WO2008015196A1 - Imidazo[1,2-a]pyridines 5,7-bis-substituées - Google Patents

Imidazo[1,2-a]pyridines 5,7-bis-substituées Download PDF

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Publication number
WO2008015196A1
WO2008015196A1 PCT/EP2007/057849 EP2007057849W WO2008015196A1 WO 2008015196 A1 WO2008015196 A1 WO 2008015196A1 EP 2007057849 W EP2007057849 W EP 2007057849W WO 2008015196 A1 WO2008015196 A1 WO 2008015196A1
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alkyl
alkoxy
hydroxy
hydrogen
fluoro
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PCT/EP2007/057849
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English (en)
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Christof Brehm
Peter Jan Zimmermann
Wilm Buhr
Andreas Palmer
Maria Vittoria Chiesa
Martin Feth
Hans Christof Holst
Wolfgang-Alexander Simon
Stefan Postius
Wolfgang Kromer
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Nycomed Gmbh
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Publication of WO2008015196A1 publication Critical patent/WO2008015196A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
  • substituted imidazo[1,2-a]pyridin-3-yl-amides and imidazo[1,2-a]pyridin-3-yl-amines are disclosed as inhibitors for nitrogen monoxide synthase.
  • imidazo pyridine derivatives which are said to inhibit exogenously or endogenously stimulated gastric acid secretion and which are thus said to be able to be used in the prevention and treatment of gastrointestinal inflammatory diseases.
  • PPI ' s proton pump inhibitors
  • rPPI ' s reversible proton pump inhibitors
  • APA ' s acid pump antagonists
  • P-CAB ' s potassium competitive acid blockers
  • the invention relates to compounds of the formula 1
  • R1 is hydrogen, 1-4C-alkyl, aryl, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkyl-3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, halogen, hydroxy, 1-4C-alkoxy, mono- or-di-1-4C-alkylamino- carbonyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, cyano-1-4C-alkyl, 1-4C-alkylcarbonyloxy- 1-4C-alkyl, carboxy, 1-4C-alkylcarbonylamino, (1-4C-alkyl)-1-4C-alkylcarbony
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, fluo- ro-1-4C-alkoxy, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1- 4C-alkyl,
  • R3 is fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy, hydroxy- 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, fluoro-1-4C- alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy, cyano, the group -CO-NR31 R32, the group SO 2 - NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, optionally substituted by a hydroxyl, oxo, halogen or 1-4C-alkyl substituent and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyra- zol and tetrazol, where
  • R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl- carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1- 4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, fluoro-1- 4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, I ⁇ C-alkoxy-I ⁇ C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,
  • X is O (oxygen) or NH
  • Y has either the meaning -CH 2 -Ar wherein
  • Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp
  • Z has the meaning -CHR8- or -CHR8-CHR9- where in Ar and/or in the group gp R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C- alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1- 4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl- 1-4C-alkoxy, fluoro-1-4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, I ⁇ C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbon
  • R5 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkyl or hydroxy,
  • R6 is hydrogen, 1-4C-alkyl or halogen
  • R7 is hydrogen, 1-4C-alkyl or halogen
  • R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- al koxy- 1 -4C-alkoxy , 1 -4C-al koxy- 1 -4C-al koxy- 1 -4C-al koxy , 3-7C-cycloalkoxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1 -4C-al koxy- 1-4C-al koxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or
  • R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- al koxy- 1 -4C-alkoxy , 1 -4C-al koxy- 1 -4C-al koxy- 1 -4C-al koxy, 3-7C-cycloalkoxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-I ⁇ C
  • 1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
  • 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
  • 3-7C-Cycloal ky I- 1 -4C-al ky I represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.
  • 1-4C-Alkyl-3-7C-cycloalkyl-1-4C-alkyl represents one of the aforementioned 3-7C-cycloalkyl-1-4C-alkyl groups, in which the 3-7C-cycloalkyl is substituted by one, two, three or more of the aforementioned 1- 4C-alkyl groups.
