EP1748997A1 - Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament - Google Patents

Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament

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Publication number
EP1748997A1
EP1748997A1 EP05745599A EP05745599A EP1748997A1 EP 1748997 A1 EP1748997 A1 EP 1748997A1 EP 05745599 A EP05745599 A EP 05745599A EP 05745599 A EP05745599 A EP 05745599A EP 1748997 A1 EP1748997 A1 EP 1748997A1
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EP
European Patent Office
Prior art keywords
group
alkyl
atom
amino
methyl
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
EP05745599A
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German (de)
English (en)
Inventor
Roland Pfau
Henning Priepke
Kai Gerlach
Wolfgang Wienen
Annette Schuler-Metz
Herbert Nar
Sandra Handschuh
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 International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP05745599A priority Critical patent/EP1748997A1/fr
Publication of EP1748997A1 publication Critical patent/EP1748997A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to new substituted thiophene-2-carboxamides of the general formula
  • the compounds of the above general formula I and their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa inhibitory effect.
  • the present application thus relates to the new compounds of the general formula I above, their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.
  • n 1 or 2
  • R 8a each independently represent a hydrogen or halogen atom or a C ⁇ alkyl -5 alkyl, hydroxy, hydroxy-C ⁇ -5, C ⁇ -5 alkoxy, C ⁇ -C ⁇ -5 alkoxy, alkyl 5 , Amino-, C ⁇ -5 -alkylamino-, Di- (C 1-5 -alkyl) -amino-, Amino-Cis-alkyl-, C ⁇ -5 -Alkylamino-C ⁇ -5 -alkyl-, Di- (C ⁇ - 5 -alkyl) -amino-C ⁇ -5 -alkyl-, Aminocarbonyl, C ⁇ -5 -alkylaminocarbonyl, di- (C -5 -alkyl) -aminocarbonyl- or C ⁇ -5-alkylcarbonylamino group means, with the above-mentioned substituted 5- to 7-membered radicals A which, optionally with R
  • R 8b each independently represents a hydrogen atom or a C 5 alkyl group
  • R 8c each independently of one another a hydrogen atom, a C- ⁇ . 5 -alkyl-, d- 5 -alkylcarbonyl-, -C ⁇ -5 -alkyloxycarbonyl- or C ⁇ -5 -alkylsulfonyl group,
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 2 is an oxygen atom or an -NR 8b group
  • X 3 is an oxygen or sulfur atom, an -NR 8c group,
  • X 4 is a carbonyl or sulfonyl group
  • X 5 is an oxygen atom, an -NR 8b - or methylene group
  • X 6 is an oxygen or sulfur atom or an -NR 8c group
  • X 7 represents a methylene or carbonyl group
  • R 1 is a hydrogen or halogen atom, a C -3 alkyl or C 3 -3 alkoxy group, where the hydrogen atoms of the C 1-3 alkyl or C 3 -C 3 alkoxy group can optionally be completely or partially replaced by fluorine atoms represents a C 2-3 alkenyl, C 2-3 alkynyl, nitrile, nitro or amino group, R 2 represents a hydrogen or halogen atom or a C 3 -3 alkyl group,
  • R 3 represents a hydrogen atom or a C ⁇ -3 alkyl group
  • R 4 and R 5 each independently of one another are a hydrogen atom, a C 2 -6-alkenyl or C 2-6 -alkynyl group, a straight-chain or branched C ⁇ - 6 -alkyl group, the hydrogen atoms of the straight-chain or branched C- ⁇ - 6 - Alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a nitrile, hydroxyl, C 1 -C 5 -alkyloxy group, where the hydrogen atoms of the C 5 -5 -alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, an allyloxy -, Propargyloxy-, benzyloxy-, C 1-5 -alkylcarbonyloxy-, C ⁇ -5 -alkyloxycarbonyloxy-, carboxy-C ⁇ -5 -alkyloxy-, C ⁇ - 5 -alkyloxycarbonyl-C
  • R 4 and R 5 together with the carbon atom to which they are attached, a C 3- 8 cycloalkyl or C 3-8 cycloalkenyl form, wherein one of the methylene groups of a C 4-8 cycloalkyl group through an oxygen or sulfur atom or a -N (R 8c ) -, or a carbonyl, sulfinyl or sulfonyl group can be replaced, and / or two directly adjacent methylene groups of a C 4 - 8 cycloalkyl group together by a -C (0) N (R 8b ) - or - S (0) 2 N (R 8b ) group can be replaced, and / or three directly adjacent methylene groups of a C ⁇ - ⁇ -cycloalkyl group together by one -OC (0) N (R 8b ) -, N (R 8) C (O) N (R 8b) - or -N (R 8b) S (O) 2 N (R 8b
  • C 4- s cycloalkenyl group which are not bonded to another carbon atom by a double bond, optionally independently of one another by in each case one or two identical or different halogen atoms or hydroxyl, C 5 -5 -alkyloxy, d- 5-alkylcarbonyloxy-, d-5-alkylsulfanyl-, C ⁇ -5 -alkylsulfonyl-, amino-, d -5 -alkylamino-, di- (C- ⁇ .
  • R 6 represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitrite group, a C -3 alkyl group or a C 3 -3 alkoxy group, the hydrogen atoms of the d -3 alkyl or C 3 - 3 -
  • the alkoxy group can optionally be completely or partially replaced by fluorine atoms,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a d- 3 -alkyl, phenyl or phenyl-C ⁇ -3 alkyl group, an oxygen or sulfur atom or an optionally by a C -3 alkyl, phenyl, amino -C 2-3 -alkyl-, C ⁇ - 3 -alkylamino-C -3 -alkyl-, di- (d -3 -alkyl) -amino-C2-3-alkyl-, a C 3 -6- cycloalkylenimino-C ⁇ - 3 -alkyl- or phenyl-C 1-3 -alkyl group substituted imino group or an oxygen or sulfur atom
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylations mentioned above Radicals, for example the dialkylamino groups, can be the same or different,
  • Examples of monocyclic heteroaryl groups are the pyridyl, N-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1, 2,3] triazinyl, [1, 3,5] triazinyl, [1 , 2,4] triazinyl, pyrrolyl, imidazolyl, [1, 2,4] triazolyl, [1, 2,3] triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1, 2 , 3] oxadiazolyl, [1, 2.4] oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1, 2.3] thiadiazolyl, [1, 2.4] thiadiazolyl or [1 , 2,5] thiadiazolyl group.
  • bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo [c] furanyl, benzothiophenyl, benzo [c] thiophenyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [e] isothiazolyl, benzooxazolyl, benzo c] isoxazolyl-, benzo [ ⁇ f
  • C 6 alkyl groups mentioned above in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, te / t-butyl, 1- Pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyi, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2-dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.
  • Examples of those mentioned above in the definitions d- 5 -Alkyloxy groups are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, ferf-butyloxy, 1-pentyloxy, 2-pentyloxy, 3- Pentyloxy or neo-pentyloxy group.
  • C 2-6 alkenyl groups are the ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-butene -1 -yl-, 1-penten-1-yl-, 2-penten-1-yl-, 3-penten-1-yl-, 4-penten-1 -yl-, 1-hexen-1-yl- , 2-Hexen-1 -yl-, 3-Hexen-1-yl-, 4-Hexen-1 -yl-, 5-Hexen-1-yl-, But-1-en-2-yl-, But- 2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, pent-1-en-2-yl, pent-2- en-2-yl-, pent-3-en-2-yl-, pent-4-en-2-yl-, pent-1-en-3-yl-, pent-2-en-3-y
  • Examples of the C 2-6 alkynyl groups mentioned above in the definitions are the ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1-yl, 1-butyn-3-yl, 2-butyne -1-yl-, 3-butyn-1-yl-, 1-pentyn-1-yl-, 1-pentyn-3-yl-, 1-pentyn-4-yl-, 2-pentyn-1-yl- , 2 .pentin-3-yl-, 3-pentin-1-yl-, 4-pentin-1-yl-, 2-methyl-1-butyn-4-yl-, 3-methyl-1-butyn-1 -yl-, 3-Methyl-1-butin-3-yl-, 1-Hexin-1-yl-, 2-Hexin-1-yl-, 3-Hexin-1-yl-, 4-Hexin-1- yl-, 5-hexin-1-yl-, 1-he
  • a group which can be converted into a carboxy group in vivo includes, for example, a carboxy group esterified with an alcohol, ii.n. "De ⁇ , r is the alcoholic moiety is preferably a d- 6 alkanol, a phenyl-C ⁇ - 3 -alkanol, a C 3-9 -CycIoalkanol, a C 5-7 -Cycloalkenol, a C 3-5 alkenol, a phenyl C 3-5 -alkenol, a C 3 - 5 -alkinol or phenyl-C 3-5 -alkinol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C 3- 8- cycloalkyl-d- 3- alkanol or an alcohol of the formula
  • R 9 is a C ⁇ -8 alkyl, C 5 -7-CycloaIkyl-, phenyl or phenyl-C ⁇ alkyl group -3,
  • R 10 represents a hydrogen atom, ad -3 -alkyl, C 5 -7-cycloalkyl or phenyl group and R 11 represents a hydrogen atom or ad- 3 -alkyl group,
  • the preferred radicals which can be split off from a carboxy group in vivo are ad- 6 -alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, ⁇ -hexyioxy or cyclohexyloxy group or one Phenyl-C ⁇ - 3 alkoxy group as the benzyloxy group into consideration.
  • a group which can be converted into a hydroxyl group in vivo is, for example, a hydroxyl group esterified with a carboxylic acid, in which the carboxylic acid part is preferably a -C 7 alkane acid, a phenyl C 3 -3 alkanoic acid, a C 3 g cycloalkyl carboxylic acid, a C 5 -7 -Cycloalkencarbonchure, a C 3-7 -AI ken Textre, a phenyl C 3-5 alkenoic, a C 3-7 -Alkinklad or phenyl-C 3-5 -alkinklad, where individual methylene groups in the carboxylic acid radical may be replaced by oxygen atoms can be understood with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond.
  • the carboxylic acid part is preferably a -C 7 alkane acid, a phenyl C 3 -3 al
  • a C 7 -acyl group such as the formyl, acetyl, n-propionyl, isopropionyl, r? -Propanoyl, n-butanoyl, ⁇ -pentanoyl, n- come as preferred residues which can be split off from a hydroxyl group in vivo.
  • Methoxyacetyl 1-methoxypropionyl; 2-methoxypropionyl or 2-methoxyethoxyacetyl group into consideration.
  • Those compounds of the general formula I in which A, R 4 and / or R 5 contain a group which can be converted into a carboxy or hydroxyl group in vivo are prodrugs for those compounds of the general formula I in which A, R 4 and / or R 5 contains a carboxy or hydroxyl group.
