz-amidine-hydrochloride Yield: 100 % of theory, C2gH34N504 x HC1 (515.62/552.08) mass spectrum: (M+H)+ - 516 ( M+Na ) + = 5 3 8 (3) 4-f[6-(1-(2-carboxymethylaminocarbonyl-pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 91.8 0 of theory, C2gH3pN605 x HCl (530.59/567.05) mass spectrum: (M+H)+ - 531 _ (M+Na)+ = 553 (4) 4-{[6-(1-(2-(2-carboxyethyl)aminocarbonyl)-pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxa-lin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 99.2 % of theory, C29H32N605 x HC1 (544.62/581.09) mass spectrum: (M+H)+ - 545 (M+Na)+ = 567 (5) 4-{[6-(1-(2-carboxymethyl-piperidin-1-yl-carbonyl)-cyclo-propyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-benzamidine-hydrochloride Yield: 88.4 0 of theory, C2gH31N504 x HCl (501.59 / 538.05) mass spectrum: (M+H)+ - 502 (M+Na)+ = 524 (6) 4-{[6-(1-(2-carboxymethylaminocarbonyl-pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-carbonyl)-benzamidine-hydrochloride Yield: 75.9 % of theory, C2gH28N606 x HC1 (544.57 / 581.04) mass spectrum: (M+H)+ - 545 (M+Na)+ = 567 (7) 4-{[6-(4-(1-(2-carboxy-ethyl)-piperidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thyl}-benzamidine-hydrochloride Yield: 80.1 % of theory, C29H33N504 x HCl (515.62 / 552.09) mass spectrum: (M+H)+ = 516 r4-{[6-(1-ethoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydro~hloride a ~. - (4- hl oro-~h~n~~l ) -4 mPt-h~rl n r,ra" ~ onP
A solution of 56 g (0.42 mol) of isocaproic acid chloride in 20 ml chlorobenzene is added dropwise to a suspension of 66.7 g (0.5 mol) of aluminium chloride in 300 ml chloroben-zene. The solution is stirred for 3 hours at 50oC and subse-quently evaporated down. The residue is carefully poured onto ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phases are washed with water, dried and evaporated down and the residue obtained is chromatogra-phed on silica gel with petroleum ether/methylene chloride (2:8) .
Yield: 72.5 g (83 % of theory), Rf value: 0.6 (silica gel; methylene chloride) b . 7 -bromo-'I - ( 4 -c~hl oro~~rl ) -4 -m hurl nPnt-an '1 on 55 g (0.344 mol) of bromine are added dropwise to a solution of 72.5 g (0.344 mol) of 1-(4-chlorophenyl)-4-methyl-pentan-1-one in 300 ml dioxane and 300 ml methylene chloride in such a way that decolorisation sets in immediately. After 10 minu-tes at ambient temperature the solvent is evaporated off.
Yield: 99 g (100 % of theory), Rf value: 0.76 (silica gel; methylene chloride) c_ 5- (4~oromhPn~r1 1 -4-i yob yrl -1H-imida n1P
38 g (0.43 mol) of 2-bromo-1-(4-chlorophenyl)-4-methyl-pentan-1-one are heated to 160oC in 400 ml formamide for 10 hours.
After 12 hours at ambient temperature the mixture is diluted with water and combined with ammonia. The precipitate formed is filtered off, then washed with water and ether.
., Yield: 19 g (66 % of theory), Rf value: 0.5 (silica gel; methylene chloride/methanol = 9:1) 19 g (0.085 mol) of 5-(4-chlorophenyl)-4-isobutyl-1H-imidazol are dissolved in 500 ml acetone and after the addition of 41.5 g (0.3 mol) of potassium carbonate and 16.7 g (0.13 mol) of ethyl bromoacetate the mixture is refluxed for 16 hours.
Then the insoluble matter is filtered off and the mother li-quor is evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/methanol (80:1).
The desired fractions are combined and evaporated down.
Yield: 5.4 g (20 % of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1) 4.8 g (0.015 mol) of ethyl [5-(4-chlorophenyl)-4-isobutyl-imi-dazol-1-yl]-acetate are dissolved in 15 ml ethanol and 40 ml water and after the addition of 2.0 g (0.05 mol) of sodium hy-droxide stirred for 2 hours at ambient temperature. The alco-hol is distilled off, the residue is diluted with water and adjusted to pH 5 with hydrochloric acid. The precipitate for-med is filtered off, washed with water and dried.
Yield: 3.9 g (89 0 of theory), Rf value: 0.38 (silica gel; methylene chloride/methanol = 5:1) f. [5-(4-chloro-3-nitro-phenyl)-4-isobutyl-imidazol-1-yl]-Prepared analogously to Example lb from [5-(4-chlorophenyl)-4-isobutyl-imidazol-1-yl]-acetic acid and fuming nitric acid at -lSoC.
Yield: 75 % of theory, Rf value: 0.4 (silica gel; methylene chloride/methanol = 5:1) g. [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol Prepared analogously to Example 7a from [5-(4-chloro-3-nitro-phenyl)-4-isobutyl-imidazol-1-yl]-acetic acid and methylamine solution (40 %) at 110oC.
-Yield: 99 % of theory, Rf value: 0.42 (reversed phase RP 18; methanol/5% saline solu-tion = 6:4) h. Ethyl [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imida-100 ml of absolute ethanol is saturated with hydrogen chloride and, after the addition of 3.6 g (0.011 mol) of [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol-1-yl]-acetic acid, stirred for 3 hours at ambient temperature. The solution is evaporated down in vacuo, the residue is dissolved in water, made basic with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down.
Yield: 2.9 g (73 0 of theory), Rf value: 0.64 (silica gel; methylene chloride/methanol - 9:1) i. Ethyl [4-isobutyl-5-(4-methylamino-3-amino-phenyl)-imida-zol -'1 -yl 1 -acetat-P
Prepared analogously to Example ld from ethyl [4-isobutyl-5-(4-methylamino-3-nitro-phenyl)-imidazol-1-yl]-acetate and palladium on activated charcoal/hydrogen in methanol.
Yield: 79 % of theory, Rf value: 0.44 (silica gel; methylene chloride/methanol = 9:1) k. 4-{[6-(1-ethoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-Prepared analogously to Example 7f from ethyl (4-isobutyl-5-(4-methylamino-3-amino-phenyl)-imidazol-1-yl]-acetate and 4-(2-oxo-propionic acid)-benzonitrile in ethanol.
Yield: 59 % of theory, Rf value: 0.58 (silica gel; methylene chloride/methanol - 9:1) 1. 4-{[6-(1-ethoxycarbonylmethyl-4-isobutyl-imidazol-5-yl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-siine-h~rdrochl on d Prepared analogously to Example if from 4-{[6-(1-ethoxycarbo--nylmethyl-4-isobutyl-imidazol-5-yl)-1-methyl-2-oxo-1,2-dihy-dro-quinoxalin-3-yl]-methyl}-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 68 % of theory, C2gH32N603 x HC1 (500.61 / 537.07) mass spectrum: (M+H)+ = 501 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -N'-(methyl-~arbonvl ox~r (m~th~rl ) mP~h~rl n ox~r arbon,~rl ) b n ami ~3i nP
(1-chl ornPth~rl -4-ni tro~~1) carbonatA
To a solution of 12.6 g (90 mmol) of p-nitrophenol in 300 ml methylene chloride and 7.2 g (91 mmol) of pyridine, 14.2 g (99 mmol) of 1-chloroethyl chlorformate are added dropwise at -lOoC. The solution is stirred for 72 hours at ambient tempe-rature and subsequently extracted with water and 0.5o sodium hydroxide solution. The combined organic extracts are dried and evaporated down. The residue is chromatographed on alu-minium oxide and eluted with methylene chloride. The combined fractions are evaporated down, triturated with petroleum ether and suction filtered.
Yield: 7.3 g (33 0 of theory), Rf value: 0.58 (silica gel; ethyl acetate/petroleum ether =
3:7) b. 'I - (4-ni .ro-t~h noxycarbon~rl ox~r;~~rl ac~Ptat-P
7.2 g (29.3 mmol) of (1-chloroethyl-4-nitrophenyl)-carbonate and 10.9 g (34.2 mmol) of mercury (II)-acetate are stirred in 200 ml glacial acetic acid for 16 hours at ambient tempera-ture. Then the mixture is evaporated to dryness, the residue is chromatographed on silica gel and extracted with methylene chloride.
Yield: 4.2 g (53 0 of theory), Rf value: 0.48 (silica gel; methylene chloride) c. 4-[{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylami-no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-N'-(me-360 mg (0.56 mmol) of 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride, 270 mg (1.0 mmol) of 1-(4-nitro-phenoxycarbonyloxy)-ethyl acetate, 0.17 ml (1.0 mmol) of N-ethyl-diisopropylamine and 25 ml methylene chloride are stirred for 5 hours at ambient temperature. The solvent is distilled off, the residue is chromatographed on aluminium oxide and eluted with methylene chloride + 0-20 ethanol. The desired fractions are combined and evaporated down.
Yield: 260 mg (65 % of theory), C35H34N6~9S (714.76) mass spectrum: (M+H)+ - 715 (M+Na)+ = 737 4-{[6-(N-cyclopentyl-N-(2-ethoxycarbonylethylsulphonyl)-ami no)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benz midi n -h~rdro .hl on d C~rc~l o~nt~rl - (4-fl ~nrn- -ni ro-ph~n~~) -ami nP
6.7 g (0.08 mol) of cyclopentanone, 12.5 g (0.08 mol) of 4-fluoro-3-nitro-aniline and 30 ml (0.1 mol) of titanium-IV-isopropoxide are stirred for 30 minutes at 40oC and one hour at ambient temperature. After the addition of 150 ml of ethanol the reaction mixture is stirred for 30 minutes and subsequently combined batchwise with 2.4 g (0.066 mol) of sodium borohydride. After 4 hours the reaction mixture is poured onto ice water and combined with ethyl acetate. After filtration the organic phase is separated off, dried and eva-porated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1). The desired fractions are combined and evaporated down.
Yield: 8.8 g (49 % of theory), Rf value: 0.68 (silica gel; petroleum ether/ethyl acetate =
4:1) n _ lv-cy m~mants 1- (4-N-m hurl ami nn-2 ni t-rn~~r~ 1 ami na Prepared analogously to Example 7a from cyclopentyl-(4-fluoro-3-nitrophenyl)-amine and methylamine solution.
Yield: 100 0 of theory, Rf value: 0.44 (silica gel; methylene chloride) c. Methyl 3-[cyclopentyl-(4-methylamino-3-nitro-phenyl)-sulph-Prepared analogously to Example le from cyclopentyl-(4-N-me-thyl-2-nitro-phenyl)-amine and methyl 3-chloro-sulphonyl-pro-pionate in pyridine.
Yield: 36 % of theory, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 50:1) d. Methyl 3-[cyclopentyl-(3-amino-4-methylamino-phenyl)-sulph-Prepared analogously to Example ld from methyl 3-[cyclopentyl-(4-methyl-amino-3-nitro-phenyl)-sulphamoyl]-propionate and palladium on activated charcoal/hydrogen in methylene chlo-ride/methanol.
Yield: 100 0 of theory, Rf value: 0.52 (silica gel; methylene chloride/ethanol = 50:1) e. 4-~[6-(N-cyclopentyl-N-(2-ethoxycarbonylethylsulphonyl)-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-_ben2oni_t_rile Prepared analogously to Example 7f from methyl 3-[cyclopentyl-(3-amino-4-methylamino-phenyl)-sulphamoyl]-propionate and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol.
Yield: 51 % of theory, Rf value: (silica gel; ethyl acetate/petroleum ether = 3:1) _ 97 _ f. 4-{[6-(N-cyclopentyl-N-(2-ethoxycarbonylethylsulphonyl)-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Prepared analogously to Example if from 4-{[6-(N-cyclopentyl-N-(2-ethoxycarbonylethylsulphonyl)-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 51 % of theory, C27H33N505S x HC1 (539.67/576.13) mass spectrum: (M+H)+ = 540 The following compounds are prepared analogously:
(1) 4-{[6-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochloride Yield: 83 % of theory, C28H33N504 x HCl (503.61/540.08) mass spectrum: (M+H)+ - 504 ( M+H+Na ) ++ = 2 6 3 . 7 (2) 4-{[6-(N-(2-ethoxycarbonylmethylcarbonyl)-N-cyclopentyl-amino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-benzamidine-hydrochloride Yield: 53 0 of theory, C27H31N504 x HCl (489.59/526.54) mass spectrum: (M+H)+ = 490 (3) 4-{[6-(N-cyclopentyl-ethoxycarbonylmethylsulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochloride Yield: 87 % of theory, C26H31N5~5S x HCl (525.64/562.11) mass spectrum: (M+H)+ = 526 _ 98 _ (4) 4-{[6-(N-cyclopentyl-N-(tetrazol-5-yl-methylcarbonyl)-ami-no-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benz-amidine-hydrochloride Yield: 19 0 of theory, C25H27N902 x HCl (485.56/522.03) mass spectrum: (M+H)+ - 486 (M+Na)+ = 508 4-~[6-(1-ethoxycarbonyl-cyclohexan-1-yl)-1-methyl-2-oxo-a l - (4-chl orn-'~-ni rn~hPn~rl~~rc~l nhPxanararhox~rl i c~ a i d Prepared analogously to Example lb from 1-(4-chlorophenyl)-cyclohexanecarboxylic acid and fuming nitric acid at -25oC.
Yield: 88.2 0 of theory.
Prepared analogously to Example 7a from 1-(4-chloro-3-nitro-phenyl)-cyclohexanecarboxylic acid and methylamine solution.
Yield: 90.6 % of theory, Rf value: 0.27 (silica gel; methylene chloride/ethanol = 95:5) c. ethyl 1-(4-methylamino-3-nitrophenyl)-cyclohexanecarb-Prepared analogously to Example 18h from 1-(4-methylamino-3-nitrophenyl)-cyclohexanecarboxylic acid and ethanolic hydro-chloric acid.
Yield: 87 % of theory, Rf value: 0.82 (silica gel; methylene chloride/ethanol - 95:5) d. ethyl 1-(3-amino-4-methylamino-phenyl)-cyclohexanecar Prepared analogously to Example ld from ethyl 1-(4-methyl-amino-3-nitrophenyl)-cyclohexanecarboxylate and palladium on activated charcoal/hydrogen in methanol/methylene chloride.
Yield: 100 % of theory.
e. 4-[(6-(1-ethoxycarbonyl)cyclohexan-1-yl-1-methyl-2-oxo-1. 2-di h~rdro gmi noxal i n-~-girl ) -mPt- ~r]~l b n oni i-ri 1 P
Prepared analogously to Example 7f from ethyl 1-(3-amino-4-me-thylamino-phenyl)-cyclohexanecarboxylate and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol.
