EP1060166A1 - 5-gliedrige benzokondensierte heterocyclen als antithrombotika - Google Patents

5-gliedrige benzokondensierte heterocyclen als antithrombotika

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Publication number
EP1060166A1
EP1060166A1 EP99907437A EP99907437A EP1060166A1 EP 1060166 A1 EP1060166 A1 EP 1060166A1 EP 99907437 A EP99907437 A EP 99907437A EP 99907437 A EP99907437 A EP 99907437A EP 1060166 A1 EP1060166 A1 EP 1060166A1
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EP
European Patent Office
Prior art keywords
group
alkyl
methyl
substituted
carboxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99907437A
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German (de)
English (en)
French (fr)
Inventor
Uwe Ries
Norbert Hauel
Gerhard Mihm
Henning Priepke
Klaus Binder
Jean Marie Stassen
Wolfgang Wienen
Rainer Zimmermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Filing date
Publication date
Priority claimed from DE1998104085 external-priority patent/DE19804085A1/de
Priority claimed from DE1998134325 external-priority patent/DE19834325A1/de
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1060166A1 publication Critical patent/EP1060166A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to new 5-membered heterocyclic condensed derivatives of the general formula
  • Ar R c (I) their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable properties.
  • the present application thus relates to the new compounds of the above general formula I and their preparation, the pharmaceutical compositions containing the pharmacologically active compounds and their use.
  • A is an oxygen or sulfur atom, a carbonyl, sulfinyl or sulfonyl group, an imino group optionally substituted by a C ⁇ __3-alkyl group or an optionally substituted by a carboxy-C ⁇ __3-alkyl or C ] __3-alkoxycarbonyl-C ⁇ __3 -alkyl group mono- or disubstituted methylene group,
  • Ar is a phenylene or naphthylene group which is optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, ⁇ - 3-alkyl or C ] __3-alkoxy group,
  • thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C ⁇ __3-alkyl group,
  • R ] _ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a C 1 _3-alkyl or C ⁇ __3-alkoxy group,
  • Y is an oxygen or sulfur atom or an -R2N group in which
  • R2 represents a hydrogen atom or a C 1-6 alkyl group
  • a C ⁇ _5-alkyl group which is replaced by a carboxy-, C; j__3-alkoxycarbonyl-, carboxy-C ] __3 -alkoxycarbonyl-, C ⁇ _3-alkoxycarbonyl-C ⁇ __3 -alkoxycarbonyl-, carboxy-C ] __3 -alkylamino-carbonyl- or C ⁇ __3-alkoxycarbonyl-C 1 _3-alkylaminocarbonyl group is substituted, or
  • n-C2- 4 ⁇ alkyl group which is terminated by a di- (C] __ 3-alkyl) amino, pyrrolidino, piperidino, morpholino, piperazino or N-Ci-3-alkyl-pierazino group - 3 -
  • R a is a hydrogen atom or a C] __ 3-alkyl group
  • Rk is R 3 -CO-C 3 _5-cycloalkylene-, R3-SO2-NR4-, R3-CO-NR4-, R5NR5-CO-, R 5 NR 6 -S0 2 - or R 5 NRg-CO-C 3 _ 5 cycloalkylene group in which
  • R3 is a C ⁇ __g alkyl or C5_7 cycloalkyl group
  • a C ⁇ _3 alkyl group which is substituted by a C5_7-cycloalkyl, phenyl, C ⁇ __3-alkylamino, di- (C ⁇ __3-alkyl) -amino, carboxy- C 1 _3-alkylamino, C 1 _3-alkoxycarbonylamino-, Phenylsulfonylamino or tetrazolyl group is substituted,
  • a C ] __3-alkyl group which is substituted by a carboxy, C ⁇ __3-alkoxy-carbonyl, carboxy-C ⁇ _3-alkoxy or C ⁇ __3-alkoxycarbonyl- C ⁇ _3-alkoxy group,
  • a C ⁇ __3-alkyl group which is substituted by an imidazolyl or benzidazolyl group, the imidazole part of the above-mentioned groups by one or two C; ] __3-alkyl groups or by a carboxy-C ⁇ __3-alkyl or C ] __3-alkoxy-carbonyl-C ⁇ __3-alkyl group,
  • a phenyl group which is optionally mono- or disubstituted by a C ] __3-alkyl, C ] __3-alkoxy, trifluoromethyl, carboxy or C ] __3-alkoxycarbonyl group, where the substituents can be identical or different, one by one phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, pyrazolyl, quinolyl or isoquinolyl group optionally substituted by a C ] __3 ⁇ alkyl group, R4 is a hydrogen atom, a C ⁇ __5-alkyl or C5_7-cycloalkyl group,
  • a C ] __5-alkyl group which is substituted by a carboxy group or by a Cx.s-alkoxycarbonyl group in which the alkoxy part in the 2- or 3-position can additionally be substituted by a hydroxyl group,
  • a C ] __3-alkyl group which is substituted by an aminocarbonyl, hydroxyaminocarbonyl, C__3-alkylaminocarbonyl, di- (C ] __3-alkyl) -aminocarbonyl or C5_7-alkyleneiminocarbonyl group, the Cg_7-alkyleneimino part additionally may be substituted in the 4-position by a di- (C; ] __3-alkyl) -amino group,
  • a C1--3 alkyl group which is replaced by a carboxy-C ⁇ __3-alkyl-aminocarbonyl-, N- (C ⁇ __3-alkyl) -carboxy-C ] __3 -alkylaminocarbonyl-, C ] __3 -alkoxycarbonyl-C ] __3 -alkylaminocarbonyl- or N- (C ⁇ __3-alkyl) -C ] __3 -alkoxycarbonyl -C ⁇ _-.