  • A is a radical of the general formula
  • n 1 or 2
  • R 8a each independently represent a hydrogen or halogen atom or a C ⁇ alkyl -5 alkyl, hydroxy, hydroxy-C ⁇ -5, C ⁇ -5 alkoxy, C ⁇ -5 alkoxy-5 C ⁇ - alkyl , Amino-, d -5 -alkylamino-, di- (-C ⁇ -5 -alkyl) -amino-, amino-C ⁇ -5 -aIkyl-, C ⁇ -5 -alkylamino-C ⁇ -5 -alkyl-, Di- (d - 5 -Alkyl) -amino-C ⁇ - 5 alkyl, aminocarbonyl, d -5 -alkylaminocarbonyl, di- (d -5 -alkyl) aminocarbonyl or d-5-alkylcarbonylamino group, with those mentioned above substituted 5- to 7-membered radicals A, the heteroatoms F, CI, Br, I, O or N optionally
  • R 8b each independently represents a hydrogen atom or a d- 5 alkyl group
  • R 8c each independently represent a hydrogen atom, a C ⁇ -5 alkyl, d-5-alkylcarbonyl, C ⁇ -5 alkyloxycarbonyl- or ds-alkylsulfonyl means
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 3 is an oxygen or sulfur atom, an -NR 8c group,
  • X 4 represents a carbonyl or sulfonyl group
  • R 1 is a halogen atom, a d-3-alkyl or d -3 -alkoxy group, where the hydrogen atoms of the C-3-alkyl or d -3 -alkoxy group can optionally be wholly or partly replaced by fluorine atoms, a C 2-3 Means alkenyl, C -3 alkynyl, nitrile, nitro or amino group, R 2 represents a hydrogen or halogen atom or ad -3 alkyl group,
  • R 3 represents a hydrogen atom or a C 3 alkyl group
  • R 4 and R 5 are each independently a hydrogen atom, a C 2-6 or C 2-6 -AlkenyI- -AlkinyIrios, a linear or branched C ⁇ -6 alkyl group, wherein the hydrogen atoms of the straight-chain or branched alkyl group C ⁇ - 6 can optionally be wholly or partly replaced by fluorine atoms, and which can optionally be replaced by a nitrile, hydroxy or a C ⁇ -5 alkyloxy group, where the hydrogen atoms of the C ⁇ -5 alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, an allyloxy , Propargyloxy-, Benzyloxy-, C ⁇ -5 -Alkylcarbonyloxy-, C ⁇ -5 -Alkyloxycarbonyloxy-, Carboxy-C ⁇ -5 -alkyloxy-, C ⁇ - 5 -Alkyloxycarbonyl-C ⁇ - 5 -alky
  • 6 -Cycloalkylcarbonylamino group can be substituted, a carboxy, aminocarbonyl, C ⁇ -5 -alkylaminocarbonyl-, C 3 - 6 -Cycioalkylaminocarbonyl-, di- (d -5 -alkyl) -aminocarbonyl-, C ⁇ - 5 -alkoxycarbonyl-, C -6 -cycloalkyleneiminocarbonyl group, a phenyl-, heteroaryl-, phenyl-d -5 -alkyl- or heteroaryl-
  • C ⁇ - 5 alkyl group which is optionally monosubstituted in the phenyl or heteroaryl moiety to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, d-5 alkyl, di (d -5 alkyl) amino, Hydroxy, C ⁇ -5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and d- 5 alkyloxycarbonyl groups can be substituted,
  • a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl- d- 5 -alkyl or cycloalkylenimino-C ⁇ -3-alkyl group in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R 8o ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) 2 - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together may optionally be replaced by a -C (O) N (R 8b ) - or -S (0) 2 N (R 8b ) group, or in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally with a substituted -OC (0) N (R 8b ) - or -N (R 8b ) C (O
  • R 4 and R 5 together with the carbon atom to which they are attached, a C 3 - 8 cycloalkyl or C 3-8 cycloalkenyl form, wherein one of the methylene groups of a ds-cycloalkyl group through an oxygen or sulfur atom or a - N (R 8c ) -, or a carbonyl, sulfinyl or sulfonyl group can be replaced, and / or two directly adjacent methylene groups of a d- 8 -cycloalkyl group together by a -C (O) N (R 8b ) - or - S (O) 2 N (R 8b ) group can be replaced, and / or three directly adjacent methylene groups of a C 6- 8 cycloalkyl group together by one -OC (0) N (R 8b ) -, - N (R 8b ) C (O) N (R 8b ) - or -N (R 8b ) S
  • Carboxy-, d -5 -alkyloxycarbonyl-, aminocarbonyl-, -C ⁇ - 5 -AI ky lami nocarbonyl-, di- (C ⁇ -5 -alkyl) -ami nocarbonyl-, C 3 - 6 -cycloalkyleniminocarbonyl-, aminosulfonyl-, C ⁇ - 5 -Alkylaminosulfonyl-, di- (-C ⁇ - 5 -alkyl) -aminosulfonyl-, C 3 -6-Cycloalkyleniminosulfonyl phenomenon can be substituted,
  • R 6 represents a fluorine, chlorine, bromine or iodine atom, a nitrite group, a C 3 alkyl group, or a C 3 alkoxy group, the hydrogen atoms of the C 3 alkyl or C 3 alkoxy group optionally can be replaced in whole or in part by fluorine atoms,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a d- 3 -alkyl, phenyl or phenyl-C 3 -C 3 -alkyl group, an oxygen or sulfur atom or an optionally by a C 3 -3 -alkyl, phenyl, amino -C 2-3 -alkyl-, C ⁇ - 3 -alkylamino-C 2 -3-alkyl-, di- (C ⁇ - 3 -alkyl) -amino-C 2-3 -alkyl-, a C 3- 6- cycloalkyIenimino -C ⁇ -3 -alkyl- or phenyl-C ⁇ -3 -alkyl group substituted im
  • ⁇ one optionally by a C ⁇ - 3 alkyl or phenyl-C ⁇ -3 alkyl group contains substituted imino group and two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a C 1-3 alkyl, hydroxy, C ⁇ -3 - Alkyloxy group, amino, C- ⁇ -3 alkylamino, di- (C ⁇ -3 alkyl) - amino or C 3 - 6 cycloalkyleneimino group substituted phenyl ring can be fused on and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylations mentioned above Radicals, for example the dialkylamino groups, can be the same or different,
  • A is a radical of the general formula
  • R 8a each independently represent a hydrogen or halogen atom or a d -5 alkyl, hydroxy, hydroxy-C ⁇ -5 alkyl, d -5 alkoxy, d- ⁇ alkoxy-d. 5-alkyl, amino, d.
  • R 8b are each independently a hydrogen atom or a C ⁇ means -5 alkyl group
  • R 8c each independently represents a hydrogen atom, a C 5 alkyl, Ci.s aikylcarbonyl, d 5 alkyloxycarbonyl or d 5 alkyl sulfonyl group,
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 3 is an oxygen atom or an -NR 8c group
  • X 4 represents a carbonyl or sulfonyl group
  • R 1 is a halogen atom, a d-3-alkyl or d- 3 alkoxy group, where the hydrogen atoms of the C 3 -3 -alkyl or d -3- alkoxy group can optionally be replaced in whole or in part by fluorine atoms, or represents a nitrite group,
  • R 2 represents a hydrogen or halogen atom or a methyl group
  • R 3 represents a hydrogen atom or a methyl group
  • R 4 is a hydrogen atom, a C 2-6 alkenyl or C 2-6 alkynyl group, a linear or branched C ⁇ -6 alkyl group, wherein the hydrogen atoms of the straight-chain or branched C ⁇ - C6 alkyl group optionally wholly or partially replaced by fluorine atoms may be, and which may optionally be replaced by a nitrile, hydroxy or a C 5 alkyloxy group, where the hydrogen atoms of the d 5 alkyloxy group may be replaced in whole or in part by fluorine atoms, a benzyloxy, d -5 alkylcarbonyloxy , C ⁇ - 5 -alkyloxycarbonyloxy-, carboxy-d -5 -alkyloxy-, d -5 -alkyloxycarbonyl- C ⁇ -5 -alkyloxy-, d- 5 -AlsuIfanyl-, d -5 -alkylsulfony
  • a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d -5 -alkyl or cycloalkylenimino-d- 3- alkyl group as defined above contains exactly two heteroatoms from the group oxygen and nitrogen an optionally substituted -CH 2 group are separated from one another is excluded,
  • the hydrogen atoms of the straight-chain or branched d- 6 -alkyl group can optionally be completely or partly replaced by fluorine atoms, and which can optionally be substituted by a C ⁇ - 5 -alkyloxy group, where the hydrogen atoms of the Ci.s-alkyloxy group can optionally be completely or partly replaced by fluorine atoms , or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-8 -cycloalkyl or C 3 form -8-cycloalkenyl group, wherein one of the methylene groups of a C -s cycloalkyl group through an oxygen atom or a -N (R 80 ) -, or a carbonyl or sulfonyl group can be replaced, and / or two directly adjacent methylene groups of a C 4-8 cycloalkyl group together by a -C (O) N (R 8b ) - or - S (0) 2 N (R 8b ) group can be replaced, and / or three directly adjacent methylene groups of a C 6-8 - cycloalkyl group together by one -OC (O) N (R 8b ) -, - N (R 8b ) C (O ) N (R 8b ) - or -N (R 8b ) S (O) 2 N (R 8
  • C 3-8 cycloalkenyl optionally substituted independently from each other by one or two identical or different C ⁇ -5 - alkyl, nitrile, carboxy-C ⁇ -5 -alkyl,. 5 -alkyloxycarbonyl-C ⁇ - 5 -alkyl, carboxy-, d -5 -alkyloxycarbonyl-, aminocarbonyl-, d- 5 -alkylaminocarbonyl-, di- (d -5 -alkyl) -aminocarbonyl-,
  • C 3 - 6 -cycloalkyleneiminocarbonyl-, aminosulfonyl, C ⁇ -5 -alkylaminosulfonyl-, di- (C ⁇ -5 -alkyl) -aminosulfonyl-, C 3-6 -cycloalkyleneiminosulfonyl groups may be substituted,
  • Cycloalkenyl group which are not bound by a double bond to another carbon atom, optionally independently of one another by one or two identical or different fluorine atoms or hydroxy ⁇ , C ⁇ -5 -alkyloxy-, C ⁇ - 5 -alkylcarbonyloxy-, C ⁇ -5 -alkylsulfanyl- , C ⁇ -5 -AkylsulfonyI-,
  • R 6 is a fluorine, chlorine, bromine or iodine atom, a Nitrii devis, a C ⁇ -3 alkyl or a C ⁇ - 3 alkoxy group, the hydrogen atoms of the d- 3 alkyl or C 1-3 alkoxy group can be completely or partially replaced by fluorine atoms, if appropriate,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a d- 3 alkyl, phenyl or phenyl-C 1-3 alkyl group, an oxygen or sulfur atom or an optionally by a C -3 alkyl, phenyl, amino-C 2-3 alkyl, d.3-alkylamino C 2-3 alkyl, di (C 3 -3 alkyl) amino C 2-3 alkyl, a C 3-6 - CycloalkyIenimino-C ⁇ - 3 alkyl or phenyl-C ⁇ -3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an optionally by a C ⁇ -3 -Alkyl-
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, can be straight-chain or branched, and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, can be the same or different,
  • A is a radical of the general formula
  • n 1 or 2
  • R 8a each independently of one another a hydrogen or halogen atom or a C 1-3 alkyl, hydroxy, hydroxy -CC -3 alkyl, -C 3 alkoxy, d. 3 -alkoxy-d. 3 -alkyl-, amino-, C ⁇ - 3 -alkylamino-, di- (C ⁇ -3 -alkyl) -amino-, amino-C ⁇ -3 -alkyl-, C ⁇ -3 -alkylamino-C ⁇ -3 -alkyl-, Di- (C ⁇ -3 -alkyl) -amino-C ⁇ - 3 -alkyl-, aminocarbonyl-, C ⁇ -3 -alkylaminocarbonyl-, di- (C ⁇ -3 -alkyl) -aminocarbonyl- or C ⁇ -3- alkylcarbonylamino group, where in the above-mentioned substituted 5- to 7-membered radicals A the hetero
  • R 8b each independently represents a hydrogen atom or a d- 3 -alkyl group
  • R 8c each independently represents a hydrogen atom, ad -3- alkyl, d-3-alkylcarbonyl, C ⁇ -4 -alkyloxycarbonyl or C 1-3 -alkylsulfonyl group,
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 3 is an oxygen atom or an -NR 8c group
  • X 4 represents a carbonyl or sulfonyl group
  • R 1 is a fluorine, chlorine, bron> or iodine atom, a C 3 alkyl or C 3 alkoxy group, the hydrogen atoms of the d 3 alkyl or C 3 alkoxy group optionally being wholly or partly by Fluorine atoms can be replaced
  • R 2 represents a hydrogen or halogen atom or a methyl group
  • R 3 represents a hydrogen atom
  • R 4 is a hydrogen atom, a C 2-4 alkenyl or C 2-4 alkynyl group, a straight-chain or branched C -4 alkyl group, the hydrogen atoms of the straight-chain or branched C -4 alkyl group optionally being replaced in whole or in part by fluorine atoms can be, and optionally by a nitrile, hydroxy ad 3 -alkyloxy group, the hydrogen atoms of the C ⁇ - 3 alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, a benzyloxy, d -3 -alkylcarbonyloxy, C ⁇ - 3 alkyloxycarbonyl-C ⁇ -3 -alkyloxy-, -C-3-alkyloxycarbonyl, aminocarbonyl, C ⁇ -3- alkylaminocarbonyl-, di- (C ⁇ -3 -alkyl) -aminocarbonyl-, C 3 - 6 -cycl
  • R is a hydrogen atom, a C 2-4 alkenyl or C 2 - alkynyl group, a straight-chain or branched C 4 alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched d- alkyl group to be replaced in whole or in part by fluorine atoms, and which may optionally be substituted by a C 3 alkyloxy group, where the hydrogen atoms of the d 3 alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, or
  • R 4 and R 5 together with the carbon atom to which they are attached a C 3-8 cycloalkyl or C 3-8 cycloalkenyl form
  • one of the methylene groups of a C 4-8 cycloalkyl group can be replaced by an oxygen atom or an -N (R 8c ) group, and / or
  • one or two carbon atoms of a C 3-8 cycloalkyl group optionally independently of one another, each with a C1-3 alkyl, hydroxy, C 3 -3 alkyloxy, C 3 -3 alkylcarbonyloxy, C 3 alkyloxycarbonyl, amino -, -C ⁇ -3- Alkylamino-, di- (C ⁇ -3 -alkyl) - amino-, d -3 -Alkylcarbonylamino-, or d -3 -Alkyl- sulfonylamino group may be substituted,
  • Alkyl groups can be substituted
  • the methoxy group can optionally be completely or partially replaced by fluorine atoms, where, unless stated otherwise, the term "heteroaryl group” mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 3 alkyl, phenyl or phenyl C 3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a -3 alkyl, phenyl or amino C 2.