Yield: 57.1 % of theory.
f. 4-{[6-(1-ethoxycarbonyl-cyclohexan-1-yl)-1-methyl-2-oxo-Prepared analogously to Example if from 4-{[(-(1-ethoxycarbo-nyl-cyclohexan-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 84.6 % of theory, C26H30N4~3 x HCl (446.55/483.01) mass spectrum: M+ = 446 The following compounds are prepared analogously:
(1) 4-{[6-(1-ethoxycarbonyl-1-methyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 63 % of theory, C23H26N4~3 x HC1 (406.48/442.94) mass spectrum: (M+H)+ = 407 (2) 4-{[6-(1-ethoxycarbonyl-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 31.6 % of theory, C23H24N4~3 x HC1 (404.48/477.41) mass spectrum: M+ = 404 (3) 4-{[6-(1-ethoxycarbonylmethylaminocarbonyl-1-methyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 78 % of theory, C25H2gN504 x HC1 (463.55/536.48) mass spectrum: M+ = 463 (4) 4-{[6-(1-ethoxycarbonylmethylaminocarbonyl-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benz-amidine-hydrochloride Yield: 55 % of theory, C25H27N504 x HCl (461.53/534.46) mass spectrum: M+ = 461 (5) 4-{[6-(1-(N-methyl-ethoxycarbonylmethylaminocarbonyl)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 80.6 % of theory, C26H2gN504 x HC1 (475.56/512.02) mass spectrum: (M+H)+ = 476 (6) 4-{[6-(1-(N-methyl-ethoxycarbonylmethylaminocarbonyl)-1-methyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-rmethyl}-benzamidine-hydrochloride Yield: 79 % of theory, C26H31N5~4 x HCl (477.57/514.04) mass spectrum: (M+H)+ = 478 (7) 4-{[6-(1-methyl-1-(piperidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hy-drochloride Yield: 89 % of theory, C26H31N5~2 x HC1 (445.57/482.04) mass spectrum: (M+H) + = 446 (8) 4-~[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzamidine-hydrochloride Yield: 69 % of theory, C25H29N5~2 x HC1 (431.55/468.01) mass spectrum: (M+H)+ = 432 (9) 4-{[6-(1-methyl-1-dimethylaminocarbonyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydro-chloride Yield: 92 0 of theory, C23H27N502 x HC1 (405.51/441.97) mass spectrum: (M+H)+ = 406 (10) 4-{[6-(1-methyl-1-(piperazin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-di-hydrochloride Yield: 59 % of theory, C25H30N6~2 x HC1 (446.56/483.03) mass spectrum: (M+H)+ = 447 (11) 4-{[6-(1-(N-(2-ethoxycarbonyl-ethyl)-N-methyl-aminocarbo-nyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benzamidine-hydrochloride Yield: 66 % of theory, C27H31N504 x HC1 (489.58/526.04) mass spectrum: (M+H)+ - 490 (M+H+Na)++ = 256.6 (12) 4-{[6-(1-(4-methyl-piperidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benzami-dine-hydrochloride Yield: 89.2 0 of theory, C27H31N502 x HC1 (457.58/494.05) mass spectrum: (M+H)+ = 458 (13) 4-~[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 33.2 % of theory, C25H27N502 x HC1 (429.56/466.0) mass spectrum: (M+H)+ = 430 (14) 4-{[6-(1-(4-methyl-piperazin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-dihydrochloride Yield: 80.2 % of theory, C26H30N6~2 x HCl (458.56/495.03) mass spectrum: (M+H)+ - 459 (M+2H)++ = 230 (15) 4-([6-(1-(3-methyl-piperidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benzami-dine-hydrochloride Yield: 77.2 % of theory, C27H31N502 x HCl (457.58/494.05) mass spectrum: (M+H)+ - 458 (M+Na) + = 480 (16) 4-{[6-(1-(2-ethoxycarbonyl-piperidin-1-yl-carbonyl)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 79 0 of theory, C2gH33N504 x HCl (515.61/552.07) mass spectrum: (M+H)+ = 516 (17) 4-([6-(1-(2-ethoxycarbonyl-pyrrolidin-1-yl-carbonyl)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 48.1 % of theory, C28H31N504 x HCl (501.59/538.06) mass spectrum: (M+H)+ - 502 (M+H+Na)++ = 262.8 (18) 4-{[6-(1-(2,3-dihydroindol-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzami-dine-hydrochloride Yield: 77.6 % of theory, C2gH27N502 x HCl (477.57/514.04) mass spectrum: (M+H)+ = 478 (19) 4-~[6-(1-(2-hydroxymethyl-pyrrolidin-1-yl-carbonyl)-cyc-lopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 62.7 % of theory, C26H29N5~3 x HCl (459.55/496.02) mass spectrum: (M+H)+ - 460 (M+H+Na)++ = 241.6 (20) 4-{[6-(1-(N-(2-dimethylaminoethyl)-N-methyl-aminocarbo-nyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-dihydrochloride Yield: 66.9 % of theory, C26H32N6~2 x HCl (460.59/497.05) mass spectrum: (M+H)+ = 461 (21) 4-((6-(1-(N-(3-dimethylaminopropyl)-N-methyl-aminocarbo-nyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl)-benzamidine-dihydrochloride Yield: 59.7 % of theory, C27H34N602 x HC1 (474.61/511,08) mass spectrum: (M+H)+ - 475 (M+2H)++ = 238 (22) 4-{[6-(1-(2-ethoxycarbonylmethyl-piperidin-1-yl-carbo-nyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 86.8 % of theory, C30H35N504 x HCl (529.64/566.11) mass spectrum: (M+H)+ - 530 (M+H+Na)++ = 276.7 (23) 4-{[6-(1-(2-(N-(2-ethoxycarbonylethyl)-aminocarbonyl)-pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-di-hydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 87.3 % of theory, C31H36N6~5 x HC1 (572.67/609.13) mass spectrum: (M+H)+ - 573 (M+H+Na)++ = 298 (24) 4-{[6-(1-(2-ethoxycarbonylmethylaminocarbonyl-pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquin-oxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 59.2 % of theory, C30H34N6~5 x HCl (558.64/595.11) -mass spectrum: (M+H)+ - 559 (M+H+Na)++ = 291 (25) 4-{[6-(1-(4-(2-methoxycarbonyl-ethyl)-piperidin-1-yl-car-bonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 47.4 % of theory, C30H35N5~4-x HC1 (529.64/566.11) mass spectrum: (M+H)+ = 530 (26) 4-{[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-difluoromethyl~-benz-amidine-hydrochloride (27) 2-~[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiophen-5-yl-amidine-hydrochloride (28) 2-~[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiazol-5-yl-amidine-hydrochloride (29) 2-~[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -pyridin-5-yl-amidine-hydrochloride (30) 5-{[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-pyridin-2-yl-amidine-hydrochloride (31) 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-difluoromethyl}-benz-amidine-hydrochloride (32) 2-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiophen-5-yl--amidine-hydrochloride (33) 2-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-thiazol-5-yl-amidine-hydrochloride (34) 2-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-pyridin-5-yl-amidine-hydrochloride (35) 5-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -pyridin-2-yl-amidine-hydrochloride (36) 5-{[6-(1-(1-methyl-pyrazol-5-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzami-dine-hydrochloride Yield: 7% of theory, C25H24N6~2 x HCl (440.51/476.96) mass spectrum: (M+H)+ - 441 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-thiono-1,2-dihydroquinoxalin-3-yl]-methyl}-benz-ami dine-h~rdro .hl on d a. 4-[(6-(quinolin-8-yl)-sulphonyl-N-ethoxycarbonylmethyl-ami-no-1-methyl-2-thiono-1,2-dihydroquinoxalin-3-yl)-methyl]
830 mg (1.5 mmol) of 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and 310 mg (0.75 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulphide are refluxed for 16 hours in 20 ml toluene. The solvent is di-stilled off, the residue chromatographed on silica gel and eluted with methylene chloride/ethanol (99:1).
Yield: 34.1 % of theory, C30H25N5~4S2 (583.68) mass spectrum: M+ = 583 b. 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonyl-amino)-1-methyl-2-thiono-1,2-dihydroquinoxalin-3-yl]-methyl}-bPn~ami_di_ne-h~rdroc-hl nri r~P
Prepared analogously to Example if from 4-{[6-(N-ethoxycarbo-nylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-thiono-1,2-dihydroquinoxalin-3-yl]-methyl -benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 19.4 0 of theory, C30H28N604S2 x HC1 (600.72/637.17) mass spectrum: (M+H)+ = 601 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquin-c»~n-3-girl 1 -mc~fih~rl ~ -b n ami r3i nP-h~rdrc~rhl nri rla a. 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydro-1.0 g (2.78 mmol) of 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile, 0.47 g (6.76 mmol) of hydroxylamine hydrochloride and 0.35 g (3.3 mmol) of potassium carbonate are refluxed for 25 hours in 100 ml methanol and 10 ml water. The solvent is distilled off, the residue chromatographed on silica gel and eluted with me-thylene chloride + 5-10% ethanol. The desired fractions are combined and evaporated down.
Yield: 0.34 g (31 0 of theory), Rf value: 0.6 (silica gel; methylene chloride/ethanol - 9:1) b. 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydro-300 mg (0.76 mmol) of 4-{[6-(1-carboxy-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -N-hydroxybenzamidine are dissolved in 30 ml of 90~% acetic acid and after the addi-tion of 400 mg palladium on activated charcoal hydrogenated with hydrogen at 60oC. The catalyst is filtered off, the solu-tion is evaporated down. The residue is chromatographed on si-lica gel and eluted with methanol. The desired fractions are evaporated down, triturated with ether, suction filtered and dried.
Yield: 70 mg (24 % of theory), C21H20N403 (376.42) mass spectrum: (M+H)+ = 377 4-([6-(1-(pyrrolidin-1-yl-carbonyl)-2-ethoxycarbonylmethyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-benzamidi~' n~-h~rdrnrhl nri ria 2- (4- .hl oro= hc?_n_~rl -1 - (~~rrrc~l i r~i n-1 girl ) PthanonP
Prepared analogously to Example 2a from p-chlorophenylacetic acid, pyrrolidine, O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyl-uroniumtetrafluoroborate and N-methylmorpholine in dimethyl-formamide.
Yield: 75 0 of theory, Rf value: 0.5 (silica gel; methylene chloride/ethanol = 19:1) nm i- m-cnloros hP_n_~W > -4-oxo-4- ~~rrrnl i ~7i n 'I girl ) bu ~rrat-P
16.8 g (0.075 mol) of 2-(4-chlorophenyl)-1-(pyrrolidin-1-yl)-ethanone are dissolved in 175 ml dimethylsulphoxide and after the addition of 8.9 g (0.08 mol) of potassium tert.butoxide, stirred for 15 minutes at ambient temperature. After the addi-tion of 18.1 ml (0.085 mol) of ethyl iodoacetate the reaction mixture is stirred for 45 hours at ambient temperature. The solution is poured onto ice water and extracted with ethyl _acetate. The combined organic extracts are washed with sodium chloride solution, dried and evaporated down. The residue is chromatographed on silica gel, eluting first with petroleum ether and later with petroleum ether/ethyl acetate (8:2 and 1:1). The desired fractions are combined and evaporated down.
Yield: 11.0 g (48 % of theory), Rf value: 0.73 (silica gel; ethyl acetate/petroleum ether =
7:3) c. Ethyl 3-(4-chloro-3-nitrophenyl)-4-oxo-4-(pyrrolidin-1-yl)-butyrate and ethyl 3-(4-chloro-2-nitrophenyl)-4-oxo-4-(pyrro-1 i di n-l -~ 1 ) -but-yrat-a 7.8 g (0.025 mol) of ethyl 3-(4-chlorophenyl)-4-oxo-4-(pyrro-lidin-1-yl)-butyrate are added batchwise to 40 ml of fuming nitric acid at -30oC. The solution is stirred for 15 minutes at -30oC and subsequently poured onto ice water. The superna-tant water is decanted off, the residue is taken up in ethyl acetate and sodium hydrogen carbonate solution and extracted.
The combined organic extracts are dried and evaporated down.
Yield: 7.9 g (89 0 of theory) of ethyl 3-(4-chloro-3-nitro-phenyl)-4-oxo-4-(pyrrolidin-1-yl)-butyrate and ethyl 3-(4-chloro-2-nitrophenyl)-4-oxo-4-(pyrrolidin-1-yl)-butyrate as an isomer mixture in the ratio 1:9, Rf value: 0.68 (silica gel; methylene chloride/ethanol = 19:1) d. Ethyl 3-(4-methylamino-3-nitrophenyl)-4-oxo-4-(pyrrolidin-7.9 g (23 mmol) of ethyl 3-(4-chloro-3-nitrophenyl)-4-oxo-4-(pyrrolidin-1-yl)-butyrate and ethyl 3-(4-chloro-2-nitro-phenyl)-4-oxo-4-(pyrrolidin-1-yl)-butyrate (isomer mixture) are dissolved in 65 ml ethanol and after the addition of 5 ml methylamine heated to 80oC in a pressure vessel for 1 hour.
After cooling to ambient temperature and adding 5 g silica gel, the mixture is evaporated to dryness. The residue is -chromatographed on silica gel, eluting first with petroleum ether and later with petroleum ether/ethyl acetate (9:1).
Yield: 330 mg (3.6 % of theory), _ Rf value: 0.58 (silica gel; methylene chloride/ethanol - 19:1) C17H23N3~5 (349.4) mass spectrum: M+ = 349 e. Ethyl 3-(4-methylamino-3-amino-phenyl)-4-oxo-4-(pyrrolidin-1-~ 1 -blyrrarP
300 mg (8.6 mmol) of ethyl 3-(4-methylamino-3-nitrophenyl)-4-oxo-4-(pyrrolidin-1-yl)-butyrate are dissolved in 60 ml ethyl acetate and 10 ml methanol and after the addition of 600 mg Raney nickel hydrogenated with hydrogen for 2.5 hours at ambient temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation.
Yield: 260 mg (94 % of theory), Rf value: 0.28 (silica gel; methylene chloride/ethanol = 19:1) f. 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-2-ethoxycarbonylmethyl-ethyl)-1-methyl-1H-benzimidazol-2-yl]-methyl}-benzonitrile and 4-{[5-(1-pyrrolidin-1-yl-carbonyl)-2-ethoxycarbonylmethyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-ben7oni ril 260 mg (0.81 mmol) of ethyl 3-(3-amino-4-methylamino-phenyl)-4-(pyrrolinocarbonyl)-butyrate and 189 mg (1.0 mmol) of 3-.(4-cyano-phenyl)-2-oxo-propionic acid are refluxed for 1 hour in 10 ml ethanol. The reaction solution is combined with g silica gel and evaporated to dryness. The residue is chro-matographed on silica gel, eluting first with petroleum ether and later with petroleum ether/ethyl acetate (9:1 and 8:2).
The desired fractions are combined and evaporated down.
Yield: 100 mg (28 % of theory) of 4-{[5-(1-(pyrrolidin-1-yl-carbonyl)-2-ethoxycarbonylmethyl-ethyl)-1-methyl-1H-benzimida-zol-2-yl]-methyl -benzonitrile, Rf value: 0.28 (silica gel; methylene chloride/ethanol = 19:1) C26H28N4~3 (444.5) -mass spectrum: M+ = 444 and 200 mg (52 0 of theory) of 4-{[6-(1-(pyrrolidin-1-yl-car-bonyl-2-ethoxycarbonylmethyl-ethyl)-1-methyl-2-oxo-1,2-dihy-droquinoxalin-3-yl]-methyl}-benzonitrile, C27H28N4~4 (472.5) mass spectrum: M+ = 472 g. 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-2-ethoxycarbonylmethyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-b n .ami dine-hydrn~hl nri rya Prepared analogously to Example if from 4-[[6-(1-(pyrrolidin-1-yl-carbonyl)-2-ethoxycarbonylmethyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 29.6 % of theory, C27H31N504 x HCl (489.57/526.03) mass spectrum: (M+H)+ = 490 4-{[6-(1-(N-cyclopentyl-ethoxycarbonylmethylcarbonylamino)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)-me-~hyl1 -h n .ami r3i nP-h~rdrc~rhl nri r3a a. 4-{[6-(1-(N-tert.butyloxycarbonylamino)-cyclopropyl)-1-me-A suspension of 10.6 g (0.03 mol) of 4-{[6-(1-carboxy-cyclo-propyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile in 110 ml tert.butanol is combined with 4.2 ml (0.03 mol) of triethylamine and 7 ml (0.03 mol) of phosphoric acid diphenylester azide under a nitrogen atmosphere and re-fluxed for 3 hours. The suspension is cooled to 20oC and com-bined with 2.7 g (0.024 mol) of potassium tert.butoxide within 30 minutes. After 2 hours the mixture is stirred with ice wa-ter and extracted with ethyl acetate. The organic phase is washed with sodium hydrogen carbonate solution and citric acid, dried and evaporated down.
Yield: 12.5 g (97 % of theory), Rf value: 0.6 (silica gel; methylene chloride/ethanol - 9:1) b. 4-{[6-(1-amino-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquin-12.5 g (0.03 mol) of 4-{[6-(1-(N-tert.butyloxycarbonylamino)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thyl}-benzonitrile are suspended in 160 ml dioxane and after the addition of 400 ml of 6N hydrochloric acid stirred for 4 hours at ambient temperature. The reaction mixture is poured onto ice water and made alkaline with conc. ammonia. Then the mixture is extracted with ethyl acetate, the combined organic extracts are washed with sodium chloride solution, dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol/ammonia (100:2:0.05, 20:1:0.025 and 10:1:0). The desired fractions are combined and evaporated down.