  • Examples which may be mentioned are the 2-methylcyclopropylmethyl, 2-(2- methylcyclopropyl)ethyl, 2-ethylcyclopropylmethyl, 2-methylcyclobutylmethyl, 2- methylcyclopentylmethyl, 2-methylcyclohexylmethyl group.
  • the aforementioned groups can have one, two or more centres of chirality.
  • the definition above also represents all stereoisomeric radicals in any desired mixing ratio to another, including the pure stereoisomeric radicals, which are preferred. Examples which may be mentioned are the (1S,2S)-2-methylcyclopropylmethyl or (1S,2R)-2- methylcyclopropylmethyl group.
  • 1-4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.
  • 1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups.
  • Examples which may be mentioned are the meth- oxymethyl, the methoxyethyl group, in particular the 2-methoxyethyl group, the ethoxyethyl group, in particular the 2-ethoxyethyl group, and the butoxyethyl group, in particular the 2-butoxyethyl group.
  • 1-4C-Alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH 3 O-C(O)-) and the ethoxycarbonyl group (CH 3 CH 2 O-C(O)-) .
  • 2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group).
  • 2-4C-Alkynyl represents straight-chain or branched alkynyl groups having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl group (propargyl group).
  • Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms. Examples which may be mentioned are the trifluoromethyl, the difluoromethyl, and the 2,2,2-trifluoroethyl group.
  • Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxym ethyl, the 2-hydroxyethyl, the 3- hydroxypropyl group, the (2S)-2-hydroxypropyl and the (2R)-2-hydroxypropyl group.
  • Hydroxy-1-4C- alkyl within the scope of the invention is understood to include 1-4C-alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutyl and in particular the 2,3- dihydroxypropyl group.
  • Cyano-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are substituted by a cyano group. Examples which may be mentioned are the cyanomethyl, the 2-cyanoethyl and the 3-cyano- ypropyl group.
  • 1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the aforementioned 1-4C-alkyl groups.
  • An example which may be mentioned is the acetyl group.
  • Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.
  • Mono- or di-1-4C-alkylamino-carbonyl represents a carbonyl group, to which one of the aforementioned mono- or di-1-4C-alkylamino groups is bonded. Examples which may be mentioned are the dimethyl- aminocarbonyl, the diethylaminocarbonyl and the diisopropylaminocarbonyl radicals.
  • Aryl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the abovementioned aryl groups.
  • An exemplary preferred aryl-1-4C-alkyl group is the benzyl group.
  • Aryloxy represents groups, which in addition to the oxygen atom contain one of the aformentioned aryl groups.
  • An example which may be mentioned is the phenoxy group.
  • Aryl-1-4C-alkoxy represents an aryl-substituted 1-4C-alkoxy radical.
  • An example which may be mentioned is the benzyloxy radical.
  • Aryl-1-4C-alkoxy-1-4C-alkyl denotes one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned aryl-1-4C-alkoxy radicals.
  • An example which may be mentioned is the benzyloxymethyl radical.
  • Halogen within the meaning of the invention is bromo, chloro and fluoro.
  • 1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH 3 -O-CH 2 -CH 2 -O-) and 2-(ethoxy)ethoxy (CH 3 -CH 2 -O-CH 2 -CH 2 -O-).
  • 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the group 2-(methoxy)ethoxymethyl (CH 3 -O-CH 2 -CH 2 -O-CH 2 -) and the 2- (ethoxy)ethoxymethyl (CH 3 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -) radicals.
  • 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy-1-4Calkoxy groups which is substituted by one of the aforementioned 1-4C-alkoxy groups.
  • Examples which may be mentioned are the group 2-(methoxy)ethoxymethoxy (CH 3 -O-CH 2 -CH 2 -O-CH 2 -O-) and the 2- (ethoxy)ethoxymethoxy (CH 3 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -O-) radicals.
  • Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group.
  • Fluoro-1-4C-alkoxy in this case represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one or more fluorine atoms.
  • fluoro- substituted 1-4C-alkoxy groups which may be mentioned are the 2-fluoro-ethoxy, 1 ,1 ,1 ,3,3,3- hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-propoxy, the perfluoro-tert- butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3- pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2- tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group.
  • fluoro-1-4C-alkoxy-1-4C-alkyl radicals which may be mentioned are, 1 ,1 ,2,2- tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluoromethoxymethyl, 2- fluoroethoxyethyl, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifluoroethoxyethyl, the trifluorometh- oxyethyl and preferably the difluoromethoxymethyl and the difluoromethoxyethyl radicals.
  • Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halogen. "Mainly” in this connection means that more than half of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms.
  • Halo-1-4C-alkoxy groups are primarily chloro- and/or in particular fluoro-substituted 1-4C-alkoxy groups.
  • halogen-substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1 ,1 ,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1 ,1 ,1-trichloro-2-methyl-2-propoxy, the 1 ,1 ,1 -trichloro-2- propoxy, the 3-bromo-1 ,1 ,1-trifluoro-2-propoxy, the 3-bromo-1 ,1 ,1-trifluoro-2-butoxy, the 4-bromo- 3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2- trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-
  • 1-7C-Alkyl represents straight-chain or branched alkyl groups having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
  • 2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the above- mentioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the 2-butenyloxy, 3- butenyloxy, 1-propenyloxy and the 2-propenyloxy group (allyloxy group).
  • Carboxy-1-4C-alkyl represents 1-4C-alkyl groups which are substituted by a carboxyl group. Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group.
  • 1-4C-Alkoxycarbonyl-1-4C-alkyl represents 1-4C-alkyl groups, which are substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Meth- oxycarbonylmethyl and the ethoxycarbonylmethyl group.
  • 1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C 3 H 7 C(O)NH-) and the acetylamino group (acetamido group) (CH 3 C(O)NH-) .
  • (1-4C-Alkyl)-1-4C-alkylcarbonylamino represents one of the aforementioned 1-4C-alkylcarbonylamino groups, which is N-substituted by one of the aforementioned 1-4C-alkyl groups.
  • Examples, which may be mentioned, are the methyl-propionylamino [C 3 H 7 C(O)N(CH 3 )-] or methyl-acetylamino [CH 3 C(O)N(CH 3 )-] groups.
  • 1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group.
  • (1-4C-Alkyl)-1-4C-alkoxycarbonylamino represents one of the aforementioned 1-4C-alkoxycarbonyl- amino groups, which is N-substituted by one of the aforementioned 1-4C-alkyl groups.
  • Examples, which may be mentioned, are the methyl-ethoxycarbonylamino [C 2 H 5 O-C(O)-N(CH 3 )-] or methyl- methoxycarbonylamino [CH 3 O-C(O)-N(CH 3 )-] groups.
  • 1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy)- ethoxycarbonyl (CH 3 -O-CH 2 CH 2 -O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH 3 CH 2 -O-CH 2 CH 2 - 0-C0-).
  • 1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group.
  • 2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred.
  • Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy group, which instead of a methylene group contains a carbonyl group.
  • An example which may be mentioned is the 2-oxopropoxy group.
  • 3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethoxy, the cyclobutylmethoxy and the cyclohexylethoxy group.
  • Hydroxy- 1-4C-alkoxy represents aforementioned 1-4C-alkoxy groups, which are substituted by a hydroxy group.
  • a preferred example which may be mentioned is the 2-hydroxyethoxy group.
  • 'MC-Alkoxy-'MC-alkoxy-'MC-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups.
  • a preferred example which may be mentioned is the methoxyethoxyethoxy group.
  • 3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups. Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexyloxyethoxy group.
  • 3-7C-Cycloalkyl-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobutylmethoxyethoxy and the cyclohexylethoxyethoxy group.