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine, where the alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, may be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,
  • A is a radical of the general formula
  • R 8b each independently represents a hydrogen atom or a d- 3 -alkyl group
  • R 8c each independently represents a hydrogen atom, ad -3 -alkyl- d- 3 -alkylcarbonyl or C ⁇ - -alkyloxycarbonyl group,
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 3 is an oxygen atom or an -NR 8c group
  • X 4 represents a carbonyl group
  • R 1 represents a fluorine, chlorine, bromine or iodine atom, a methyl or methoxy group, it being possible for the hydrogen atoms of the methyl or methoxy group to be replaced in whole or in part by fluorine atoms,
  • R 2 represents a hydrogen or fluorine atom
  • R 3 represents a hydrogen atom
  • R 4 is a hydrogen atom, a straight-chain or branched d -4 -alkyl group, where the hydrogen atoms of the straight-chain or branched C -4 alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a hydroxy, a C 1.
  • a phenyl, heteroaryl, phenyl-d -3 -alkyl or heteroaryl-d- 3 -alkyl group which, in the phenyl or heteroaryl part, is optionally selected one to three times by identical or different substituents selected from the group consisting of halogen atoms, 3 alkyl, di (C 3 -3 alkyl) amino, hydroxyl, C 3 3 alkyloxy, mono-, di or trifluoromethoxy groups may be substituted,
  • a straight-chain or branched C ⁇ - alkyl group where the hydrogen atoms of the straight-chain or branched C ⁇ -4 alkyl group can optionally be wholly or partly replaced by fluorine atoms, and optionally by a d-3-alkyloxy group, the hydrogen atoms of the C ⁇ -3 - Alkyloxy group can optionally be completely or partially replaced by fluorine atoms, can be substituted, means or
  • R 4 and R together with the carbon atom to which they are attached, a C 3 5 - wherein one of the methylene groups of a C -8 cycloalkyl be replaced by an oxygen atom or a group -N (R 8c) form 8 cycloalkyl group, can, and / or two directly adjacent methylene groups of a C -8- cycloalkyl group together can be replaced by a -C (O) N (R 8b ) - or - S (0) 2 N (R 8b ) group, and / or three directly adjacent methylene groups of a C 6- 8 cycloalkyl group together by a -OC (0) N (R 8b ) -, - N (R 8b ) C (O) N (R 8 ) - or -N (R 8b ) S (O) 2 N (R 8b ) group can be replaced, where one or two carbon atoms of a C 3-8 cycloalkyl group, if appropriate
  • R 6 represents a fluorine, chlorine, bromine or iodine atom, a methyl group or a methoxy group, where the hydrogen atoms of the methyl group or methoxy group can optionally be wholly or partly replaced by fluorine atoms,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a d- 3 -alkyl, phenyl or phenyl-C ⁇ -3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a C ⁇ > -3 alkyl, phenyl, Amino-C 2 - 3 -alkyl-, C ⁇ -3 -alkylamino-C 2 -3-alkyl-, di- (C ⁇ -3-alkyl) -amino-C 2 - 3 -alkyl-, a C 3-6 - Cycloalkylenimino-C ⁇ .3-alkyl or phenyl-d -3 -Alkyl distr substituted imino
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl and alkoxy groups contained in the definitions mentioned above which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylated radicals mentioned above, for example the dialkylamino groups, can be identical or different . and the hydrogen atoms of the methyl or ethyl groups contained in the definitions mentioned above can be replaced in whole or in part by fluorine atoms,
  • A is a radical of the general formula
  • n 1 or 2
  • R 8a are each independently a hydrogen or.
  • Halogen atom or a C -3 alkyl, hydroxy, hydroxy C -3 alkyl, d -3 alkoxy, C -3 alkoxy C 3 alkyl, amino, C -3 alkyl amino-, di- (C ⁇ -3- alkyl) -amino-, amino-C ⁇ -3 -alkyl-, ds-alkylamino-Ci-s-alkyl-, or di- (C ⁇ - 3 -alkyl) -amino-C ⁇ -3- alkyl group means, in the case of the above-mentioned substituted 5- to 7- membered radicals A, the heteroatoms F, CI, Br, I, O or N, optionally introduced with R 8a as substituents, are not separated from a heteroatom from the group N, 0, S by exactly one carbon atom,
  • R 8c each independently represents a hydrogen atom, ad -3 -alkyl-, d- 3 -alkylcarbonyl-, or -CC -alkyloxycarbonyl,
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 3 is an oxygen atom or an -NR 8c group
  • X 4 represents a carbonyl group
  • R 1 represents a fluorine, chlorine, bromine or iodine atom, a methyl or methoxy group, it being possible for the hydrogen atoms of the methyl or methoxy group to be replaced in whole or in part by fluorine atoms,
  • R 2 represents a hydrogen or fluorine atom
  • R 3 represents a hydrogen atom
  • R 4 is a hydrogen atom, a straight-chain or branched C ⁇ - alkyl group, where the hydrogen atoms of the straight-chain or branched C ⁇ -4 alkyl group can optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a hydroxy, a C ⁇ .
  • R> 5 ° is a hydrogen atom, a straight-chain or branched C 1 -C 4 -alkyl group, where the hydrogen atoms of the straight-chain or branched d- 4 -alkyl group can optionally be completely or partially replaced by fluorine atoms, and which may optionally be replaced by a d- 3 - Alkyloxy group, where the hydrogen atoms of the -C 3 alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, means, or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C3 -8- cycloalkyl group, whereby one of the methylene groups of a C -8- cycloalkyl group can be replaced by an oxygen atom or an -N (R 8o ) group .
  • R 8o -N
  • one or two carbon atoms of a C 3 . 8 -CycloaIkyl optionally independently of each other by a C ⁇ -3 - alkyl, hydroxy, d -3 -alkyloxy, or di- (d -3 -alkyl) amino group may be substituted,
  • R 6 represents a fluorine, chlorine, bromine or iodine atom
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 3 alkyl, phenyl or phenyl d 3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a C 3 alkyl, phenyl, amino C 2-3 alkyl, C ⁇ -3 alkylamino-C2-3-alkyl, di- (3 C ⁇ - -alkyl) -amino-C 2-3 -alkyl, C 3-6 - Cycloalkylenimino-d-3-alkyl - or phenyl-C 1-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a
  • alkyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylated radicals mentioned above, for example the dialkylamino groups, can be identical or different .
  • A is a radical of the general formula
  • R 8a are each independently a hydrogen or halogen atom or ad -3 alkyl, hydroxy, hydroxy d -3 alkyl, C -3 alkoxy, d 3 alkoxy d. 3 -alkyl-, amino-, C ⁇ -3 -alkylamino-, di- (C ⁇ -3 -alkyl) -amino-, amino-C ⁇ -3 -alkyl-, C ⁇ -3 -alkylamino-C ⁇ -3 -alkyl-, or di- (-C 3 -alkyl) -amino-C ⁇ - 3 alkyl group, wherein in the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, CI, Br, I optionally introduced with R 8a as substituents , O or N are not separated from a hetero atom from the group N, O, S by exactly one carbon atom,
  • R 8c each independently represents a hydrogen atom, a C 3 alkyl, C 3 alkylcarbonyl or C 1 alkyloxycarbonyl group,
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • X 3 is an oxygen atom or an -NR 8o group
  • R 1 represents a fluorine, chlorine or bromine atom, a methyl, trifluoromethyl or methoxy group
  • R 2 represents a hydrogen or fluorine atom
  • R 3 represents a hydrogen atom
  • R 4 is a straight-chain or branched C -4 alkyl group, where the hydrogen atoms of the straight-chain or branched C -4 alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a hydroxy, a d- 3 alkyloxy group, where the hydrogen atoms of the d- 3 -alkyloxy group can optionally be completely or partially replaced by fluorine atoms, a benzyloxy-, d- 3 -alkylcarbonyloxy-, d-3-alkyloxycarbonyl-, aminocarbonyl-, C ⁇ -3 -alkylaminocarbonyl-, di- (C ⁇ -3 -alkyl) -aminocarbonyl-, C 3 -6-cycloalkyleniminocarbonyl-, aminosulfonyl-, C ⁇ , 3 -alkylaminosulfonyl-, di- (C 1-3 -al
  • R 5 is a hydrogen atom, or a straight-chain or branched d -4 -alkyl group, where the hydrogen atoms of the straight-chain or branched C ⁇ - 4 alkyl group can optionally be wholly or partly replaced by fluorine atoms, and which may be replaced by a C ⁇ - 3 alkyloxy group, where the hydrogen atoms of the d- 3- alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, means, or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl group, one of the methylene groups of a C 4-8 cycloalkyl group can be replaced by an oxygen atom or an -N (R 8c ) group,
  • Alkyl, hydroxy, C ⁇ -3 alkyloxy or di (C ⁇ -3 alkyl) amino group may be substituted
  • R 6 represents a chlorine or bromine atom
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 3 alkyl, phenyl or phenyl C 3 alkyl group, an oxygen or sulfur atom or an optionally by a d 3 alkyl, phenyl, amino C 2-3 -alkyl-, C ⁇ -3 -alkylamino-C 2-3 -alkyl-, di- (C ⁇ -3 -alkyl) -amino-C 2-3 -alkyl-, a C 3-6 - cycloalkylenimino-d- 3 - contains alkyl or phenyl-C -3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imin
  • alkyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylated radicals mentioned above, for example the dialkylamino groups, can be identical or different .
  • An eighth embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 1, 2, 3, 4, 5, 6 and 7 in which R 4 and R 5 are not hydrogen.