Yield: 6.6 g (69 % of theory), Rf value: 0.28 (silica gel; methylene chloride/ethanol = 9:1) c. 4-{[6-(1-cyclopentylamino-cyclopropyl)-1-methyl-2-oxo-3.0 g (9 mmol) of 4-{(6-(1-amino-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and 1.0 ml (11.2 mmol) of cyclopentanone are dissolved in 150 ml tetrahy-drofuran and 0.54 ml (9 mmol) of glacial acetic acid, combined batchwise with 2.5 g (12 mmol) of sodium triacetoxyborohydride under a nitrogen atmosphere at 22oC and stirred for 24 hours at ambient temperature. Then the mixture is poured onto ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The aqueous phase is made alkaline with conc.
ammonia and extracted with ethyl acetate. The combined organic extracts are washed with sodium chloride solution, dried and evaporated down.
Yield: 3.3 g (92 s of theory), Rf value: 0.58 (silica gel; ethyl acetate/ethanol - 9:1) d. 4-~[6-(1-(N-cyclopentyl-ethoxycarbonylmethylcarbonylamino)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-~~1 ~ -ben_2oni t ri 1 P
To a solution of 2.0 g (5 mmol) of {[(6-(1-cyclopentyl-amino-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thyl}-benzonitrile in 40 ml tetrahydrofuran are added 0.77 ml (5.5 mmol) of triethylamine and then 0.7 ml (5.5 mmol) of monoethyl malonate chloride are added dropwise. The reaction mixture is cooled to 20oC, stirred for 30 minutes and combined with ice water. Then the mixture is made alkaline with conc.
.. ammonia, extracted with ethyl acetate, the organic phases are washed with hydrochloric acid and water, dried and evaporated down. The residue is chromatographed on silica gel and eluted with cyclohexane/ethyl acetate/glacial acetic acid (1:1:0.001). The desired fractions are combined and evaporated down.
Yield: 2.1 g (82 % of theory), Rf value: 0.22 (silica gel; cyclohexane/ethyl acetate = 1:1) e. 4-{[6-(N-cyclopentyl-ethoxycarbonylmethylcarbonylamino)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-Prepared analogously to Example if from 4-{[6-(1-(N-cyclo-pentyl-ethoxycarbonylmethylcarbonylamino)-cyclopropyl)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl -benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
C30H35N5~4 x HC1 (529.64/566.11) mass spectrum: (M+H)+ - 530 (M+H+Na)++ = 276.7 The following compound is prepared analogously:
(1) 4-{[6-(1-(N-cyclopentyl-N-(3-ethoxycarbonylpropionyl)-amino)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 98 0 of theory, C31H37N504 x HCl (543.67/580.13) mass spectrum: (M+H)+ = 544 4-{[6-(1-ethoxycarbonylmethylcarbonylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-thvl l -bPnzami di nP-h~rdro hl on d 10.0 g (4.45 mmol) of 5-(4-chlorophenyl)-5-methyl-imidazoli-din-2,4-dione are added batchwise to 50 ml of fuming nitric acid at -25°C to -35°C. After 45 minutes at -25°C to -20°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: 173-178°C
Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate = 1:1) b 2-ami nn-7- (4-c~l,l nrn ~ ni trnrl ) ~ rnpi nni r a i r3 10.5 g (0.044 mol) of 5-(4-chloro-3-nitrophenyl)-5-methyl-imidazolidin-2,4-dione are refluxed for 5 days in 200 ml dioxane and 700 ml 6N hydrochloric acid. The solution is cooled and evaporated down, taken up in water and extracted with ethyl acetate. The aqueous phase is evaporated down, combined with toluene and evaporated to dryness. The residue is triturated with ether, suction filtered and dried.
Yield: 6.8 g (63 0 of theory), Rf value: 0.24 (reversed phase RPB; 5% saline solution/methanol = 1:1) c. 2-tert.butoxycarbonylamino-2-(4-chloro-3-nitrophenyl)-pro-r~i oni c acid 6.8 g (0.028 mol) of 2-amino-2-(4-chloro-3-nitrophenyl)-pro-pionic acid are dissolved in 100 ml dioxane, 20 ml water and 0.5 ml (0.061 mol) of triethylamine and, after the addition of 7.3 g (0.033 mol) of pyrocarbonic acid-di-tert.butyldicarbo-nate, stirred for 16 hours at ambient temperature. Then the mixture is diluted with ethyl acetate and washed with potas-sium hydrogen sulphate solution and water. The organic ex-tracts are combined, dried and evaporated down.
Yield: 9.6 g (100 0 of theory), Rf value: 0.31 (reversed phase RPB; 5o saline solution/methanol = 1:2) d. tert. Butyl [1-(4-chloro-3-nitrophenyl)-1-methyl-2-oxo Prepared analogously to Example 2a from 2-tert.butoxycarbonyl-amino-2-(4-chloro-3-nitrophenyl)-propionic acid, O-(benzotria-zol-1-yl)-N,N,N'N'-tetramethyluroniumtetrafluoroborate, pyrro-lidine and N-methylmorpholine in dimethylformamide.
Yield: 94 % of theory, Rf value: 0.11 (silica gel; cyclohexane/ethyl acetate = 1:1) e. tert. Butyl [1-(4-methylamino-3-nitrophenyl)-1-methyl-2-oxo-2-~~rr of i ~3i n-'I -girl -~~rl ) -~arhami nafiP
Prepared analogously to Example 7a from tert.butyl [1-(4-chlo-ro-3-nitrophenyl)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl]-carbaminate and methylamine solution in dimethylformamide at 160oC.
Rf value: 0.79 (silica gel; ethyl acetate/ethanol - 9:1) f. tert.butyl [1-(3-amino-4-methylamino-phenyl)-1-methyl Prepared analogously to Example ld from tert.butyl [1-(4-me-thylamino-3-nitrophenyl)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl]-carbaminate and palladium on activated charcoal/hydrogen in methanol.
Yield: 100 % of theory, Rf value: 0.63 (silica gel; ethyl acetate/ethanol - 9:1) g. 4-{[6-(1-tert.butoxycarbonylamino-1-(pyrrolidin-1-yl-car-bonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-me-th~rl ~ -benzonitrile Prepared analogously to Example 7f from tert.butyl [1-(3-ami-no-4-methylamino-phenyl)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl]-carbaminate and 4-(2-oxo-propionic acid)-benzonitrile in ethanol.
Yield: 54 % of theory, Rf value: 0.18 (silica gel; cyclohexane/ethyl acetate = 1:1) 4-{[6-(1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2 -oxo-1 ,. 2 -dih~rdro guinoxal in- 3 -girl ] -meth~rl ~ -benzoni t ri 1 a Prepared analogously to Example 25b from 4-{[6-(1-tert.butoxy-carbonylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and 6N
hydrochloric acid in dioxane.
Yield: 89 % of theory, Rf value: 0.11 (silica gel; ethyl acetate/ethanol/ammonia =
9:1:0.01) i. 4-{[6-(1-ethoxycarbonylmethylcarbonylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-X11-meth~rl~-benzonitrile Prepared analogously to Example 25d from 4-{[6-(1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-di-hydroquinoxalin-3-yl]-methyl -benzonitrile, monoethyl malonate chloride and triethylamine in tetrahydrofuran.
Yield: 78 % of theory, Rf value: 0.58 (silica gel; ethyl acetate/ethanol = 9:1) k. 4-{[6-(1-ethoxycarbonylmethylcarbonylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3- ~rll -meth~rl ~ -benzami__dine-hydrochloride Prepared analogously to Example if from 4-{[6-(1-ethoxycarbo-nylmethylcarbonylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzoni-trile and hydrochloric acid/ammonium carbonate in ethanol.

Yield: 73 % of theory, C29H34N6~5 x HC1 (546.63/583.11) mass spectrum: (M+H) + - 547 ( M+H+Na ) ++ = 2 8 5 The following compounds were prepared analogously:
(1) 5-f[6-(1-(2-ethoxycarbonyl-ethylcarbonylamino)-1-ethoxy-carbonyl-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl~-benzamidine-hydrochloride Yield: 930 of theory, C28H33N506 x HCl (535.61/572.08) mass spectrum: (M+H)' - 536 (M+H+Na)++ - 279.5 (2) 5-f[6-(1-ethoxycarbonylmethylamino-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride Yield: 85 % of theory, C27H35N703 x HC1 (518.62/555.08) mass spectrum: (M+H)+ - 519 (M+Na)' - 541 -4-{[7-(4-methyl-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benz-amidine-h~rdrochlo_ri cla a. N- ('~-bromo-nhen~rl ) -'l-oxo-b~t~rrami r7P
10.9 g (0.1 mol) of 3-bromaniline are added dropwise at 160oC
to 52 ml (0.4 mol) of ethyl acetate. After 15 minutes at 160oC
the excess ethyl acetate is distilled off under high vacuum.
After cooling the residue is dissolved in methylene chloride and chromatographed on silica gel, eluting with methylene chloride/ethanol 9:1. The desired fractions are combined and evaporated down.

Yield: 17.7 g (69 % of theory), Rf value: 0.83 (silica gel; ethyl acetate/ethanol = 9:1) b_ 7-bromo-4-meth~rl-1H-c~ ~inol i n- -on 3.5 g (0.013 mol) of N-(3-bromo-phenyl)-3-oxo-butyramide are added batchwise at 85oC to 4.7 ml conc. sulphuric acid and then stirred for 15 minutes at 105oC. Then the mixture is coo-led to 60oC, stirred into ice water and made alkaline with conc. Ammonia. The product precipitated is suction filtered, washed with water and dried.
Yield: 2.2 g (68 % of theory), Rf value: 0.66 (silica gel; ethyl acetate/ethanol = 9:1) c _ 7-bromo- hl oro-4-m - hurl-iLi noline 2.1 g (9.2 mmol) of 7-bromo-4-methyl-1H-quinolin-2-one are re-fluxed in 30 ml of phosphorus oxychloride for 30 minutes and subsequently mixed with water at 30 to 50oC. After the addi-tion of conc. ammonia, the product precipitated is suction filtered, washed with water and dried.
Yield: 2.0 g (85 % of theory), Rf value: 0.71 (silica gel; cyclohexane/ethyl acetate = 2:1) d. 4- [~7-bromo-4-meth~rl-ci ~i nol i n- -girl oxy] -benzoni trig 1.9 g (7.4 mmol) of 7-bromo-2-chloro-4-methyl-quinoline are melted with 1.8 g (14.8 mmol) of 4-hydroxybenzonitrile for -1 hour at 175oC. After cooling the reaction product is decocted with ethyl acetate. After filtration the mother liquor is washed with sodium hydroxide solution and water, dried and evaporated down. The residues are chromatographed over silica gel, eluting with cyclohexane/ethyl acetate (9:1 and 5:1). The desired fractions are combined and evaporated down.
Yield: 1.6 g (66 % of theory), Rf value: 0.46 (silica gel; petroleum ether/ethyl acetate =
4:1) e. 4-[(7-(4-methyl-phenyl)-4-methyl-quinolin-2-yl)-oxo]-benzo-To a suspension of 1.5 g (4.4 mmol) of 4-[(7-bromo-4-methyl-quinolin-2-yl)oxy]-benzonitrile in 20 ml toluene and 0.94 g (8.8 mmol) of sodium carbonate in 6 ml water are added 0.14 g (0.12 mmol) of tetrakis-(triphenylphosphine)-palladium(0) and 0.6 g (4.4 mmol) of 4-methylphenylboric acid. The suspension is refluxed for 6 hours and stirred for 3 days at ambient tem-perature. Then it is extracted with ethyl acetate and washed with water and sodium chloride solution, the organic phase is dried and evaporated down. The residue is chromatographed on silica gel and eluted with cyclohexane/ethyl acetate (1:0 and 9:1). The desired fractions are combined and evaporated down.
Yield: 1.1 g (71 % of theory), Rf value: 0.43 (silica gel; petroleum ether/ethyl acetate =
4:1) f. 4-([7-(4-methyl-phenyl)-4-methyl-quinolin-2-yl)-oxo]-benz-Prepared analogously to Example if from 4-~[7-(4-methyl-phe-nyl)-4-methyl-quinolin-2-yl)-oxo]-benzonitrile and hydrochlo-ric acid/ammonium carbonate in ethanol.
Yield: 11 % of theory, C24H31N4C x HCl (367.46/403.92) mass spectrum: (M+H)+ - 368 (2M+H) + = 735 The following compounds are prepared analogously:
(1) 4-[(7-bromo-4-methyl-quinolin-2-yl)-oxo]-benzamidine-hydrochloride Yield: 75 % of theory, C17H14BrN30 x HCl (356.24/392.70) mass spectrum: (M+H) + = 356/8 (Br) (2) 4-{[7-(2-methyl-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benz-amidine-hydrochloride Yield: 71 % of theory, C24H21N30 x HC1 (367.46/403.92) mass spectrum: (M+H)+ = 368 (3) 4-{[7-(2-ethoxycarbonyl-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 16 % of theory, C26H23N303 x HC1 (425.49/461.95) mass spectrum: (M+H)+ = 426 (4) 4-{[7-(4-ethoxycarbonyl-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 61 % of theory, C26H23N3~3 x HC1 (425.49/461.95) mass spectrum: (M+H)+ = 426 (5) 4-{[7-(3-ethoxycarbonyl-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 57 % of theory, C26H23N3~3 x HC1 (425.49/461.95) mass spectrum: (M+H)+ = 426 _(6) 4-~[7-(3-amino-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benz-amidine-hydrochloride Yield: 93 % of theory, C23H20N4~ x HC1 (368.45/404.91) mass spectrum: (M+H)+ = 369 (7) 4-{[7-(3-ethoxycarbonylmethylamino-phenyl)-4-methyl-quino-lin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 98 % of theory, C27H26N403 x HC1 (454.54/491.00) mass spectrum: (M+H)+ = 455 (8) 4-{[7-(3-nitro-phenyl)-4-methyl-quinolin-2-yl]-oxo~-benz-amidine-hydrochloride Yield: 79 % of theory, C23H18N403 x HCl (398.43/434.89) mass spectrum: (M+H)+ = 399 (9) 4-{[7-(4-ethoxycarbonylmethylaminocarbonyl-phenyl)-4-me-thyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 86 % of theory, C28H26N404 x HC1 (482.54/519.0) mass spectrum: (M+H)+ = 483 (10) 4-[(4-methyl-quinolin-2-yl)-oxo]-benzamidine-hydrochlo-ride Yield: 35 % of theory, C17H15N30 x HC1 (277.33/313.79) mass spectrum: M+ = 277 (11) 4-[(7-bromo-4-methyl-quinolin-2-yl)-thio]-benzamidine-hy-drochloride Yield: 100 % of theory, C17H14BrN3S x HC1 (372.31/408.77) mass spectrum: (M+H) + = 372/4 (Br) (12) 4-{[7-(N-(2-ethoxycarbonylpropionyl)-N-ethyl-amino)-4-me-thyl-quinolin-2-yl]-oxo)-benzamidine-hydrochloride Yield: 43 %~of theory, C25H28N404 x HCl (448.5/484.97) mass spectrum: (M+H)+ = 449 (13) 4-{[7-(N-ethyl-ethoxycarbonylmethylcarbonylamino)-4-me-thyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 60 % of theory, C24H26N4~4 x HC1 (434.49/470.96) mass spectrum: (M+H)+ = 435 (14) 4-{[7-(N-ethoxycarbonylmethylaminocarbonyl-N-ethyl-amino)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 73 % of theory, C24H27N504 x HC1 (449.51/485.97) mass spectrum: (M+H)+ = 450 (15) 4-~[7-(N-(1H-tetrazol-5-yl-methylcarbonyl)-N-ethyl-ami-no)-4-methyl-quinolin-2-yl]-amino}-benzamidine-hydrochloride Yield: 42.8 % of theory, C22H23N90 x HC1 (429.49/465.96) mass spectrum: (M+H)+ = 430 (16) 4-~[7-(1-ethoxycarbonylmethylcarbonylamino-ethyl)-4-me-thyl-quinolin-2-yl]-oxy}-benzamidine-hydrochloride Yield: 10.6 % of theory, C24H26N4~4 x HCl (434.49/470.97) mass spectrum: (M+H)+ = 435 (17) 4-~[7-(1-(2-ethoxycarbonylethylcarbonylamino)-ethyl)-4-methyl-quinolin-2-yl]-oxy}-benzamidine-hydrochloride Yield: 12.4 % of theory, C25H28N404 x HCl (448.53/485.00) mass spectrum: (M+H)+ = 449 (18) 4-([7-(1-acetylamino-ethyl)-4-methyl-quinolin-2-yl]-oxy}-benzamidine-hydrochloride Yield: 55 % of theory, C21H22N4~2 x HC1 (362.44/398.9) mass spectrum: (M+H)+ = 363 4-{[7-(2-(2-(E)-ethoxycarbonylethenyl)-phenyl)-4-methyl-quino-l ; n-,~~rl ] -ox -henzamidine-h~rdrochloride a. 4-{[7-(2-formyl-phenyl)-4-methyl-quinolin-2-yl]-oxy}-benzo-Prepared analogously to Example 27e from 4-[(7-bromo-4-methyl-quinolin-2-yl)oxy]-benzonitrile, 2-formylbenzeneboric acid, sodium carbonate and tetrakis-(triphenylphosphine)-palla-dium(0) in toluene/water.
