WO2004058743A1 - Nouveaux composes heterobicycliques azotes substitues et leur utilisation en tant qu'inhibiteurs du facteur xa - Google Patents

Nouveaux composes heterobicycliques azotes substitues et leur utilisation en tant qu'inhibiteurs du facteur xa Download PDF

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WO2004058743A1
WO2004058743A1 PCT/EP2003/014378 EP0314378W WO2004058743A1 WO 2004058743 A1 WO2004058743 A1 WO 2004058743A1 EP 0314378 W EP0314378 W EP 0314378W WO 2004058743 A1 WO2004058743 A1 WO 2004058743A1
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chloro
alkyl
carbonyl
group
benzimidazol
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PCT/EP2003/014378
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German (de)
English (en)
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Henning Priepke
Roland Pfau
Kai Gerlach
Uwe Ries
Wolfgang Wienen
Eckhart Bauer
Herbert Nar
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority to AU2003298192A priority Critical patent/AU2003298192A1/en
Priority to EP03795904A priority patent/EP1583757A1/fr
Priority to CA002511349A priority patent/CA2511349A1/fr
Priority to JP2004562769A priority patent/JP2006515301A/ja
Publication of WO2004058743A1 publication Critical patent/WO2004058743A1/fr

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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel substituted nitrogen-containing heterobicyclics 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 acceptable salts with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic activity and a factor Xa-inhibiting effect.
  • the present application thus provides the novel compounds of the above general formula I, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and use.
  • R 1 is an amino, C ⁇ . 5- Alkylamino-, C3-7-Cycloalkylamino- or (phenyl-C ⁇ - 3 -alkyl) -amino group, each additionally on the amine nitrogen atom by a Phenylcarbonyl- or
  • 5- alkyl or Ci-s-alkylcarbonyl may be substituted, wherein in the substitution of the above-mentioned C ⁇ . 5 alkyl group two heteroatoms are separated from each other by at least two carbon atoms,
  • Cycloalkylenimino, a phenyl or a 5- to 6-membered heteroaryl group may be substituted with the proviso that in the substitution of one of the imino group adjacent methylene group two heteroatoms are separated by at least two carbon atoms, and / or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or a methylene group in the 2-position of a 5-membered cycloalkyleneimino group may be replaced by an -NH group or
  • Sulfinyl or sulfonyl or by an optionally by a -C. 3- alkyl, hydroxy, formyl, C 1-3 -alkylcarbonyl or phenylcarbonylamino substituted -NH group may be replaced, wherein additionally a methylene group adjacent to an above -NH group may be replaced by a carbonyl or sulfonyl group , with the proviso that
  • a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced with the proviso that
  • cycloalkyleneimino groups mentioned above in the radicals may additionally be substituted by a carboxy or C 1-5 -alkyloxycarbonyl group,
  • the methylene group in the 2-, 3- or 4-position in a C 3 . 7 -Cycloalkylcarbonyl distr may be replaced by an oxygen or sulfur atom, a carbonyl, sulfinyl, sulfonyl or an -NH group, in the
  • the hydrogen atom of the -NH group may be replaced by a C 1-3 -alkyl or C 1-3 -alkyl-carboyl group,
  • the phenyl part by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ⁇ .3-alkyl, amino-C 3 -alkyl, C 3 -alkylamino-C ⁇ .3-alkyl, di (C 3- alkyl) amino
  • Cycloalkylenimino-3 C ⁇ - alkyl group or C 3 alkoxy may be substituted and / or
  • a methylene group which is adjacent to the nitrogen atom may be replaced by a carbonyl group in a 5- to 7-membered cycloalkyleneimino group
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ . 3- alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C 2 - 3 alkenyl, C 2 -3 alkynyl, nitro, amino, C ⁇ .3 alkoxy, a mono- , Di- or trifluoromethoxy group,
  • R 3 is a hydrogen atom or a C 1-3 -alkyl group
  • R 4 is a hydrogen atom or a straight-chain or branched C. 5 alkyl group optionally substituted by a fluorine atom, a C 2 - 3 alkenyl, C 2 - 3 alkynyl, mono-, di- or trifluoromethyl, a hydroxy, C ⁇ -5-alkyloxy, allyloxy, Propargyloxy, phenyloxy, heteroaryloxy, benzyloxy, C ⁇ . 5- Alkylcarbonyloxy-, C ⁇ _ 5 -Alkyloxycarbonyloxy-, carboxy -C.
  • p is one of the numbers 0, 1, 2 or 3,
  • R 11 is a hydrogen atom or a C. 3- alkyl group
  • a a C 3 . 7 cycloalkyl group in which the methine group in position 1 may be replaced by a nitrogen atom if p is one of the numbers 2, 3, 4 or 5, and / or
  • Oxygen or sulfur atom a -NH-, -N (OH) -, -N (d- 3- alkyl) -, -N (-C 3 alkylcarbonyl) - or -N (heteroaryl) group may be replaced with with the proviso that in a so-formed radical -N (R 11 ) - (CH 2 ) P -A two heteroatoms are separated by at least two carbon atoms, and / or
  • a methylene group adjacent to a -NH-, -N (OH) -, -N (C 1-3 -alkyl) -, -N (C 1-3 -alkylcarbonyl) - or -N (heteroaryl) -group by a carbonyl, Sulfinyl or sulfonyl group may be replaced,
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a carbonyl, sulfinyl or sulfonyl group, or
  • a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or by an optionally by a C 1-3 alkyl or Heteroar lised substituted -NH group may be replaced and additionally a methylene group adjacent to an above-mentioned -NH- or -N (C ⁇ - 3- alkyl) group may be replaced by a carbonyl group and / or
  • two geminal hydrogen atoms of a methylene group in a cycloalkyleneimino group mentioned above may be substituted by a 5- to 7-membered carbocycle to form a spiro compound
  • one or two non-adjacent methylene groups of the abovementioned carbocycle being independently of one another represented by an oxygen or sulfur atom or a NH, -N (OH) -, or -N (C 1, 3 -alkyl) group may be replaced and additionally one to a -NH-, -N (OH) -, or -N (C 3 -) Alkyl) group adjacent methylene group of the carbocycle may be replaced by a carbonyl, sulfinyl or sulfonyl group, or
  • a phenyl or heteroaryl group may be fused to two adjacent methylene groups in the 2- and 3-position of a 5-membered cycloalkyleneimino group mentioned above or in the 3- and 4-position of a 6- to 7-membered cycloalkyleneimino group mentioned above a phenyl or heteroaryl group,
  • 3- alkyl-, aminocarbonyl-C 3 -alkyl-, C 1-3 -alkylaminocarbonyl-C 1-3 -alkyl, di- (C 3-3 -alkyl) -aminocarbonyl-C 1-3 -alkyl group may be substituted,
  • a methylene group of the cycloalkyleneimine moiety through an oxygen or sulfur atom, a carbonyl, sulfinyl or sulfonyl group, an -NH-, -N (OH) -, -N (d- 3- alkyl) -, or -N (C 1 . 3- alkylcarbonyl) group may be replaced,
  • a 4- to 7-membered cycloalkyl-C ⁇ - 5- alkyl group in which in the cyclic part of a methylene group may be replaced by a -NH- or -N (C ⁇ - 3- alkyl) - group and in which one of the -NH- or -N (C 1-3 -alkyl) group adjacent methylene group may each be replaced by a carbonyl group, with the proviso that a cycloalkyleneimino group as defined above in which two nitrogen atoms are separated by exactly one -CH 2 - group , excluded are,
  • R 5 is a hydrogen atom or a -C. 3- alkyl group or
  • R 4 and R 5 together with the carbon atom to which they are attached, a C 3 -7-cycloalkyl group, wherein
  • one of the methylene groups of the C 3 -7-cycloalkyl group by an imino, C ⁇ . 3- alkyl-imino, acylimino or sulfonylimino group may be replaced,
  • n is the number 1 or 2
  • R 6 is a hydrogen atom or a C 1-3 -alkyl, hydroxy, amino, or D 3 -alkylamino group
  • R 7 is a hydrogen, fluorine, chlorine or bromine atom, a C 1-3 -alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C 2 -3 alkenyl or C 2-3 alkynyl, represent a hydroxy, -C-3-alkoxy, trifluoromethoxy or cyano group, and
  • X 1 to X 3 are each independently a nitrogen atom, a ⁇ / oxide or an optionally substituted by C ⁇ - 3 alkyl group CH group,
  • heteroaryl group a carbon skeleton optionally substituted by a C 1-3 -alkyl, carboxy, d 3 -alkoxycarbonyl or C 1-3 -alkoxy carbonyl-amino group substituted monocyclic 5- or 6-membered heteroaryl group is to be understood, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl one or two, optionally substituted by a C ⁇ - 3 alkyl or phenyl C-. 3 -alkyl group substituted imino groups, an oxygen or sulfur atom or
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms
  • the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched, and the alkyl groups in the above-mentioned dialkylated groups, for example, the dialkylamino groups, the same or different could be,
  • Examples of monocyclic heteroaryl groups are the pyridyl, ⁇ / -oxypyridyl, 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 [] isothiazolyl, benzo [] isothiazolyl, benzooxazolyl, benzo [c] isoxazolyl, benzo [] isoxazolyl, benzo [1, 2,5] oxadiazolyl, benzo [1, 2,5] thiadiazolyl, benzo [1, 2,3] thiadiazolyl, benzo [c ] [1,2,3] triazinyl, benzo [1,2,4] triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, / V-oxy-quinolinyl, isoquinolinyl, quinazolinyl, ⁇ / -oxy-
  • Ci-s-alkyl groups are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl , 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl , 2-octyl, 3-octyl or 4-octyl group.