  • 1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom.
  • An example which may be mentioned is the acetoxy group (CH 3 CO-O-).
  • 1-4C-Alkylcarbonyloxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkylcarbonyloxy groups.
  • An example which may be mentioned is the acetoxymethyl group (CH 3 CO-O-CH 2 ).
  • Mono- or di-'MC-alkylamino-'MC-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy group.
  • 'MC-Alkoxy-'MC-alkylcarbonyloxy represents one of the aforementioned 1-4C-alkylcarbonyloxy radicals which is substituted by one of the aforementioned 1-4C-alkoxy groups.
  • An example which may be mentioned is the methoxymethylcarbonyloxy group.
  • Hydroxy- 1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy radicals which is substituted by a hydroxy group. Examples which may be mentioned are the the 2-hydroxyethoxy and the 3- hydroxypropoxy group.
  • Fluoro-1-4C-alkoxy has the meaning as defined under fluoro-1-4C-alkoxy-1-4C-alkyl.
  • Fluoro-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a fluoro-1-4C-alkoxy group.
  • fluoro-1-4C-alkoxy-1-4C-alkoxy radicals which may be mentioned are 1 ,1 ,2,2-tetrafluoroethoxymethoxy, the 2,2,2-trifluoroethoxymethoxy, the trifluoromethoxymethoxy, 2-fluoroethoxyethoxy, the 1 ,1 ,2,2-tetrafluoroethoxyethoxy, the 2,2,2- trifluoroethoxyethoxy, the trifluoromethoxyethoxy and preferably the trifluoromethoxyethoxy and the difluoromethoxyethoxy radicals.
  • Salts of compounds according to the invention include all inorganic and organic acid addition salts, depending on the substitution. Particular mention may be made of the pharmaceutically acceptable salts of the inorganic and organic acids customarily used in pharmacy. Suitable salts include water-insoluble and, particularly, water-soluble acid addition salts.
  • acids used for the acid addition salts include, but are not limited to, (1 ) inorganic acids such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, (2) carboxylic acids, such as, for example, (a) aliphatic, alicyclic, saturated or unsaturated carboxylic acids like acetic acid, trifluoracetic acid, succinic acid, oxalic acid, maleic acid, fumaric acid, (b) aromatic or heterocyclic carboxylic acids like benzoic acid, embonic acid, (c) hydroxylated or carbohydrate-derived carboxylic acids like citric acid, tartaric acid, lactic acid, malic acid, D-glucuronic acid, lactobionic acid (4-O-beta-D-Galactopyranosyl-D-gluconic acid), galactaric acid, (3) sulfonic acids like toluenesulfonic acid (forming tosilate salts),
  • Salts of the compounds of formula 1 according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid, or to which the desired acid is then added, if necessary upon heating.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol
  • the acid can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained for example by evaporating the solvent, by re-precipitating or by precipitating upon cooling or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts.
  • pharmaceutically unacceptable salts which can be obtained, for example, as process products in the production of the compounds according to the invention on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
  • the invention relates to all stereoisomers in any desired mixing ratio to another, including the pure stereoisomers, which are a preferred subject of the invention.
  • the pure stereoisomers of the compounds of the formula 1 and salts according to the present invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up stereoisomeric mixtures obtained in synthesis.
  • the pure stereoisomers of the compounds of the formula 1 are obtained by using chiral starting compounds.
  • Stereoisomeric mixtures of compounds of the formula 1 can be split up into the pure stereoisomers by methods known to a person skilled in the art. Preferably, the mixtures are separated by chromatography or (fractional) crystallization.
  • the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral acids, subsequent resolution of the salts and release of the desired compound from the salt.
  • derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group.
  • enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
  • One embodiment (embodiment a) of the invention relates to compounds of the formula 1 , in which
  • R1 , R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
  • Another embodiment (embodiment b) of the invention relates to compounds of the formula 1 , in which
  • X is NH
  • R1 , R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
  • preferred compounds are those compounds of formula 1 , in which
  • R1 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, halogen, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxycarbonyl
  • R3 is carboxyl, 1-4C-alkoxycarbonyl or the group -CO-NR31R32, where
  • R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, mor- pholino, aziridino or azetidino group, optionally substituted by a hydroxyl or halogen substitu- ent,
  • X is O (oxygen) or NH
  • Y has either the meaning -CH 2 -Ar wherein
  • Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp
  • Z has the meaning -CHR8- or -CHR8-CHR9- where in Ar and/or in the group gp
  • R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C- alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1- 4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl- 1-4C-alkoxy, fluoro-1-4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, I ⁇ C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or sulfonyl,
  • R5 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkyl or hydroxy,
  • R6 is hydrogen, 1-4C-alkyl or halogen
  • R7 is hydrogen, 1-4C-alkyl or halogen
  • R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- al koxy- 1 -4C-alkoxy , 1 -4C-al koxy- 1 -4C-al koxy- 1 -4C-al koxy , 3-7C-cycloalkoxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1 -4C-al koxy- 1-4C-al koxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or
  • R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- al koxy- 1 -4C-alkoxy , 1 -4C-al koxy- 1 -4C-al koxy- 1 -4C-al koxy, 3-7C-cycloalkoxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-
  • the invention relates to compounds of the formula 1-1 in which
  • R1 is hydrogen, 1-4C-alkyl, aryl, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkyl-3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, halogen, hydroxy, 1-4C-alkoxy, mono- or-di-1-4C-alkylannino- carbonyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, cyano-1-4C-alkyl, 1-4C-alkylcarbonyloxy- 1-4C-alkyl, carboxy, 1-4C-alkylcarbonylamino, (1-4C-alkyl)-1-4C-alkylcarbon
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, fluo- ro-1-4C-alkoxy, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylannino or 1-4C-alkylcarbonyloxy-1- 4C-alkyl,
  • R3 is fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy, hydroxy- 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, fluoro-1-4C- alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy, cyano, the group -CO-NR31 R32, the group SO 2 - NR31 R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, optionally substituted by a hydroxyl, oxo, halogen or 1-4C-alkyl substituent, and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyra- zol and tetrazol, where
  • R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl- carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1- 4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, fluoro-1- 4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, I ⁇ C-alkoxy-I ⁇ C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, fluoro-1-4C-alkyl or hydroxy,
  • X is O (oxygen) or NH
  • Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, in- dolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where
  • R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C- alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1- 4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl- 1-4C-alkoxy, fluoro-1-4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, I ⁇ C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or sulfonyl,
  • R5 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkyl or hydroxy,
  • R6 is hydrogen, 1-4C-alkyl or halogen
  • R7 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, fluoro-1-4C-alkyl, nitro, fluoro-1-4C-alkoxy, hydroxy and cyano, and the salts of these compounds.