Yield: 73 % of theory, Rf value: 0.29 (silica gel; petroleum ether/ethyl acetate =
4:1) b. 4-{[7-(2-(2-(E)-carboxyethenyl)-phenyl)-4-methyl-quinolin-2-~rl,L-oxo~ -henzonitrile A suspension of 1.8 g (5 mmol) of 4-[[7-(2-formyl-phenyl)-4-methyl-quinolin-2-yl]oxy~-benzonitrile in 8 ml pyridine is heated to 125oC with 0.9 g (8.6 mmol) of malonic acid and 0.05 ml of piperidine for 2.5 hours. After cooling the solu-tion formed is poured onto ice water and adjusted to pH 3-4 with citric acid. Then the mixture is extracted with ethyl acetate, the organic phase is washed with water and sodium chloride solution, dried and evaporated down.
Yield: 1.6 g (79 % of theory), -Rf value: 0.59 (silica gel; ethyl acetate/ethanol = 9:1) c.~ 4-{ [7- (2- (2- (E) -ethoxycarbonylethenyl) -phenyl-4) -methyl-Prepared analogously to Example if from 4-{[7-(2-(2-(E)-carb-oxyethenyl)-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 87 a of theory, C28H27N303 x HCl (453.55/490.01) mass spectrum: (M+H)+ = 454 4-{[7-(2-(2-ethoxycarbonylethyl)-phenyl)-4-methyl-quinolin-2-~rl ] -oxo~~ -b -n .ami di nP-h~rdro .hl or' d _ a. 4-{[7-(2-(2-carboxyethyl)-phenyl)-4-methyl-quinolin-2-yl]
0.8 g (2 mmol) of 4-{ [7- (2- (2- (E) -carboxyethenyl) -phenyl) -4-methyl-quinolin-2-yl]-oxo~-benzonitrile are dissolved in 20 ml dimethylformamide and, after the addition of 0.2 g pal-ladium on activated charcoal, hydrogenated with hydrogen at ambient temperature. The catalyst is filtered off, the mother liquor is evaporated down, combined with ice water and extrac-ted with ethyl acetate. The combined organic extracts are washed with water and sodium chloride solution, dried and eva-porated down.
Yield: 0.8 g (98 % of theory), Rf value: 0.68 (silica gel; ethyl acetate) b. 4-{[7-(2-(2-ethoxycarbonylethyl)-phenyl)-4-methyl-quinolin-Prepared analogously to Example if from 4-{(7-(2-(2-ethoxy-carbonylethyl)-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzoni-trile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 87 % of theory, JC28H27N303 x HC1 (453.55/490.01) mass spectrum: (M+H)+ = 454 The following compounds are prepared analogously:
(1) 4-{[7-(2-ethoxycarbonyl-2-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 71.8 % of theory C23H25N3~3 x HC1 (391.48/427.94) mass spectrum: (M+H)+ = 392 (2) 4-~[7-(2-ethoxycarbonyl-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 93.7 % of theory, C23H25N3~3 x HCl (391.48/427.94) mass spectrum: (M+H)+ = 392 (3) 4-f[7-(2-ethoxycarbonylmethylaminocarbonyl-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride Yield: 14.8 % of theory, C25H28N404 x HCl (448.52/484.98) mass spectrum: (M+H)+ = 449 (4) 4-[(7-methoxycarbonyl-4-methyl-quinolin-2-yl)-oxo]-benz-amidine-hydrochloride Yield: 86 0 of theory, C19H17N3~3 x HC1 (335.37/371.83) mass spectrum: (M+H)+ = 336 (5) 4-~[7-(N-(2-ethoxycarbonyl-ethyl)-N-(pyridine-2-yl)-amino-carbonyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochlo-ride Yield: 61 0 of theory, C2gH27N504 x HC1 (497.56/534.03) mass spectrum: (M+H)+ - 498 (M+2H) ++ = 249 . 6 4-{[7-(2-methyl-phenyl)-4-methyl-quinolin-2-yl]-amino}-benz-amidine-hydrochloride _ 4 - [! 7-bromo-4 -meth~rl-z ~ i nol i n- -girl ) -ami noL b n .oni ri l 17.7 g (0.069 mol) of 7-bromo-2-chloro-4-methyl-quinoline and 9.0 g (0.076 mol) of 4-aminobenzonitrile are refluxed in 150 ml glacial acetic acid for 5 hours. The solvent is distil-led off, the residue is stirred with water and made alkaline with ammonia. The crude product is suction filtered and then chromatographed on silica gel, eluting with methylene chlo-ride/ethanol (99:1 and 98:2).
Yield: 17.5 g (75 % of theory), Rf value: 0.41 (silica gel; methylene chloride/ethanol = 98:2) b. 4-{[7-(2-methyl-phenyl)-4-methyl-quinolin-2-yl]-amino}-hPnzcmit_ri1e Prepared analogously to Example 27e from 4-[(7-bromo-4-methyl-quinolin-2-yl)-amino]-benzonitrile, 2-methylphenylboric acid, tetrakis-(triphenylphosphine)-palladium(0) and sodium carbo-nate in toluene/water.
Yield: 68 % of theory, Rf value: 0.21 (silica gel; petroleum ether/ethyl acetate =
4:1) c. 4-{[7-(2-methyl-phenyl)-4-methyl-quinolin-2-yl]-amino}-b -n .am' dine-h~rdrochloride Prepared analogously to Example if from 4-{[7-(2-methyl-phe-nyl)-4-methyl-quinolin-2-yl]-amino}-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 68.4 % of theory, C24H22N4 x HC1 (366.47/402.93) mass spectrum: M+ = 366 The following compounds are prepared analogously:
(1) 4-{[7-(N-ethoxycarbonylmethylcarbonyl-N-ethyl-amino)-4-me-thyl-quinolin-2-yl]-amino}-benzamidine-hydrochloride Yield: 2.3 % of theory, C24H2gN603 x HCl (448.52/484.99) mass spectrum: (M+H)+ = 449 (2) 4-[(7-acetyl-4-methyl-quinolin-2-yl)-amino]-benzamidine-hydrochloride Yield: 100 % of theory, C1gH18N40 x HCl (318.39/354.85) mass spectrum: (M+H)+ = 319 (3) 4-[(7-bromo-4-methyl-quinolin-2-yl)-amino]-benzamidine-hydrochloride Yield: 77.9 % of theory, C17H15BrN4 x HC1 (355.26/391.72) mass spectrum: (M+H)+ = 355/7 (Br) 4-{[7-(4-carboxy-phenyl)-4-methyl-quinolin-2-yl]-oxo}-benzami 250 mg (0.5 mmol) of 4-{[7-(4-ethoxycarbonyl-phenyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydrochloride are stirred in 6 ml of 1-molar lithium hydroxide solution and 6 ml of tetra-hydrofuran for 5 hours at ambient temperature and combined with 10 ml of 1N hydrochloric acid. The organic solvent is distilled off, 10 ml ammonium chloride solution are added and the mixture is stirred overnight at ambient temperature. The product precipitated is suction filtered and dried.
Yield: 140 mg (60 % of theory), -C24H19N3~3 x HC1 (397.44/433.9) mass spectrum: (M+H)+ = 398 4-{[7-((E/Z)-2-ethoxycarbonyl-2-methyl-ethylenyl)-4-methyl-qLinolin-2-yl ] -oxo~ -b n .ami c3i nP-h~rdro .hl on d .
a. 4-{[7-((E/Z)-2-ethoxycarbonyl-2-methyl-ethylenyl)-4-methyl-1.7 g (5 mmol) of 4-[(7-bromo-4-methyl-quinolin-2-yl)-oxo]-benzonitrile, 0.71 g (6,25 mmol) of ethyl methacrylate, 1.3 g (12.5 mmol) of triethylamine, 0.26 g (0.1 mmol) of triphenyl-phosphine and 0.11 g (0.05 mmol) of palladium(II)-acetate are heated to 120oC in 10 ml xylene under a nitrogen atmosphere for 7 hours. Then the mixture is cooled, diluted with water and extracted with ethyl acetate. The organic phases are dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (4:1). The desired fractions are combined and evaporated down.
Yield: 0.48 g (25.8 % of theory), Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate =
4:1) b. 4-{[7-((E/Z)-2-ethoxycarbonyl-2-methyl-ethylenyl)-4-methyl-~Linolin-2-girl ] -ox -b n .amidi n -h~rdro .hl on d Prepared analogously to Example if from 4-{[7-((E/Z)-2-ethoxy-carbonyl-2-methyl-ethylenyl)-4-methyl-quinolin-2-yl]-oxo}-benzonitrile and hydrochloric acid/ammonium carbonate in etha-rnol.
Yield: 78.8 0 of theory, C23H23N3~3 x HC1 (389.46/425.92) mass spectrum: (M+H)+ = 390 The following compound is prepared analogously:
(1) 4-{[7-((E)-2-ethoxycarbonyl-1-methyl-ethylenyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 24 % of theory, C23H23N3~3 x HC1 (389.46/425.92) mass spectrum: (M+H)+ = 390 4-[(7-ethoxycarbonylmethyl-4-methyl-quinolin-2-yl)-oxo]-benz-amidine-h~rdrochloride s3_ 4- [ (7-al l~rl-4-meth~rl-guinolin-2-girl -ox~r1 -benzonitr;1e 6.8 g (0.02 mol) of 4-[(7-bromo-4-methyl-quinolin-2-yl)-oxy]-benzonitrile, 6.8 g (5.9 mmol) of tetrakis-(triphenylphos-phine)-palladium(0) and 6.8 ml (0.022 mol) of allyltributyltin are refluxed in 50 ml toluene under a nitrogen atmosphere for 2 hours. The toluene is distilled off, the residue triturated with ether and suction filtered. The mother liquor is combined with silica gel and evaporated down. Then the mixture is chro-matographed on silica gel and eluted with cyclohexane/ethyl acetate (95:5 and 9:1). The desired fractions are combined and evaporated down.
Yield: 6.0 g (88 % of theory), Rf value: 0.51 (silica gel; petroleum ether/ethyl acetate =
4:1) b. 4-[(7-ethoxycarbonylmethyl-4-methyl-quinolin-2-yl)-oxo]-3 g (0.01 mol) of 4-[(7-allyl-4-methyl-quinolin-2-yl)-oxy]-benzonitrile are dissolved in 50 ml methylene chloride and 40 ml acetonitrile and combined with a solution of 15.7 g (0.073'mol) of sodium periodate and 50 mg of ruthenium tri-chloride in 90 ml water with stirring. After 24 hours at am-bient temperature the mixture is diluted with water and ex-tracted with methylene chloride. The organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (1:0 and 50:1). The desired fractions are combined and evaporated down.
Yield: 1.25 g (40 % of theory), Rf value: 0.12 (silica gel; methylene chloride/ethanol = 30:1) c. 4-[(7-ethoxycarbonylmethyl-4-methyl-quinolin-2-yl)-oxo]-Prepared analogously to Example if from 4-[(7-ethoxycarbonyl-methyl-4-methyl-quinolin-2-yl)-oxo]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 43 % of theory, C21H21N3~3 x HCl (363.42/399.89) mass spectrum: (M+H)+ = 364 The following compounds are prepared analogously:
(1) 4-[(7-allyl-4-methyl-quinolin-2-yl)-oxo]-benzamidine-hy-drochloride Yield: 88 % of theory, C2pH19N30 x HCl (317.4/353.86) mass spectrum: (M+H)+ = 318 (2) 4-~[7-(1-ethoxycarbonyl-cyclopentyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 88 % of theory, C25H27N303 x HCl (417.52/453.98) mass spectrum: (M+H)+ = 418 ~(3) 4-{[7-(1-hydroxy-but-3-yn-4-yl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 47.2 % of theory, ' C21H19N3~2 x HC1 (345.4/381.86) mass spectrum: (M+H)+ = 346 (4) 4-{[7-(1-methoxycarbonyl-1-methyl-ethyl)-4-methyl-quino-lin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 72 % of theory, C22H23N3~3 x HC1 (377.45/413.92) mass spectrum: (M+H)+ = 378 (5) 4-{[7-(1-ethoxycarbonyl-propyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 81 % of theory, C23H25N3~3 x HCl (391.48/427.94) mass spectrum: (M+H)+ = 392 (6) 4-{[7-(Bis-ethoxycarbonyl-methyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 91 % of theory, c24H25N3~5 x HC1 (435.49/471.95) mass spectrum: (M+H)+ = 436 (7) 4-{[7-(1-aminocarbonyl-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo)-benzamidine-hydrochloride Yield: 87 % of theory, C21H22N4~2 x HCl (362,44/398.9) mass spectrum: (M+H)+ = 363 (8) 4-{[7-(1-(N-(2-hydroxyethyl)-aminocarbonyl)-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 82 0 of theory, C23H26N4~3 x HCl (406.49/442.96) mass spectrum: (M+H)+ = 407 (9) 4-{[7-(1-ethoxycarbonylmethylaminocarbonyl-1-methyl-ethyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine-hydrochloride Yield: 44 % of theory, C25H28N404 x HC1 (448.53/485.0) mass spectrum: M+ = 448 (10) 4-{[7-(cyclopenten-1-yl)-4-methyl-quinolin-2-yl]-oxo)-benzamidine-hydrochloride Yield: 92 % of theory, C22H21N3~ x HCl (343.3/379.9) mass spectrum: (M+H)+ = 344 (11) 4-{[7-(1-(N-(2-ethoxycarbonyl-ethylcarbonyl)-amino)-1-me-thyl-ethyl)-4-methyl-quinolin-2-yl]-oxo~-benzamidine-hydro-chloride Yield: 91 % of theory, C26H30N4~4 x HC1 (462.56/499.02) mass spectrum: (M+H)+ = 463 4-{[7-(2-methyl-5-ethoxycarbonyl-phenyl)-4-methyl-quinolin-2-girl]-oxo~-benzamidine-hydrochloride a_ 4-carbox~r-2-meth~rl-phen~rlboric acid 11.3 ml (18 mmol) of n-butyllithium (1.6 molar in hexane) are added dropwise to a solution of 0.9 g (4 mmol) of 3-bromo-4-methyl-benzoic acid in 15 ml n-hexane under a nitrogen atmos-phere at -78oC. After 1 hour at -78oC, 0.6 ml (5 mmol) of tri-methylborate is added dropwise. After a further 2 hours at -78oC, the reaction mixture is heated to ambient temperature and combined with ethyl acetate and ice water. Then it is aci-dified with hydrochloric acid, the organic phase is separated off, dried and evaporated down.