  • Examples of the above mentioned in the definitions C ⁇ . 8- alkyloxy groups are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, ⁇ -butyloxy, sec-butyloxy, tert-butyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy , 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-heptyloxy, 2-heptyloxy, 3-heptyloxy, 4-heptyloxy, 1-octyloxy, 2-octyloxy, 3-octyloxy or 4-octyloxy group.
  • 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 1-6 -alkanol, a phenyl-d. 3 -alkanol, a C 3 -9-cycloalkanol, a C 5 . 7 cycloalkenol, a C 3 .
  • R 8 is -CO-O- (R 9 CR 10 ) -OH, in the
  • R 8 is a Ci-s-alkyl, C 5-7 cycloalkyl, phenyl or phenyl-C ⁇ . 3- alkyl group,
  • R 9 is a hydrogen atom, a C ⁇ - 3 alkyl, C 5 -7 cycloalkyl or phenyl and
  • R 10 represents a hydrogen atom or a C 1-3 -alkyl group
  • a carboxy group in vivo may be cleaved a C ⁇ - 6 alkoxy group such as methoxy, ethoxy, n-propyloxy, isopropyloxy, ⁇ -butyloxy, n-pentyloxy, hexyloxy or cyclohexyloxy group ⁇ -or Phenyl-d-3-alkoxy group such as the benzyloxy group into consideration.
  • R 1 is an amino, C ⁇ - 5- alkylamino, C 3 . 7- Cycloalkylamino- or (phenyl-C 3 -alkyl) -amino group, in each case at the amine nitrogen atom additionally by a in the alkyl part, if necessary, by a hydroxy, C 1-3 alkoxy or carboxy group, one in vivo in a Carboxy group convertible group, an amino, C ⁇ - 3 -alkylamino, di (d- 3 -alkyl) - amino or a 4- to 7-membered cycloalkyleneimino substituted C ⁇ .
  • 5- alkyl or C ⁇ - 5 alkylcarbonyl may be substituted, wherein in the substitution of the above-mentioned C ⁇ - 5- alkyl group two heteroatoms are separated from each other by at least two carbon atoms,
  • a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group wherein the Cycloalkyleniminoteil in the carbon skeleton by one or two C 3 alkyl, phenyl C 3 -alkyl, 1, 1-diphenyl -C. 3 -alkyl, hydroxy-C 3 -alkyl, C ⁇ . 3 -Alkyloxy- -C ⁇ . 3 -alkyl-, heteroaryl-C ⁇ - 3 -alkyl-, carboxy-C. 3 -alkyl, C 3 -alkyloxycarbonyl-C 3 -alkyl, amino-C. 5 -alkyl, C ⁇ . 5- alkylamino-C. 5- alkyl, C 3 -6-cycloalkylamino-C 3 -alkyl,
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
  • a methylene group in the 2-position of a 5-membered cycloalkyleneimino group may be replaced by an -NH group or
  • 3- alkylcarbonyl or phenylcarbonylamino substituted -NH group may be replaced, wherein additionally a methylene group may be replaced by a carbonyl or sulfonyl group adjacent to an aforementioned -NH group, with the proviso that
  • Sulfur atom, a sulfinyl or sulfonyl group is replaced, two heteroatoms are separated by at least two carbon atoms, and / or
  • a -CH-CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) -CO Group may be replaced with the proviso that
  • C 3 -alkyl amino-C 3 -alkyl, C 3 -alkyl-amino-C ⁇ . 3 alkyl-, di- (C ⁇ -3-alkyl) -amino-3 C ⁇ - alkyl, 4- to 7-membered alkyl Cycloalkylenimino- C ⁇ - 3 or C 3 - 6 ⁇ cycloalkylamino C ⁇ - 3 - 5- to 7-membered cycloalkenyleneiminocarbonyl group substituted with alkyl groups, wherein the double bond is not bonded to a nitrogen atom and may be condensed with a 5- or 6-membered heteroaryl group,
  • Cycloalkylenimino phenomenon 5 alkyloxycarbonyl group may additionally be substituted by a carboxy or C ⁇ -,
  • a -CH 2 -CH - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -NH-S0 2 -, -S0 2 NH-, -CO-N ( CH 3 ) - or a -N (CH 3 ) -CO- group or
  • a methylene group which is adjacent to the nitrogen atom may be replaced by a carbonyl group in a 5- to 7-membered cycloalkyleneimino group
  • R 2 is a chlorine or bromine atom, a C ⁇ - 3 alkyloxy-, C ⁇ - 3 alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a C 2 - 3 alkenyl group,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a straight-chain or branched-C 5-alkyl group which is optionally substituted by a C 2 - 3 alkenyl, C 2 . 3 alkynyl, hydroxy, C ⁇ - 5 alkyloxy, phenyl oxy, heteroaryloxy, benzyloxy, C ⁇ - 5 alkylcarbonyloxy, carboxy-d- 3 -alkyloxy, C ⁇ - 5- alkyloxycarbonyl-C ⁇ - 3 -alkyloxy, C ⁇ - 5 -alkyloxycarbonylamino, mercapto, C 3 -alkyl sulfanyl, C 3 -alkylsulfinyl, C 3 -alkylsulfonyl, carboxy, C ⁇ - 5- alkyloxycarbonyl, allyl - Oxycarbonyl-, Propargykoxycarbonyl-, Benzyloxycarbonyl-, amino, C ⁇ - 3 -alky
  • p is one of the numbers 0, 1, 2 or 3,
  • R 11 is a hydrogen atom or a C 1-3 alkyl group
  • A is a C 3 .7-cycloalkyl group in which the methine group in position 1 may be replaced by a nitrogen atom if p is one of the numbers 2 or 3, and / or
  • an above-mentioned cycloalkyl groups through an oxygen or sulfur atom an -NH-, -N (OH) -, -N (C ⁇ - 3 alkyl) -, -N (C ⁇ - 3 -alkylcarbonyl) - or -N ( Heteroaryl) group can be replaced with the proviso that in a so-formed radical -N (R 11 ) - (CH 2 ) P -A two heteroatoms are separated by at least two carbon atoms, and / or
  • a methylene group adjacent to a -NH-, -N (OH) -, -N (C 1-3 -alkyl) -, -N (C 1-3 -alkylcarbonyl) - or -N (heteroaryl) -group by a carbonyl, Sulfinyl or sulfonyl group may be replaced,
  • Cycloalkyleniminoteils by an optionally represented by a hydroxy, amino, C ⁇ - alkylamino, di- (C ⁇ - 3 -alkyl) -amino, a 4- to 7-membered cycloalkylenimi-, morpholino, piperazinyl -, / V- (-C 3 -alkyl) -piperazinyl- or
  • C ⁇ . 5- alkyloxycarbonylamino substituted C 1 . 3- alkyl group and a non-imino group adjacent the methylene group of Cycloalkyleniminoteils by a hydroxy, amino, C ⁇ - 3- alkylamino, di (C ⁇ - 3- alkyl) amino, aminocarbonyl, C 1 - 3 -AI- kylaminocarbonyl or di- (C ⁇ .3-alkyl) aminocarbonyl group may be substituted and / or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a carbonyl, sulfinyl or sulfonyl group, or
  • 3- alkyl or heteroaryl group-substituted -NH group may be replaced and in addition a methylene group adjacent to an above-mentioned -NH- or -N (C ⁇ - 3- alkyl) group may be replaced by a carbonyl group and / or
  • two geminal hydrogen atoms of a methylene group in a cycloalkyleneimino group mentioned above may be substituted by a 5- to 7-membered carbocycle to form a spiro compound
  • one or two non-adjacent methylene groups of the abovementioned carbocycle being independently of each other denoted by an oxygen or sulfur atom or NH-, -N (OH) -, or -N (-C- 3- alkyl) group may be replaced and additionally one to a -NH-, -N (OH) -, or -N (C ⁇ - 3 alkyl )
  • Group adjacent methylene group of the carbocycle may be replaced by a carbonyl, sulfinyl or sulfonyl group, or
  • a phenyl or heteroaryl group may be fused to two adjacent methylene groups in the 2- and 3-position of a 5-membered cycloalkyleneimino group mentioned above or in the 3- and 4-position of a 6- to 7-membered cycloalkyleneimino group mentioned above a phenyl or heteroaryl group,
  • a phenyl or heteroaryl phenyl-C 3 -alkyl or heteroaryl-C. 3 -alkyl group, optionally substituted by a chlorine atom, a hydroxy, -C. 4 alkyloxy, trifluoromethoxy, carboxy or C
  • 3- alkyloxycarbonyl group is substituted, a 4- to 7-membered cycloalkyleneimino-C ⁇ - 5- alkyl group, in the
  • a methylene group of the cycloalkyleneimine moiety may be replaced by an oxygen or sulfur atom, a carbonyl or sulphonyl group, or
  • CycloalkyI -C. 5- alkyl group in which in the cyclic part of a methylene group may be replaced by a -NH- or -N (C ⁇ - 3 alkyl) - group and in which one of the -NH- or -N (C ⁇ - 3- alkyl) -
  • Each adjacent methylene group may be replaced by a carbonyl group, provided that a cycloalkyleneimino group as defined above, in which two nitrogen atoms are separated by exactly one -CH 2 group, are excluded,
  • R 5 is a hydrogen atom
  • n is the number 1
  • R 6 is a hydrogen atom or a C 1-3 -alkyl, hydroxy, amino, ds-alkylamino group,
  • R 7 represents a hydrogen, fluorine, chlorine or bromine atom and X 1 to X 3 independently of one another each represent a nitrogen atom or an optionally substituted by a methyl group CH group,
  • heteroaryl means a superviseden- in the carbon skeleton substituted by a d-C3 alkyl, carboxy, C ⁇ - 3 alkoxy or C ⁇ - carbonyi-. 3 - Alkoxy-carbonyl-amino group substituted monocyclic 5- or 6-membered heteroaryl group is to be understood, wherein
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group one or two optionally substituted by a -C-3-alkyl or phenyl-C ⁇ - 3 -alkyl group-substituted imino group, an oxygen or sulfur atom or
  • an imino group which is optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and contains two or three nitrogen atoms,