  • 3 -alkylaminocarbonyl - group which are additionally substituted on each carbon atom of the alkylamino part by a carboxy or C ] __3-alkoxycarbonyl group,
  • a C ⁇ __ 3 -alkyl group which is substituted by a di- (C ] __3-alkyl) -amino-carbonyl group in which an alkyl part is additionally in the 2- or 3-position by a di- (Ci-.3-alkyl) -amino group can be substituted
  • a C ⁇ __3-alkyl group which is substituted by a 4- (morpholinocarbonyl- C 1 _ 3 alkyl) piperazinocarbonyl, N- (C 1 _ 3 alkyl) pyrrolidinyl or N- (C 1 _3 alkyl) piperidinyl group is, or
  • n-C2_4-alkyl group which is terminally substituted by a di- (C 1 _3-alkyl) -amino, C5_7-alkyleneimino or morpholino group,
  • R5 is a C ⁇ __5 alkyl or C5_7 cycloalkyl group
  • a phenyl-C 1 _3-alkyl group which can be substituted in the alkyl part by a carboxy or C 1 _3-alkoxycarbonyl group,
  • n-C2_4-alkyl group which is substituted in the 2-, 3- or 4-position by a hydroxy, C ⁇ .-3-alkylamino or di- (C ⁇ __3-alkyl) -amino group,
  • a phenyl group which is optionally mono- or disubstituted by C 1 _3-alkyl, C ] __3-alkoxy, trifluoromethyl, carboxy or C;] __ 3-alkoxycarbonyl groups, where the substituents can be the same or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, quinolyl or isoquinolyl group,
  • Rg is a C ] __5-alkyl group which is optionally substituted by a carboxy or C ⁇ _3-alkoxycarbonyl group,
  • n-C2_4-alkyl group which is substituted in the 2-, 3- or 4-position by a hydroxy, C 1 _3-alkylamino or di- (C 1 _3-alkyl) -amino group, or one of the radicals R5 or Rg is a hydrogen atom, the other of the radicals having the meanings mentioned above for R 5 and Rg, or
  • R5 and Rg together with the nitrogen atom in between represent a pyrrolidino or piperidino group which is optionally substituted by one or two C ⁇ __3-alkyl groups and which are additionally substituted by a carboxy-C ] __3-alkyl or C ⁇ __3-alkoxy-C ⁇ __3-alkyl group can represent or onto which a benzene ring can be fused via two adjacent carbon atoms,
  • R__ is an amino, C ] __3-alkylamino or C5_7-cycloalkylamino group which is substituted on the nitrogen atom by a phenylaminocarbonyl, N-phenyl-C ] __3 -alkylaminocarbonyl-, phenylsulfonylamino- C] __ 3-alkylcarbonyl-, C ⁇ __3 -Alkyloxycarbonyl-C ] __3-alkyl-, N- (C3_5-cycloalkyl) -C ⁇ __3-alkylaminocarbonyl -, N- (hydroxycarbonyl-C ⁇ __3-alkyl) -aminocarbonyl-, N- (C ⁇ __3-alkoxycarbonyl - C; ] __3 - alkyl) -aminocarbonyl-C3-.5 -cycloalkylamino group is
  • a methyl group substituted by a C5_7-cycloalkyleneiminocarbonyl group in which the methyl group is substituted by a carboxy- C 1 -3 -alkyl- or C ⁇ _3-alkoxy-C ⁇ _3-alkyl group, a carbonyl or methyl group substituted by a C3_5-cycloalkyl or C3_5-alkyl group, where the cycloalkyl part can additionally be substituted by a C ⁇ __3-alkyl, carboxy-C ⁇ - ⁇ - alkyl or C ⁇ __3-alkoxycarbonyl-C ⁇ __3-alkyl group and the Methyl part is substituted by a C ⁇ __ 3 -alkoxy or C ] __4-alkylamino group,
  • a phosphinyl group by a C] __g alkyl or C 5-7 cycloalkyl group and by a hydroxy, j _- 3 alkoxy, carboxy-C ⁇ alkoxy or C ⁇ -3 _- 3 alkoxycarbonyl C ⁇ __3.. - alkoxy group is substituted,
  • a tetrazolyl group optionally substituted by a C ⁇ __5-alkyl group
  • a phenyl or phenylsulfonyl group optionally mono- or disubstituted by a C _-- 3-alkyl, C ⁇ _-. 3 alkoxy, trifluoromethyl, carboxy or C ] __3-alkoxycarbonyl group, the substituents being the same or different can,
  • a Sufimidoyl distr that loalkyl proceed at the sulfur atom by a C5_ 7 -Cyc- substituted alkyl and additionally at the nitrogen atom by a C2-4 "alkanoyl, carboxy-C 1 _ 3, C] __ _ 3 alkoxycarbonyl -C ⁇ .. 3 - alkyl, carboxy-C2-4-alkanoyl or C ⁇ - ⁇ - lk-oxycarbonyl-C2-4-alkanoyl group may be substituted,
  • a C ] __3 -alkyl group which can be substituted by a 1-imidazolyl group, the imidazolyl part being additionally substituted by one or two C ⁇ __3 -alkyl groups, or by one in the 2-position by a carboxy-C ⁇ _3 -alkyl or C ⁇ _-. 3 -alkoxycarbonyl - C Q __3 -alkyl group substituted 1-benzimidazolyl group, or
  • R c is a cyano group or an amidino group which can be substituted by a hydroxy group, by one or two C ⁇ -3-alkyl groups, by one or two C ⁇ __8-alkoxycarbonyl groups or by a radical which can be split off in vivo, especially those in which
  • A, X, Y and R a to R -__ are defined with the proviso that
  • Ar represents a 1,4-phenylene group
  • R3 no pyrazolyl group or no naphthyl, pyridinyl, pyrazolyl, quinolyl or isoquinolyl group substituted by a C ⁇ __3 alkyl group and
  • Rb does not represent any furanyl-1-pyrazolyl group optionally substituted by a C ⁇ _-- 3 -alkyl group.
  • a residue that can be split off from an imino or amino group in vivo is, for example, a hydroxyl group, an acyl group such as the benzoyl or pyridinoyl group or one C] __ ⁇ _g-alkanoyl group such as the for yl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C ⁇ _ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycar, bonyl, butoxycarbonyl, tert.