-Yield: 0.43 g (60 % of theory), Rf value: 0.1 (silica gel; cyclohexane/ethyl acetate = 1:1) b. 4-{[7-(2-methyl-5-carboxy-phenyl)-4-methyl-quinolin-2-yl]-A solution of 0.75 g (2.2 mmol) of 4-[(7-bromo-4-methyl-quino-lin-2-yl)oxy]-benzonitrile and 75 mg (0.064 mmol) of tetrakis-(triphenylphosphine)-palladium(0) in 9 ml toluene are combined under a nitrogen atmosphere with a solution of 0.47 g (4.4 mmol) of sodium carbonate in 3 ml water and 0.4 g (2.2 mmol) of 4-carboxy-2-methyl-phenylboric acid in 5 ml me-thanol and stirred for 4 hours at 95oC. After 12 hours at am-bient temperature the reaction mixture is mixed with ice wa-ter, adjusted to pH 5 with glacial acetic acid and extracted with ethyl acetate. The organic phase is washed with sodium hydrogen carbonate, dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chlo-ride/ethanol (1:0, 100:1 and 30:1). The desired fractions are combined and evaporated down.
Yield: 0.13 g (15 0 of theory), Rf value: 0.36 (silica gel; cyclohexane/ethyl acetate = 1:1) c. 4-~[7-(2-methyl-5-ethoxycarbonyl-phenyl)-4-methyl-quinolin-2-fir]"] -oxo~-benzamidine-h~rdrochloride Prepared analogously to Example if from 4-{[7-(2-methyl-5-carboxy-phenyl)-4-methyl-quinolin-2-yl]-oxo~-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 75 0 of theory, C27H25N303 x HCl (439.52/475.99) mass spectrum: (M+H)+ = 440 The following compound is prepared analogously:
(1) 4-~[7-(2-methyl-5-ethoxycarbonylmethylaminocarbonyl-phe-nyl)-4-methyl-quinolin-2-yl]-oxo)-benzamidine-hydrochloride Yield: 90 0 of theory, -C2gH2gN404 x HCl (496.58/533.04) mass spectrum: (M+H)+ = 497 4-[(7-acetylamino-4-methyl-quinolin-2-yl)-oxo]-benzamidine-h~rdrochloride 225 mg (6.9 mmol) of 4-[(7-amino-4-methyl-quinolin-2-yl)-oxo]-benzamidine-hydrochloride are refluxed with 2 ml methanol and ml acetic anhydride for 40 minutes. The solution is cooled, diluted with ether, the precipitate is suction filtered and dried.
Yield: 90 mg (29.7 % of theory), C1gH18N402 x HC1 (334.38/370.84) mass spectrum: (M+H)+ = 335 4-{[7-(3-ethoxycarbonylmethyl-4,5-dihydroimidazol-2-on-1-yl)-4-meth~rl_-sLinolin-2-yl~ -oxo~ -b n .ami di nP-h~rd_ro hl on d a. 4-{[7-(2-chlorethylaminocarbonylamino)-4-methyl-quinolin 2.25 g (8.5 mmol) of 4-[(7-amino-4-methyl-quinolin-2-yl)-oxo]-benzonitrile are dissolved in 25 ml dimethylformamide and after the addition of 2.25 g (21 mmol) of chloroethyl isocy-anate the mixture is stirred for 20 hours at ambient tempera-ture. Then it is stirred into ice water and extracted with ethyl acetate. The organic extracts are washed with sodium chloride solution, dried, combined with silica gel and evapo-rated down. Then the mixture is chromatographed on silica gel and eluted with ethyl acetate/petroleum ether (1:9 and 3:7).
The desired fractions are combined and evaporated down.
Yield: 1.8 g (56 0 of theory), Rf value: 0.61 (silica gel; methylene chloride/ethanol - 19:1) b. 4-{[7-(4,5-dihydroimidazol-2-on-1-yl)-4-methyl-quinolin-1.8 g (6 mmol) of 4-{[(7-(2-chloroethylaminocarbonylamino)-4-methyl-quinolin-2-yl]-oxo}-benzonitrile are dissolved in 75 ml tert.butanol and combined batchwise with 1.1 g (0.01 mol) of potassium-tert.butoxide. Then the mixture is stirred for a further 1 hour, the precipitate formed is suction filtered, washed with 2N acetic acid and water and dried.
Yield: 1.55 g (75 % of theory), Rf value: 0.57 (silica gel; methylene chloride/ethanol = 19:1) c. 4-{[7-((3-ethoxycarbonylmethyl-4,5-dihydroimidazol-2-on 1.5 g (6.1 mmol) of 4-{[7-(4,5-dihydroimidazol-2-on-1-yl)-4-methyl-quinolin-2-yl]-oxo}-benzonitrile and 3.6 g (0.026 mol) of potassium carbonate are taken up in 250 ml acetone and refluxed. After 30 minutes 3.2 g (0.02 mol) of ethyl bromoacetate are added. The reaction mixture is refluxed for 30 hours, then, after cooling, it is filtered and evapora-m ted down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (1:0 and 50:1). The desired fractions are combined and evaporated down.
Yield: 675 mg (56.8 % of theory).
d. 4-{[7-(3-ethoxycarbonylmethyl-4,5-dihydroimidazol-2-on-Prepared analogously to Example if from 4-{[7-(3-ethoxycarbo-nylmethyl-4,5-dihydroimidazol-2-on-1-yl)-4-methyl-quinolin-2-yl]-oxo}-benzonitrile and hydrochloric acid/ammonium car-bonate in ethanol.
Yield: 41.5 % of theory, C24H25N5~4 x HC1 (447.49/483.97) mass spectrum: (M+H)+ = 448 4-{[7-(1-ethoxycarbonylmethyloxyimino-ethylene)-4-methyl-~uinolin-2-girl]-amino}-b_n.amidine-hydrochloride a. 4-{(7-(1-ethoxy-vinyl)-4-methyl-quinolin-2-yl]amino}-benzo-6.8 g (0.02 mol) of 4-(7-bromo-4-methyl-quinolin-2-yl)-amino-benzonitrile are dissolved in 40 ml of dimethylformamide at 100oC and after the addition of 7.2 g (0.02 mol) of (1-ethoxy-vinyl)-tributyltin and 0.7 g of bis(triphenylphosphine)-pal-ladium(II)-chloride the mixture is stirred for 5 hours at 100oC. Then it is evaporated down, the residue is combined with 400 ml of saturated methanolic potassium fluoride solu-tion and stirred overnight at ambient temperature. The metha-nol is distilled off and the residue chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (9:1). The de-sired fractions are combined and evaporated down.
Yield: 4.6 g (69.8 % of theory), Rf value: 0.54 (silica gel; petroleum ether/ethyl acetate =
2:1) b_ 4- [~7-air t~rl - -m hurl-gLi_nolin-2-girl y ami nol -bPn .oni ri 1 3.2 g (0.01 mol) of 4-{[7-(1-ethoxy-vinyl)-4-methyl-quinolin-2-yl]amino}-benzonitrile are dissolved in 85 ml acetone and after the addition of 21 ml of 1N hydrochloric acid the mix-ture is stirred overnight at ambient temperature . The cry-stalline precipitate is diluted with water, suction filtered and dried.
Yield: 2.3 g (78.5 % of theory), Rf value: 0.42 (silica gel; methylene chloride/ethanol = 95:5) c. 4-{[7-(1-carboxymethyloxyimino-ethylene)-4-methyl-quinolin 300 mg (1.0 mmol) of 4-[(7-acetyl-4-methyl-quinolin-2-yl)-ami-no]-benzonitrile, 330 mg (1.5 mmol) of carboxymethoxylamine and 0.21 ml (1.5 mmol) of triethylamine are refluxed for 3 hours in 20 ml methanol and 10 ml toluene after the addition of 3 g each of molecular sieve 3A and 4A. The solvent is di-stilled off and the residue is chromatographed on silica gel, eluting with methylene chloride/ethanol (4:1).
Yield: 370 mg (100 % of theory), Rf value: 0.23 (silica gel; methylene chloride/ethanol - 4:1) d. 4-{[7-(1-ethoxycarbonylmethyloxyimino-ethylene)-4-methyl-Prepared analogously to Example if from 4-{[7-(1-ethoxycarbo-nylmethyloxyimino-ethylene)-4-methyl-quinolin-2-yl)-amino]-benzonitrile and hydrochloric acid/ammonium carbonate in etha-nol.
Yield: 41 % of theory, C23H25N5~3 x HCl (419.49/455.88) mass spectrum: (M+H)+ = 420 4-[(6-ethoxycarbonylmethyloxy-4-methyl-quinolin-2-yl)-oxo]-h n .ami di n -h~rdrochl_oride a _ 2-c_h_1oro-6-h~rd_rox~r-4-mPth~rl_-cs ~; nil i nP
22.1 g (0.106 mol) of 2-chloro-6-methoxy-4-methyl-quinoline are refluxed for 4 hours in 210 ml of 48% hydrobromic acid.
After cooling the precipitate formed is suction filtered, washed and dried.
Yield: 20.5 g (100 % of theory), Rf value: 0.72 (silica gel; methylene chloride/ethanol = 9:1) b_ 2-chloro-6-ethoxycarbon~rlmeth~rl_c~xy-4-meth~l_-siin~linP
2.0 g (10.3 mmol) of 2-chloro-6-hydroxy-4-methyl-quinoline are dissolved in 10 ml dimethylformamide and after the addition of J1.7 g (12 mmol) of potassium carbonate and 1.3 ml (12 mmol) of ethyl bromoacetate the mixture is refluxed under a nitrogen atmosphere for 4 hours. The solvent is distilled off, the residue is triturated with water, suction filtered and dried.
Yield: 2.6 g (80 0 of theory), Rf value: 0.65 (silica gel; methylene chloride/ethanol - 95:5) c. 4-[(6-ethoxycarbonylmethyloxy-4-methyl-quinolin-2-yl)-oxo]-Prepared analogously to Example 27d from 2-chloro-6-ethoxy-carbonylmethyloxy-4-methyl-quinoline, 4-hydroxybenzonitrile and potassium carbonate in dimethylformamide at 170oC.
Yield: 29 % of theory, Rf value: 0.51 (silica gel; methylene chloride/ethanol/glacial acetic acid = 95:5:0.01) d. 4-((6-ethoxycarbonylmethyloxy-4-methyl-quinolin-2-yl)-oxo]-Prepared analogously to Example if from 4-[(6-ethoxycarbonyl-methyloxy-4-methyl-quinolin-2-yl)-oxo]-benzonitrile and hydro-chloric acid/ammonium carbonate in ethanol.
Yield: 14.2 % of theory, C21H21N3~4 x HCl (379.42/415.89) mass spectrum: M + = 379 ,, a _ 2- [2-hyano-~hPri~~) -acetyl ami no] -hPn .ami d 11.8 g (0.06 mol) of 4-cyanophenylacetic acid chloride are dissolved in 250 ml chlorobenzene and after the addition of _8.2 g (0.06 mol) of anthranilic acid amide the mixture is re-fluxed for 2 hours. After cooling it is diluted with water and the crystalline precipitate is suction filtered. , Yield: 10.5 g (63 0 of theory), Rf value: 0.63 (silica gel; methylene chloride/ethanol - 19:1) b _ 4- j (4-oxo-3 , 4-di h~rdro z mt ' nab i n- .-girl ) mPt-h~rl ] -b n .oni ri 1 9.9 g (0.034 mol) of 2-[2-(4-cyano-phenyl)-acetylamino]-benz-amide are dissolved in a solution of 3.9 g sodium in 400 ml ethanol and refluxed for 1 hour. The solvent is distilled off down to 100 ml, the residue is diluted with ice water and neu-tralised with hydrochloric acid. The crystalline precipitate is suction filtered and dried.
Yield: 6.9 g (74.8 % of theory), Rf value: 0.44 (silica gel; methylene chloride/ethanol - 19:1) 4- f (4-chloro-~ ~,~na~ol i_n-2-girl L-mP h~rL] -bc~n~nni tri 1 P
Prepared analogously to Example 27c from 4-[(4-oxo-3,4-dihy-droquinazolin-2-yl)methyl]-benzonitrile and phosphorus oxy-chloride.
Yield: 51.2 % of theory, -Rf value: 0.72 (silica gel; methylene chloride/ethanol - 19:1) d. 4- f (4-meth~rlamino- ~Linazol i n- -girl ) -m~th~rl] -b n oni tri 1 P
Prepared analogously to Example 12c from 4-[(4-chloro-quina-zolin-2-yl)methyl]-benzonitrile, methylamine solution and iso-propanol at 100oC.
Yield: 86.5 % of theory, Rf value: 0.58 (silica gel; methylene chloride/ethanol - 8:2) e. 4-[(4-methylamino-quinazolin-2-yl)-methyl]-benzamidine-ace-Prepared analogously to Examples 23a and 23b from 4-[(4-me-thylamino-quinazolin-2-yl)-methyl]-benzonitrile, hydroxylamine in methanol and palladium on activated charcoal in acetic acid.
Yield: 21.8 0 of theory, C17H17N5 x CH3COOH (291.35/351.4) mass spectrum: (M+H)+ = 292 4 -meth~rl -'1 H- s ~ i na .ol i n - -on ' 17.4 g (0.128 mol) of 2-amino-acetophenone are dissolved in 250 ml glacial acetic acid and combined within 1 hour with a solution of 12.5 g (0.155 mol) of potassium cyanate in 50 ml water and stirred for 60 hours at ambient temperature. The precipitate is suction filtered, dried, dissolved in 170 ml cone. hydrochloric acid, combined with 950 ml water and stir-red for 12 hours at 5°C. Then the mixture is adjusted to pH 7 with sodium hydroxide solution at 5 to lOoC, the crystalline precipitate is suction filtered and dried.
Yield: 3.85 g (18.8 % of theory), CgH8N20 (160.2) mass spectrum: M+ = 160 b ?.- hl oro- -m hyl_-c=Linazoli_ne Prepared analogously to Example 27c from 4-methyl-1H-quina-zolin-2-one and phosphorus oxychloride in hydrochloric acid.
Yield: 67 % of theory, Rf value: 0.81 (silica gel; petroleum ether/ethyl acetate =
7:3) c 4- [~4-mPt-h~rl~cs ~i na .ol ' n-2-girl ) - mi no], -bPn7onitrile Prepared analogously to Example 30a from 2-chloro-4-methyl-quinazoline and 4-aminobenzonitrile in glacial acetic acid.
Yield: 15.9 % of theory, d. 4-[(4-methyl-quinazolin-2-yl)-amino]-benzamidine-hydro Prepared analogously to Example if from 4-[(4-methyl-quina-zolin-2-yl)-amino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 24.8 0 of theory, C16H15N5 x HCl (277.33/313.79) mass spectrum: M + = 277 4-[(7-bromo-4-methyl-quinoxalin-2-on-3-yl)-amino]-benzamidine-h~rclrn~hl on d a 5-promo-2-meth~rlamino-ni rob-n. ne Prepared analogously to Example 7a from 2,5-dibromo-nitroben-zene and methylamine solution in ethanol.
Yield: 92.8 0 of theory, Rf value: 0.45 (silica gel; ethyl acetate/petroleum ether =
1:9) b 5-bromo-2-meth~,lamino-aniline Prepared analogously to Example 3d from 5-bromo-2-methylamino-nitrobenzene and Raney nickel/hydrogen in ethyl acetate/etha-nol.
Yield: 76.7 % of theory, Rf value: 0.55 (silica gel; methylene chloride/ethanol = 19:1) 6-bromo-~ -mP h~rl~~ ,~-di h~dro- = i noxal i n-2,. 3-di_one 360 mg (4.12 mmol) of oxalic acid dichloride are placed in 30 ml of o-dichlorobenzene and combined batchwise with 760 mg (3.8 mmol) of 5-bromo-2-methylamino-aniline at 60oC. Then the mixture is stirred for 30 minutes at 60°C and for 60 minutes at 130oC. After cooling the crystalline product is suction filtered and washed with ether.
Yield: 650 mg (67.7 % of theory), Rf value: 0.3 (silica gel; methylene chloride/ethanol = 19:1) 6 -bromo-'~ -~hl oro-~ -m h~, -'i H- m i noxal_ in-2 -one Prepared analogously to Example 27c from 6-bromo-1-methyl-1,4-dihydro-quinoxalin-2,3-dione and phosphorus oxychloride.