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms
  • the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring, wherein the alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched, and the alkyl groups in the above-mentioned dialkylated groups, for example, the dialkylamino groups, the same or different could be,
  • R 1 is an amino, C- ⁇ -5-alkylamino, C 3 . -Cycloalkylamino- or (phenyl-C ⁇ - 3 -alkyl) -amino- group, in each case at the amino nitrogen atom additionally by a in the Aikylteil optionally by a hydroxy, C ⁇ - 3 -alkoxy or carboxy, in vivo into a carboxy group convertible group, an amino, C ⁇ - 3 -alkylamino, di- (C ⁇ - 3 -alkyl) - amino or a 4- to 7-membered cycloalkyleneimino substituted C ⁇ - 5 -alkyl or C ⁇ - 5- alkylcarbonyl be substituted in which two heteroatoms are separated from one another by at least two carbon atoms in the substitution of the abovementioned C 1-5 -alkyl group,
  • Hydroxy-, C ⁇ - 3 alkyloxy, benzyloxy, amino, C ⁇ - 3- alkylamino, di- (C 3 -alkyl) - amino, a 4- to 7-membered cycloalkyleneimino, a phenyl or a 5- to 6-membered heteroaryl group may be substituted with the proviso that in the substitution of a methylene group adjacent to the imino group two heteroatoms are separated by at least two carbon atoms, and / or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
  • a methylene group in the 2-position of a 5-membered cycloalkyleneimino group may be replaced by an -NH group or
  • Hydroxy, formyl, C- ⁇ - 3- alkylcarbonyl or phenylcarbonylamino substituted -NH group may be replaced, wherein in addition a methylene group adjacent to an above -NH group may be replaced by a carbonyl or sulfonyl group with the proviso that
  • a -CH 2 -CH 2 - group in a 5- to 6-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced with the proviso that a cycloalkyleneimino group as defined above, in which two nitrogen atoms are separated by exactly one -CH 2 group, is excluded,
  • C 1 -5-alkyl groups by one or two hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, benzyloxy C 1-3 -alkyl, amino-C 1 3- alkyl-, C 1-3 -alkylamino-C 1-3 -alkyl-, di- (C 1-3 -alkyl) -amino-C 1-3 -alkyl, 4- to 7-membered cycloalkylenimino-d- 3-alkyl, OPyrrolidinyl-, C 3 -6-Cycloalkylamino-C ⁇ . 3 -alkyl or 4- bis
  • Cycloalkylenimino phenomenon 5 alkyloxycarbonyl group may additionally be substituted by a carboxy or C ⁇ -,
  • n 1 or 3
  • R 2 is a chlorine or bromine atom, a -C. 3 -Alkyloxy- or -C. 3- alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a linear or branched C 5 alkyl group optionally substituted by a C - 3 alkynyl, hydroxy, C ⁇ - oxy- 5 alkyloxy-, phenyl, heteroaryloxy - 3 alkenyl, C 2 -, Benzyloxy-, C ⁇ - 5 -Alkylcarbonyloxy-, carboxy-C 3 -alkyloxy, C ⁇ - 5 -alkyloxycarbonyl-C 3 -alkyloxy, C 8 -alkyloxycarbonylamino, mercapto, C 3 -alkyl sulfanyl, C ⁇ .
  • p is one of the numbers 0, 1, 2 or 3,
  • R 11 is a hydrogen atom or a C 1-3 alkyl group
  • a a C 3 . 7 cycloalkyl group in which the methine group in position 1 may be replaced by a nitrogen atom if p is one of the numbers 2 or 3, and / or
  • Oxygen or sulfur atom, a -NH-, -N (OH) -, -N (-C 3 -alkyl) -, -N (-C 3 -alkylcarbonyl) - or -N (heteroaryl) group may be replaced with with the proviso that in a so-formed radical -N (R 11 ) - (CH 2 ) P -A two heteroatoms are separated by at least two carbon atoms, and / or
  • a methylene group adjacent to a -NH-, -N (OH) -, -N (C 1-3 -alkyl) -, -N (C 1-3 -alkylcarbonyl) - or -N (heteroaryl) -group by a carbonyl, Sulfinyl or sulfonyl group may be replaced,
  • Cycloalkyleniminoteils by a optionally substituted by a hydroxy, amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - alkyl) -amino group, a 4- to 7-gliedri- ge Cycloalkylenimino-, morpholino, Piperazinyl, / V- (C 1-3 alkyl) piperazinyl or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a carbonyl, sulfinyl or sulfonyl group, or
  • 3- alkyl or Heteroaryl group-substituted -NH group may be replaced and additionally a methylene group adjacent to an above-mentioned -NH- or -N (C ⁇ - 3- alkyl) group may be replaced by a carbonyl group and / or
  • two geminal hydrogen atoms of a methylene group in a cycloalkyleneimino group mentioned above may be substituted by a 5- to 7-membered carbocycle to form a spiro compound
  • one or two non-adjacent methylene groups of the abovementioned carbocycle being independently of one another represented by an oxygen or sulfur atom or a NH-, -N (OH) -, or -N (-C- 3- alkyl) group may be replaced and additionally one to a -NH-, -N (OH) -, or -N (C ⁇ - 3 alkyl )
  • Group adjacent methylene group of the carbocycle may be replaced by a carbonyl, sulfinyl or sulfonyl group, or
  • a phenyl or heteroaryl group may be fused to two adjacent methylene groups in the 2- and 3-position of a 5-membered cycloalkyleneimino group mentioned above or in the 3- and 4-position of a 6- to 7-membered cycloalkyleneimino group mentioned above a phenyl or heteroaryl group,
  • a methylene group of the cycloalkyleneimine moiety may be replaced by an oxygen or sulfur atom, a carbonyl or sulphonyl group, or
  • a 4- to 7-membered cycloalkyl-C 3 -alkyl group in which in the cyclic part of a methylene group may be replaced by a -NH- or -N (-CC 3-alkyl) - group and in which one of the -NH- or -N (C 1-3 alkyl) group adjacent methylene group may each be replaced by a carbonyl group, with the proviso that a cycloalkylene as defined above, in which two nitrogen atoms are separated by exactly one -CH 2 - group excluded are,
  • R 5 is a hydrogen atom
  • n is the number 1
  • R 6 is a hydrogen atom
  • R 7 represents a fluorine, chlorine or bromine atom
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • heteroaryl group means a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C 1-3 -alkyl group in the carbon skeleton
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is one or two imino groups optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group
  • an imino group which is optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and contains two or three nitrogen atoms,
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms
  • the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions may be straight-chain or branched, and the alkyl groups in the above-mentioned dialkylated groups, for example, the dialkylamino group, the same or different could be, and wherein the hydrogen atoms of the methyl or ethyl groups contained in the above-mentioned definitions may be wholly or partly replaced by fluorine atoms,
  • R 1 is a 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein
  • the cycloalkyleneimine moiety in the carbon skeleton is replaced by one or two C 1-3 -alkyl, phenyl-C 1-3 -alkyh-1, 1-diphenyl-C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkyloxy- C 3 -alkyl-, carboxy-C 3 -alkyl-, C ⁇ . 3 -alkyloxycarbonyl -C. 3- alkyl, amino-C ⁇ - 5- alkyl,
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or a methylene group in the 2-position of a 5-membered cycloalkyleneimino group may be replaced by an -NH group or
  • Sulfinyl or sulfonyl group or by an optionally substituted by a C ⁇ - 3 alkyl, hydroxy, formyl, C ⁇ - 3 -alkylcarbonyl- or phenylcarbonylamino-substituted -NH group may be replaced, wherein additionally a methylene group adjacent to an above - NH group may be replaced by a carbonyl or sulfonyl group, with the proviso that
  • a -CH 2 -CH 2 - group in a 5- to 6-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced with the proviso that
  • C ⁇ . 5- alkyl groups by one or two amino-C ⁇ - 3 -alkyl-, C ⁇ - 3 -alkylamino-C 3 -alkyl, di- (C 3 -alkyl) -amino-C 3 -alkyl-, 4- to 7-membered cycloalkyleneimino-C ⁇ - 3 -alkyl-, OPyrrolidinyl-, C 3 . 6 -cycloalkylamino
  • cycloalkyleneimino groups mentioned above in the radicals may additionally be substituted by a carboxy or C 1-5 -alkyloxycarbonyl group,
  • n 1 or 3
  • R 2 is a chlorine or bromine atom, a C ⁇ -3-alkyloxy or d- 3 alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a straight-chain or branched C ⁇ - 5 alkyl group, optionally substituted by a C 2 - 3 alkynyl, hydroxy, -C. 5 alkyloxy, benzyloxy, C 1 - 5 kylcarbonyloxy- -AI-, carboxy-C - 3 alkyloxy, C ⁇ .5 alkyloxycarbonyl-d. 3 -alkyloxy, C 3 -alkyl sulfanyl, C 3 -alkylsulfinyl, C 3 -alkylsulfonyl, carboxy, C ⁇ .