  • a ninth embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 1, 2, 3, 4, 5, 6, 7 and 8 in which R 6 denotes a bromine atom.
  • a 10th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 1, 2, 3, 4, 5, 6, 7, 8 and 9 in which R 4 and R 5 are not hydrogen and R 6 is a bromine atom ,
  • An 11th embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula
  • R 8a each independently represent a hydrogen or fluorine atom or a C ⁇ -5 alkyl, hydroxy, hydroxy-alkyl C ⁇ -5, d -5 alkoxy, C1-5 alkoxy-C ⁇ . 5 -alkyl-, amino-, d -5 -alkylamino-, di- (C ⁇ -5 -alkyl) -amino-, amino-C ⁇ -5 -alkyl-, d -5 -alkylamino-C ⁇ .
  • R 8b each independently represents a hydrogen atom or a C 5 alkyl group
  • X 1 is an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group,
  • R 8c each independently represents a hydrogen atom, a d-5-alkyl, C ⁇ - 5 alkylcarbonyl, C ⁇ -5 -alkyloxycarbonyl or d -5 -alkylsulfonyl group,
  • X 2 is an oxygen atom or an -NR 8b group
  • X 3 is an oxygen or sulfur atom, an -NR 8c group,
  • X 4 is a carbonyl or sulfonyl group
  • X 5 is an oxygen atom, an -NR 8b - or methylene group
  • X 6 is an oxygen or sulfur atom or an -NR 8c group
  • X 7 represents a methylene or carbonyl group
  • R 1 is a hydrogen, fluorine, chlorine, bromine or iodine atom, a C 3 alkyl or C 3 alkoxy group, the hydrogen atoms of the d 3 alkyl or C 3 alkoxy group optionally completely or partly due to fluorine atoms can be replaced, means a C 2-3 alkenyl, C 2 -3 alkynyl, nitrile, nitro or amino group,
  • R 2 represents a hydrogen or halogen atom or a C- ⁇ -3 alkyl group
  • R 3 represents a hydrogen atom or a C 3 alkyl group
  • R 4 and R 5 each independently represent a hydrogen atom, a C 2-6 alkenyl or C 2-6 alkynyl group, a straight-chain or branched d -6 -alkyl group, the hydrogen atoms of the straight-chain or branched d-6-alkyl group optionally may be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a C3-5-cycloalkyl group, a nitrile, hydroxyl or a Ci.s-alkyloxy group, the hydrogen atoms of the d-5-alkyloxy group optionally being wholly or partly replaced by fluorine atoms can be an allyloxy, propargyloxy, benzyloxy, C ⁇ -5 -Alkylcarbonyloxy-, d -5 -alkyloxycarbonyloxy-, carboxy-d-5-alkyloxy-, C ⁇ -5 -alkyloxycarbonyl-C ⁇ -5 -alky
  • 5 -alkyla ⁇ ino- or C3-6-cycloalkylcarbonylamino group can be substituted, a carboxy, aminocarbonyl, d -5 -alkylamino nocarbonyl, C 3 -6-cycloalkylaminocarbonyl, di - (-C ⁇ -5 -alkyl) -aminocarbonyl-, d- 5 alkoxycarbonyl, C 4-6 cycloalkyleneiminocarbonyl group,
  • a phenyl, heteroaryl, phenyl-C ⁇ -5 -alkyl or heteroaryl-d- 5 -alkyl group which in the phenyl or heteroaryl part optionally one to three times selected by the same or different substituents from the group consisting of halogen atoms, C ⁇ - 5 ⁇ alkyl, di (C ⁇ -5 -alkyl) amino, hydroxy, C ⁇ -5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and C ⁇ - 5 alkyloxycarbonyl groups can be substituted,
  • a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl, Ci.s-alkyl or cycioalkylenimino-d -3 -alkyl group in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R 8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) 2 - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together can optionally be replaced by a -C (O) N (R 8b ) - or -S (O) 2 N (R 8b ) group, or in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally with a substituted -OC (0) N (R 8b ) - or -N (R 8b )
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or C 3-8 cycloalkenyl form, wherein a C 3-8 cycloalkyl or C ⁇ -cycloalkenyl group at a single Carbon atom can be substituted by a C 2-5 alkylene group or at the same time on two different carbon atoms by a C ⁇ -4 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C 4- s cycloalkyl or C 5 -s cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen or sulfur atom or an -N (R 8c ) -, or a carbonyl, sulfinyl or sulfonyl group, and / or two directly adjacent methylene groups of a C -8-
  • R 4 and R 5 is C 3-8 cycloalkyl or formed C 3-8 cycloalkenyl group or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system, in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH 2 group, and / or in which one or both methylene groups of the cycle which are connected directly to the carbon atom on which the radicals R 4 and R 5 are connected, are replaced by a hetero atom from the group oxygen, nitrogen and sulfur, and / or in which a substituent bound to the cyclic group, which is characterized in that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom directly is bound to the cyclic group by another heteroatom from the group of oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one given if substituted, methylene group is separated, and / or in which two
  • R 6 represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitrite group, a C 3 alkyl group, or a C 3 alkoxy group, the hydrogen atoms of the C 3 alkyl or C 3 group Alkoxy group can optionally be completely or partially replaced by fluorine atoms,
  • R 7 is, independently of one another, a C 3 alkyl, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy, C 3 3 alkyloxy, where the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino , d- 3 -Alkylamino-, di- (C ⁇ -3 -alkyl) -amino-, C3- 6 -cycloalkylenimino-, carboxy-, nitrile-, C ⁇ - 3 -alkoxycarbonyl-, aminocarbonyl-, C - ⁇ -3 - Alkylaminocarbonyl- or a di (C ⁇ -3 alkyl) aminocarbonyl group, where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, wherein the 6-membered heteroaryl group has one, two or three nitrogen
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, can be straight-chain or branched, and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,
  • definitions containing methyl or ethyl groups can be replaced in whole or in part by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.
  • Examples of monocyclic heteroaryl groups are the pyridyl, ⁇ / -oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1, 2,3] triazinyl,
  • bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo [c] furanyl, benzothiophenyl, benzo [c] thiophenyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [ ⁇ sothiazolyl, benzooxazolyl, benzo [ ] isoxazolyl, benzo [c /] isoxazolyl, benzo [1, 2.5] oxadiazolyl, benzo [1, 2.5] thiadiazolyl, benzo [1, 2.3] thiadiazolyl, benzo [ ⁇ f
  • C ⁇ -6 alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, ⁇ -butyl, sec-butyl, 1 tert-butyl, -pentyl , 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 3-methyl-2-pentyl, 4- Methyl 2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2-dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.
  • Examples of the d- 5 alkyloxy groups mentioned above in the definitions are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, ferf-butyloxy, 1-pentyloxy , 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.
  • Examples of the C 2-6 alkenyl groups mentioned above in the definitions are the ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 2-butene 1-yl, 3-buten-1-yl, 1-pentene-1-yl, 2-pentene-1-yl, 3-pentene-1-yl , 4-penten-1-yl-, 1-hexen-1-yl-, 2-hexen-1-yl-, 3-hexen-1-yl-, 4-hexen-1 -yl-, 5-hexen 1-yl-, but-1-en-2-yl-, but-2-en-2-yl-, but-1-en-3-yl-, 2-methyl-prop-2-en- 1 - yl, pent-1-en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1 - en-3-yl-, pent-2
  • C 2 - 6 alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1 -yl, 1-butyn-3-yl, 2-butyne -1-yl-, 3-butyn-1-yl-, 1-pentyn-1-yl-, 1-pentyn-3-yl-, 1-pentyn-4-yl-, 2-pentyn-1-yl- , 2-pentyn-3-yl-, 3-pentyn-1-yl-, 4-pentyn-1-yl-, 2-methyl-1-butyn-4-yl-, 3-methyl-1-butyn-1 -yl-, 3-Methyl-1-butyn-3-yl-, 1-Hexin-1-yl-, 2-Hexin-1-yl-, 3-Hexin-1-yl-, 4-Hexin-1- yl-, 5-hexin
  • a group which can be converted into a carboxy group in vivo is, for example, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C 6 alkanol, a phenyl C 3 alkanol, a C 3-9 cycloalkanol, a C 5-7 -CycloaIkenol, a C 3-5 alkenol, a phenyl C 3-5 alkenol, a C 3-5 -alkynol or phenyl-C 3-5 -alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C 3-8 -cycloalkyl-d- 3- alkanol or an alcohol of the formula
  • R 9 is a C 8 alkyl, C 5-7 cycloalkyl, phenyl or phenyl C 3 -3 alkyl group
  • R 10 is a hydrogen atom, a C 3 alkyl, C 5 - 7 cycloalkyl or Phenyl group and
  • R 11 represents a hydrogen atom or a C -3 alkyl group
  • the preferred radicals which can be split off from a carboxy group in vivo are a C 6 alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy or cyclohexyloxy group or one Phenyl-C ⁇ - 3 alkoxy group as the benzyloxy group into consideration.
  • a group which can be converted into a hydroxyl group in vivo is, for example, a hydroxyl group esterified with a carboxylic acid, in which the carboxylic acid part is preferably a -C 7 alkane acid, a phenyl C 3 alkanoic acid, a C 3-9 cycloalkyl carboxylic acid
  • the preferred radicals which can be split off from a hydroxyl group in vivo are ad-7-acyl groups such as formyl, acetyl, n-propionyl, isopropionyl, n-propanoyl, n-butanoyl, n-pentanoyl, n-hexanoyl - or
  • Cyclohexylcarbonyl or a benzoyl group and also a methoxyacetyl, 1-methoxypropionyl, 2-methoxypropionyl or 2-methoxyethoxyacetyl group into consideration.
  • Those compounds of the general formula I in which A, R 4 and / or R 5 contain a group which can be converted into a carboxy or hydroxyl group in vivo are prodrugs for those compounds of the general formula I in which A, R 4 and / or R 5 contains a carboxy or hydroxyl group.