  • an acyl group such as the benzoyl or pyridinoyl group or one C] __ ⁇ _g-alkanoyl group such as the for yl, acetyl, propionyl, butanoyl, pentanoyl or hexan
  • R7 is a C ⁇ __s alkyl, C5_7 cycloalkyl, phenyl or phenyl - C ⁇ _ _ 3 - alkyl group,
  • R is a hydrogen atom, a C1-.3-alkyl, C 5 _7-cycloalkyl or phenyl group and
  • Rg represents a hydrogen atom or a C 1-3 alkyl group
  • saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
  • A, X, Y and R a to R c are as defined in claim 1, in particular those compounds of the general formula Ia in which
  • A is a methylene group optionally substituted by a carboxy-C ] __3-alkyl or C Q __ 3 -alkoxycarbonyl-C ] __3 -alkyl group, a carbonyl or imino group,
  • R ] _ represents a hydrogen, fluorine, chlorine or bromine atom, a _L-3-alkyl or C] __ 3-alkoxy group,
  • Y is an oxygen or sulfur atom or an -R2N group in which
  • R2 represents a hydrogen atom or a C] __ 5 alkyl group
  • a benzyl group which can be substituted in the phenyl part by a carboxy or C ⁇ __3-alkoxycarbonyl group,
  • a C ] __3 alkyl group which is substituted by a carboxy-C ] _-- 3 -alkoxycarbonyl, carboxy-C ⁇ __3-alkylaminocarbonyl or C ⁇ __3-alkoxycarbonyl -C ] __3 -alkylaminocarbonyl group, or
  • n-C2 -4 -alkyl group which is terminally substituted by a di- (C ⁇ __3-alkyl) -amino or morpholino group,
  • R a is a hydrogen atom or a methyl group
  • Rb an R 3 -CO-C3_ 5 -cycloalkylene-, R 3 -S0 2 -NR 4 -, R3-CO-NR4-, R 5 NR 6 -CO-, R 5 NRg-S0 2 - or R 5 NRg- CO-C3_ 5 cycloalkylene group in which - 11 -
  • R3 is a C ⁇ __4-alkyl, cyclopentyl, cyclohexyl or benzyl group,
  • a C ⁇ __3 alkyl group which is replaced by a tetrazolyl, carboxy, C ⁇ _3 alkoxycarbonyl, carboxy-C ] __3 -alkoxy-, C ⁇ _3-alkoxycarbonyl -C ⁇ __3 -alkoxy-, carboxy-C ⁇ __3-alkylamino-, C __-- 3 -alkoxycarbonylamino group is substituted,
  • a phenyl group which is mono- or disubstituted by methyl, methoxy, trifluoromethyl, carboxy or methoxycarbonyl groups, where the substituents may be the same or different, one by a phenyl group substituted by 3 or 4 methyl groups, one in the 1-position by a C ] __3 alkyl group substituted 5-pyrazolyl group, a naphthyl, pyridinyl, quinolyl or isoquinolyl group,
  • R 4 is a hydrogen atom, a C ] __5-alkyl or C5_7-cycloalkyl group,
  • a C ] __ 5 -alkyl group which is substituted by a carboxy group or by a C ⁇ - ⁇ - alkoxycarbonyl group in which the alkoxy part in the 2- or 3-position can additionally be substituted by a hydroxyl group,
  • a C ⁇ __3 alkyl group which is substituted by an aminocarbonyl, hydroxyaminocarbonyl or piperidinocarbonyl group, where the piperidino part can additionally be substituted in the 4-position by a dimethylamino group,
  • a C __-- 3 -alkyl group which is replaced by a carboxy-C ⁇ __3-alkyl-aminocarbonyl-, N- (C; j__3-alkyl) -carboxy-C ] _-- 3 -alkylaminocarbonyl-, C 1 _3 -alkoxycarbonyl-C] __3 -alkylaminocarbonyl-, N- (C] __ 3 -alkyl) -C ⁇ __3 -alkoxycarbonyl-C ⁇ __3 -alkylaminocarbonyl-, morpholinocarbonyl- or 4- (C 1 _3-alkyl) -piperazinocarbonyl- group is substituted, - 12 -
  • a C] __ 3 -alkyl group which is replaced by a carboxy-C ⁇ __3 -alkyl-aminocarbonyl-, N- (C ⁇ - 3-alkyl) -carboxy-C ⁇ __3 -alkylaminocarbonyl-, C ⁇ _-3-alkoxycarbonyl-C ⁇ _3 -alkylaminocarbonyl- or N - (C 1 _3-alkyl) -C ⁇ _-- 3 -alkoxycarbonyl-C ] _-.
  • 3 -alkylaminocarbonyl group which are each additionally substituted on a carbon atom of the alkylamino part by a carboxy or C ] __3-alkoxycarbonyl group,
  • Alkyl part can additionally be substituted in the 2- or 3-position by a di- (C] __ 3-alkyl) -amino group,
  • a C. -3 alkyl group which is substituted in the alkyl part by a 4- (morpholino carbonyl-C ⁇ __3-alkyl) -piperazinocarbonyl or N- (C ⁇ __3-alkyl) -pyrrolidinyl group, or
  • n-C2-3 -alkyl group which is terminally substituted by a di- (C ⁇ __3-alkyl) -amino, C5_7-alkyleneimino or morpholino group,
  • R5 is a C ] __5-alkyl or C5_7-cycloalkyl group
  • a phenyl -C ⁇ _-- 3 -alkyl group which can be substituted in the alkyl part by a carboxy or C ⁇ __3-alkoxycarbonyl group,
  • Rg is a C ] _.5 alkyl group which is optionally substituted by a carboxy or C ⁇ __3 alkoxycarbonyl group,
  • a C] __ 3 -alkyl group which is in the alkyl part by a C ⁇ -. 3 -Alkylaminocarbonyl-, di- (C ⁇ _3-alkyl) -aminocarbonyl-, carboxy- - 13 -
  • n-C2 -3 alkyl group which is substituted in the 2- or 3-position by a C 1 _3-alkylamino or di- (C; ______3-alkyl) -amino group, or
  • one of the radicals R5 or Rg is a hydrogen atom, the other of the radicals having the meanings mentioned above for R5 and Rg, or
  • R5 and Rg together with the nitrogen atom in between represent a pyrrolidino or piperidino group, optionally substituted by a C ] __3-alkyl, carboxy-C ⁇ __3-alkyl or C_-3-alkoxy-C ⁇ __3-alkyl group, to which an additional via two adjacent carbon atoms Benzene ring may be fused,
  • a cyclohexyl-N- (carboxymethoxy) -iminomethylene or cyclohexyl -N- (C ] __3-alkoxycarbonylmethoxy) -iminomethylene group which in the cyclohexyl part can each be additionally substituted by a methyl group
  • phosphinyl group which is substituted by a C3_g alkyl group and by a hydroxy, C ⁇ __3 alkoxy, carboxymethoxy or C ⁇ __3 alkoxycarbonylmethoxy group,
  • a tetrazolyl group which is optionally substituted by a C 1-5 alkyl group
  • a phenyl or phenylsulfonyl group optionally substituted by a methyl group
  • a sufimidoyl group which is substituted on the sulfur atom by a cyclohexyl group and on the nitrogen atom additionally by a C2-4-alkanoyl-, carboxymethyl-, C ⁇ .. 3 -alkoxy-carbonylmethyl-, carboxy-C2-.3 -alkanoyl- or C] _-. 3 -alkoxycarbonyl-C2-3-alkanoyl group may be substituted,
  • a C ⁇ __3 -alkyl group which can be substituted by a 1-imidazolyl group, the imidazolyl part being additionally substituted by one or two C ⁇ __3 -alkyl groups, or by a 2-position by a carboxy-C ⁇ _-. 3 -alkyl- or C __- .3 -Alkoxycarbonyl - C ⁇ __3 -alkyl group substituted 1-benzimidazolyl group is substituted, or