  • p is one of the numbers 0, 1, 2 or 3,
  • R 11 is a hydrogen atom or a d. 3- alkyl group
  • A is a C 3-7 cycloalkyl group, in the
  • the methine group in position 1 may be replaced by a nitrogen atom if p is one of the numbers 2 or 3, and / or
  • a methylene group of a cycloalkyl group mentioned above by an oxygen or sulfur atom an -NH-, -N (OH) -, -N (C 1-3 -alkyl) -, -N (C 1-3 -alkylcarbonyl) - or -N ( Heteroaryl) group can be replaced with the proviso that in a so-formed radical -N (R 11 ) - (CH 2 ) P -A two heteroatoms are separated by at least two carbon atoms, and / or
  • Sulfinyl or sulfonyl group may be replaced, a 5- to 6-membered Cycloalkyleniminocarbonyl-C ⁇ - 5- alkyl group, wherein
  • Cycloalkyleniminoteils by an optionally represented by a hydroxy, amino, C 1 .
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a carbonyl, sulfinyl or sulfonyl group, or
  • two geminal hydrogen atoms of a methylene group in a cycloalkyleneimino group mentioned above may be substituted by a 5- to 7-membered carbocycle to form a spiro compound
  • one or two non-adjacent methylene groups of the abovementioned carbocycle being independently of one another represented by an oxygen or sulfur atom or a NH-, -N (OH) -, or -N (-C 3 alkyl) group may be replaced and additionally one to a -NH-, -N (OH) -, or -N (C 1-3 alkyl )
  • Group adjacent methylene group of the carbocycle may be replaced by a carbonyl, sulfinyl or sulfonyl group, or
  • 4- alkyloxy, trifluoromethoxy, carboxy or C 3 -alkyloxycarbonyl distr is substituted,
  • Sulfur atom, a carbonyl or sulfonyl group may be replaced,
  • R 5 is a hydrogen atom
  • n the number 1
  • R 6 is a hydrogen atom
  • R 7 is a chlorine or bromine atom
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • heteroaryl group means a monocyclic 5- or 6-membered heteroaryl group which is optionally substituted by a C 1-3 -alkyl group in the carbon skeleton,
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group one or two optionally substituted by a C ⁇ - 3 alkyl or phenyl-C ⁇ - 3 alkyl substituted imino group or a
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms and the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched, and the alkyl groups in the above-mentioned dialkylated groups, for example, the dialkylamino groups, the same or different could be,
  • R 1 is a 2,5-dihydro-1 - / - pyrrole-1-yl-carbonyl, pyrrolidin-1-yl-carbonyl, 2- (aminomethyl) -pyrrolidin-1-yl-carbonyl-, 2 - (/ V-te / f.-butyloxycarbonylaminomethyl) -pyrrolidin-1-yl-carbonyl-, 3-oxo-piperazine-1-yl-carbonyl, morpholin-4-yl-carbonyl, carboxy, 3-amino- methyl-pyrrolidine-1-yl-carbonyl, thiazolidin-3-yl-carbonyl, 3-aminomethyl-pyrrolidin-1-yl-carbonyl, pyrazolidin-3-one-1-yl-carbonyl, pyrrolidin-2 ylmethylamino-carbonyl, 1-tert-butyloxycarbonyl-pyrrolidin-2-yl-methyla
  • R 2 is a hydrogen, chlorine or bromine atom, a C 1-3 alkyloxy or a C 1-3 -alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom, a methyl, propyl, 2-methylsulfanyl-ethyl, 2-methylsulfonyl-ethyl, hydroxymethyl, 2-carboxyethyl, 2-benzyloxycarbonyl-ethyl, 2-methoxy-ethyl, 2- Methylsulfinyl-ethyl, te / i-butyloxycarbonylmethoxy-methyl, 2-ethoxycarbonyl-ethyl, carboxymethoxy-methyl, o-chlorophenyl, p-chlorophenyl, methoxymethyl, 2-diethylaminocarbonyl-ethyl, 2- Propargyloxycarbonyl-ethyl, 2- (pyrrolidin-1-yl-carbonyl) -ethyl, 2- [ ⁇ / -methyl-A-piperidin-4-yl-amino] -carbonyl-ethyl, 2-
  • R 5 is a hydrogen atom
  • R 6 is a hydrogen atom
  • R 7 represents a chlorine or bromine atom
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • R 1 is an amino, C ⁇ . 5- alkylamino, C 3 . 7 -cycloalkylamino- or (phenyl-C 3 -alkyl) -amino group, in each case on the amine nitrogen atom by a phenylcarbonyl or phenylsulfonyl group or by an alkyl moiety optionally substituted by a carboxy group, a group convertible in vivo into a carboxy group, an amino, C ⁇ - 3 -alkylamino, di (d- 3 -alkyl) -amino or C 3 - 6 -cycloalkylenimino phenomenon substituted C ⁇ - 5 alkyl or C ⁇ - 5 alkylcarbonyl may be substituted, wherein two nitrogen atoms at least by two carbon atoms are separated from each other,
  • V- (phenyl-C ⁇ - 3 -alkyl) -C ⁇ . 5 -alkylaminocarbonyl or di- (C ⁇ - 3 -alkyl) aminocarbonyl group may be substituted or
  • C 3 . 6 -Cycloalkyleniminooli may be substituted and / or a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
  • -N-C ⁇ - 3 alkyl -N (C 2 - 3 alkanoyl) -, sulfinyl or sulfonyl group.
  • sulfinyl or sulfonyl group can be replaced and / or
  • a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced,
  • a methylene group not adjacent to the imino group by a hydroxyl, Benzyloxy, C ⁇ - 3 alkoxy, amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - -alkyl) -amino or C 3 - 6 -Cycloalkylenimino distr may be substituted,
  • the methylene group in the 2-, 3- or 4-position in a C 3 . 7 -Cycloalkylcarbonyl distr may be replaced by an oxygen or sulfur atom, a carbonyl, sulfinyl, sulfonyl or an -NH group, in the
  • a phenylcarbonyl or heteroarylcarbonyl group which in the phenyl or heteroaryl moiety is substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-d. 3-alkyl-, di- (C 3 -alkyl) -amino-C. 3- alkyl,
  • the phenyl part by a fluorine, chlorine or bromine atom, by a trifluoromethyl, -C. 3- alkyl, amino-C 3 -alkyl, C 3 -alkylamino-C 3 -alkyl, di- (C 3 -alkyl) -amino C ⁇ . 3- alkyl, C 3 .6-Cycloalkylenimino-d- 3- alkyl or -C. 3 alkoxy group may be substituted and / or
  • a methylene group which is adjacent to the nitrogen atom may be replaced by a carbonyl group in a 5- to 7-membered cycloalkyleneimino group
  • n 1 or 2
  • R is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ - 3 alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C 2 - 3 alkenyl, C 2 -3-alkynyl, C 1-3 -alkoxy or trifluoromethoxy group,
  • R 3 is a hydrogen atom or a C- ⁇ - 3 alkyl group
  • R 4 is a Wasserstorfatom or a straight-chain or branched C ⁇ - 5 alkyl group, optionally substituted by a hydroxy, -C. 3 alkyloxy, mercapto, C ⁇ . 3- alkylsulfanyl, C 3 -alkylsulfinyl, C 3 -alkylsulfonyl, carboxy, aminocarbonyl, C 3 -alkylamino-carbonyl, di (C 3 -alkyl) aminocarbonyl, C 3 . ⁇ -Cycloalkyleniminocarbonyl, amino, C 3 -alkylamino, di (C 3 -alkyl) amino, C 3 .