  • a 12th embodiment of the present invention comprises those compounds of the general formula I in which
  • A is a radical of the general formula
  • n 1 or 2
  • R 8a alkyl- are each independently a hydrogen or fluorine atom or a C ⁇ -5 alkyl, hydroxy, hydroxy-C ⁇ -5, d -5 alkoxy, C ⁇ -5 -alkoxy-C ⁇ - 5 -alkyl-, amino-, C ⁇ -5 -alkylamino-, di- (C ⁇ -5 -alkyl) -amino-, amino-C ⁇ -5 -alkyl-, d -5 -alkylamino-C 1-5 -alkyl- , Di- (-C -5 -alkyl) -amino -C ⁇ -5 -alkyl-, aminocarbonyl-, d -5 -alkylaminocarbonyl-, di- (d -5 -alkyl) -aminocarbonyl- or C ⁇ -5 -alkylcarbonylamino group, in the case of the above-mentioned substituted 5- to 7-membered radical
  • R 8b each independently represents a hydrogen atom or a C 5 alkyl group
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • R 8c each independently represents a hydrogen atom, a C 5 alkyl, C 5 alkylcarbonyl, Ci.s alkyloxycarbonyl or d -5 alkylsulfonyl group,
  • X 3 is an oxygen or sulfur atom, an -NR 8c group,
  • X 4 represents a carbonyl or sulfonyl group
  • R 1 is a halogen atom, a d- 3 alkyl or d -3 alkoxy group, where the hydrogen atoms of the d -3 alkyl or C 3 -3 alkoxy group can optionally be completely or partially replaced by fluorine atoms, a C 2-3 Means alkenyl, C 2-3 alkynyl, nitrile, nitro or amino group,
  • R 2 represents a hydrogen or halogen atom or a C 3 -3 alkyl group
  • R 3 represents a hydrogen atom or ad -3 alkyl group
  • R 4 and R 5 are each independently a hydrogen atom, a C 2-6 alkenyl or C 2-6 alkynyl group, a straight-chain or branched de-alkyl group, the hydrogen atoms of the straight-chain or branched C 6 alkyl group optionally being whole or can be partially replaced by fluorine atoms, and which may optionally be replaced by a C 3-5 cycloalkyl group, a nitrile, hydroxyl, ad 5 -alkyloxy group, the hydrogen atoms of the C ⁇ - 5 -AlkyIoxyily optionally being completely or partially replaced by fluorine atoms can, an allyloxy, propargyloxy, benzyloxy, C ⁇ - 5 alkylcarbonyloxy, ds-alkyloxycarbonyloxy, carboxy-d- 5 -alkyloxy, C ⁇ -5 -alkyloxycarbony
  • a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl- d- 5 -alkyl or cycloalkylenimino -CC -3 alkyl group in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R 8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together can optionally be replaced by a -C (O) N (R 8b ) - or -S (O) 2 N (R 8b ) group, or in which in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally by a substituted -OC (O) N (R 8b ) - or -N (R 8b ) C
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or C3-8 cycloalkenyl group
  • one C 3-8 cycloalkyl or C 4-8 cycloalkenyl group on one single carbon atom can be substituted by a C 2-5 alkylene group or at the same time on two different carbon atoms by a C ⁇ -4 -AlkyIenement to form a corresponding spirocycle or a bridged bicyclus
  • one of the methylene groups of a C -s-cycloalkyl or C 5-8 - Cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen or sulfur atom or an -N (R 8c ) -, or a carbonyl, sulfinyl or sulfonyl group, and / or two directly adjacent methylene groups of a C 4-8
  • C ⁇ -5-alkylaminosulfonyl-, di- (d- 5 -alkyl) -aminosulfonyl-, C 3-6 -cycloalkyleniminosulfonyl-, amino-, C ⁇ - 5 -alkylamino-, di- (C ⁇ - 5 -alkyl) -amino- , d -5 -alkylcarbonylamino-, C ⁇ -5 -AlkyI- sulfonylamino-, / V- (d -5 -alkylsulfonyl) -C ⁇ -5 -alkylamino- or C 3-6 -cycloalkylcarbonylamino groups may be substituted,
  • 1 3-8 cycloalkenyl optionally substituted independently by a C ⁇ -5 alkyl, nitrile, carboxy-d- alkyl or 2 carbon atoms of a C 5, Ci- ⁇ alkyloxycarbonyl-Ci ⁇ alkyl, carboxy -, d-5-alkyloxycarbonyl, aminocarbonyl,
  • C ⁇ - 5 -alkylaminocarbonyl-, di- (C ⁇ - 5 -alkyl) -aminocarbonyI-, C 3 - 6 -cycloalkyleniminocarbonyl-, aminosulfonyl-, C ⁇ - 5 -alkylaminosulfonyl-, di- (d- 5 -alkyl) -aminosulfonyl- , C 3 - 6 -CycloalkyleniminosulfonyI fate may be substituted,
  • Amino-, d -5 -alkylamino-, di- (C ⁇ . 5 -alkyl) -amino-, d-5-alkylcarbonylamino-, d -5 -alkylsulfonylamino-, ⁇ / - (C ⁇ -5 -alkylsulfonyl) -C ⁇ - 5 alkylamino or C 3 - 6 -Cycloalkylcarbonylamino phenomenon may be substituted,
  • R 6 represents a fluorine, chlorine, bromine or iodine atom, a nitrite group, a d- 3 alkyl group, or a d -3 alkoxy group, the hydrogen atoms of the C 3 -3 alkyl or C 3 -3 alkoxy group entirely or can be partially replaced by fluorine atoms,
  • R 7 independently of one another ad -3 -alkyl-, where the hydrogen atoms may optionally be replaced in whole or in part by fluorine atoms, hydroxy-, C ⁇ -3 -alkyloxy-, where the hydrogen atoms may in whole or in part be replaced by fluorine atoms, amino- , C ⁇ -3 -alkylamino-, di- (C ⁇ -3 -alkyl) -amino-, C 3 -6-cycloalkylenimino-, carboxy-, nitrile, C ⁇ -3-alkoxycarbonyl-, aminocarbonyl-, C 1-3 - Represents alkylaminocarbonyl or a di (C ⁇ -3 alkyl) aminocarbonyl group,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 1-3 alkyl, phenyl or phenyl C -3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a C 1-3 alkyl, phenyl, amino-C 2-3 -alkyl-, C ⁇ .
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, can be the same or different,
  • a 13th embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula
  • n 1 or 2
  • R 8a each independently represent a hydrogen or fluorine atom or a C ⁇ -5 alkyl, hydroxy, hydroxy-d alkyl -5, d -5 alkoxy, C ⁇ - 5 alkoxy-C ⁇ . 5 -alkyl-, amino-, -C-5-alkylamino-, di- (C 1-5 -alkyl) -amino-, amino-C ⁇ - 5 -alkyl-, C ⁇ - 5 -alkylamino-C ⁇ -5-alkyl- , Di- (d -5 -alkyl) amino-C ⁇ - 5 alkyl, aminocarbonyl, d -5- alkylaminocarbonyl, di- (C 1-5 -alkyl) aminocarbonyl or Ci.s-alkylcarbonylamino group , wherein in the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R 8a as substituents are not separated
  • R 8b each independently represents a hydrogen atom or a Ci.s-alkyl group
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • R 8c each independently represents a hydrogen atom, a C 1-5 alkyl, ds-alkylcarbonyl, C 1-5 alkyloxycarbonyl or ds-alkylsulfonyl group,
  • X 3 is an oxygen atom or an -NR 8o group
  • X 4 represents a carbonyl or sulfonyl group
  • R 1 is a fluorine, chlorine, bromine or iodine atom, a C 3 alkyl or C 3 alkoxy group, the hydrogen atoms of the C 1-3 alkyl or C 3 alkoxy group optionally being wholly or partly by Fluorine atoms can be replaced, or means a nitrile group,
  • R 2 represents a hydrogen or halogen atom or a methyl group
  • R 3 represents a hydrogen atom or a methyl group
  • R 4 is a C 2-6 alkenyl or C 2-6 alkynyl group, a straight-chain or branched C 1-6 alkyl group, where the hydrogen atoms of the straight-chain or branched d- 6 alkyl group can optionally be replaced in whole or in part by fluorine atoms , and which may be replaced by a C 3-5 ⁇ cycloalkyl group, a nitrile, hydroxy, a C ⁇ -5 -alkyloxy group, where the hydrogen atoms of the d -5 -alkyloxy group may be replaced in whole or in part by fluorine atoms, a benzyloxy, d- 5 -alkylcarbonyloxy-, C ⁇ -5 -alkyloxycarbonyloxy-, carboxy- C ⁇ -5 -alkyloxy-, C ⁇ -5 -alkyloxycarbonyl-C ⁇ - 5 -alkyloxy-, C ⁇ -5 -alkylsulf
  • a phenyl, heteroaryl, phenyl-C ⁇ -5 -alkyl or heteroaryl-d- 5 -alkyl group which in the phenyl or heteroaryl part optionally one to three times selected by the same or different substituents from the group consisting of halogen atoms, d - 5 -alkyl-, di- (C ⁇ -5 -alkyl) -amino-, hydroxy-, -C ⁇ -5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and d- 5 -alkyloxycarbonyl groups can be substituted,
  • a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl- d- 5 -alkyl or cycloalkylenimino -CC -3 alkyl group in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R 8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) 2 group may be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together may optionally be replaced by a -C (O) N (R 8b ) - or -S (O) 2 N (R 8b ) group, or in which in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together, optionally substituted by one - OC (0) N (R 8b ) - or -N (R 8b ) C
  • R 5 is a hydrogen atom, a C 2-6 -alkenyl or C 2 - 6 alkynyl group, a linear or branched C ⁇ -6 alkyl group, wherein the hydrogen atoms are replaced of linear or branched d- 6 -AIkyl distr optionally fully or partially substituted by fluorine atoms , and which may optionally be substituted by a d- 5- alkyloxy group, where the hydrogen atoms of the Ci.s-alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or C 3-8 cycloalkenyl group, the Qa-s-cycloalkyl or C. 8 cycloalkenyl group on one single carbon atom by a C 2 - 5 alkylene group or simultaneously to different two carbon atoms by a d-4-alkylene group to form a corresponding spirocyclic or a bridged bicyclic system may be substituted,
  • C ⁇ - 5 -alkylcarbonylamino-, d -5 -alkylsulfonylamino-, ⁇ / - (C ⁇ - 5 -alkylsulfonyl) -C ⁇ - 5 alkylamino or C 3-6 cycloalkylcarbonylamino groups can be substituted,
  • R 4 and R 5 is C 3-8 cycloalkyl or formed C 3-8 cycloalkenyl group or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system, in which two heteroatoms are separated from one another in the cycle from the group oxygen and nitrogen by exactly one optionally substituted -CH 2 group, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom to which the radicals R 4 and R 5 are attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which one the cyclic group-bound substituent, which is characterized in that one hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, is separated by exactly one, optionally substituted, methylene group, and /
  • C 3 alkyl group, or ad 3 alkoxy group means, where the hydrogen atoms of the C 3 alkyl or C 3 alkoxy group may optionally be wholly or partly replaced by fluorine atoms, R 7 independently of one another ad -3 -alkyl-, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy-, C ⁇ - 3 -alkyloxy-, where- the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino -, C ⁇ - 3 -alkylamino-, di- (d -3 -alkyl) -amino-, C 3-6 -cycloalkylenimino-, carboxy-, nitrile-, d- 3 -Aikoxycarbonyl-, aminocarbonyl-, C - ⁇ - 3 -Alkylaminocarbonyl- or a di- (-C-3-alkyl) -amin
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 3 alkyl, phenyl or phenyl C 3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a 3 alkyl, phenyl, amino C 2 - 3 -alkyl-, C ⁇ -3 -alkylamino-C 2- 3 -alkyl-, di- (C ⁇ -3 -alkyl) -amino-C 2-3 -alkyl-, a C 3- 6-, cycloalkylenimino-C -3 -alkyl- or phenyl-C ⁇ -3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, may be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,
  • a 14th embodiment of the present invention comprises those compounds of the general formula I in which
  • A is a radical of the general formula
  • n 1 or 2
  • R 8a each independently of one another is a hydrogen or fluorine atom or a -C 3 alkyl, hydroxy, hydroxy C 3 -3 alkyl, C 3 alkoxy, C 3 alkoxy C 3 alkyl , Amino-, d -3 -alkylamino-, di- (d -3 -alkyl) -amino-, amino-C ⁇ -3 -alkyl-, C ⁇ -3-alkylamino-C ⁇ - 3 -alkyl-, Di ⁇ ds- alky -amino-ds-alkyl-, aminocarbonyl-, d -3 -alkylaminocarbonyl-, di- (C ⁇ -3 -alkyl) -aminocarbonyl- or C ⁇ -3-alkylcarbonylamino group, with the above-mentioned substituted 5- to 7- membered radicals A, the heteroatoms F, O or N, optionally introduced with R 8a as substituent
  • R 8b each independently represents a hydrogen atom or a C 3 alkyl group
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • R 8c each independently represents a hydrogen atom, a C -3 alkyl, d -3 alkylcarbonyl, C -4 alkyloxycarbonyl or d -3 alkyl sulfonyl group, X 3 is an oxygen atom or an -NR 8c group,
  • X 4 represents a carbonyl or sulfonyl group
  • R is a fluorine, chlorine, bromine or iodine atom, a d -3 alkyl or a C 3 alkoxy group, the hydrogen atoms of the d -3 alkyl or C 3 alkoxy group optionally in whole or in part by fluorine atoms can be replaced
  • R 2 represents a hydrogen or halogen atom or a methyl group
  • R 3 represents a hydrogen atom
  • R 4 is a C 2-4 alkenyl or C. 4 -alkynyl group, a straight-chain or branched C 1 -C alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched C 1 -C alkyl group to be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a C 3 - 5 cycloalkyl group, a nitrile, Hydroxy-, ad -3 -alkyloxy group, where the hydrogen atoms of the C ⁇ -3 -alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, a benzyloxy-, -C ⁇ -3-alkylcarbonyloxy-, d -3 -alkyloxycarbonyl-C- ⁇ - 3 -alkyloxy-, C ⁇ - 3 -alkyloxycarbonyl-, aminocarbonyl-, d -3 -alkylaminocarbon
  • 3 -alkyl) -aminosulfonyl-, C 3 - 6 -cycloalkyleniminosulfonyl-, amino-, C ⁇ . 3 -Alkylamino-, di- (C ⁇ -3 alkyl) - amino, C ⁇ -3 alkylcarbonylamino, C ⁇ - 3 alkylsulfonylamino, or a ⁇ / - (C ⁇ - 3 alkylsulfonyl) -C ⁇ -3 alkylamino group can be substituted, a phenyl, heteroaryl, phenyl -CC 3 alkyl or heteroaryl d 3 alkyl group, those in the phenyl or heteroaryl moiety optionally mono- to triple-selected by the same or different substituents selected from the group consisting of halogen atoms, C 3 -3 alkyl, di (C 3 -3 alkyl) amino, hydroxy, C 3 -3 Alkyloxy, mono-
  • R 5 is a hydrogen atom, a C 2-4 alkenyl or C 2- alkynyl group, a straight-chain or branched C 1 -C alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched C 4 -4 alkyl group to be replaced in whole or in part by fluorine atoms , and which may be substituted by a C ⁇ - 3 alkyloxy group, where the hydrogen atoms of the d- 3 alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, means, or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or C 3-8 cycloalkenyl group
  • the C 3- 8 cycloalkyl or C 4 -8 cycloalkenyl group on a single carbon atom by a C 2-5 alkylene group or simultaneously on two different carbon atoms by a C ⁇ - 4 alkylene group to form a corresponding spirocycle or one bridged bicyclic may be substituted, wherein one of the methylene groups of a C -s-cycloalkyl or C 5-8 - cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above by an oxygen or sulfur atom or a sulfonyl or -N (R 8c ) group can be replaced, and or
  • a -C (0) N (R 8b) -, - C may be replaced (0) 0-, or -S (0) 2 N (R 8b) group , and or
  • R 6 represents a fluorine, chlorine, bromine or iodine atom, a methyl group or a methoxy group, it being possible for the hydrogen atoms of the methyl or methoxy group to be replaced in whole or in part by fluorine atoms,
  • R 7 independently of one another is a C 3 alkyl, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy, C 3 -3 alkyloxy, where the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino , d- 3 -Alkylamino-, di- (C ⁇ - 3 -alkyl) -amino-, C 3-6 -cycloalkyleneimino-, carboxy-, nitrile-, C ⁇ -3-alkoxycarbonyl-, aminocarbonyl-, C ⁇ - 3 - Represents alkylaminocarbonyl or a di (C ⁇ - 3 alkyl) aminocarbonyl group,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 3 alkyl, phenyl or phenyl C 3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a C 3 alkyl, phenyl, amino C 2-3 -alkyl-, C ⁇ . 3 -Alkylamino-C 2 - 3 -alkyl-, di- (C ⁇ .