  • R c is a cyano group or an amidino group which can be substituted by one or two C ] __3-alkyl groups, by one or two C ⁇ __g alkoxycarbonyl groups or by a hydroxy group,
  • A is a methylene or imino group
  • R ] _ represents a hydrogen, fluorine, chlorine or bromine atom or a methyl group
  • Y is an oxygen or sulfur atom or an -R2N group in which
  • R2 is a hydrogen tom, a methyl, benzyl, 4-carboxy-benzyl or 4-methoxycarbonylbenzyl group,
  • R a is a hydrogen atom
  • R3 a C ⁇ . -3 alkyl, cyclopentyl or cyclohexyl group
  • R4 is a hydrogen atom, a C ⁇ __3 alkyl or cyclopentyl group,
  • a C ⁇ __3 alkyl group which is replaced by a carboxy-methylaminocarbonyl, N- (C 1 _3-alkyl) -carboxymethylaminocarbonyl-, C 1 _3-alkoxycarbonylmethylaminocarbonyl- or N- (C ] __3-alkyl) -C 1 _3 -alk- oxycarbonylmethyla inocarbonyl distr is substituted, - 17 -
  • a C ⁇ __3 -alkyl group which is substituted by a di- (C1-.3-alkyl) -amino-carbonyl group, in which an alkyl part is additionally in the 2- or 3-position by a di- (-CC-3-alkyl) amino group is substituted,
  • a -C2-3 alkyl group which is terminally substituted by a di- (Ci-.3-alkyl) amino, pyrrolidino or morpholino group,
  • R5 is a C 1-5 alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, quinolyl or isoquinolyl group,
  • Rg is a C 5 -alkyl group which is optionally substituted by a carboxy or C ] __3-alkoxycarbonyl group,
  • a C__3 alkyl group which is substituted by a C ] __3 alkylaminocarbonyl, carboxymethylaminocarbonyl or C ⁇ __3 alkyloxycarbonyl ylmethylaminocarbonyl group, or
  • R5 and Rg together with the nitrogen atom in between represent a pyrrolidino group or a pyrrolidino group which is substituted by a carboxymethyl or C] __ 3-alkoxy ⁇ ethyl group and to which a benzene ring is additionally fused via two adjacent carbon atoms,
  • a cyclohexyl -N- (carboxymethoxy) -iminomethylene or cyclohexyl -N- (C ⁇ __3-alkoxycarbonylmethoxy) -iminomethylene group which is additionally substituted in the cyclohexyl part by a methyl group,
  • phosphinyl group which is substituted by a C3_g alkyl group and by a C ⁇ __3 alkoxymethoxy group
  • a Sufimidoyl distrin, hexyl group and the sulfur atom by a cyclo is additionally substituted by a C2 4 alkanoyl group on the nitrogen atom, or
  • R c represents an amidino group
  • A is a methylene group
  • Y is an oxygen or sulfur atom or an -R2N group in which
  • R2 represents a hydrogen atom, a methyl, benzyl or C ] __3-alkoxycarbonylmethyl group
  • R a is a hydrogen atom, - 19 -
  • Rb is an R 5 NRg-S0 2 -, R 5 NRg-CO-, R 3 -S0 2 -NR 4 -, R3-CO-NR4- or R5NRg-CO-C3_5- (1, 1-cyclopropylene) group, in which
  • R3 is a cyclopentyl, cyclohexyl, phenyl, naphthyl, 1-methyl -5-pyrazolyl, quinolyl or isoquinolyl group or a methyl group which is replaced by a carboxymethylamino, C ⁇ __3-alkoxycarbonylmethylamino, carboxymethoxy, C; j _-. 3 alkoxycarbonyl methoxy or tetrazolyl group is substituted,
  • R4 is a hydrogen atom or a methyl group which is substituted by a carboxy-, C ] _-. 3 -alkoxycarbonyl-, morpholinocarbonyl-, 4 -dirnethylamino-piperidinocarbonyl-, 4-methyl-piperazinocarbonyl-, 4-morpholinocarbonylmethyl-piperazinocarbonyl-, carb - oxymethylaminocarbonyl-, N-methyl-carboxymethylaminocarbon- yl-, C ] __3-alkoxycarbonylmethylaminocarbonyl-, N-methyl- C ] __3-alkoxycarbonylmethylaminocarbonyl-, N- (C ] __3-alkyl) - N- (2-dimethylamino-ethyl) -aminocarbonyl-, N- (1-carboxy-2-aminocarbonyl-ethyl) -aminocarbon
  • R5 is a C ] __5 alkyl, phenyl or pyridyl group and
  • Rg C] __ 5 -alkyl group which may be substituted by a carboxy or C ] __3-alkoxycarbonyl group, or C ⁇ __3 -alkyl group which may be substituted by a methylaminocarbonyl, carboxymethylaminocarbonyl or C ⁇ __3-alkoxycarbonylmethyl-aminocarbonyl group or in the 2- or 3-position is substituted by a dimethylamino group, or
  • R5 and together with Rg and the intermediate nitrogen atom represent a pyrrolidino group or a pyrrolidino group optionally substituted by a C ⁇ __3-alkoxycarbonyl group, to which a benzo ring is fused via two adjacent carbon atoms, - 20 -
  • a cyclohexyl-N- (carboxymethoxy) -iminomethylene or cyclohexyl-N- (C ⁇ __3-alkoxycarbonylmethoxy) -iminomethylene group which in the cyclohexyl part is additionally substituted in the 1-position by a methyl group
  • phosphinyl group which is substituted by a C3_ -alkyl group and by a C j __3 -alkoxymethoxy group
  • R c represents an amidino group
  • A is a methylene group
  • Y is an oxygen or sulfur atom or an -R2 group in which
  • R2 represents a hydrogen atom, a methyl, benzyl or C ⁇ __3-alkoxycarbonylmethyl group
  • R a is a hydrogen atom
  • Rb is an R 5a NRg a -S ⁇ 2 group in which
  • R5 a is a C ⁇ __3 alkyl or phenyl group and - 21 -
  • Rg a C. _5-alkyl group which is terminally substituted by a carboxy or C ⁇ __3-alkoxycarbonyl group or in the 2- or 3-position by a dirnethylamino group, or
  • R5 a and together with Rg a and the nitrogen atom in between represent a pyrrolidino group or a pyrrolidino group optionally substituted by a C__3-alkoxycarbonyl group, to which a benzo ring is fused via two adjacent carbon atoms,
  • R3 a is a cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl or isoquinolyl group and
  • R4 a is a hydrogen atom or a methyl group which is substituted by a carboxy, C ⁇ _-. 3 -alkoxycarbonyl, morpholinocarbonyl, 4-dimethylamino-piperidinocarbonyl, 4-methyl-piperazino-carbonyl, 4-morpholinocarbonylmethyl-piperazinocarbonyl, carboxymethylaminocarbonyl , N-methyl-carboxymethylamino-carbonyl-, C ⁇ __3-alkoxycarbonylmethylaminocarbonyl-, N-methyl- C ⁇ __3 -alkoxycarbonylmethylaminocarbonyl-, N- (C] __ 3-alkyl) - N- (2-dimethylamino-ethyl) -aminocarbonyl-, N- ( 1-carboxy-2-aminocarbonyl-ethyl) -aminocarbonyl- or N- (1-C] __ 3 -
  • R5b is a C3 _ 5 alkyl, phenyl or pyridyl group and
  • Rgb is a C ] __5 alkyl group or a C ] __3 alkyl group which is replaced by a carboxy, C ] __3 alkoxycarbonyl, methylaminocarbonyl, carboxymethylaminocarbonyl or C ] __3 alkoxycarbonylmethylaminocarbonyl group or in 2- or 3 - Position is also substituted by a dimethylamino group, - 22 -