  • phenyl- or heteroaryl phenyl-C 1-3 -alkyl- or heteroaryl-C 1-3 -alkyl group which is optionally substituted by a hydroxy, C 1-5 -alkyloxy, benzyloxy, hydroxycarbonyl-
  • a 4- to 7-membered cycloalkyl-C ⁇ - 3 -alkyl group in which one or two methylene groups may be replaced by a -NH- or -N (C ⁇ - 3- alkyl) - group and in which one or two of the -NH or -N (C 1-3 -alkyl) -group adjacent methylene groups may each be replaced by a carbonyl group, with the proviso that a cycloalkyl group as defined above in which two -NH- or -N (C-. 3 - Alkyl) groups are separated by exactly one -CH 2 group, are excluded,
  • R 5 is a hydrogen atom or a C 1-3 alkyl group or
  • one of the methylene groups of C 3 . 7 -cycloalkyl group by an imino, d. 3- alkyl-imino, acylimino or sulfonylimino group may be replaced,
  • n the number 1 or 2
  • R 6 is a hydrogen atom or a C 1-3 -alkyl, hydroxy, amino, C 1-3 -alkylamino group,
  • R 7 is a hydrogen, fluorine, chlorine or bromine atom, a C 1-3 -alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a dwrAlkenyl- or C 2 - 3 -alkynyl-, a hydroxy, C ⁇ _ 3 alkoxy, trifluoromethoxy or cyano represent, and
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • heteroaryl in the carbon skeleton optionally substituted by a C ⁇ - 3 alkyl, carboxy, C ⁇ - 3 -alkoxycarbonyl or C ⁇ - 3 -A! koxy-carbonylamino-substituted monocyclic 5- or 6-membered heteroaryl group is to be understood, wherein
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, an oxygen or sulfur atom or
  • a d- 3 alkyl amino-C ⁇ - 3 -alkyl-, C ⁇ .
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms
  • the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the definitions, unless otherwise mentioned, may be straight-chain or branched,
  • R 1 is an amino, C 5 -alkylamino, C 3 . 7 -cycloalkylamino- or (phenyl-C 1-3 -alkyl) -amino group, in each case on the amine nitrogen atom by a phenylcarbonyl or phenylsulfonyl group or by an alkyl moiety optionally substituted by a carboxy group, a group convertible in vivo into a carboxy group, an amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - -alkyl) -amino or C. 3 6 -Cycloalkyleniminouite substituted Ci- ⁇ -alkyl or C ⁇ - 5 alkylcarbonyl may be substituted, wherein two nitrogen atoms are separated from each other by at least two carbon atoms,
  • a non-adjacent imino group of the methyl group by a hydroxy, benzyloxy, C ⁇ - 3 alkoxy, amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - -alkyl) -amino or C 3 - 6 -Cycloalkylenimino distr may be substituted and / or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
  • -N-C ⁇ - 3 alkyl, -N (C 2 - 3 alkanoyl) -, sulfinyl or sulfonyl group may be replaced and / or
  • a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced,
  • C 1-3 alkyl amino C ⁇ - 3 alkyl, C ⁇ . 3- alkyl-amino-C. 3- alkyl-, di- (C ⁇ - 3 -alkyl) amino-C ⁇ . 3 -alkyl-, C 3 - 6 -cycloalkylenimino-C ⁇ - 3 -alkyl, C ⁇ - 6 -cycloalkylamino-C ⁇ . 3 -alkyl-, aminocarbonyl, -C.
  • each one of the C ⁇ - alkyl 5 alkyl groups by one or two 3 C ⁇ - alkyl, C ⁇ - 3 alkoxy C ⁇ -3-alkyl, amino-C ⁇ - 3, C ⁇ . 3- Alkylamino-C ⁇ - 3 -alkyl-, di- (C ⁇ - 3 -alkyl) amino C ⁇ . 3- alkyl, C 3 . 6 -Cycloalkylenimino-C ⁇ - 3 -alkyl, C ⁇ - 5 -Alkyloxycarbonylamino- -C ⁇ . 3- alkyl, C 3 . 6 -Cycloalkylamino-C ⁇ - 3 -alkyl-, aminocarbonyl, -C.
  • the methylene group in the 2-, 3- or 4-position in a C 3 . 7 -Cycloalkylcarbonyl distr may be replaced by an oxygen or sulfur atom, a carbonyl, sulfinyl, sulfonyl or an -NH group, in the
  • the hydrogen atom of the -NH group can be replaced by a C 1-3 -alkyl or C 1-3 -alkyl-carbonyl group,
  • a phenylcarbonyl or heteroarylcarbonyl group which in the phenyl or heteroaryl moiety is substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 3- alkyl-, di-ds-alky-amino-ds-alkyl-,
  • the phenyl part by a fluorine, chlorine or bromine atom, by a trifluoromethyl, -C. 3- alkyl, amino-C ⁇ . 3 alkyl, C ⁇ - 3 alkylamino-3 C ⁇ - alkyl, di- (d. 3 alkyl) amino
  • C ⁇ - 3 -alkyI-, C 3 - 6 -cycloalkylenimino-C 3 -alkyl or C 1-3 -alkoxy may be substituted and / or
  • a methylene group which is adjacent to the nitrogen atom may be replaced by a carbonyl group in a 5- to 7-membered cycloalkyleneimino group
  • n 1 or 2
  • R is a chlorine or bromine atom, a -C. 3- alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a C 2 - 3 alkenyl group, R 3 is a hydrogen atom or a C 1-3 -alkyl group,
  • R 4 is a hydrogen atom or a straight-chain or branched C ⁇ - 5 alkyl group, optionally substituted by a hydroxy, -C. 3 -Alkyloxy-, mercapto, -C 3 -alkylsulfanyl-, -C. 3 alkylsulfinyl, C ⁇ - 3 alkylsulfonyl, carboxy, aminocarbonyl, C ⁇ - carbonyl-3 alkylamino, di- (3 C ⁇ - alkyl) aminocarbonyl, C 3 .6-Cycloalkyleniminocarbonyl-, amino , C 3 -alkylamino, di (C 3 -alkyl) amino, C 3 .
  • a phenyl- or heteroaryl phenyl-C 1-3 -alkyl- or heteroaryl-C 1-3 -alkyl group which is optionally substituted by a hydroxy-, C 1-6 -alkyloxy-, benzyloxy-, hydroxycarbonyl- C 1-3 -alkoxy-, 3 -Alkyloxycarbonyl-C ⁇ - 3 -alkyloxy, aminocarbonyl -C.
  • R 5 is a hydrogen atom or a C 1-3 alkyl group or
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3 . 7 -cycloalkyl group, wherein
  • one of the methylene groups of C 3 . 7 -cycloalkyl group may be replaced by an imino, C 1-3 -alkyl-imino, acylimino or sulfonylimino group
  • B is a group of formulas
  • n is the number 1
  • R 6 is a hydrogen atom or a C 3 -alkyl, hydroxy, amino, C ⁇ . 3- alkylamino group,
  • R 7 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ - 3 alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C 2 - 3 alkenyl or C2-3 alkynyl, a, hydroxy, C 3 -alkoxy, trifluoromethoxy or
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • heteroaryl group in the carbon skeleton optionally substituted by a C ⁇ - 3 alkyl, carboxy, C ⁇ - 3 -alkoxycarbonyl or C ⁇ - 3 alkoxy-carbonylamino## monocyclic substituted 5 or 6-membered heteroaryl group is understood, wherein
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group is optionally substituted by a. 3- alkyl or phenyl-C ⁇ - 3 -alkyl group substituted imino group, an oxygen or sulfur atom or
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms
  • the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the definitions, unless otherwise mentioned, may be straight-chain or branched,
  • R 1 is an amino, C 1 .5-AI kyl amino, C 3 -7-Cycloalkylamino- or (phenyl-C ⁇ - 3 -alkyl) - amino group, each at the amine nitrogen atom by a Phenylcarbonyl- or Phenylsulfonyl or by a in the alkyl moiety optionally by a carboxy group, a in vivo into a carboxy group convertible group, an amino, C ⁇ - 3 -Alkylamino-, di- (C ⁇ - 3 -alkyl) -amino or C 3 - 6 -Cycloalkyleniminouite substituted C 1 -C 5 -alkyl or C 1 -C 5 -alkylcarbonyl group may be substituted, wherein two nitrogen atoms are separated from each other by at least two carbon atoms,
  • a di- (C ⁇ - 5 alkyl) amino or / V- (C. 3 7 cycloalkyl) -C ⁇ - 5 alkylamino group wherein the alkyl portion C ⁇ - 5 with the exception of the 1-position in each case by a hydroxy, C- ⁇ - 3 alkoxy, amino, C ⁇ - 3 alkylamino, di- (C ⁇ -3-alkyl) -amino or C 3 -6-cycloalkyleneimino group may be substituted,
  • a non-adjacent imino group of the methyl group by a hydroxy, benzyloxy, C ⁇ - 3 alkoxy, amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - -alkyl) -amino or C. 3 6 -Cycloalkylenimino distr may be substituted and / or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
  • a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom or by an -NH-, -N-C ⁇ - 3 alkyl, -N (C 2 - 3 alkanoyl) -, sulphinyl - or sulfonyl group may be replaced and / or a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced,
  • each one of the 5 C ⁇ - alkyl groups by one or two 3 C ⁇ - alkyl, C ⁇ - 3 alkoxy C ⁇ - 3 alkyl, amino-3 C ⁇ - alkyl, C ⁇ - 3 -alkylamino-C ⁇ - 3 alkyl, di- (C ⁇ - 3 -alkyl) -amino- C ⁇ - 3 -alkyl-, C 3 .6-Cycloalkylenimino-C ⁇ - 3 -alkyl, C ⁇ - 5 -alkyloxycarbonylamino-
  • a methylene group not adjacent to the imino group by a hydroxy, benzyloxy, C 1-3 alkoxy, amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino or C 3 . 6 -Cycloalkylenimino distr may be substituted,
  • a methylene group which is adjacent to the nitrogen atom may be replaced by a carbonyl group in a 5- to 7-membered cycloalkyleneimino group
  • n 1 or 2
  • R 2 is a chlorine or bromine atom, a C ⁇ - 3 alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a C 2 - 3 alkenyl group,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a straight-chain or branched ds-alkyl group, the optionally by a hydroxy, d. 3 alkyloxy, mercapto, C ⁇ . 3- Alkylsulfanyl-, C ⁇ . 3- alkylsulfinyl, C 3 -alkylsulfonyl, carboxy, aminocarbonyl, d. 3 alkylamino- carbonyl, di- (3 C ⁇ - alkyl) aminocarbonyl, C 3 - 6 -Cycloalkyleniminocarbonyl-, amino, C ⁇ - 3 alkylamino, di- (C ⁇ .3-alkyl) amino , C 3 .