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, may be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,
  • a 15th embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula
  • n 1 or 2
  • R 8a each independently of one another a hydrogen or fluorine atom or a d-3-alkyl, hydroxy, hydroxy-C ⁇ -3 alkyl, d -3 alkoxy, d-3-alkoxy-d. 3 -alkyI-, amino-, C ⁇ .
  • 3 -alkylamino-, di- (C 1-3 -alkyl) -amino-, amino-C ⁇ s-alkyl-, ds-alkylamino-Ci-s-alkyl-, or di- (C ⁇ -3 -alkyl) - amino-C ⁇ -3 -alkyl group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R 8a as substituents are not replaced by exactly one carbon atom from a heteroatom from the group N, O, S are separated, and two substituents R 8a on the same or different carbon atoms can represent a C -5 alkylene group,
  • R 8b each independently represents a hydrogen atom or a d- 3 -alkyl group
  • X 1 is an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8o group
  • R 8c each independently represents a hydrogen atom, a C 3 alkyl, d 3 alkyl carbonyl group or a C 1 alkyloxycarbonyl group
  • X 3 is an oxygen atom or an -NR 8c group
  • X 4 represents a carbonyl group
  • R 1 represents a fluorine, chlorine, bromine or iodine atom, a methyl or a methoxy group, where the hydrogen atoms of the methyl or methoxy group can optionally be completely or partially replaced by fluorine atoms,
  • R 2 represents a hydrogen or fluorine atom or a methyl group
  • R 3 represents a hydrogen atom
  • R 4 is a C 2 - alkenyl or C 2- alkynyl group, a straight-chain or branched C 1-4 alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched C -4 alkyl group to be replaced in whole or in part by fluorine atoms, and which may be replaced by a nitrile, hydroxyl, ad 3 -alkyloxy group, where the hydrogen atoms of the C 3 -3 -alkyloxy group may be replaced in whole or in part by fluorine atoms, a benzyloxy, C 1-3 alkylcarbonyloxy-d- 3 -Alkyloxycarbonyl-, Aminocarbonyl-, C 1-3 -Alkylaminocarbonyl-, Di- (ds-alky -aminocarbonyl-, C 3 -6-Cycloalkyleniminocarbonyl-, aminosulfonyl-, C ⁇ -3 -
  • R is a hydrogen atom, a straight-chain or branched C ⁇ -4 -alkyl group, where the hydrogen atoms of the straight-chain or branched C ⁇ - alkyl group can optionally be wholly or partly replaced by fluorine atoms, and optionally by a C ⁇ - 3 alkyloxy group, the hydrogen atoms being the d- 3 alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, means, or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3 -s-cycloalkyl or C -8 -cycloalkenyl group, the C 3-8 -cycloalkyl or C -8- cycloalkenyl group on a single Carbon atom can be substituted by a C 2-5 alkylene group or at the same time on two different carbon atoms by a C ⁇ -4 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C 4-8 cycloalkyl or C 5 - 8 - Cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above through an oxygen or sulfur atom or a sulfonyl or -N (R 8c ) group can be replaced, and / or
  • R 6 represents a fluorine, chlorine, bromine or iodine atom, a methyl group or a methoxy group, it being possible for the hydrogen atoms of the methyl or methoxy group to be replaced in whole or in part by fluorine atoms,
  • R 7 independently of one another, is a C -3 alkyl, where the hydrogen atoms can optionally be wholly or partly replaced by fluorine atoms, hydroxy, d -3 alkyloxy, the hydrogen atoms optionally can be replaced in whole or in part by fluorine atoms, amino, C ⁇ - 3 alkylamino, di (C ⁇ -3 alkyl) amino, C 3 - 6 cycloalkyleneimino, carboxy nitrile, C -3 -3 alkoxycarbonyl -, Aminocarbonyl-, C 1-3 -AkkylaminocarbonyI- or a di- (-C-3-alkyl) -aminocarbonyl group,
  • heteroaryl group mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C 3 -C 3 -alkyl, phenyl or phenyl-d -3- alkyl group, an oxygen or sulfur atom or an optionally substituted by a -3 -3- alkyl, phenyl, amino-C 2-3 -alkyl-, -C-3-alkylamino-C 2-3 -alkyl-, di- (C ⁇ -3 -alkyl) -amino-C 2 -3-alkyl-, a C 3-6 - cycloalkylenimino-C- ⁇ - 3-alkyl or phenyl-C ⁇ -3 -alkyl group substituted imino group or an oxygen or
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, can be straight-chain or branched, and the alkyl groups in the above-mentioned dialkylated radicals, for example the dialkylamino groups, are identical or are contained in the abovementioned definitions can be different
  • a 16th embodiment of the present invention comprises those compounds of the general formula I in which
  • A is a radical of the general formula
  • n 1 or 2
  • R 8b represents a hydrogen atom or a C -3 alkyl group
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • R 8c each independently represent a hydrogen atom, a C ⁇ -3 alkyl, d- 3 alkylcarbonyl, or a C 1-4 alkyloxycarbonyl group,
  • X 3 is an oxygen atom or an -NR 8c group
  • X 4 represents a carbonyl group
  • R 1 is a fluorine, chlorine, bromine or iodine atom, a methyl or a Means methoxy group, where the hydrogen atoms of the methyl or methoxy group can optionally be completely or partially replaced by fluorine atoms,
  • R 2 represents a hydrogen or fluorine atom
  • R 3 represents a hydrogen atom
  • R 4 is a straight-chain or branched C 1 -C alkyl group, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a hydroxyl group, a d-3-alkyloxy group, the hydrogen atoms in the C 1-3 alkyloxy group entirely or can be partially replaced by fluorine atoms, a benzyloxy, C ⁇ - 3 -alkylcarbonyloxy-, C 1-3 -alkyloxycarbonyl, aminocarbonyl, C ⁇ -3 -alkylaminocarbonyl-, di- (d -3 -alkyl) -aminocarbonyl-, C3- 6 -Cycloalkyleniminocarbonyl-, aminosulphonyl, d -3 -AI- kylaminosulfonyl-, di- (C ⁇ -3 alkyl) -aminosulfonyl-, C 3-6 -
  • R 5 is a hydrogen atom, a straight-chain or branched C 1 -C alkyl group, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, and which can optionally be replaced by a d- 3 -alkyloxy group, the hydrogen atoms in the d- 3- alkyloxy group optionally being completely or partially replaced by fluorine atoms may, may be substituted, means, or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl or C -7 cycloalkenyl group
  • the C 3-7 cycloalkyl or C 4-7 cycloalkenyl group on one single carbon atom can be substituted by a C 2-5 alkylene group or at the same time on two different carbon atoms by a C- ⁇ - alkylene group to form a corresponding spirocycle or a bridged bicyclus
  • one of the methylene groups being a C -7 cycloalkyl or C4 7 - cycloalkenyl group or one
  • a corresponding spirocyclic as described above or a corresponding bridged bicyclic group may be replaced by an oxygen or sulfur atom or a sulfonyl or -N (R 8G) group
  • / or two directly adjacent methylene groups a C 4-8 cycloalkyl group together can be replaced by a -C
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylated radicals mentioned above, for example the dialkylamino groups, can be identical or different .
  • a 17th embodiment of the present invention comprises those compounds of the general formula I in which
  • A is a radical of the general formula
  • n 1 or 2
  • R 8a each independently of one another is a hydrogen or fluorine atom or a C -3 alkyl, hydroxy, hydroxy C 3 -3 alkyl, C 3 alkoxy, C 3 alkoxy C 1.