  • R3b is a phenyl group
  • R 4 b c l-3 alkyl group which is substituted by a carboxy or C ⁇ _-- 3 alkoxycarbonyl group, or
  • R3b is a methyl group which is substituted by a carboxymethylamino, C__3-alkoxycarbonylmethylamino, carboxymethoxy, C ⁇ __3-alkoxycarbonylmethoxy or tetrazolyl group, and
  • R4b represent a cyclopentyl group
  • R5 C and together with Rg c and the nitrogen atom in between represents a 1-methyl-5-pyrazolyl group, a pyrrolidino group optionally substituted by a C1-3 alkoxycarbonyl group or a pyrrolidino group to which a benzo ring is fused via two adjacent carbon atoms,
  • Rb is an N-pyrrolidinocarbonyl-methylamino, phenylsulfonyl, 4-0x0-2, 3-diaza-spiro [5.5] undec-1-en-l-yl or C3_5-alkyl-tetrazolyl group,
  • a cyclohexyl-N- (carboxymethoxy) -iminomethylene or cyclohexyl -N- (C1 . _3-alkoxycarbonylm.etb.oxy) -iminomethylene group which in the cyclohexyl part is additionally substituted in the 1-position by a methyl group, - 23 -
  • R c represents an amidino group
  • the compounds of the general formula I are obtained by known processes, for example by the following processes:
  • Le are defined at the outset, Z and Z ", which may be the same or different, optionally substituted by alkyl groups having 1 to 6 carbon atoms, amino, hydroxyl or mercapto groups or Z and Z, together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylene dithio group each having 2 or 3 carbon atoms.
  • the cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess of those used to prepare the compound of the general Formula II used acylating agents, for example in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between - 25 -
  • a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess of those used to prepare the compound of the general Formula II used
  • a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in Presence of a base such as potassium ethylate or potassium tert.butylate performed.
  • a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in Presence of a base such as potassium ethylate or potassium tert.butylate performed.
  • the cyclization can also be carried out without a solvent and / or condensing agent.
  • reaction is particularly advantageously carried out in such a way that a compound of the general formula II in the reaction mixture by reducing an appropriate o-nitro compound, optionally in the presence of a carboxylic acid of the general formula
  • a and Ar are as defined in the introduction, is produced by acylation of a corresponding amino compound formed in the reaction mixture.
  • Rb is an R3-SO2-NR 4 -, R3-CO-NR4- or
  • R a , R4, A, Ar, X and Y are defined as mentioned at the outset, with an acid of the general formula
  • R ⁇ _0 has the meanings mentioned for R3 to Rg and
  • W represents a carbonyl or sulfonyl group, or with their reactive derivatives.
  • reaction of an acid of the general formula V is optionally in a solvent or solvent mixture such as methylene chloride, diethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, e.g.
  • reaction of a corresponding reactive compound of the general formula V such as its esters, imidazolides or halides is preferably carried out in a 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. - 27 -
  • R a , R3, A, Ar, X and Y are as defined in the introduction, with a compound of the general formula
  • R4 is defined as mentioned at the beginning and
  • Z3 is a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulfonic acid ester residue, e.g. a trifluoromethanesulfonyloxy, methanesulfonyloxy or p-toluenesulfonyloxy group.
  • a halogen atom e.g. a chlorine, bromine or iodine atom
  • a sulfonic acid ester residue e.g. a trifluoromethanesulfonyloxy, methanesulfonyloxy or p-toluenesulfonyloxy group.
  • the reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethyl formamide, optionally in the presence of an inorganic or a tertiary organic base such as sodium hydride, potassium carbonate, potassium tert. butylate or N-ethyl-diisopropylamine at temperatures between 20 ° C and the boiling point of the solvent used, preferably at temperatures between 0 and 60 ° C.
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethyl formamide
  • an inorganic or a tertiary organic base such as sodium hydride, potassium carbonate, potassium tert. butylate or N-ethyl-diisopropylamine at temperatures between 20 °
  • R a , R3, A, Ar, X and Y are defined as mentioned at the outset and Rb 'is one of the radicals mentioned at the outset for Rb, which contains a phosphinyl and sulfimidoyl group, with a compound of the general formula
  • Z4 is a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, and
  • R ⁇ . ⁇ mean one of the alkyl parts, which in the definition of the alkylated phosphinyl and
  • the reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base such as sodium hydride, potassium carbonate, potassium tert-butylate or N-ethyl diisopropylamine at temperatures between 20 ° C and the boiling point of the solvent used, preferably at temperatures between 0 and 60 ° C.
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide
  • an inorganic or a tertiary organic base such as sodium hydride, potassium carbonate, potassium tert-butylate or N-ethyl diisopropylamine
  • R a , R c , A, Ar, X and Y are defined as mentioned at the outset and Rb "is one of the radicals mentioned at the outset for Rb which contains a sulfimidoyl group, with a compound of the general formula
  • R ⁇ _2 means one of the acyl parts mentioned in the definition of the acylated sulfimidoyl groups mentioned at the beginning for the radical Rb, or with their reactive derivatives.
  • reaction of an acid of the general formula XI is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, tri-methylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / - N-hydroxysuccinimide, N, N 'dicyclohexylcarbodiimide
  • reaction of a corresponding reactive compound of general formula XI such as its esters, imidazolides or halides is preferably carried out in a 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.