  • the invention relates to compounds of the formula 1-2
  • R1 is hydrogen, 1-4C-alkyl, aryl, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkyl-3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, halogen, hydroxy, 1-4C-alkoxy, mono- or-di-1-4C-alkylamino- carbonyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, cyano- 1-4C-alkyl, 1-4C-alkylcarbonyloxy- 1-4C-alkyl, carboxy, "MC-alkylcarbonylamino, (1-4C-alkyl)-1-4C-alkylcarbony
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, fluo- ro-1-4C-alkoxy, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylannino or 1-4C-alkylcarbonyloxy-1- 4C-alkyl,
  • R3 is fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkyl, I ⁇ C-alkoxy-I ⁇ C-alkoxy-I ⁇ C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy, hydroxy- 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, I ⁇ C-alkoxy-I ⁇ C-alkoxy-I ⁇ C-alkoxy, fluoro-1-4C- alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy, cyano, the group -CO-NR31 R32, the group SO 2 - NR31 R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, optionally substituted by a hydroxyl, oxo, halogen or 1-4C-alkyl substituent and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyra- zol and tetrazol, where
  • R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl- carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1- 4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, fluoro-1- 4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, I ⁇ C-alkoxy-I ⁇ C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, fluoro-1-4C-alkyl or hydroxy,
  • R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy, 2- 4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C- alkoxycarbonyl-1-4C-alkyl, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, fluoro-1- 4C-alkyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R5 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkyl or hydroxy
  • X is O (oxygen) or NH
  • Z has the meaning -CHR8- or -CHR8-CHR9- where
  • R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C- alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C- al koxy- 1 -4C-alkoxy , 1 -4C-al koxy- 1 -4C-al koxy- 1 -4C-al koxy , 3-7C-cycloalkoxy- 1 -4C- alkoxy, 3-7C-cycloalkyl-1 -4C-al koxy- 1-4C-al koxy, 1-4C-alkylcarbonyloxy, halo-1-4C- alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or
  • the compounds of the formula 1-2 have two or more chiral centres in the parent structure.
  • the invention thus relates to all conceivable stereoisomers in any desired mixing ratio to one another, including the pure stereoisomers, which are a preferred subject of the invention.
  • R1 is hydrogen, 1-4C-alkyl, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkyl-3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, halogen, hydroxy, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkyl, 1-4C- alkylcarbonylamino, (1-4C-alkyl)-1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or (1- 4C-alkyl)-1-4C-alkoxycarbonylamino,
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, fluoro-1-4C-alkyl, 1-4C-alkoxycarbonyl or hydroxy-1- 4C-alkyl,
  • R3 is carboxyl, 1-4C-alkoxycarbonyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, optionally substituted by a hydroxyl, oxo, halogen or 1-4C-alkyl substituent,
  • X is O (oxygen) or NH
  • R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxycarbonyl, hydroxy, fluoro-1-4C-alkyl, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino,
  • R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, fluoro-1-4C-alkyl, ni- tro, fluoro-1-4C-alkoxy, hydroxy and cyano, and the salts of these compounds.
  • R1 is hydrogen, 1-4C-alkyl, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkyl-3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, halogen, hydroxy, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, 1-4C-alkylcarbonyloxy-1-4C-alkyl, 1-4C- alkylcarbonylamino, (1-4C-alkyl)-1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or (1- 4C-alkyl)-1-4C-alkoxycarbonylamino,
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1- 4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy, fluoro-1-4C-alkyl, 1-4C-alkoxycarbonyl or hydroxy-1- 4C-alkyl,
  • R3 is carboxyl, 1-4C-alkoxycarbonyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, optionally substituted by a hydroxyl, oxo, halogen or 1-4C-alkyl substituent,
  • R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R5 is hydrogen or 1-4C-alkyl
  • X is O (oxygen) or NH
  • R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C- alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alk- ylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-I ⁇ C-alkylamino-I ⁇ C-alkylcarbony- loxy, 1-4C-alkoxy-1-4
  • R1 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, halogen, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxycarbonyl
  • R3 is carboxyl, 1-4C-alkoxycarbonyl or the group -CO-NR31R32, where
  • R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, mor- pholino, aziridino or azetidino group, X is O (oxygen) or NH, and
  • R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy
  • R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy
  • R1 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, halogen, 1-4C-alkoxy or 1-4C- alkoxy-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxycarbonyl,
  • R3 is carboxyl, 1-4C-alkoxycarbonyl or the group -CO-NR31R32, where
  • R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, mor- pholino, aziridino or azetidino group, optionally substituted by a hydroxyl or fluoro substituent,
  • R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R5 is hydrogen
  • X is O (oxygen) or NH
  • R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 1-4C- alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkyl- carbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and the salts of these compounds.