  • 3-alkyl, amino, C ⁇ -3 alkylamino, di- (C ⁇ -3 alkyl) -amino, amino-C ⁇ -3 alkyl, C ⁇ -3 alkylamino-d -3 alkyl, Di- (-C 3 alkyl) -C -3 alkyl group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R 8a as substituents are not by exactly a carbon atom is separated from a hetero atom from the group N, O, S,
  • R 8b represents a hydrogen atom or ad -3 alkyl group
  • X 1 represents an oxygen atom or a -CH 2 -, -CHR 8a - or -NR 8c group
  • R 8c represents a hydrogen atom, ad -3 -alkyl-, d -3 -alkylcarbonyl-, or a C ⁇ - -alkyloxycarbonyl group,
  • X 3 represents an oxygen atom or an -NR 8c group
  • R 1 represents a chlorine or bromine atom, a methyl, trifluoromethyl or a methoxy group
  • R 2 represents a hydrogen or fluorine atom
  • R 3 represents a hydrogen atom
  • R 4 is a methyl group which may optionally be substituted by a hydroxy, methoxy, benzyloxy, methoxycarbonyl or pyridin-4-yl group, or represents a furan-2-yl, 1-methyl-pyrazin-3-yI, phenyl, pyridin-3-yl or pyrazin-2-yl group,
  • R 5 represents a hydrogen atom or a methyl group
  • R 4 and R 5 together with the carbon atom to which they are attached, a C 3 - 6 cycloalkyl, or form a C 5- 6-cycloalkenyl group, wherein the C 3 -6 cycloalkyl or C 5 -6-cycloalkenyl group of a single carbon atom can be substituted by a C 2-4 alkylene group or at the same time on two different carbon atoms by a C ⁇ -3 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C 4-6 cycloalkyl- or C 5 - ⁇ - cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen atom or an -N (R 8c ) group, with the proviso that such a group, consisting of R 4, and R 5 is C 3-6 cycloalkyl or formed C 5 - 6 cyclo
  • R 6 represents a chlorine or bromine atom
  • halogen atom means an atom from the group fluorine, chlorine, bromine and iodine
  • alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the above-mentioned dialkylated radicals, for example the dialkylamine groups, are the same or different could be,
  • An 18th embodiment of the present invention includes those
  • a 19th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, in which R 4 and R 5 together with the carbon atom to which they are attached form a cyclic group which is defined as in the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th or 18th embodiment.
  • a 20th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, in which R 4 and R 5 together with the carbon atom to which they are attached form a cyclic group, each as in the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th or 19th embodiment is defined, in the case of the cyclic group a methylene group being replaced by an oxygen atom or an N (R 8c ) group.
  • a 21st embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, in which R 4 and R 5 together with the The carbon atom to which they are attached form a cyclic group which, as in the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th or 19th embodiment described by corresponding substitution represents a bridged bicyclus or a spirocyclic group.
  • a 22nd embodiment of the present invention includes those
  • a 23rd embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, in which R 4 and R 5 together with the carbon atom to which they are attached is a bridged bicyclic group
  • a 24th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, in which the rest A the group
  • a 25th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, in which the rest A the group
  • a 26th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 in which R 6 represents a bromine atom.
  • a 27th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 in which R 6 represents a chlorine atom.
  • a 28th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 , 26 or 27, in which R 1 represents a fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group.
  • a 29th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 , 26 or 27 in which R 1 represents a hydrogen atom.
  • the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
  • the reduction of the nitro group is advantageously carried out, for example, in a solvent or solvent mixture such as water, aqueous ammonium chloride solution, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, acetic anhydride with base metals such as iron, zinc, tin or sulfur compounds such as ammonium sulfide, sodium sulfide or Sodium dithionite or by catalytic hydrogenation with hydrogen, for example under a pressure between 0.5 and 100 bar, but preferably between 1 and 50 bar, or with hydrazine as a reducing agent, advantageously in the presence of a catalyst such as Raney nickel, palladium-carbon, platinum oxide, platinum on mineral fiber or rhodium, or with complex hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride, advantageously in a solvent or solvent mixture such as water, methanol, ethanol, isopropanol
  • R 1 and R 2 are defined as mentioned in claim 1.
  • the nucleophilic substitution is advantageously carried out in a solvent or solvent mixture such as ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, / V-methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulfolane or methylene chloride, chloroform, chloroform -Ethyl- diisopropylamine, ⁇ / -C ⁇ .
  • a solvent or solvent mixture such as ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, / V-methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulf
  • bases such as potassium carbonate, sodium carbonate, potassium ferf-butoxide, sodium ethanolate, potassium hexamethyldisilazane, sodium hydride or lithium diisopropylamide.
  • R 1 and R 2 are defined as mentioned in claim 1 and Z 1 represents a chlorine, bromine or iodine atom or a triflate group.
  • the reaction is advantageously carried out in a solvent or solvent mixture such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, fer-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, N- Methyl pyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or carbon tetrachloride, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, advantageously in the presence of transition metal catalysts such as nickel on activated carbon, palladium carbon, tetrakis (triphenylphosphine ) palladium (0), tris (dibenzylideneacetone) dipalladium (O), palladium (II) acetate, palladium (II) chloride, bis
  • Y 1 represents a hydroxyl, amino, hydrazino or thiol function optionally blocked by a corresponding protective group and n represents a number between 0 and 4, on the aromatic of the general formula
  • a carboxylic acid or sulfonic acid protective group such as methyl or tert-butyl groups and Z 3 a nucleofugic leaving groups such as chlorine, bromine or iodine atoms or triflate, mesylate or tosylate groups, E the carbonyloxy or sulfonyloxy group and n a number represents between 0 and 4, wherein individual methylene groups can be substituted as described in claim 1 or replaced by optionally substituted heteroatoms or other groups.
  • the subsequent alkylation of the resulting compound with the compound of general formula (VIII) is advantageously carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulfolane, methylene chloride , Chloroform, carbon tetrachloride, ⁇ / -ethyl-diisopropylamine, ⁇ / -C ⁇ -5 alkylmorpholine, ⁇ / -C ⁇ -5-alkylpiperidine, ⁇ / -C ⁇ .
  • a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone,
  • 5- alkylpyrrolidine, triethylamine, pyridine for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, advantageously in the presence of bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium terf. -butylate, sodium methoxide, sodium ethanolate or basic ion exchanger.
  • bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium terf. -butylate, sodium methoxide, sodium ethanolate or basic ion exchanger.
  • a ring closure by intramolecular acylation / sulfonylation is expediently carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulfoxide, sulfolane, tetrachloro-chloroform diisopropylamine, ⁇ / -C ⁇ -5 alkylmorpholine, ⁇ / -C ⁇ -5 alkylpiperidine, ⁇ / -d -5 alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, expediently achieved in the presence of bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbon
  • R 1 and R 2 are defined as mentioned in claim 1 and Z 1 represents a chlorine, bromine or iodine atom or a triflate group.
  • the reaction is advantageously carried out in a solvent or solvent mixture such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, te / t-butyl methyl ether, ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether, sulfolane, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or carbon tetrachloride, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 200 ° C, advantageously in the presence of transition metal catalysts such as tetrakis (triphenylphosphine) - palladium (O), tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, palladium (II) chloride, bis (tripheylphoshin) pal
  • Sodium hydride optionally carried out in the presence of a complexing agent such as 18-crown-6-ether and expediently using an inert gas atmosphere (for example nitrogen or argon) and optionally under pressure.
  • a complexing agent such as 18-crown-6-ether
  • expediently using an inert gas atmosphere for example nitrogen or argon
  • Z 7 is an optionally substituted amino group or the nitro group
  • E is a bond or a methylene, iminocarbonyl or imino group which is optionally substituted in accordance with the description mentioned in claim 1 or an oxygen atom
  • I and o independently of one another represent identical or different numbers between 1 and 3 which, for example, by a sequence of nucleophilic substitution according to (a) 1) i) a) and alkylation according to (a) 1) i) b) described procedure can be obtained with appropriate reagents or other methods known from the literature, optionally followed by reduction, if Z 7 represents a nitro group, according to the procedure described under (a) 1) i).
  • the ring closure by metathesis reaction is expediently carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, methanol, ethanol, propanol, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, ⁇ / - Methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulfolane, methylene chloride, chloroform, carbon tetrachloride, pyridine, in the presence of a catalyst such as benzylidene-bis (tricyclohexylphosphine) dichloro-ruthenium (Grubbs 1st generation catalyst) or benzylidene [1, 3-bis ( 2,4,6-trimethylphenyl) -2-imidazolidinylidene
  • the cyclic systems obtained in this way contain a double bond, which by hydrogenation with hydrogen, advantageously in a solvent or solvent mixture such as methanol, ethanol, propanol, ethyl acetate, propyl formate, tetrahydrofuran, dioxane, an / -Methylmorpholin, ⁇ / -Methylpyrrolidin, triethylamine, Acetic acid, formic acid, ⁇ /, ⁇ / -dimethylformamide or diethyl ether and expediently in the presence of a catalyst such as Raney nickel, palladium-carbon, platinum, platinum oxide or rhodium on mineral fiber for example at temperatures between -10 and 250 ° C, but preferably between 0 and 150 ° C, can be converted into a saturated cyclic compound, optionally with simultaneous reduction of any nitro group present as R 7 , or by a suitable addition reaction or an epoxidation, for example with
  • metal oxides such as
  • Z 7 represents an optionally substituted amino group blocked by a protective group or the nitro group, which can be obtained, for example, by oxidation of an aniline, for example with potassium peroxodisulfate, using processes known from the literature a compound of the general formula
  • R 8a and m are defined as described in claim 1, optionally followed by reduction, if Z 7 represents a nitro group, according to the procedure described under (a) 1) i), or cleavage of a protective group which may be present.
  • the ring closure by hetero-Diels-Alder reaction is expediently carried out in a solvent or solvent mixture such as methanol, ethanol, propanol, diethyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone, tetralin, Dimethyl sulfoxide, sulfolane, methylene chloride, chloroform, carbon tetrachloride, pyridine, optionally in the presence of a catalyst such as aluminum trichloride, boron trifluoride, zinc chloride, titanium (IV) chloride, lithium perchlorate, ytterbium (III) triflate or chloro-trimethylsilane, for example at temperatures between -30 and 250 ° C, but preferably between -10 and 150 ° C.
  • a solvent or solvent mixture such as methanol,
  • R 3 aldehyde (formaldehyde or paraformaldehyde for R 3 methyl, acetaldehyde or paraldehyde for R 3 ethyl, propionaldehyde for R 3 propyl) is advantageously carried out in a solvent or solvent mixture such as methanol, ethanol, propanol, isopropanol, Butanol, tetrahydrofuran, dioxane, diethyl ether, te / ⁇ .-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, sulfolane, Dimethylformamide, / V-methylpyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or carbon tetrachloride, for example at temperatures between -30 and 250 ° C, but preferably between -10 and 150 ° C, optionally in the presence of a base
  • R 6 is defined as mentioned in claim 1 and Q represents a hydroxy or -CC alkoxy group, a halogen atom or an acyloxy group.
  • the acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulfolane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulfolane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C
  • the acylation can also be carried out with the free acid, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of Isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, ⁇ /, / V-dicyclohexylcarbodiimide, / V, / V-dicyclohexyl-carbodiimide / 1-V / dehydroxy-hydroxydimide / 1-benzodydroxy-1 / V-dicyclohexyl-carbodiimide / 1-benzodydroxy-1 / V-carbonyldiimidazole, 0- (benzotriazol-1-yl) - ⁇ /, / V, / V, ⁇ r-
  • Q is a hydroxy or C 1 alkoxy group, a halogen atom or an acyloxy group and Z 6 represents a protective group which can subsequently be split off by processes known from the literature, it being possible to obtain (XVIII) by the procedure described under (b) 1).
  • the acylation can be carried out analogously to that described under (b) 1).
  • the acylation can also conveniently be carried out in a solvent or solvent mixture such as dichloromethane, trichloromethane, benzene, chlorobenzene, toluene, xylene, hexamethyldisiloxane, acetonitrile,, / -ethyl-diisopropylamine, ⁇ / -C 1-5 -alkylmorpholine, ⁇ / -C 1 -5- alkylpiperidine, ⁇ / -C -5 - alkylpyrrolidine, triethylamine, pyridine, in the presence of 4-trifluoromethylbenzoic acid anhydride, silver triflate and titanium (IV) chloride, advantageously in the presence of a dehydrating agent such as molecular sieve, sodium sulfate, magnesium sulfate, or in the presence of 4-trifluoromethyl-benzoic anhydride and ytterbium (III) triflate
  • any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups
  • the protective radical for a hydroxyl group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, ferf.butyl, benzyl or tetrahydropyranyl group and
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, te / t.-butoxycarbonyl,
  • the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. 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, e.g. B. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base such as lithium hydro
  • a benzyl, methoxybenzyl or benzyloxycarbonyl residue 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 1 to 5 bar.