  • R a , A, Ar, X and Y are defined as mentioned at the beginning and
  • U represents a HO-CO-C3_ 5 -cycloalkylene-, HO-CO- or HO-S0 2 -, or with their reactive derivatives, with a
  • R5 and Rg has the meanings mentioned at the beginning.
  • reaction of an acid of general formula XII is optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane - 31 -
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane - 31 -
  • a dehydrating agent e.g. in the presence of isobutyl chloroformate, tetraethyl ortho carbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimidodimidodimidodimidodimidodimidodimidodimidodimidium N'-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3, 3 -tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1 , 1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-benz
  • reaction of a corresponding reactive compound of general formula XII such as its esters, imidazolides or halides is preferably carried out in a 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, performed.
  • R a , A, Ar, X and Y are defined as mentioned at the beginning and
  • Rb '" represents an R 3 - (HCOH) -C3_5 cycloalkylene group.
  • the oxidation is preferably carried out in a solvent such as ether, tetrahydrofuran, methylene chloride, glacial acetic acid or acetonitrile in the presence of an oxidizing agent such as manganese dioxide, potassium permanganate, potassium dichromate, dimethyl sulfoxide / oxalyl chloride or dimethyl sulfoxide / dicyclohexylcarbodiimide at temperatures between 0 and 50 ° C., preferably at 0 to 50 ° C. Temperatures between 15 and 25 ° C, carried out.
  • a solvent such as ether, tetrahydrofuran, methylene chloride, glacial acetic acid or acetonitrile
  • an oxidizing agent such as manganese dioxide, potassium permanganate, potassium dichromate, dimethyl sulfoxide / oxalyl chloride or dimethyl sulfoxide / dicyclohexylcarbodiimide at temperatures between
  • R a , R c , A, Ar, X and Y are defined as mentioned at the outset and Rb "" represents one of the radicals mentioned at the outset for Rb, which is linked via a carbonyl group to the adjacent bicyclic part, with an amine of the general formula
  • R] _3 represents an optionally substituted amino group, as mentioned at the beginning for Rb, when Rb is linked to the adjacent bicyclic part via a methyl group substituted by an optionally substituted amino group.
  • the reductive amination is carried out in the presence of a solvent such as methanol, methanol / water, diethyl ether, tetrahydrofuran or dioxane in the presence of a reducing agent such as a complex metal hydride, e.g. with sodium borohydride, lithium borohydride or sodium cyanoborohydride, preferably at a pH between 6 and 7 or with catalytically excited hydrogen, e.g. with hydrogen in the presence of palladium, at temperatures between 0 and 50 ° C, preferably at temperatures between 15 and 30 ° C.
  • a solvent such as methanol, methanol / water, diethyl ether, tetrahydrofuran or dioxane
  • a reducing agent such as a complex metal hydride, e.g. with sodium borohydride, lithium borohydride or sodium cyanoborohydride, preferably at a pH between 6 and 7 or with catalytically excited hydrogen,
  • R a , A, Ar, X and Y are defined as mentioned at the beginning and
  • V represents a trifluoromethanesulfonyloxy group, a bromine or iodine atom, with a compound of the general formula
  • R ⁇ _4 represents one of the optionally substituted phenyl radicals mentioned at the beginning for Rb and
  • Z 5 represents a boronic acid residue or a tri (C ⁇ __3 alkyl) tin group.
  • the reaction is preferably carried out in a solvent such as toluene / water, dimethoxyethane or dimethylformamide in the presence of a phosphine such as bis (triphenylphosphine) palladium (II) choride or tetrakis (triphenylphosphine) palladium (0) in the presence of a - 34 -
  • a solvent such as toluene / water, dimethoxyethane or dimethylformamide
  • a phosphine such as bis (triphenylphosphine) palladium (II) choride or tetrakis (triphenylphosphine) palladium (0) in the presence of a - 34 -
  • ner base such as sodium carbonate at temperatures between 20 and 100 ° C, preferably at temperatures between 40 and 80 ° C.
  • R a ' R b' A, Ar, X and Y are defined as mentioned at the outset and Z is an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of the general formula
  • R ⁇ _5 and Rig which may be the same or different, each represent a hydrogen atom or a C__3-alkyl group, or with its salts.
  • the reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, with an amine of the general formula XX or with a corresponding acid addition salt such as ammonium carbonate or ammonium acetate.
  • a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane
  • a compound of general formula XIX is obtained, for example, by reacting a corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding nitrile with hydrogen sulfide, advantageously in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.
  • a corresponding cyano compound with a corresponding alcohol such as
  • R a ' R b' A, Ar, X and Y are defined as mentioned at the beginning, with
  • the reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran, tetrahydrofuran / water, dioxane or dioxane / water at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C.
  • a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran, tetrahydrofuran / water, dioxane or dioxane / water at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C.
  • R c represents an amidino group optionally substituted by a hydroxyl group or by one or two C] __ 3-alkyl groups:
  • R a , A, Ar, X and Y are defined as mentioned at the outset and Rb '"" and R c ' have the meanings mentioned at the outset for Rb and R c with the proviso that Rb is obtained by hydrolysis, treatment with an acid or base ,
  • Thermolysis or hydrogenolysis contains a group which can be converted into a carboxy group and R c is defined as mentioned at the beginning or R c is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into one optionally by a hydroxyl group or by one or two C ] __3- Represents alkyl group-substituted amidino group convertible group and Rb is defined as mentioned above,
  • Rb contains a carboxy group and R c is defined as mentioned at the beginning or Rb is defined as mentioned at the beginning and R c is optionally a represents a hydroxyl group or amidino group substituted by one or two C__3-alkyl groups.
  • a group which can be converted into a carboxy group is, for example, a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are expediently converted into a carboxyl group by means of hydrolysis, - 37 -
  • a protective radical such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are expediently converted into a carboxyl group by means of hydrolysis, - 37 -
  • esters with tertiary alcohols e.g. the tert. Butyl esters which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and
  • esters with aralkanols e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.
  • the hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, eg at temperatures between room temperature and the boiling point of the reaction mixture.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a suitable solvent such as water, water / methanol, water
  • a compound of the formula XXII contains, for example, the tert-butyl or tert-butyloxycarbonyly group, these can also be treated by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, Chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or thermally, if appropriate, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesul
  • a compound of the formula XXII contains the benzyloxy or benzyloxycarbonyl group
  • these can also be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, for example at room temperature and a hydrogen pressure of 1 to 5 bar.