  • a phenyl or heteroaryl, phenyl-C ⁇ - 3 -alkyl or heteroaryi-C ⁇ - 3- alkyl group optionally substituted by a hydroxy, -C. 4 alkyloxy, benzyloxy, hydroxycarbonyl C ⁇ - 3 -alkoxy, C ⁇ - 3 -alkyloxycarbonyl-C ⁇ - 3 -alkyloxy, aminocarbonyl -C. 3 -alkyloxy, C ⁇ - 3 -Alkylaminocarbonyl -C ⁇ . 3 -alkyloxy, di- (C 3 -alkyl) aminocarbonyl -C. 3 -alkyloxy-,
  • a 4- to 7-membered cycloalkyl-C ⁇ - 3 -alkyl group in which one or two methylene groups may be replaced by a -NH- or -N (C ⁇ - 3- alkyl) - group and in which one or two of the -NH - or -N (C ⁇ - 3 alkyl) group adjacent methylene groups may be replaced by a carbonyl group, respectively, with the proviso that a cycloalkyl group as defined above, in the two -NH- or -N (C 1 3 alkyl. ) Groups are separated by exactly one -CH 2 group, are excluded,
  • R is a hydrogen atom
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3 . 7 -cycloalkyl group, wherein
  • one of the methylene groups of C 3 . 7 -cycloalkyl group by an imino, -C. 3- alkyl-imino, acylimino or sulfonylimino group may be replaced,
  • B is a group of formulas or
  • n is the number 1
  • R 6 is a hydrogen atom or a C 1-3 -alkyl, hydroxy, amino, C 1-3 -alkylamino group,
  • R 7 is a fluorine, chlorine or bromine atom, a -C 3 alkyl group in which the hydrogen atoms may be wholly or partially replaced by fluorine atoms, a C 2 - 3 alkenyl, C 2 - 3 alkynyl or a hydroxy group represent, and
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • heteroaryl in the carbon skeleton optionally substituted by a C ⁇ - 3 alkyl, carboxy, C 1, 3 -alkoxycarbonyl or C 3 -alkoxy-carbonylamino-substituted monocyclic 5 or 6-membered heteroaryl group is understood, wherein
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, an oxygen or sulfur atom or an optionally by a -C 3 alkyl, amino-C ⁇ - 3 -alkyl-, C ⁇ _ 3 -Al kylami no- d. 3 -alkyl-, di- (C ⁇ - 3 -alkyl) -amino-C ⁇ - 3 -alkyl-, C 3 . 6 -Cycloalkylenimino -C ⁇ . 3 -alkyl-, or phenyl-C ⁇ - 3 -alkylgru ⁇ pe substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or
  • an imino group which is optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and contains two or three nitrogen atoms,
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms
  • the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the definitions, unless otherwise mentioned, may be straight-chain or branched,
  • R 1 is an amino, C ⁇ - 5 -Alkylamino-, C 3 -7-Cycloalkylamino- or (phenyl-C ⁇ - 3 -alkyl) - amino group, each at the amine nitrogen atom by a phenylcarbonyl or phenylsulfonyl or by an alkyl moiety in optionally a carboxy group, a group which can be converted into a carboxy group in vivo, an amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino or C 3 . 6 -Cycloalkyleniminooire substituted -C-5-alkyl or C ⁇ - 5 alkylcarbonyl may be substituted, wherein two Nitrogen atoms are separated by at least two carbon atoms,
  • C 3 - 6 -Cycloalkyleniminooli may be substituted and / or
  • a methylene group in the 3-position of a 5-membered cycloalkyleneimino group may be replaced by a sulfur atom, a sulfinyl or sulfonyl group, or
  • a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom or by an -NH-, -N-C ⁇ - 3 alkyl, -N (C 2 - 3 alkanoyl) -, sulphinyl - or sulfonyl group may be replaced and / or
  • a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) - CO group can be replaced, an optionally substituted by one or two C 1-3 alkyl, amino-C ⁇ .
  • each one of the. 5 alkyl groups by one or two C 3 alkyl, -C. 3 -alkoxy- C ⁇ - 3 -alkyl-, amino-C ⁇ . 3- alkyl-, d- 3 -alkylamino-C 3 -alkyl-, di- (C 3 -alkyl) -amino-d- 3- alkyl-, C 3-6 -cycloalkylenimino-C 1-3 -alkyl-, C ⁇ - 5- Alkyloxycarbonylamino- -C ⁇ . 3 -alkyl, C 3 -6-cycloalkylamino-C 3 -alkyl, aminocarbonyl, C ⁇ .
  • a non-adjacent imino group of the methyl group by a hydroxy, benzyloxy, C ⁇ -3-alkoxy, amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - -alkyl) -amino or C. 3 6 -Cycloalkylenimino distr may be substituted,
  • C ⁇ . 3- alkyl, amino-C ⁇ - 3 -alkyl-, C ⁇ . 3- Alkylamino-C ⁇ . 3- alkyl-, di- (C 1 3 -alkyl) -amino- C 3 -alkyl-, C 3 . 6 -Cycloalkylenimino -C ⁇ . 3 -alkyl or C 1-3 alkoxy group may be substituted and / or wherein a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group by a -NH-CO-, -CO-NH-, -CO-N (CH 3 ) - or a -N (CH 3 ) -CO group or
  • a methylene group which is adjacent to the nitrogen atom may be replaced by a carbonyl group in a 5- to 7-membered cycloalkyleneimino group
  • n 1 or 2
  • F .r2 is a chlorine or bromine atom, a C 1-3 -alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a C 2 . 3- alkenyl group,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or a straight-chain or branched d. 5- alkyl group, optionally substituted by a hydroxy, C ⁇ - 3 alkyloxy, mercapto, C ⁇ . 3- Alkylsulfanyl-, • C ⁇ - 3 -alkylsulfinyl-, C ⁇ - 3 -alkylsulfonyl, carboxy, aminocarbonyl, -C.