Yield: 64.5 % of theory, Rf value: 0.8 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[(7-bromo-4-methyl-quinoxalin-2-on-3-yl)-amino]-benzo-nitrile 270 mg (1 mmol) of 6-bromo-3-chloro-1-methyl-1H-quinoxalin-2-one and 240 mg (2 mmol) of 4-aminobenzonitrile are heated to 100oC in 3 ml methanol. The precipitate is cooled to 40oC, di-luted with methanol and suction filtered.
Yield: 350 mg (98.6 0 of theory), Rf value: 0.28 (silica gel; ethyl acetate/petroleum ether 2:8) f. 4-[(7-bromo-4-methyl-quinoxalin-2-on-3-yl)-amino]-benzami-d'~ne-h~rdrochloride Prepared analogously to Example if from 4-[(7-bromo-4-methyl-quinoxalin-2-on-3-yl)-amino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 48.5 0 of theory, C16H14BrN50 x HC1 (372.23/408.69) mass spectrum: (M+H) + = 372/4 (Br) 4-[(7-amino-4-methyl-1,8-naphthyridin-2-yl)-oxy]-benzamidine-hydrochloride a. 7-amino-4-meth~rl-1H- [l, 81 nar~hth~rridin-2-one 20 g (0.184 mol) of 2,6-diaminopyridine are refluxed in 28 g (0.215 mol) of ethyl acetate for 2 hours using a water separa-tor. After cooling the crystalline precipitate is suction fil-tered, washed with ether and dried.
Yield: 18.5 g (46.2 0 of theory), CgHgN30 x HC1 (175.2/211.66) mass spectrum: M + = 175 b . hl oro-4 -m th~rl -7-ami no- f'I , 81 na= hth~rri_ ' di n~
Prepared analogously to Example 27c from 7-amino-4-methyl-1H-[1,8]naphthyridin-2-one and phosphorus oxychloride.
Yield: 95.5 0 of theory, Rf value: 0.38 (silica gel; methylene chloride/ethanol = 9:1) c. 4-[(7-amino-4-methyl-1,8-naphthyridin-2-yl)-oxy]-benzoni-Prepared analogously to Example 27d from 2-chloro-4-methyl-7-amino-[1,8]naphthyridine and 4-hydroxybenzonitrile.
Yield: 37.9 0 of theory, Rf value: 0.76 (silica gel;~methylene chloride/ethanol/glacial acetic acid = 4:1: 0.01) d. 4-[(7-amino-4-methyl-1,8-naphthyridin-2-yl)-oxy]-benzami-Prepared analogously to Example if from 4-[(7-amino-4-methyl-1,8-naphthyridin-2-yl)-oxy]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 52.8 % of theory, C16H15N5~ x HC1 (293.3/329.76) mass spectrum: (M+H)+ = 294 The following compounds are prepared analogously:
(1) 4-([7-(4-ethoxycarbonyl-n-butylamino)-4-methyl-1,8-napht-hyridin-2-yl]-oxy}-benzamidine-hydrochloride Yield: 24.2 % of theory, '' C23H27N503 x HCl (421.5/457.96) i mass spectrum: (M+H)+ = 422 (2) 4-[(7-acetylamino-4-methyl-1,8-naphthyridin-2-yl)-oxy]-benzamidine-hydrochloride Yield: 44.4 0 of theory, C18H17N502 x HC1 (335.36/371.87) mass spectrum: (M+H)+ = 336 4-[(7-bromo-4-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]-pyrazin-~-girl ~meth~,l1 -b n .am' di nP-h~rdrochl oridP
a 5-bromo-'~-ni tro-~~rri di n - -of -h~rdrobromi dP
3.6 ml of bromine are added dropwise to a suspension of 10.0 g (0.071 mol) of 2-hydroxy-3-nitro-pyridine in 25 ml of carbon tetrachloride whilst cooling with ice. The reaction mixture is refluxed for 2 hours. The solvent is distilled off in vacuo, the crystalline product is suction filtered and recrystallised from water.
Yield: 7.5 g (35.1 0 of theory).
b -bromo- hl oro-'~ -ni ro-~~rri d, i n~
Prepared analogously to Example 27c from 5-bromo-3-nitro-pyri-dine-2-ol-hydrobromide and phosphorus oxychloride/phosphorus pentachloride by refluxing.
Yield: 53.5 0 of theory, Rf value: 0.77 (silica gel; methylene chloride/ethanol = 4:1) c _ 5-promo-'~-ni ro- -m rh~rl ami no-p,~r_ridine Prepared analogously to Example 12c from 5-bromo-2-chloro-3-nitro-pyridine, methylamine solution and isopropanol at 100oC.
Yield: 83 % of theory, Rf value: 0.51 (silica gel; methylene chloride/ethanol = 19:1) d. 3-amino-5-b_romo-2-meth~rl ami no-~~r_ri_dine Prepared analogously to Example 3d from 5-bromo-3-nitro-2-me-thylamino-pyridine and Raney nickel/hydrogen in ethyl acetate.
Yield: 92.5 0 of theory, Rf value: 0.18 (silica gel; methylene chloride/ethanol = 19:1) e. 4-[(7-bromo-4-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]-pyra-Prepared analogously to Example 7f from 3-amino-5-bromo-2-me-thylamino-pyridine and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol.
Yield: 26.2 0 of theory, Rf value: 0.68 (silica gel; methylene chloride/ethanol/glacial acetic acid = 4:1:0,01) f. 4-[(7-bromo-4-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]-pyra-Prepared analogously to Example if from 4-[(7-bromo-4-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-2-yl)methyl]-benzoni-trile and hydrochloric acid/ammonium carbonate in ethanol.
Yield: 20.5 0 of theory, C16H14BrN50 x HC1 (372.22/408.72) mass spectrum: (M+H)+ = 372/4 (Br) E~camr~le 44 4-[(6-chloro-1-methyl-2-oxo-1,2-dihydro-pyrido[2,3-b]-pyrazin-'~ -~rL) meth~rl 1 -b .n .ami di n _-h~rdrochl o_ri de a. 2-amino-3-benz~rl_ox~r .a~~rl ami no-6- .hl oro-~y_ri_di_ne 1.2 g (8.8 mmol) of 2,3-diamino-6-chloro-pyridine are dissol-ved in 20 ml tetrahydrofuran and, after the addition of 2 ml pyridine at OoC, mixed with 2 ml of benzyl chloroformate.
After heating to ambient temperature the mixture is combined with ice water, adjusted to pH 4 with glacial acetic acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1 and l:l).
Yield: 0.55 g (22.5 0 of theory), Rf value: 0.62 (silica gel; ethyl acetate/petroleum ether =
1:1) (.
;J

b ~-ami no-'~-meth~rl amino-6- _hl oro-~~rridine 7.0 g (25.4 mmol) of benzyl (2-amino-4-chlorophenyl)-carb-aminate are dissolved in 250 ml tetrahydrofuran, combined batchwise with 3.8 g (0.1 mol) of lithium aluminium hydride and then refluxed for 15 minutes. The mixture is then combined with ice water, adjusted to pH 4with glacial acetic acid, fil-tered over kieselguhr and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with pe-troleum ether/ethyl acetate (9:1, 8:2 and 1:1).
Yield: 1.95 g (48.6 0 of theory), Rf value: 0.35 (silica gel; methylene chloride/ethanol = 19:1) c. 4-[(6-chloro-1-methyl-2-oxo-1,2-dihydro-pyrido[2,3-b]-pyra-Prepared analogously to Example 7f from 2-amino-3-methylamino-6-chloro-pyridine and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol.
i Yield: 26.2 % of theory, 's Rf value: 0.66 (silica gel; methylene chloride/ethanol/glacial acetic acid = 8:2:0,01) d. 4-[(6-chloro-1-methyl-2-oxo-1,2-dihydro-pyrido[2,3-b]-pyra-zin-'~-girl )~meth~rl] -b n2amidine-h~rdrochloride Prepared analogously to Example if from 4-[(6-chloro-1-methyl-l 2-oxo-1,2-dihydro-pyrido[2,3-b]pyrazin-3-yl)methyl]-benzoni-trile and hydrochloric acid/ammonium carbonate in ethanol.
t Yield: 2.5 0 of theory, C16H14C1N50 x HC1 (327.78/364.25) mass spectrum: (M+H)+ = 328/30 (C1) 5-{[6-(1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-1-(pyr-rolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquinoxalin-3 -girl ~ -meth~rl ~ -b n .ami di n -h~rdrochl_o_ri_de a _ Meth~rl_rl_ 2- (4- .hl oro- hPn~rl -~ydroxy-2-meth~rl -trop i ona P
35 ml of a 1.6 molaric solution of n-butyl lithium (61 mmol) in hexane were dropped to a solution of 8.1 ml (85 mmol) of diisopropylamine in 20 ml of tetrahydrofurane at -78°C. Sub-sequently, a solution of 10.0 g (50 mmol) of methyl 2-(4-chlo-ro-phenyl)-propionate in 30 ml of tetrahydrofurane were drop-ped into the reaction mixture at -78°C and subsequenty form-aldehyde was introduced as gas at -20°C within 30 minutes. The reaction mixture was extracted with ethyl acetate after addi-tion of 5 percent citric acid and glacial acetic acid. The or-ganic phase was washed with 1N sulfuric acid, water, saturated sodium bicarbonate solution and sodium chloride solution and died over magnesium sulfate. The raw product was purified over silica gel whereby the eluation was carried out with cyclo-hexane/ethyl acetate (19:1; 9:1; 4:1; l:l; and 0:1). The uni-form fractions were combined and evaporated down.
Yield: 9.7 g (840 of theory) yellow oil, Rf value: 0.25 (silica gel; petroleum ether/ethyl acetate =
4:1) h _ (4-chloro-p _h_P_n_~rl J -'~-h~rdrox~r-~~rl -~= i oni c~ ari d Prepared analogously to Example 10 from methy 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium hydroxide solution in ethanol.
Yield: 830 of theory, Rf value: 0.55 (silica gel; ethyl acetate/Cyclohexan = 2:1 +
glacial acetic acid) ) c. 2-(4-chloro 3-vitro-phenyl)-2-methyl-3-nitrooxy-propionic Prepared analogously to Example lb aus 2-(4-chlorophenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid.
Yield: 90% of theory, melting point: 129°C-132°C
ClpH~C1N207 (304.64) d. 2-(4-chloro-3-vitro-phenyl)-2-methyl-3-hydroxy-propionic -ac i d Prepared analogously to Example 14b from 2-(4-chloro-3-nitro-phenyl)-3-nitrooxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxan.
Yield: 98 0 of theory, C10H10C1N05 (259.65) mass spectrum: (M-H)- - 258/60 (C1) (2M-H)- - 517/9 (C12) e. 2-[4-(N-benzyl-methylamino)-3-vitro-phenyl]-2-methyl-3-hy-drox~r fro ionic acs d Prepared analogously to Example 7a from 2-(4-chloro-3-nitro-phenyl)-3-hydroxy-2-methyl-propionic acid and N-methyl-benzyl-amine.
Yield: 81% of theory, C18H20C1N205 (344.37) mass spectrum: M+ - 344 f. 2-[4-(N-benzyl-methylamino)-3-vitro-phenyl]-2-methyl-3-hy-~y '1 ~~rrrolidin-1-yl -fan-'I -on Prepared analogously to Example 2a from 2-[4-(N-benzyl-methyl-amino)-3-vitro-phenyl]-3-hydroxy-2-methyl-propionic acid and pyrrolidine.
Yield: 960 of theory, C22H27N304 (397.48) mass spectrum: M+ - 398 (M+Na) + - 420 t;

g. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-me-A solution of 1.2 g (3.0 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one in 20 ml of tetrahydrofuran was mixed with 1.3 ml of (9.3 mmol) of triethylamine at room temperature. Subsequently, 0.27 ml (3.5 mmol) of methanesulfonylchloride were dropped to the reaction mixture at 2-5°C. The formed precipitate was fil-tered after 2 hours at room temperature and the filtrate eva-_, porated down. The raw product was further processed without purification.
Yield: 1.4 g (98% of theory).
h. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-me-t$~rl ami no-1 -~~rrrol i di n-l -~~p rot~an-1-one A solution of 1.4 g (2.9 mmol) of 2-[4-(N-Benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methansulfonyloxy-1-pyrrolidin-1-yl-propan-1-one in 10 ml of dimethylformamide was mixed with 20 ml of a 40 percent aqueous solution of methylamine and hea-ted up to 100°C for 70 minutes. After cooling the reaction mix-ture was mixed with ice water and extracted with ethyl ace-tate. The organic phase was washed with water and sodium chlo-ride solution, dried over magnesium sulfate and evaporated down. The raw product was purified on silica gel, whereby the eluation was carried out with ethyl acetate/ethanol (10:1, i 9:1, 4:1 + to conc. ammonia). The uniform fractions were com-bined and evaporated down.
r Yield: 740 mg (61% of theory), Rf value: 0.45 (silica gel; methylene chloride/ethanol - 9:1 + 0.1 o ammonia) i. 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-girl -tzorOraan-1-on Prepared analogously to Example 7d from 2-[4-(N-benzyl-me-thylamino)-3-nitro-phenyl]-2-methyl-3-methylamino-1-pyrro-lidin-1-yl-propan-1-one and methyl malonate acid chloride.
Yield: 84% of theory, Rf value: 0.65 (silica gel; ethyl acetate/ethanol 9:1 + 0.1 % ammonia) C27H34N4~6 (510.60) mass spectrum: (M-H)- - 509 (M+Na)' - 533 j. 2-(4-methylamino-3-amino-phenyl)-2-methyl-3-(N-methoxy-carbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-~-on Prepared analogously to Example ld from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethylcar-bonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one and hydro-gen/palladium on charcoal.
Yield: 1000 of theory, Rf value: 0.40 (silica gel; ethyl acetate/ethanol 9:1 + 0.1 o ammonia) C20H30N4~4 (390.49) mass spectrum: M+ - 390 k. 5-{[6-(1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-s 1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquin-oxalin-~-~rl~th~rll -benzoni tril a Prepared analogously to Example 7f from 2-(4-methylamino-a 3-amino-phenyl)-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one and 3-(4-cyano-phenyl)-oxo-propionic acid in ethanol.
Yield: 23 % of theory, Rf value: 0.55 (silica gel; ethyl acetate/ethanol 9:1) C31H39N505 (557.65) ry ~) mass spectrum: (M-H)' - 556 (M+Na)+ - 580 1. 5-{[6-(1-(N-ethoxycarbonylmethylcarbonyl-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquin-~xalin-~-~r~ 1 -me h~r~~-benzamidine-h~rdro .hloride Prepared analogously to Example if from 5-{(6-(1-(N-ethoxycar-bonylmethylcarbonyl-methylamino)-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzonitrile and hydrochloric acid/ammonium carbonate.
Yield: 35 0 of theory, C31H3gN605 x HC1 (574.69/611.14) mass spectrum: (M+H)' - 575 (M-H)+ - 573 (M+Na)' - 609/611 Composition:
Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation:
Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solu-tion ready for use, the product is dissolved in water for in-jections.

Composition:
Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is dissolved in water for injections.
Composition:
(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg stearate 2.0 m~
i (5) um Magnes 215.0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, fa-ceted on both sides and with a dividing notch on one side.

Diameter of the tablets: 9 mm.
Preparation: .
(1) Active substance 350.0 mg _ (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4_0 mg 600.0 mg (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
Composition:
(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate ?._0 mQ
160.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.
Composition:
(1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4_0 mg 430.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 hard gelatin capsu-les in a capsule filling machine.