  • A, Ar, X and Y are defined as mentioned at the outset and R c "denotes an amidino group, with a compound of the general formula
  • R_7 denotes a Ci-.g-alkoxycarbonyl group or the acyl residue of one of the residues which can be cleaved in vivo and
  • Z7 is a nucleofugic leaving group such as a halogen atom, e.g. represents a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
  • a halogen atom e.g. represents a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
  • the reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic - 3 9 -
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide
  • Base preferably at temperatures between 20 ° C and the boiling point of the solvent used.
  • the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium -tert. butylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide
  • a base such as sodium hydride, potassium carbonate, potassium -tert. butylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.
  • the subsequent alkylation is expediently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, diethyl sulfoxide, dimethylformamide or acetone, if appropriate in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a 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 , carried out .
  • a solvent such as methylene chloride, tetrahydrofuran, dioxane, diethyl sulfoxide, dimethylformamide or acetone
  • a reaction accelerator such as sodium or potassium iodide
  • the subsequent hydrolysis is advantageously carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol , Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane and the subsequent decarboxylation in the presence of an acid as described above at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in
  • the subsequent esterification is expediently carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, Ci ö tr cn N CQ su Cd Qf ⁇ ö ⁇ ! tn 0 ⁇ öd ⁇ ; CQ Hi tQ rt TJ ⁇ - 0 ⁇ i ⁇ ; TJ ⁇ ⁇ ; ⁇ CQ
  • any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.
  • a protective radical used is carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide or by means of ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C., preferably at temperatures between 10 and 50 ° C. - 43 -
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon 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 room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethyl in or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature - 44 -
  • a compound of the general formula II is obtained by acylation of a corresponding o-diamino compound with a corresponding reactive derivative of a compound of the general formula III,
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
  • optically active substances which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, apple- - 46 -
  • optically active alcohols are, for example, (+) - or (-) menthol
  • optically active acyl radicals in amides are, for example, the (+) - or (-) - menthyloxycarbonyl radicals.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of the formula I obtained in this way if they contain a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I and their salts have valuable properties.
  • the compounds of general formula I, in which R c represents a cyano group are valuable intermediates for the preparation of the other compounds of general formula I
  • the compounds of general formula I, in which R c represents one of the amidino groups mentioned at the outset, and their tautomers, their stereoisomers and their physiologically acceptable salts have valuable pharmacological properties, particularly an antithrombotic activity which is preferably on an effect on thrombin or factor Xa effect is based, for example on a thrombin-inhibiting or factor Xa-inhibiting ⁇ effect, on a the aPTT time prolonging effect and on a - 47 -
  • A 4- [(5- (N-carboxymethyl-quinolin-8-yl) sulfonylamino) - 1-methyl-1H-benzimidazol-2-yl) methyl] benzamidine hydrochloride,
  • G 4- [(5- (N-cyclopentyl-3-carboxypropionylamino) -1-methyl-1H-benzimidazol-2-yl) methyl] benzamidine hydrochloride,
  • the aTTP time was determined using a Biomatic BIO coagulometer from Desaga.
  • test substance was placed in the test vessels prescribed by the manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of PTT reagent. The mixture was incubated for three minutes at 37 ° C. The coagulation reaction was started by adding 0.1 ml of calcium solution. Depending on the device, the calcium solution is measured and the time taken for the batch to clot is measured. Batches in which 0.1 ml of DBA buffer were added served as a control.
  • the effective substance concentration at which the aTTP time was doubled compared to the control was determined via a dose-response curve.
  • the compounds produced according to the invention are well tolerated, since no toxic side effects could be observed at therapeutic doses.
  • the new compounds and their physiologically compatible salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.
  • venous and arterial thrombotic diseases such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A)
  • PT ( C) A) angioplasty
  • peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.
  • the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with rt-PA or streptokinase, for preventing long-term restosis after PT (C) A, for preventing metastasis and the growth of coagulation-dependent tumors and of fibrin-dependent inflammatory processes suitable .
  • C restosis after PT
  • the dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration and 0.1 to 50 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g.
  • Example le Prepared analogously to Example le from 4- [(6-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5-phenylaminosulfonyl-1-methyl-1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example 1b Prepared analogously to Example 1b from 4- [(5-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) methyl] benzonitrile and ethyl bromoacetate in potassium carbonate / acetone.
  • Example ld Prepared analogously to Example ld from 4- [(5-amino-1-methyl-1H-benzimidazol-2-yl) methyl] benzonitrile and methanesulfonic acid chloride in pyridine.
  • Example 1b Prepared analogously to Example 1b from 4- [(5-methanesulfonylamino-1-methyl-1H-benzimidazol-2-yl) methyl] benzonitrile, benzyl chloride and potassium carbonate in acetone.
  • Example le Prepared analogously to Example le from 4- [(5- (N- (3-ethoxycarbonyl-n-propyl) -quinoline-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N-ethoxycarbonylmethyl-quinoline-8-yl-sulfonylamino) -1-methyl-IH-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N- (3-dimethylamino-n-propyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimid-azol-2-yl) methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N-phenyl-N- (3-ethoxycarbonyl-n-propyl) aminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / Ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N- (2-dimethylaminoethyl) benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol .
  • Example le Prepared analogously to Example le from 4- [(5- (N- (2-dimethylaminoethyl) benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol .
  • Example le Prepared analogously to Example le from 4- [(5- (N-ethoxycarbonylmethyl-isoquinolin-5-yl-sulfonylamino) -methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N-methyl-piperidinocarbonylamino-1- (3-ethoxycarbonyl-propyl) -1H-benzimidazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.
  • Example le Prepared analogously to Example le from 4- [(5- (N- (2-dimethylaminoethyl) aminosulfonyl) -1- (3-ethoxycarbonyl-propyl) -1H-benzimizazol-2-yl) methyl] benzonitrile and hydrochloric acid / ammonium carbonate in ethanol.

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DE1998104085 DE19804085A1 (de) 1998-02-03 1998-02-03 5-Gliedrige heterocyclische kondensierte Benzoderivate, deren Herstellung und deren Verwendung als Arzneimittel
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Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
AR023510A1 (es) 1999-04-21 2002-09-04 Astrazeneca Ab Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina.