  • a phenyl or heteroaryl, phenyl-C ⁇ - 3 -alkyl or heteroaryl-C ⁇ - 3 -alkyl group which may be substituted by a hydroxy, d. 4 -alkyloxy, benzyloxy, hydroxycarbonyl-C 3 -alkoxy, C 3 -alkyloxycarbonyl-C 3 -alkyloxy, aminocarbonyl-C-3-alkyloxy, C ⁇ .3-Alkylaminocarbonyl -C ⁇ .3 -alkyloxy, di- (C 1 3 -alkyl) -aminocarbonyl-C 3 -alkyloxy, C 3 -C 6 -cycloalkyleneiminocarbonyl-C 3 -alkyloxy, carboxy, d. 3- alkyloxycarbonyl group is substituted,
  • a 4- to 7-membered cycloalkyl-C 3 -alkyl group in which one or two methylene groups may be replaced by a -NH- or -N (C 1-3 -alkyl) group and in which one or two of the -NH or -N (C 1-3 -alkyl) group adjacent methylene groups may each be replaced by a carbonyl group, with the proviso that a cycloalkyl group as defined above in which two -NH- or -N (C 1-3 -alkyl) Groups are separated by exactly one -CH 2 group, are excluded,
  • R 5 is a hydrogen atom
  • n is the number 1
  • R 6 is a hydrogen atom or a C 1-3 -alkyl, hydroxy, amino, C 1-3 -alkylamino group,
  • R 7 is a fluorine, chlorine or bromine atom, a d- 3 alkyl group in which the hydrogen atoms may be wholly or partially replaced by fluorine atoms, a C 2 - 3 alkenyl, C 2 - 3 alkynyl or a hydroxy group represent, and
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • heteroaryl group in the carbon skeleton optionally substituted by a C ⁇ - 3 alkyl, carboxy, C ⁇ - 3 -alkoxycarbonyl or C ⁇ - 3 alkoxy-carbonylamino## monocyclic substituted 5 or 6-membered heteroaryl group is understood, wherein
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, an oxygen or sulfur atom or
  • an imino group which is optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and contains two or three nitrogen atoms,
  • a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups through two adjacent carbon atoms and the bond is via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • alkyl and alkoxy groups having more than two carbon atoms contained in the definitions, unless otherwise mentioned, may be straight-chain or branched,
  • R 1 is a 2,5-dihydro-1H-pyrrole-1-yl-carbonyl, pyrrolidin-1-yl-carbonyl, 2- (aminomethyl) -pyrrolidin-1-yl-carbonyl-, 2- ( ⁇ / - tert-butyloxycarbonylaminomethyl) -pyrrolidine-1-ylcarbonyl, 3-oxo-piperazine-1-yl-carbonyl or morpholin-4-yl-carbonyl group,
  • R 2 is a hydrogen, chlorine or bromine atom or a C 1-3 -alkyl group in which the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom or the methyl group
  • R 5 is a hydrogen atom
  • R is a hydrogen atom
  • R 7 represents a chlorine atom
  • X 1 to X 3 independently of one another each represent a nitrogen atom or a CH group
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • R 3 to R 5 are defined as mentioned above and Z 1 is the hydrogen atom or a protective group and B "is a group of the formula (IV)
  • R 6 and R 7 are defined as mentioned above and X is the nitrogen atom or the CH group:
  • R 3 to R 7 are defined as mentioned above, X is the nitrogen atom or the CH group and Z 1 is the hydrogen atom or a protective group, with subsequent removal of any protecting group present.
  • the Cycimaschine is suitably in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide or tetralin, dimethyl sulfoxide, methylene chloride, chloroform, carbon tetrachloride, for example at temperatures between 0 and 250 ° C, but preferably between 20 and 100 ° C, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, ⁇ /, / V Dicyclohexylcarbod
  • R 3 to R 5 are defined as mentioned above, Z 1 is the hydrogen atom or a protective group and B 'is a group of the formula
  • R 6 and R 7 are defined as mentioned above and X is the nitrogen atom or the CH group:
  • R 4 is a phenyl or heteroaryl group and R 5 is a hydrogen atom and R 1 is a hydrogen atom or a C 1-3 -alkyl group, with a compound of the general formula
  • R 7 is defined as mentioned above, X represents the nitrogen atom or the CH group and Z 1 represents a protective group, for example an acetyl or methylsulfonyl group, this protective group being subsequently split off.
  • reaction sequence is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, ⁇ / -methylpyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or tetrachloromethane
  • transition metal catalysts such as bis (triphenylphoshin) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II ) chloride, bis (triethylphosphine) palladium (II) chloride or bis (tri-o-tolylphosphine) palladium (II
  • R 6 and R 7 are defined as mentioned above, X is the nitrogen atom or the CH group and Y is a hydroxy, C ⁇ - alkyloxy, Hydroxylamino-, C ⁇ . 4- Alkyl- oxyamino- or a C ⁇ - 4 alkyloxy-C ⁇ - 4- alkylamino group, with a compound of the general formula
  • R 4 is as defined above, with the proviso that a phenyl or heteroaryl group is excluded, and M is a metal such as lithium, sodium or potassium, or a metal such as magnesium, cadmium, copper or zinc, with a suitable counterion, such as
  • suitable counterions such as cyanide, chloride, bromide or iodide, and their combinations containing grouping, and subsequent reductive amination of the compounds thus obtained.
  • the alkylation is expediently carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, glycol dimethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, / V-methylpyrrolidinone, tetralin, dimethylsulfoxide, methylene chloride, chloroform, carbon tetrachloride, diethyl ether, tert-butyl - Methyl ether or tetrahydrofuran, for example, at temperatures between -100 and + 100 ° C, but preferably between -100 and 30 ° C, with Alkyl mecanicsreagentien as Grignard reagents, organolithium reagents, Gilman or Knochel cuprates produced by literature methods if necessary using an inert gas atmosphere (nitrogen or argon).
  • a solvent or solvent mixture such as benzene, chlorobenzene, tolu
  • the subsequent reductive amination of the ketones formed after alkylation is carried out by reaction with, for example, ammonia, hydroxylamine, alkoxyamines, primary amines, hydroxyalkylamines or alkoxyalkylamines with subsequent or accompanied by reduction for example with hydride donors such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride or Diisobutylaluminum hydride in a solvent or solvent mixture such as ethanol, isopropanol, benzene, toluene, pyridine, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ⁇ / -alkylmorpholine, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, Hexane or cyclohexane or by hydrogenation, if appropriate under pressure and expediently in the presence of a catalyst such as Raney nickel, palla
  • R 1 , R 2 and X 1 to X 3 are defined as mentioned above and Z is a leaving group such as a halogen atom, a sulphonyloxy or aryloxy group, for example a chlorine, bromine or iodine atom, a trifluoromethylsulfonyloxy, phenoxy or p-nitrophenoxy group, with a compound of the general formula
  • the coupling reaction is conveniently carried out in a solvent such as toluene, dioxane, dimethoxyethane, dimethylformamide or tetrahydrofuran preferably in the presence of a base such as sodium ferric butylate, bis (trimethylsilyl) lithium amide, potassium carbonate, cesium carbonate or triethylamine at a temperature between 0 ° C and 150 ° C, preferably between 0 ° C and 100 ° C, optionally using a suitable catalyst, for example bis (tri-c-tolylphosphine) palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0 ) / Tris-o-tolylphosphine, tris (dibenzylideneacetone) dipalladium (0) / tris (2-furyl) phosphine, tris (dibenzylideneacetone) dipalladium (0) / 2,2'-bis- (
  • the coupling reaction can also be carried out without addition of solvent in bulk by melting the compounds of the general formulas V and VI at temperatures between room temperature and 150 ° C., if appropriate in the presence of one of the abovementioned bases and / or if appropriate using one of the abovementioned catalysts, be performed.
  • R 1 and R 2 are defined as mentioned above, X 1 and X 3 are each a nitrogen atom, X 2, if appropriate, by a C. 3- alkyl group substituted CH group, and Z is a leaving group such as a halogen atom, for example a chlorine or bromine atom, represent:
  • R 1 and R 2 are as hereinbefore defined and X is a hydroxy group or C ⁇ - 4 alkoxy or a halogen atom, with formamide or C ⁇ - 3 -Alkylcarbonylamid and then reacting the resulting compound of general formula
  • R 1 and R 2 are defined as mentioned above and X 2 is a group optionally substituted by a -C 3 -Al group alkyl-substituted CH group, with a halogenating agent, for example with thionyl chloride, thionyl bromide or oxalyl chloride.
  • the cyciization is carried out, for example, in a high-boiling solvent such as chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or even without further solvent in the presence of excess formamide at temperatures between 100 and 200 ° C, preferably between 130 and 170 ° C.
  • a high-boiling solvent such as chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or even without further solvent in the presence of excess formamide at temperatures between 100 and 200 ° C, preferably between 130 and 170 ° C.
  • a halogenating agent for example with thionyl chloride, thionyl bromide or oxalyl chloride is conveniently added either without solvent in bulk in the presence of dimethylformamide as a catalyst or by addition of a solvent such as dimethylformamide, pyridine, benzene, carbon tetrachloride, 1, 2-dichloroethane or chloroform Temperatures between 20 and 120 ° C performed.
  • R 1 to R 5 and B are defined as mentioned above and X 3 represents a nitrogen atom or a CH group:
  • R 1 to R 5 and B are defined as mentioned above and X 3 represents a nitrogen atom or a CH group, with an oxidizing agent, for example with H 2 0 2 , m-chloroperbenzoic acid or monoperoxyphthalic acid.
  • an oxidizing agent for example with H 2 0 2 , m-chloroperbenzoic acid or monoperoxyphthalic acid.
  • the oxidation is carried out, for example, in a solvent which is inert under the oxidation conditions chosen, such as acetic acid, trifluoroacetic acid, water or chloroform, at temperatures between -10.degree. C. and 100.degree.
  • a solvent which is inert under the oxidation conditions chosen such as acetic acid, trifluoroacetic acid, water or chloroform, at temperatures between -10.degree. C. and 100.degree.
  • optionally present reactive groups such as hydroxyl, carboxy, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction.
  • the protective group for a hydroxy group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, fe / t-butyl, trityl, benzyl or tetrahydropyranyl group.
  • a protecting group for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, te / t-butyloxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the Amino group additionally the phthalyl group into consideration.
  • the optional subsequent cleavage of a protective moiety used is carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide or by ether cleavage, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium
  • cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical is for example effected 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.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • the cleavage of a methoxybenzyl group can also be carried out in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • the removal of a methoxy group is conveniently carried out in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.
  • cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
  • the cleavage of a te / t-butyl or te / t-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid optionally using a solvent such as methylene chloride, dioxane or ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • a solvent such as methylene chloride, dioxane or ether.
  • the cleavage of a Phthalylrestes preferably takes place 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.
  • a primary amine such as methylamine, ethylamine or n-butylamine
  • a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • the cleavage of an allyloxycarbonyl radical is carried out 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 (I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo [2.2.2] octane at temperatures between 20 and 70 ° C.
  • a catalytic amount of tetrakis (triphenylphosphine) palladium (0) preferably in a solvent such as tetrahydrofuran and preferably in the presence
  • the compounds of the general formula I which are obtained in racemates can be prepared by 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 having at least two asymmetric carbon atoms, because of their physicochemical differences, can be separated into their diastereomers by methods known per se, for example by chromatography and / or fractional crystallization, which, if they are obtained in racemic form, then as mentioned above can be separated into the enantiomers.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts or derivatives such as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
  • optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid.
  • optically active alcohol for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example, the (+) - or (-) - Menthyloxycarbonylrest into consideration.
  • the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids.
  • Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • novel compounds of the formula I thus obtained can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerated salts.
  • suitable bases are 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 acceptable salts have valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on a thrombin or factor Xa influencing effect, for example one Thrombinhemmenden or factor Xa-inhibitory effect on an aPTT-prolonging effect and on an inhibitory effect on related serine proteases such.
  • an antithrombotic effect which is preferably based on a thrombin or factor Xa influencing effect, for example one Thrombinhemmenden or factor Xa-inhibitory effect on an aPTT-prolonging effect and on an inhibitory effect on related serine proteases such.
  • urokinase Factor VIIa, Factor IX, Factor XI and Factor XII.
  • Enzyme kinetic measurement with chromogenic substrate The amount of -nitroaniline (pNA) released by the human factor Xa from the colorless chromogenic substrate 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) by the test substance is determined at different concentrations of test substance and from this the IC 5 o calculated as the concentration which inhibits the factor Xa used by 50%.
  • pNA -nitroaniline
  • 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 according to the invention are generally well tolerated.
  • novel compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the prevention and treatment of deep vein thrombosis, the prevention of reoccusion after bypass surgery or angioplasty (PT (PT).
  • occlusion in peripheral arterial diseases as well as prevention and treatment of pulmonary embolism, disseminated intravascular coagulation, prophylaxis and treatment of coronary thrombosis, prophylaxis of stroke, and prevention of occlusion of shunts.
  • the compounds of the invention are useful for antithrombotic support in thrombolytic treatment, such as alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for the prevention of long-term restenosis according to PT (C) A, for the prophylaxis and treatment of ischemic events in patients of all forms coronary heart disease, for preventing the metastasis and growth of tumors and inflammatory processes, eg in 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 to promote wound healing processes suitable.
  • thrombolytic treatment such as alteplase, reteplase, tenecteplase, staphylokinase or streptokinase
  • C PT
  • C prophylaxis and treatment of ischemic events in patients of all forms
  • novel compounds and their physiologically acceptable salts can be used therapeutically in combination with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (eg abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogues (eg protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (eg clopidogrel, ticlopidine), with P 2 T receptor antagonists (eg cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (eg Terbogrel).
  • fibrinogen receptor antagonists eg abciximab, eptifibatide, tirofiban, roxifiban
  • physiological activators and inhibitors of the coagulation system and their recombinant analogues eg protein C, TFPI,
  • the dose required to achieve a corresponding effect is expediently when intravenously administered 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg, and when administered orally 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, each 1 " up to 4 times a day.
  • the compounds of formula I according to the invention optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable Mixtures, in common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories incorporate.
  • inert conventional carriers and / or diluents e.g. with corn starch, lactose
  • inert conventional carriers and / or diluents e.g. with corn starch, lactose
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • silica gel from Millipore MATREX TM, 35-70 my was used. If further information on the configuration is missing, it is unclear whether they are pure stereoisomers or mixtures of enantiomers / diastereomers.
  • TBTU 0- (benzotriazol-1-yl) - ⁇ /, ⁇ /, ⁇ . ', ⁇ /' - tetramethyluronium tetrafluoroborate tert. tertiary
  • HPLC / MS data were generated on the following system: Waters ZMD, Alliance 2690 HPLC, Waters 2700 autosampler, Waters 996 diode array detector.
  • the mobile phase used was: A: water with 0.1% trifluoroacetic acid B: acetonitrile with 0.1% trifluoroacetic acid
  • the stationary phase used was a column of Waters X-Terra TM MSC 8 3.5 ⁇ m, 4.6 mm ⁇ 50 mm (column temperature: constant at 25 ° C.).
  • 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 950
  • HPLC data for Examples 49. 83-125 and 227 were generated on the following system:
  • A water with 0.1% trifluoroacetic acid
  • B acetonitrile with 0.1% trifluoroacetic acid
  • the stationary phase used was a column of Waters X-Terra TM MS C 18 2.5 ⁇ m, 4.6 mm ⁇ 30 mm (column temperature: constant at 25 ° C.).
  • 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 950
  • the stationary phase was a Waters X-Terra TM column MS d 8 3.5 // m, 2.1 mm x 50 mm (column temperature constant at 30 ° C)
  • the diode array detection was carried out in the wavelength range 210-550 nm range of mass spectrometric detection: m / z 120 to m / z 1000.

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Abstract

L'invention concerne de nouveaux composés hétérocycliques azotés substitués de formule générale (I), dans laquelle B, X1 à X3 et R1 à R5 sont tels que définis dans la revendication n°1, ainsi que leurs tautomères, énantiomères, diastéréoisomères, mélanges et sels, en particulier leurs sels physiologiquement tolérables contenant des acides ou des bases inorganiques ou organiques, ces composés présentant des propriétés intéressantes. Les composés de formule générale (I) et leurs tautomères, énantiomères, diastéréoisomères, mélanges et sels, en particulier leurs sels physiologiquement tolérables contenant des acides ou des bases inorganiques ou organiques, ainsi que leurs stéréoisomères présentent des propriétés pharmacologiques intéressantes, notamment un effet antithrombotique et un effet d'inhibition du facteur Xa.
PCT/EP2003/014378 2002-12-23 2003-12-17 Nouveaux composes heterobicycliques azotes substitues et leur utilisation en tant qu'inhibiteurs du facteur xa WO2004058743A1 (fr)

Priority Applications (4)

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AU2003298192A AU2003298192A1 (en) 2002-12-23 2003-12-17 Novel substituted nitrogen-containing heterobicycles and use thereof as factor xa inhibitors
EP03795904A EP1583757A1 (fr) 2002-12-23 2003-12-17 Nouveaux composés heterobicycliques azotes substitués et leur utilisation en tant qu'inhibiteurs du facteur xa
CA002511349A CA2511349A1 (fr) 2002-12-23 2003-12-17 Nouveaux composes heterobicycliques azotes substitues, leurs preparations et leurs utilisations comme compositions pharmaceutiques
JP2004562769A JP2006515301A (ja) 2002-12-23 2003-12-17 新規置換窒素含有二環式複素環化合物、これらの調製及び医薬組成物としてのそれらの使用

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DE10260730A DE10260730A1 (de) 2002-12-23 2002-12-23 Neue substituierte stickstoffhaltige Heterobicyclen, deren Herstellung und deren Verwendung als Arzneimittel
DE10260730.3 2002-12-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7446210B2 (en) 2004-10-26 2008-11-04 Janssen Pharmaceutica N.V. Factor Xa compounds
CN103265524A (zh) * 2013-05-15 2013-08-28 华东师范大学 β-氨基-2,5-二氧六环内酯衍生物的制备方法
US8741890B2 (en) 2007-11-15 2014-06-03 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003069A1 (fr) 1995-07-13 1997-01-30 Glaxo Group Limited Composes heterocycliques et compositions pharmaceutiques a base desdits composes
WO1998037075A1 (fr) 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114448A1 (en) * 2001-05-31 2003-06-19 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
PE20040804A1 (es) * 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003069A1 (fr) 1995-07-13 1997-01-30 Glaxo Group Limited Composes heterocycliques et compositions pharmaceutiques a base desdits composes
WO1998037075A1 (fr) 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7446210B2 (en) 2004-10-26 2008-11-04 Janssen Pharmaceutica N.V. Factor Xa compounds
US8741890B2 (en) 2007-11-15 2014-06-03 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments
CN103265524A (zh) * 2013-05-15 2013-08-28 华东师范大学 β-氨基-2,5-二氧六环内酯衍生物的制备方法
CN103265524B (zh) * 2013-05-15 2016-01-20 华东师范大学 β-氨基-2,5-二氧六环内酯衍生物的制备方法

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EP1583757A1 (fr) 2005-10-12
PE20040806A1 (es) 2004-12-23
UY28143A1 (es) 2004-07-30
JP2006515301A (ja) 2006-05-25
CA2511349A1 (fr) 2004-07-15
DE10260730A1 (de) 2004-07-01
TW200424194A (en) 2004-11-16
AR043685A1 (es) 2005-08-10
CL2003002697A1 (es) 2005-01-14

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