1 suppository contains:
Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840_0 mg 2,000.0 mg

Claims (12)

Claims
1. Bicyclic compounds of general formula R a - Het - A - Ar - R b, (I) wherein A denotes an oxygen or sulphur atom, a difluoromethylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group, a methylene group optionally mono- or disubstituted by a carboxy-C1-3-alkyl group, Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoro-methyl, C1-3-alkyl or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon structure by a C1-3-alkyl group, Het denotes a 1-(C1-3-alkyl)-2-oxo-1,2-dihydro-thieno [2,3-b]-pyrazinyl group, a quinolinylene, isoquinolinylene, quinazolinylene, phthalazinylene, cinnolinylene or quinoxazolinylene ring, which may be substituted in the aromatic heterocyclic moiety by a C1-3-alkyl, amino, C1-3-alkyl amino or di-(C1-3-alkyl) amino group, a quinolinylene, isoquinolinylene, quinazolinylene or quinoxazolinylene ring, which are di- or tetrahydrogenated in the heterocyclic moiety, whilst in one of the abovementioned dihydrogenated rings, which may additionally be substituted by a C1-3-alkyl group, a methylene group adjacent to a nitrogen atom is replaced by a carbonyl or thiocarbonyl group, or in one of the abovementioned tetrahydrogenated rings, which may additionally be substituted by one or two C1-3-alkyl groups, two methylene groups adjacent to a nitrogen atom are each replaced by a carbonyl group, and the phenyl moiety of the abovementioned bicyclic rings, wherein additionally a methine group may be replaced by a nitrogen atom, is linked to the group R a, R a denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl, C1-3-alkoxy, C2-3-alkenyl or C2-3-alkynyl group, which may be substituted by a hydroxymethyl or carboxy group, a C1-3-alkyl group, which is substituted by a C1-3-alkanoylamino or carboxy-C1_3-alkylcarbonylamino group, a R1-CO-CH2 group which may be substituted in the methylene moiety by one or two C1-3-alkyl groups, or a C3-6-cycloalkylene group which is substituted in the 1 position by an R1-CO group, whilst R1 is a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl amino, pyrrolidino, piperidino, morpholino, piperazino or N-(C1-3-alkyl)-piperazino group, whilst the abovementioned amino, C1-3-alkylamino, pyrrolidino and piperidino groups may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl, carboxy-C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-amino-n-C2-4-alkyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, a phenyl, naphthyl or monocyclic 5 or 6 membered heteroaryl group optionally substituted by a C1-3-alkyl group, whereby a 6 membered heteroaryl group contains one, two or three nitrogen atoms and a 5 membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom group or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and the before mentioned alkyl substituent may be substituted by a carboxy, carboxy-C1_3-alkoxy, carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-carboxy-C1-3-alkylamino group, a C1-4-alkyl group which is substituted by one or two carboxy groups, a C1-4-alkyl group which is substituted by a C1-3-alkyl-Y1-C1-3-alkyl, HOOC-C1-3-alkyl-Y1-C1-3-alkyl, tetrazoly-C1-3-alkyl-Y2-, R2NR3- or R2NR3-C1-3-alkyl group and by a carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C5-7-cycloalkyleniminocarbonyl group, whereby the C5-7-cycloalkylenimino moiety in the before mentioned groups may be substituted by one or two C1-3-alkyl groups and at the same time additionally one alkyl moiety or alkyl substituent of the before mentioned C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C5-7-cycloalkylenimino-carbonyl groups may be substituted by a carboxy group, and the remaining hydrogen atoms of a C1-4-alkyl group may be totally or partly replaced by fluorine atoms, wherein R2 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a carboxy group and R3 denotes a C1-3-alkyl-Y1-C1-3-alkyl-Y2, carboxy-C1-3-alkyl-Y1 C1-3-alkyl-Y2, C1-3-alkyl-Y2 or carboxy-C1-3-alkyl-Y2 group or R2 and R3 together with the attached nitrogen atom denotes a C3-7-cycloalkylenimino group optionaylly substituted by a carboxy, C1-3-alkyl or carboxy-C1-3-alkyl group, wherein Y1 denotes a carbon-carbon bond, an oxygen atom, a sulphenyl, sulphinyl, sulphonyl, -NH-, -NH-CO- or -NH-CO-NH- group and Y2 denotes a carbon-nitrogen bond or a carbonyl, sulphonyl or -NH-CO- group, whereby the carbonyl group of the -NH-CO-group is attached to the nitrogen atom of the R2NR3 group, and the imino groups mentioned at the definition of the radicals Y1 and Y2 may be additionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group, a nitro group or an amino group optionally substituted by a C1-3-alkanoyl or carboxy-C1-4-alkyl group, a hydroxyimino-C1-3-alkylene group which may be substituted at the oxygen atom by a carboxy-C1-3-alkyl group, a C3-7,-cycloalkyl or C5-6-cycloalkenyl group, a phenyl group which may be substituted by a C1-3-alkyl, C2-3-alkenyl, carboxy, nitro or amino group, whilst the amino group may additionally be substituted by a C1-3-alkanoyl, carboxy-C1-3-alkyl, carboxy-C1-3-alkylcarbonyl or carboxy-C1-3-alkylamino-carbonyl group, a phenyl group which is substituted by a C1-3-alkyl group and by a carboxy or carboxy-C1-3-alkylaminocarbonyl group, a carbonyl group which is substituted by a C1-6-alkyl, C5-7-cycloalkyl, C1-6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl group and the hydrogen atom of the abovementioned amino groups is replaced by a carboxy-C1-3-alkyl or tetrazolyl-C1-3-alkyl group, a carboxy-C1-3-alkylsulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesul-phonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkyl amino-C1-3-alkyl or di- (C1-3-alkyl) -amino-C1-3-alkyl group, a C1-6-alkyl amino or C3-7-cycloalkylamino group, wherein the hydrogen atom of the amino group is replaced by a carboxy-C1-3-al-kylcarbonyl, carboxy-C1-3-alkylsulphonyl, tetrazolyl-C1-3-alkyl-carbonyl or carboxy-C1-3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 position is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a phenylsulphonyl group or a C1-5-alkylsulphonyl group wherein the alkyl moiety may be substituted by an amino, C1-3-alkylamino or di- (C1-3-alkyl) -amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-C1-3-alkyl group, a C3-7-cycloalkyl group which is substituted in the 1 position by a C4-7-cycloalkylamino or C1-4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carboxy-C1-3-alkylcarbonyl group, and R b denotes a cyano group or an amidino group, whereby the carboxy groups mentioned above at the definition of the radicals may be replaced by a group convertable in-vivo into a carboxy group or by a group convertable under physiologically conditions into a negatively charged group or the amino or imino groups groups mentioned above at the definition of the radicals may be substituted by a group which can be splitt off in-vivo, the tautomers, stereoisomers and salts thereof.
2. Bicyclic compounds of the general formula as claimed in claim 1, wherein A denotes an oxygen or sulphur atom, a difluoromethylene, carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group, a methylene group optionally mono- or disubstituted by a carboxy-C1-3-alkyl or C1-3-alkoxy-carbonyl-C1-3-alkyl group, Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon structure by a C1-3-alkyl group, Het denotes a 1- (C1-3-alkyl) -2-oxo-1, 2-dihydro-thieno [2, 3-b] -pyrazinyl group, a quinolinylene, isoquinolinylene, quinazolinylene, phthalazinylene, cinnolinylene or quinoxazolinylene ring, which may be substituted in the aromatic heterocyclic moiety by a C1-3-alkyl, amino, C1-3-alkyl amino or di- (C1-3-alkyl) amino group, a quinolinylene, isoquinolinylene, quinazolinylene or quinoxazolinylene ring, which are di- or tetrahydrogenated in the heterocyclic moiety, whilst in one of the abovementioned dehydrogenated rings, which may additionally be substituted by a C1-3-alkyl group, a methylene group adjacent to a nitrogen atom is replaced by a carbonyl or thiocarbonyl group, or in one of the abovementioned tetrahydrogenated rings, which may additionally be substituted by one or two C1-3-alkyl groups, two methylene groups adjacent to a nitrogen atom are each replaced by a carbonyl group, and the phenyl moiety of the abovementioned bicyclic rings, wherein additionally a methine group may be replaced by a nitrogen atom, is linked to the group R a, R a denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl, C1-3-alkoxy, C2-3-alkenyl or C2-3-alkynyl group, which may be substituted by a hydroxymethyl, carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted by a C1-3-alkanoylamino, carboxy-C1-3-alkylcarbonylamino or C1-3-alkoxycarbonyl-C1-3-alkyl-carbonylamino group, a C1-4-alkyl group which is substituted by one or two carboxy or C1-3-alkoxycarbonyl groups or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, N- (C1-3-alkyl) -carboxy-C1-3-alkyl-amino or N- (C1-3-alkyl) -C1-3-alkoxycarbonyl-C1-3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moieties may be additionally substituted by one or two C1-3-alkyl groups, a nitro group or an amino group optionally substituted by a C1-3-alkanoyl, carboxy-C1-4-alkyl or C1-3-alkoxycarbonyl-C1-4-alkyl group, a hydroxyimino-C1-3-alkylene group which may be substituted at the oxygen atom by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a C3-7-cycloalkyl or C5-6-cycloalkenyl group, a phenyl group which may be substituted by a C1-3-alkyl, C2-3-alkenyl, carboxy, C1-3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a C1-3-alkanoyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a phenyl group which is substituted by a C1-3-alkyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a carbonyl group which is substituted by a C1-6-alkyl, C5-7-cycloalkyl, C1-6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl group and the hydrogen atom of the abovementioned amino groups is replaced by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl or tetrazolyl-C1-3-alkyl group, a carboxy-C1-3-alkylsulphonamido, C1-3-alkoxycarbonyl-C1-3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkyl amino-C1-3-alkyl or di- (C1-3-alkyl) -amino-C1-3-alkyl group, a C1-6-alkyl amino or C3-7-cycloalkylamino group, wherein the hydrogen atom of the amino group is replaced by a carboxy-C1-3-al-kylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylsulphonyl, C1-3-alkoxycarbonyl-C,-3-alkylsulphonyl, tetrazolyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 position is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a phenylsulphonyl group or a C1-5-alkylsulphonyl group wherein the alkyl moiety may be substituted by an amino, C1-3-alkylamino or di- (C1-3-alkyl) -amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a C3-7-cycloalkyl group which is substituted in the 1 position by a C4-7-cycloalkylamino or C1-4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carboxy-C1-3-alkylcarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl group, a R1-CO-CH2 group which may be substituted in the methylene moiety by one or two C1-3-alkyl groups, or a C3-6-cycloalkylene group which is substituted in the 1 position by an R1-CO group, whilst R1 is a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl amino, pyrrolidino, piperidino, morpholino, piperazino or N-(C1-3-alkyl)-piperazino group, whilst the abovementioned amino, C1-3-alkylamino, pyrrolidino and piperidino groups may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl or di- (C1-3-alkyl) -amino-n-C2-4-alkyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a pyrazolyl group optionally substituted by a C1-3-alkyl group, and R b denotes a cyano group or an amidino group optionally substituted by a hydroxy, by one or two C1-3-alkyl groups or by a C1-16-alkoxycarbonyl group, the tautomers, stereoisomers and salts thereof.
3. Bicyclic compounds of the general formula as claimed in claim 1 or 2, wherein Het denotes a 1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl, 1-oxo-1,2-dihydro-1H-isoquinolin-2-yl, quinolin-2-yl, 1,4-dihydro-2H-quinazolin-2,4-dion-3-yl, 4H-quinazolin-4-on-3-yl, 4-oxo-3,4-dihydro-quinazolin-2-yl, 2-oxo-1,2-dihydro-quinoxalin-3-yl, 2-thio-1,2-dihydro-quinoxalin-3-yl, 1,8-naphthyridin-2-yl, 3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-2-yl or 2-oxo-1,2-dihydro-pyrido[2,3-b]pyrazin-3-yl-group, the tautomers, stereoisomers and salts thereof.
4. Bicyclic compounds of the general formula as claimed in claim 1, wherein A denotes an oxygen atom, a methylene or imino group, Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon structure by a C1-3-alkyl group, Het denotes a 4,4-di-(C1-3-alkyl)-1,3-dioxo-3,4-dihydro-1H-iso-quinolinyl-2-yl, 4-(C1-3-alkyl)-1-oxo-1,2-dihydro-1H-isoquino-linyl-2-yl, 4-(C1-3-alkyl)-quinolinyl-2-yl, 4-amino-quinazolin-2-yl, 4-(C1-3-alkyl amino) -quinazolin-2-yl, 4-[di-(C1-3-alkyl)-amino] -quinazolin-2-yl, 4- (C1-3-alkyl) -quinazolin-2-yl, 3-(C1-3-alkyl) -4H-quinazol in-4 -on-2 -yl, 3-(C1-3-alkyl)-4 -oxo-3,4-dihydro-quinazolin-2-yl, 1-(C1-3-alkyl)-2-oxo-1,2-dihydro-quinazolin-3-yl, 1-(C1-3-alkyl)-2-thio-1,2-dihydro-quinazolin 3-yl-, 1-(C1-3-alkyl)-1,8-naphthyridin-2-yl, 3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-2-yl or 2-oxo-1,2-dihydro-pyrido[2,3-b]-pyrazin-3-yl group each attached via the phenyl moiety with the radical R a, R a denotes a hydrogen, chlorine or bromine atom, a C1-3-alkyl, C2-3-alkenyl or C2-3-alkynyl group, which may be substituted by a hydroxymethyl, carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted by a C1-3-alkanoylamino, carboxy-C1-3-alkylcarbonylamino or C1-3-alkoxycarbonyl-C1-3-alkyl-carbonylamino group, a C1-4-alkyl group which is substituted by a carboxy or C1-3-alkoxycarbonyl group or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkyl amino, C1-3-alkoxycarbonyl-C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkyl-amino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moieties may be additionally substituted by one or two C1-3-alkyl groups, a nitro group or an amino group optionally substituted by a C1-3-alkanoyl, carboxy-C1-4-alkyl or C1-3-alkoxycarbonyl-C1-4-alkyl group, a hydroxyimino-C1-3-alkylene group which may be substituted at the oxygen atom by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a C3-7-cycloalkyl or C5-6-cycloalkenyl group, a phenyl group which may be substituted by a C1-3-alkyl, C2-3-alkenyl, carboxy, C1-3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a C1-3-alkanoyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a phenyl group which is substituted by a C1-3-alkyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a carbonyl group which is substituted by a C1-6-alkyl, C5-7-cycloalkyl group, C1-6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl group and the hydrogen atom of the abovementioned amino groups is replaced by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl or tetrazolyl-C1-3-alkyl group, a carboxy-C1-3-alkylsulphonamido, C1-3-alkoxycarbonyl-C1-3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di- (C1-3-alkyl) -amino-C1-3-alkyl group, a C1-6-alkyl amino or C3-7-cycloalkylamino group, wherein the hydrogen atom of the amino group is replaced by a carboxy-C1-3-al-kylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylsulphonyl, C1-3-alkoxycarbonyl-C1-3-alkylsulphonyl, tetrazolyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a piperidino group, wherein a methylene group in the 2 position is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a phenylsulphonyl group or a C1-5-alkylsulphonyl group wherein the alkyl moiety may be substituted by a di-(C1-3-alkyl)-amino group, an imidazolidin-2-on-1-yl group which may be substituted in the 3 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a C3-7-cycloalkyl group which is substituted in the 1 position by a C5-7-cycloalkylamino or C1-4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carboxy-C1-3-alkylcarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl group, a R1-CO-CH2 group which is substituted in the methylene moiety by one or two C1-3-alkyl groups, or a C3-6-cycloalkylene group which is substituted in the 1 position by an R1-CO group, whilst R1 is a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl amino, pyrrolidino, piperidino, morpholino, piperazino or N-(C1-3-alkyl)-piperazino group, whilst the abovementioned amino, C1-3-alkyl-amino, pyrrolidino and piperidino groups may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a pyrazolyl group optionally substituted by a C1-3-alkyl group, and R b denotes a cyano group or an amidino group optionally substituted by a hydroxy, C1-16-alkoxycarbonyl or 17-(1,5-di-methyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,-16,17-tetradecahydro-1H-cyclopenta[a]phe-nanthren-3-yl]-oxy-carbonyl group, the tautomers, stereoisomers and salts thereof.