EP1214330A1 (en) * 1999-09-21 2002-06-19 LION Bioscience AG Benzimidazole derivatives and combinatorial libraries thereof
DK1220844T3 (da) * 1999-09-24 2003-07-28 Boehringer Ingelheim Pharma Arylsulfonamid-substituerede benzimidazolderivater og deres anvendelse som tryptase-inhibitorer
US6407130B1 (en) 1999-11-10 2002-06-18 Boehringer Ingelheim Pharma Kg Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity
DE19953899A1 (de) * 1999-11-10 2001-05-17 Boehringer Ingelheim Pharma Carboxamid-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US6451832B2 (en) 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
DE19962329A1 (de) * 1999-12-23 2001-06-28 Boehringer Ingelheim Pharma Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US6670364B2 (en) 2001-01-31 2003-12-30 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US6962926B2 (en) 2001-01-31 2005-11-08 Telik, Inc. Antagonist of MCP-1 function, and compositions and methods of use thereof
US6656956B2 (en) 2001-02-08 2003-12-02 Boehringer Ingelheim Pharma Kg Benzimidazole derivatives, processes for preparing them and their use as pharmaceutical compositions
DE10105628A1 (de) * 2001-02-08 2002-08-22 Boehringer Ingelheim Pharma Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
TWI245761B (en) 2001-03-01 2005-12-21 Telik Inc Antagonists of MCP-1 function and methods of use thereof
TWI236474B (en) 2001-04-03 2005-07-21 Telik Inc Antagonists of MCP-1 function and methods of use thereof
HUP0400467A3 (en) * 2001-04-19 2012-08-28 Eisai R & D Man Co 2-iminopyrrolidine derivatives, pharmaceutical compositions containing them and their use
DE10125478A1 (de) * 2001-05-25 2002-11-28 Boehringer Ingelheim Pharma Verwendung bicyclischer Heterocyclen zur Behandlung und Vorbeugung arterieller thrombotischer Erkrankungen
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 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
EP1569912B1 (en) 2002-12-03 2015-04-29 Pharmacyclics, Inc. 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors
AU2003215664A1 (en) * 2002-03-21 2003-10-08 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, methods for producing the same, use thereof for combating harmful fungi and agents containing said substances
JP4628678B2 (ja) * 2002-03-29 2011-02-09 ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド 置換ベンズアゾールおよびＲａｆキナーゼ阻害剤としてのそれらの使用
JP4334476B2 (ja) * 2002-07-29 2009-09-30 株式会社静岡カフェイン工業所 １，３アゾール誘導体及び同誘導体を含む血栓症治療のための医薬組成物
PE20040804A1 (es) * 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa
AU2004218187C1 (en) 2003-02-19 2011-04-07 Eisai R&D Management Co., Ltd. Methods for producing cyclic benzamidine derivatives
BRPI0515522A (pt) * 2004-09-21 2008-07-29 Athersys Inc composto, composição farmacêutica. métodos de inibir a ligação de ligandos endógenos ao receptor crth-2 em uma célula, de tratar, melhorar ou prevenir um distúrbio responsivo à inibição da ligação de ligandos endógenos ao receptor crth-2 em um animal e de preparar um composto, e, kit
ES2318556T3 (es) * 2004-11-02 2009-05-01 Pfizer, Inc. Derivados de sulfonil bencimidazol.
US7514460B2 (en) 2004-12-22 2009-04-07 4Sc Ag Benzazole analogues and uses thereof
CA2670103C (en) 2006-12-04 2012-10-16 Boehringer Ingelheim International Gmbh Inhibitors of hiv replication
EP2078711A1 (en) * 2007-12-28 2009-07-15 AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. (Aza)indole derivative substituted in position 5, pharmaceutical composition comprising it, intermediate compounds and preparation process therefor
MX2013001612A (es) * 2010-08-10 2013-07-05 Abbvie Inc Moduladores de trpv3 novedosos.
WO2012129491A1 (en) 2011-03-24 2012-09-27 Abbott Laboratories Trpv3 modulators
CA2853097A1 (en) 2011-10-24 2013-05-02 Abbvie Inc. Novel trpv3 modulators
US9056874B2 (en) 2012-05-04 2015-06-16 Novartis Ag Complement pathway modulators and uses thereof
DK2897939T3 (en) 2012-09-21 2017-05-08 Sanofi Sa BENZOIMIDAZOLCARBOXYL ACID AMIDE DERIVATIVES FOR THE TREATMENT OF METABOLIC OR CARDIOVASCULAR DISEASES
JP6488239B2 (ja) 2013-01-18 2019-03-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｒｏｃｋ阻害剤としてのフタラジノンおよびイソキノリノン
JP6387391B2 (ja) 2013-03-14 2018-09-05 ノバルティス アーゲー 眼科疾患の処置に有用な補体因子Ｂ阻害剤としての２−（１Ｈ−インドール−４−イルメチル）−３Ｈ−イミダゾ［４，５−ｂ］ピリジン−６−カルボニトリル誘導体
EP3089963A1 (en) 2013-10-30 2016-11-09 Novartis AG 2-benzyl-benzimidazole complement factor b inhibitors and uses thereof
US9902702B2 (en) 2014-07-15 2018-02-27 Bristol-Myers Squibb Company Spirocycloheptanes as inhibitors of rock
WO2016187620A2 (en) * 2015-05-21 2016-11-24 The Regents Of The University Of California Anti-cancer compounds
KR102494294B1 (ko) 2016-06-24 2023-01-31 더 리전트 오브 더 유니버시티 오브 캘리포니아 Parp1, pap2 및/또는 튜블린의 저해제로서 암 치료에 유용한 프탈라진 유도체
WO2024243692A1 (en) * 2023-05-30 2024-12-05 Queen's University At Kingston Cyp26b1 inhibitor compounds and methods of use thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3531658A1 (de) * 1985-09-05 1987-03-12 Boehringer Mannheim Gmbh Heterocyclisch substituierte indole, zwischenprodukte, verfahren zu ihrer herstellung und arzneimittel
DE3701277A1 (de) * 1987-01-17 1988-07-28 Boehringer Mannheim Gmbh Neue tricyclische benzimidazole, verfahren zu ihrer herstellung und verwendung als arzneimittel
DE4129603A1 (de) * 1991-09-06 1993-03-11 Thomae Gmbh Dr K Kondensierte 5-gliedrige heterocyclen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
ZA928276B (en) * 1991-10-31 1993-05-06 Daiichi Seiyaku Co Aromatic amidine derivates and salts thereof.
DE4213919A1 (de) * 1992-04-28 1993-11-04 Thomae Gmbh Dr K Cyclische iminoderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
US5342851A (en) * 1992-10-07 1994-08-30 Mcneil-Ppc, Inc. Substituted thiazole derivatives useful as platelet aggregation inhibitors
CA2134192A1 (en) * 1993-11-12 1995-05-13 Michael L. Denney 5, 6-bicyclic glycoprotein iib/iiia antagonists
PE121699A1 (es) * 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
DE19718181A1 (de) * 1997-04-30 1998-11-05 Boehringer Ingelheim Pharma Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9940072A1 *

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