  • R1 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, halogen, 1-4C-alkoxy, 1-4C- alkoxy-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy, 1-4C-alkoxy, fluoro-1-4C-alkoxy, fluoro-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or 1-4C-alkoxycarbonyl,
  • R3 is carboxyl, 1-4C-alkoxycarbonyl or the group -CO-NR31R32, where
  • R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, mor- pholino, aziridino or azetidino group, optionally substituted by a hydroxyl or fluoro substituent,
  • R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R5 is hydrogen
  • X is O (oxygen) or NH
  • R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 1-4C- alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkyl- carbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and the salts of these compounds.
  • R1 is hydrogen or 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is carboxyl, 1-4C-alkoxycarbonyl or the group -CO-NR31 R32 where
  • R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl, and
  • R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, mor- pholino, aziridino or an azetidino group X is NH, and
  • R4 is hydrogen or 1-4C-alkyl
  • R5 is hydrogen or 1-4C-alkyl
  • the salts of these compounds
  • Exemplary preferred compounds according to the invention are those compounds of the formula 1-1-1 , wherein R1 , R2, R3, X, R4 and R5 have the meanings as given in Table A and the salts of these compounds. These compounds are either described by way of example as final products or can be prepared in an analogous manner using for example the process steps described below.
  • Exemplary particularly preferred compounds according to the invention are those compounds which are described by way of example and the salts of these compounds.
  • the compounds according to the invention can be synthesized from corresponding starting compounds, for example according to the reaction schemes given below. The synthesis is carried out in a manner known to the expert, for example as described in more detail in the following examples.
  • the compounds of the general formula 1 can be obtained for example according to the reaction sequence as shown in schemei .
  • compounds of the formula 6 can be obtained by mono-alkylation (e.g. using one equivalent of alkylating agent) of one amino group in pyridines of the formula 5 (the alkylation can be performed by methods known to persons skilled in the art for example by direct alkylation in the presence of a base (e.g. potassium carbonate) or by reductive alkylation using carbonyl compounds of formula Ar-CHO.
  • a base e.g. potassium carbonate
  • the reaction of compounds of the general formula 6 with ⁇ -halogen substituted carbonyl compounds of the general formula 3 leads to the desired imidazo[1 ,2- a]pyridines of the formula 1a-1.
  • reaction sequence can alternatively be inverted.
  • Forming first imidazo[1 ,2-a]pyridines of the general formula 7 by the reaction of the starting compound 5 with ⁇ -halogen substituted carbonyl compounds of the general formula 3 and subsequent alkylation delivers the desired compounds of the formula 1a-1 as well.
  • 2,6-Diaminopyridines of the formula 5 are known, for example from B. Brodbeck, B. P ⁇ llmann, S. Schmitt, M. Nettekoven, Tetrahedron Lett. 2003, 44, 1675-1678 or can be prepared in an analogous manner.
  • Epoxyindane is described for example in W. F. Whitmore; A. I. Gebhart, J. Am. Chem. Soc. 1942, 64, 912.
  • substituted epoxyindanes can be prepared from the corresponding substituted indenes by methods known from the literature (e.g. epoxidation).
  • the leaving group Lg in imidazo[1 ,2-a]pyridines of the general formula 4 can be substituted by a group Pg-O by reacting with alcohols Pg-OH in the presence of a base (as described in scheme 1 ).
  • the part Pg of alcohols Pg-OH is a suitable protecting group (as for example an allyl or a benzyl group) and can be removed in the following step by methods known to persons skilled in the art (e.g. hydrogenation in case of Pg is a benzyl group) forming the desired compounds of the general formula 13-2.
  • reaction steps outlined above are carried out in a manner known per se, e. g. as described in more detail in the examples.
  • the derivatization, if any, of the compounds obtained according to the above scheme 1 , 2, 4 or 5 e.g. conversion of a group R3 into another group R3 or conversion of a hydroxyl group into an alkoxy or ester group
  • conversion of a group R3 into another group R3 or conversion of a hydroxyl group into an alkoxy or ester group is likewise carried out in a manner known per se.