5. Bicyclic compounds of the general formula as claimed in claim 1, wherein A denotes an oxygen atom, a methylene or imino group, Ar denotes a phenylene group, Het denotes a 4-(C1-3-alkyl) -quinolinyl-2-yl or 1-(C1-3-alkyl)-2-oxo-1,2-dihydro-quinazolin-3-yl group each attached via the phenyl moiety with the radical R a, R a denotes a hydrogen, chlorine or bromine atom, a C1-3-alkyl group which is substituted by a C1-3-alkanoylamino, carboxy-C,-3-alkylcarbonylamino or C1-3-alkoxycarbonyl-C1-3-alkyl-carbonylamino group, a C1-4-alkyl group which is substituted by a carboxy or C1-3-alkoxycarbonyl group or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkyl amino, C1-3-alkoxycarbonyl-C1-3-alkyl amino, N- (C1-3-alkyl) -carboxy-C1-3-alkyl-amino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moieties may be additionally substituted by one or two C1-3-alkyl groups, a R1-CO-CH2 group which is substituted in the methylene moiety by one or two C1-3-alkyl groups, or a C3-6-cycloalkylene group which is substituted in the 1 position by an R1-CO group, whilst R1 is a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl amino, pyrrolidino, piperidino, piperazino or N-(C1-3-alkyl)-piperazino group, whilst the abovementioned amino, C1-3-alkylamino, pyrrolidino and piperidino groups may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkoxycar-bonyl-C1-3-alkyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a pyrazolyl group optionally substituted by a C1-3-alkyl group, a hydroxyimino-C1-3-alkylene group which may be substituted at the oxygen atom by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a phenyl group which may be substituted by a C1-3-alkyl, C2-3-alkenyl, carboxy, C1-3-alkoxycarbonyl, nitro or amino group, whilst the amino group may additionally be substituted by a C1-3-alkanoyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkyl-aminocarbonyl group, a phenyl group which is substituted by a C1-3-alkyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a carbonyl group which is substituted by a C1-6-alkyl, C5-7-cycloalkyl group, C1-6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl group and the hydrogen atom of the abovementioned amino groups is replaced by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl or tetrazolyl-C1-3-alkyl group, a carboxy-C1-3-alkylsulphonamido, C1-3-alkoxycarbonyl-C1-3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, a C1-6-alkyl amino or C3-7-cycloalkylamino group, wherein the hydrogen atom of the amino group is replaced by a carboxy-C1-3-al-kylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylsulphonyl, C1-3-alkoxycarbonyl-C1-3-alkylsulphonyl, tetrazolyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a C3-7-cycloalkyl group which is substituted in the 1 position by a C5-7-cycloalkylamino or C1-4-alkyl amino group, wherein the hydrogen atom of the amino moiety may be replaced by a carboxy-C1-3-alkylcarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl group, and R b denotes an amidino group optionally substituted by a hydroxy, C1-16-alkoxycarbonyl or 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetra-decahydro-1H-cyclopenta[a]phenanthren-3-yl]-oxycarbonyl group, the tautomers, stereoisomers and salts thereof.
6. Bicyclic compounds of the general formula as claimed in claim 1, wherein A denotes an oxygen atom, a methylene or imino group, Ar denotes a 1,4-phenylene group, Het denotes a 4-methyl-quinolinyl-2-yl or 1-methyl-2-oxo-1,2-dihydro-quinazolin-3-yl group each attached via the phenyl moiety with the radical R a, R a denotes a hydrogen atom, a C1-3-alkyl group which is substituted by a C1-3-alkanoylamino, carboxy-C1-3-alkylcarbonylamino or C1-3-alkoxycarbonyl-C1-3-alkyl-carbonylamino group, a C1-4-alkyl group which is substituted by a carboxy or C1-3-alkoxycarbonyl group or by a pyrrolidinocarbonyl or piperidinocarbonyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylamino, C1-3-alk-oxycarbonyl-C1-3-alkylamino, N-(C1-3-alkyl)-carboxy-C1-3-alkyl-amino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkyl amino group, whereby the before mentioned pyrrolidino and piperidino moieties may be additionally substituted by one or two methyl groups, a R1-CO-CH2 group which is substituted in the methylene moiety by one or two C1-3-alkyl groups, or a C3-6-cycloalkylene group which is substituted in the 1 position by an R1-CO group, whilst R1 is a hydroxy, C1-3-alkoxy, amino, C1-3-alkyl amino, pyrrolidino, piperidino or N-(C1-3-alkyl)-piperazino group, whilst the abovementioned amino, C1-3-alkylamino, pyrrolidino and piperidino groups may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-al-kylaminocarbonyl group and a phenyl group may additionally be fused to the abovementioned pyrrolidino and piperidino moieties via two adjacent carbon atoms, or a 1-(C1-3-alkyl)-pyrazol-5-yl group, a hydroxyimino-C1-3-alkylene group which may be substituted at the oxygen atom by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a phenyl group which may be substituted by a C1-3-alkyl, C2-3-alkenyl, carboxy, C1-3-alkoxycarbonyl or amino group, whilst the amino group may additionally be substituted by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl-aminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a phenyl group which is substituted by a methyl group and by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a carbonyl group which is substituted by a C1-6-alkyl, C5-7-cycloalkyl group, C1-6-alkylamino, phenylamino or pyridylamino group, whilst in the abovementioned groups the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl group and the hydrogen atom of the abovementioned amino groups is replaced by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl or tetrazolyl-C1-3-alkyl group, a carboxy-C1-3-alkylsulphonamido, C1-3-alkoxycarbonyl-C1-3-alkyl-sulphonamido, phenylsulphonylamido, naphthylsulphonylamido, quinolinesulphonamido or isoquinolinesulphonamido group, wherein the hydrogen atom of the amido moiety may be substituted by a carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, a C1-6-alkyl amino or C3-7-cycloalkylamino group, wherein the hydrogen atom of the amino group is replaced by a carboxy-C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylsulphonyl, C1-3-alkoxycarbonyl-C1-3-alkylsulphonyl, tetrazolyl-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a C3-7-cycloalkyl group which is substituted in the 1 position by a C5-7-cycloalkylamino or C1-4-alkylamino group, wherein the hydrogen atom of the amino moiety may be replaced by a carboxy-C1-3-alkylcarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl group, and R b denotes an amidino group optionally substituted by a hydroxy, C1-16-alkoxycarbonyl or 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phe-nanthren-3-yl]-oxycarbonyl group, the tautomers, stereoisomers and salts thereof.
7. The following bicyclic compounds of the general formula as claimed in claim 1:
(a) 4-{[6-(N-carboxymethyl-quinolin-8-yl-sulphonylamino)-1-me-thyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine, (b) 4-{[6-(1-(N-cyclopentyl-carboxymethylcarbonylamino)-cyclo-propyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine, (c) 4-{[7-(N-carboxymethylaminocarbonyl-ethylamino)-4-methyl-quinolin-2-yl]-oxo}-benzamidine, (d) 4-{[7-(N-(pyridin-2-yl)-N-(2-carboxyethyl)-aminocarbonyl)-4-methyl-quinolin-2-yl]-oxo}-benzamidine, (e) 4-{[6-(1-methyl-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl-benzamidine, (f) 4-{[6-(1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl-benzamidine, (g) 4-{[6-(1-(N-methyl-carboxymethylcarbonylaminomethyl)-1-(pyrrolidin-1-yl-carbonyl)-ethyl)-2-oxo-1,2-dihydroquin-oxalin-3-yl]-methyl}-benzamidine and the salts thereof.
8. Physiologically acceptable salts of the compounds according to claims 1 to 7, wherein R b denotes one of the amidino groups mentioned in claims 1 to 7.
9. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 7, wherein R b denotes one of the amidino groups mentioned in claims 1 to 7, or a salt according to claim 8 optionally together with one or more inert carriers and/or diluents.
10. Use of a compound according to at least one of claims 1 to 7, wherein R b denotes one of the amidino groups mentioned in claims 1 to 7, or a salt according to claim 8 for preparing a pharmaceutical composition with a thrombin time-prolonging effect, a thrombin-inhibiting action and an inhibitory effect on related serine proteases.
11. Process for preparing a pharmaceutical composition according to claim 9, characterised in that a compound according to at least one of claims 1 to 7, wherein R b denotes one of the amidino groups mentioned in claims 1 to 7, or a salt according to claim 8, is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
12. Process for preparing the compounds according to claims 1 to 8, characterised in that a) in order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 1,4-dihydro-2H-qui-nazolin-2,4-dion-3-yl group and R b denotes a cyano group:
a compound of general formula wherein Ar and R a are defined as in claims 1 to 7, is cyclised in the presence of a carbonic acid diester derivative, or b) in order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 4-oxo-3,4-dihydro-quinazolin-2-yl group and R b denotes a cyano group:
a compound of general formula wherein Ar and R a are defined as in claims 1 to 7 and Z1 denotes a leaving group, is cyclised in the presence of an ammonium salt, or c) in order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 2-oxo-1,2-dihydro-quinoxalin-3-yl group and R b denotes a cyano group:
a diamine of general formula wherein R a is defined as in claims 1 to 7 and R5 denotes a hydrogen atom or a C1-3-alkyl group, is reacted with a ketone of general formula HOCO-CO-CH2-Ar-CN ,(V) wherein Ar is defined as in claims 1 to 7, or the reactive derivatives thereof, or d) in order to prepare a compound of general formula I wherein A denotes a methylene group, Het denotes a 4-oxo-3,4-dihydro-quinazolin-2-yl group and R b denotes a cyano group:
a compound of general formula wherein Ar and R a are defined as in claims 1 to 7, is cyclised in the presence of a basic condensing agent, or e) in order to prepare a compound of general formula I wherein Het is linked to A via a nitrogen atom and A denotes a methylene group and R b denotes a cyano group:
a compound of general formula R a - Het - H ~~~, (VII) wherein R a is defined as in claims 1 to 7 and Het contains a hydrogen atom bound to a cyclic nitrogen atom, is reacted with a compound of general formula Z2-A-Ar-CN ~~~, (VIII) wherein A and Ar are defined as in claims 1 to 7 defined and Z2 denotes a leaving group, or f) in order to prepare a compound of general formula I wherein Het is linked to A via a C1-3-alkylimino group, an oxygen, sulphur or nitrogen atom and A denotes a methylene group and R b denotes a cyano group:
a compound of general formula R a - Het - Z3~, (IX) wherein R a and Het are defined as in claims 1 to 7, with the proviso that Z3 is linked to a carbon atom of the Het group and denotes a leaving group, is reacted with a compound of general formula H-A'-Ar-CN ~ ,(X) wherein Ar is as defined as in claims 1 to 7 and A' denotes an imino or C1-3-alkylimino group, an oxygen or sulphur atom, or g) in order to prepare a compound of general formula I wherein R a denotes one of the optionally substituted -CONH- and -SO2NH-groups mentioned for R a claimed in claims 1 to 7 which is linked to the Het group either via the nitrogen atom or via the carbonyl or sulphonyl group:
a compound of general formula U-Het-A-Ar-CN ~,(XI) is reacted with a compound of general formula V - R a'~~~, (XII) wherein A, Ar and Het are defined as in claims 1 to 7, one of the groups U or V denotes an HOCO- or HOSO2 group or the reactive derivatives thereof and the other one of the groups U or V denotes one of the optionally substituted amino groups mentioned for R a defined as in claims 1 to 7, which is linked to the Het group either via the nitrogen atom or via the carbonyl or sulphonyl group, or h) in order to prepare a compound of general formula I wherein R a denotes one of the optionally substituted phenyl and alkenyl groups mentioned for R a defined as in claims 1 to 7 and R b denotes a cyano group:
a compound of general formula Z4-Het-A-Ar-CN ~~~~,(XIII) wherein A, Ar and Het are defined as in claims 1 to 7 and Z4 denotes a trifluoromethanesulphonyloxy group, a bromine or iodine atom, is reacted with a compound of general formula R6 - Z5 ~, (XIV) wherein R6 denotes one of the optionally substituted phenyl and alkenyl groups mentioned for R a defined as in claims 1 to 7 and Z5 denotes a boric acid group or a tri-(C1-4-alkyl)-tin group, or i) in order to prepare a compound of general formula I wherein R b denotes an amidino group, which may be substituted by a hydroxy group, by one or two C1-3-alkyl groups:

a compound of general formula optionally formed in the reaction mixture wherein A, Ar, Het and R a are defined as in claims 1 to 7 and Z6 denotes a hydroxy, alkoxy, aralkoxy, alkylthio or aralkylthio group, is reacted with an amine of general formula R6NH - R7~~~,(XVI) wherein R6 denotes a hydrogen atom, a C1-3-alkyl or a hydroxy group and R7 denotes a hydrogen atom or a C1-3-alkyl group, or j) in order to prepare a compound of general formula I wherein R b denotes an amidino group substituted by a pro-drug group:
a compound of general formula wherein A, Ar, Het and R a are defined as in claims 1 to 7, is reacted with a compound of general formula Z7 - R8 ,(XVIII) wherein R8 denotes one of the abovementioned prodrug groups and Z7 denotes a leaving group such as a halogen atom or a p-nitro-phenyl group, and if desired subsequently a compound of general formula I thus obtained which contains an esterified carboxy group is converted by hydrolysis into a corresponding carboxy compound or a compound of general formula I thus obtained which contains a nitro group is converted by reduction into a corresponding amino compound or a compound of general formula I thus obtained which contains an imino group in the Het moiety is converted by alkylation into a correspondingly alkylated compound or a compound of general formula I thus obtained which contains a primary or secondary amino group is converted by alkylation or reductive alkylation into a corresponding alkyl or dialkyl compound or a compound of general formula I thus obtained which contains a primary or secondary amino group is converted by acylation into a corresponding aryl compound or a compound of general formula I thus obtained which contains a carbonyl group in the Het moiety is converted by means of a sulphurising agent into a corresponding thiocarbonyl compound or a compound of general formula I thus obtained which contains a carbonyl group in the Het moiety is converted by means of a halogen-introducing agent and subsequent reaction with an amine into a corresponding amino compound or a compound of general formula I thus obtained which contains an alkenyl or alkynyl function, is converted by catalytic hydrogenation into a corresponding saturated compound or a compound of general formula I thus obtained which contains an alkenyl function is converted by oxidation into a corresponding carboxylic acid or a compound of general formula I thus obtained which contains an enolether group is converted by hydrolysis into a corresponding carbonyl compound or a compound of general formula I thus obtained which contains an aliphatic carbonyl group is converted by reacting with a hydroxylamine into a corresponding oxime and if necessary any protecting group used during the reactions to protect reactive groups is cleaved and/or if desired a compound of general formula I thus obtained is subsequently resolved into its stereoisomers and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
CA002323606A 1998-04-17 1999-04-13 Bicyclic compounds having an anti-thrombitic effect Abandoned CA2323606A1 (en)

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DE19816983A DE19816983A1 (en) 1998-04-17 1998-04-17 New bicyclic heteroaromatic amidine or nitrile compounds, used as thrombin inhibitors, antithrombotic agents or intermediates
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PCT/EP1999/002464 WO1999054313A1 (en) 1998-04-17 1999-04-13 Bicyclic compounds having an anti-thrombitic effect

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US8222403B2 (en) 2009-11-12 2012-07-17 The United States Of America, As Represented By The Secretary Of The Navy Heteroaromatic phthalonitriles

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US6794412B1 (en) 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
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JP2001322986A (en) * 1999-11-15 2001-11-20 Sumitomo Chem Co Ltd Method for producing 3-phenyluracil compound
WO2001072712A1 (en) * 2000-03-24 2001-10-04 Cor Therapeutics, Inc. ISOQUINOLONE INHIBITORS OF FACTOR Xa
AU2001249398A1 (en) * 2000-03-24 2001-10-08 Cor Therapeutics, Inc. Bicyclic sulfonyl amino inhibitors of factor xa
AU2002214546A1 (en) * 2000-09-29 2002-04-08 Cor Therapeutics, Inc. Bicyclic pyrimidin-4-one based inhibitors of factor xa
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
CA2538884C (en) 2003-09-16 2010-09-21 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
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US8178556B2 (en) 2008-03-05 2012-05-15 Merck Patent Gesellschaft Mit Beschraenkter Haftung Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
US8609689B2 (en) 2008-03-05 2013-12-17 Merck Patent Gmbh Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
US8642617B2 (en) 2008-03-05 2014-02-04 Merck Patent Gmbh Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
US8222403B2 (en) 2009-11-12 2012-07-17 The United States Of America, As Represented By The Secretary Of The Navy Heteroaromatic phthalonitriles

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