  • 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 1 to 5 bar.
  • 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 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 at temperatures between 0 and 50 ° C, but preferably at room temperature.
  • a methoxy group is advantageously eliminated in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a finished butyl or te / t-butoxycarbonyl 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, ethylamine 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 and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (l) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo [2.2. 2] octane at temperatures between 20 and 70 ° C.
  • a catalytic amount of tetrakis (triphenylphosphine) palladium (0) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of
  • the compounds of general Formula I which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of the general formula I with at least two asymmetrical ones Due to their physicochemical differences, carbon atoms can be separated into their diastereomers by methods known per se, for example by chromatography and / or fractional crystallization, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to 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.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • Suitable optically active alcohols are, for example, (+) - or (-) - menthol, and 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, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained if they contain a carboxy group, can then optionally be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compounds of the general formula I and their tautomers, their enantiomers, their diastereomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic action, which is preferably based on an action which influences thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect which prolongs the aPTT time and / or on an inhibiting effect on related serine proteases such as, for. B. urokinase, factor VIIa, factor IXa, factor Xla and factor Xlla.
  • Enzyme kinetic measurement with a chromogenic substrate The amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of enzyme activity (relative to the solvent control) is determined by the test substance concentrations of test substance at different therefrom and the IC 5 o calculated as the concentration which inhibits the factor Xa used by 50%.
  • pNA p-nitroaniline
  • Substrate S 2765 (Chromogenix), final concentration: 0.3 mM / l (1 KM) per reaction mixture
  • Test substance final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 ⁇ mol / l
  • the compounds prepared according to the invention are generally well tolerated.
  • the new compounds and their physiologically tolerable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as, for example, the prevention and treatment of deep vein thrombosis, the prevention of reocclusion after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases, as well as prevention and treatment of pulmonary embolism, disseminated intravascular coagulation and severe sepsis, prevention and prophylaxis of DVT in patients with exacerbation of COPD, treatment of uicerative colitis, prophylaxis and treatment of coronary thrombosis, prophylaxis of stroke, and prevention of occlusion of shunts.
  • venous and arterial thrombotic diseases such as, for example, the prevention and treatment of deep vein thrombosis, the prevention of reocclusion after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases, as well as prevention
  • the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients of all forms coronary heart disease, to prevent metastasis and growth of tumors and inflammatory processes, e.g. suitable for the treatment of pulmonary fibrosis, for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue adhesions and / or scar tissue formation and for the promotion of wound healing processes.
  • C PT
  • the new compounds and their physiologically tolerable salts are also suitable for the treatment of Alzheimer's and Parkinson 's diseases.
  • a rational this results, for example, from the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or activity, could represent valuable medicaments in the treatment of Alzheimer's and Parkinson 's disease.
  • Clinical and experimental studies suggest that neurotoxic mechanisms, for example the inflammation associated with the activation of proteases in the coagulation cascade, are involved in the death of neurons as a result of brain trauma.
  • thrombin is involved in neurodegenerative processes, for example as a result of a stroke, repeated bypass surgery or traumatic brain injuries.
  • thrombin causes neurite retraction, as well as glia proliferation and apoptosis in primary cultures of neurons and neuroblastoma cells (for an overview, see: Neurobiol. Aging 2004, 25 (6), 783-793).
  • various in vitro studies on the brains of patients with Alzheimer's disease indicate that thrombin plays a role in the pathogenesis of this disease (Neurosci. Lett. 1992, 146, 152-54). Enrichment of immunoreactive thrombins has been demonstrated in neurite plaques in the brains of Alzheimer's patients.
  • thrombin also plays a role in the regulation and stimulation of the production of the "amyloid precursor protein” (APP) and in the cleavage of the APP into fragments which are detected in the amyloid plaques in the brain of Alzheimer's patients can. Furthermore it could be shown that thrombin-induced microglial activation leads to degeneration of nigral dopaminergic neurons in vivo. These findings lead to the conclusion that microglial activation - triggered by endogenous substance (s) such as thrombin - is involved in the neuropathological process of cell death of dopaminergic neurons, as occurs in patients with Parkinson 's disease (J. Neurosci. 2003, 23 , 5877-86).
  • endogenous substance s
  • the dosage required to achieve an appropriate effect is expediently in the case of intravenous administration 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg, and in the case of oral administration 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, in each case 1 to 4 times a day.
  • the compounds of 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. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin,
  • inert customary carriers and / or diluents e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin,
  • the new compounds and their physiologically tolerable salts can be used therapeutically in combination with acetylsalicylic acid, with platelet aggregation inhibitors such as fibrinogen receptor antagonists (for example abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogs, for example C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with P 2 T receptor antagonists (e.g. Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (e.g. Terbogrel).
  • fibrinogen receptor antagonists for example abciximab, eptifibatide, tirofiban, roxifiban
  • physiological activators and inhibitors of the coagulation system and their recombinant analogs for example C, TFPI,
  • R f values were determined using ready-made silica gel 60 F 254 TLC plates (E. Merck, Darmstadt, Item No. 1.05714) without chamber saturation.
  • the R f values determined under the name Alox were determined using ready-made aluminum oxide 60 F 25 TLC plates (E. Merck, Darmstadt, Item No. 1.05713) without chamber saturation.
  • the Rf values determined under the name Reversed-Phase-8 were determined using ready-made RP-8 F 25 4s DC plates (E. Merck, Darmstadt, Article No. 1.15684) without chamber saturation.
  • the ratios given for the flow agents relate to volume units of the respective solvents.
  • Silica gel from Millipore MATREX TM, 35-70 ⁇ m was used for chromatographic purifications. If further details on the configuration are missing, it remains open whether it is pure stereoisomers or enantiomer / diastereomer mixtures.
  • the mobile phase used was: A: water with 0.1% TFA B: acetonitrile with 0.1% TFA
  • the diode array detection was carried out in the wavelength range 210-500 nm Range of mass spectrometric detection: m / z 120 to m / z 1000
  • HPLC data of the other examples were generated under the following conditions as far as indicated:
  • Trifluoroacetic acid stirred for 18 h at room temperature, then heated to reflux for 1 h, a further 10 ml of trifluoroacetic acid was added and heated to reflux for a further 2 h. After that i. Vak. concentrated, the residue taken up twice in toloule and completely concentrated. Yield: 24.7 g (95%)
  • the following compounds can be prepared analogously: 1) 5-chloro-thiophene-2-carboxylic acid ⁇ / - ⁇ 1 - [3-methyl-4- (morpholin-4-yl) - phenylcarbamoyl] -1-methyl-ethyl ⁇ - amide, 2) 5-bromo-thiophene-2-carboxylic acid / V - ⁇ (1?) - 1 - [3-tfhlor-4- (morpholin-4-yr) - phenylcarbamoyl] -2-methoxy-ethyl ⁇ - amide, 3) 5-bromo-thiophene-2-carboxylic acid / V- ⁇ 1 - [3-chloro-4 - ([1, 2] oxazinan-2-yi) - phenylcarbamoyl] -1-methyl-ethyl ⁇ - amide, 4) 5-chloro-thiophene-2-carboxy
  • Active ingredient 75.0 mg mannitol 50.0 mg water for injections ad 10.0 ml
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • (1), (2) and (3) are mixed and granulated with an aqueous solution of (4).
  • (5) is added to the dried granulate. Tablets are pressed from this mixture, biplane with a facet on both sides and a notch on one side.
  • (1) is triturated with (3). This trituration is the mixture of (2) and (4) added with intensive mixing.
  • This powder mixture is filled into size 3 hard gelatine capsules on a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled into size 0 hard gelatin capsules on a capsule filling machine.
  • 1 suppository contains: active ingredient 100.0 mg
  • Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MG 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg 2000.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate.
  • the milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Abstract

La présente invention concerne de nouveaux amides d'acide thiphène-2-carboxylique substitués correspondant à la formule générale (I), dans laquelle A et R1 à R8c correspondent aux définitions données dans la revendication 1, leurs tautomères, leurs énantiomères, leurs diastéréomère, leurs mélanges et leurs sels, en particulier leurs sels physiologiquement compatibles, avec des acides ou des bases inorganiques ou organiques, lesquels présentent de précieuses propriétés.
EP05745599A 2004-05-13 2005-05-07 Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament Withdrawn EP1748997A1 (fr)

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EP05745599A EP1748997A1 (fr) 2004-05-13 2005-05-07 Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament

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EP04011387 2004-05-13
EP05745599A EP1748997A1 (fr) 2004-05-13 2005-05-07 Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament
PCT/EP2005/004974 WO2005111013A1 (fr) 2004-05-13 2005-05-07 Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament

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EP1748997A1 true EP1748997A1 (fr) 2007-02-07

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EP05745599A Withdrawn EP1748997A1 (fr) 2004-05-13 2005-05-07 Amides d'acide thiophene-2-carboxylique substitues, leur production et leur utilisation comme medicament

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US (1) US20050256107A1 (fr)
EP (1) EP1748997A1 (fr)
JP (1) JP2007537179A (fr)
CA (1) CA2562714A1 (fr)
WO (1) WO2005111013A1 (fr)

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PE20070171A1 (es) * 2005-06-30 2007-03-08 Boehringer Ingelheim Int GLICINAMIDAS SUSTITUIDAS CON EFECTO ANTITROMBOTICO E INHIBIDOR DEL FACTOR Xa
PE20081834A1 (es) * 2006-12-31 2009-01-16 Boehringer Ingelheim Int Proceso para la sintesis de derivados de acido 3-amino-tetrahidrofuran-3-carboxilico y uso de los mismos como medicamentos
JP5524852B2 (ja) 2007-11-15 2014-06-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 置換アミド、それらの製造及び医薬品としての使用
GB201820166D0 (en) * 2018-12-11 2019-01-23 Ucb Biopharma Sprl Therapeutic agents
AU2020406139A1 (en) 2019-12-20 2022-06-30 Bayer Aktiengesellschaft Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof
TW202135662A (zh) 2019-12-20 2021-10-01 德商拜耳廠股份有限公司 噻吩基㗁唑啉酮及類似物
CN116406266A (zh) 2020-11-06 2023-07-07 勃林格殷格翰国际有限公司 2-[(噻吩-2-基)甲酰胺基]-n-(苯基)-2-甲基丙酰胺衍生物及其作为药物的用途

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DE19962924A1 (de) * 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
GB0030305D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds
CA2428184C (fr) * 2000-11-10 2010-03-30 Yamanouchi Pharmaceutical Co., Ltd. Derive de thiazolylphenylcarbamoylmethylamide
DE10063008A1 (de) * 2000-12-16 2002-06-20 Merck Patent Gmbh Carbonsäureamidderivate
EP1558606A4 (fr) * 2002-10-02 2008-05-07 Bristol Myers Squibb Co Diaminoalkyle contenant du lactame, acides amines beta, acides amines alpha et leurs derives utilises en tant qu'inhibiteurs du facteur xa
DE10254336A1 (de) * 2002-11-21 2004-06-03 Merck Patent Gmbh Carbonsäureamide
MXPA06013213A (es) * 2004-05-13 2007-02-08 Boehringer Ingelheim Int Nuevas amidas sustituidas del acido tiofencarboxilico, su obtencion y su uso como medicamentos.
DE102004047840A1 (de) * 2004-09-29 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Thiophencarbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel

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Title
See references of WO2005111013A1 *

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JP2007537179A (ja) 2007-12-20
CA2562714A1 (fr) 2005-11-24
WO2005111013A1 (fr) 2005-11-24
US20050256107A1 (en) 2005-11-17

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