  • an appropriate derivatization can be performed in a manner known per se (e. g.
  • R3 hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1- 4C-alkoxy or fluoro-1-4C-alkoxy-1-4C-alkoxy
  • an appropriate derivatization can be performed in a manner known per se, for example by nucleophilic substitution of R3 at the stage of a compound of the formula 6, 7, or preferably at the stage of a compound of the formula 1 , wherein R3 is a suitable leaving group, like for example a chloro atom.
  • Derivatization of compounds of the formula 1 regarding group R1 or R2 can be performed for example by aromatic substitution reaction in case of R1 or R2 is hydrogen (for example halogenation reactions for example using N-bromosuccinimide or N-chlorosuccinimide or formylation reactions for example using Vilsmeier conditions).
  • the introduced groups R1 or R2 furthermore can be derivatized in a manner known per se, e.g. reduction of the obtained formyl group to a hydroxymethyl group (for example using sodium boron hydride) or oxidation of the obtained formyl group to a carboxylic group (for example using sodium hypochlorite) or by any other methods known to a person skilled in the art.
  • the present invention thus further relates to a process for preparation of compounds of formula 1a-1 ,
  • the present invention further relates to a process for conversion of a compound of formula 1 into another compound of formula 1 , comprising either
  • the present invention further relates to compounds of the formula (6) or (12) mentioned in the schemes above and shown below, which are intermediates in the process of producing the compounds of the formula 1 according to the present invention.
  • the substituents R3 and Ar have the meanings as defined for compounds according to the invention.
  • the present invention further relates to compounds of the formula (13) mentioned in the schemes above and shown below, which are intermediates in the process of producing the compounds of the formula 1 according to the present invention.
  • the substituents R1 , R2, R3 and X have the meanings as defined for compounds according to the invention.
  • the excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models.
  • the compounds of the formula 1 according to the invention investigated in the model mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples.
  • the substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
  • the body temperature of the animals was kept at a constant 37.8-38 0 C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
  • Methyl 2-amino-6-chloro-isonicotinate (9.33 g, 50.0 mmol) was suspended in n-propanol.
  • 1-Bromo-2,2-dimethoxypropan (20.26 ml, 150 mmol) was added dropwise.
  • n-propanol was removed in vacuo and the residue was recrystallized from diisopropyl ether. 14.55 g (95%) of the title compound were obtained as pale brown solid.
  • the compounds of the formulae 1 , 1-1 , 1-1-1 , 1-2, 1-2-1 , 1-2-1-a and 1 -2-1 -b and their pharmaceutically acceptable salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective or curative action in warm-blooded animals, in particular humans.
  • the active compounds according to the invention are distinguished by a high selectivity of action, a fast onset of action, an advantageous duration of action, efficient control of the duration of action by the dosage, a particularly good antisecretory efficacy, the absence of significant side effects and a large therapeutic range.
  • Gastric and intestinal protection or cure in this connection is understood to include, according to general knowledge, the prevention, the treatment and the maintenance treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duodenal ulcer]), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, drugs (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations.
  • gastrointestinal diseases is understood to include, according to general knowledge,
  • GSD gastroesophageal reflux disease
  • GERD extra-esophageal manifestations of GERD that include, but are not limited to, acid-related asthma, bronchitis, laryngitis and sleep disorders.
  • C) other diseases that can be connected to undiagnosed reflux and/or aspiration include, but are not limited to, airway disorders such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease).
  • gastrointestinal diseases comprise other gastrointestinal conditions that might be related to acid secretion, such as Zollinger-Ellison syndrome, acute upper gastrointestinal bleeding, nausea, vomiting due to chemotherapy or post-operative conditions, stress ulceration, IBD (inflammatory bowel disease) and particularly IBS (irritable bowel syndrome).
  • the active compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcero- genic and the antisecretory properties are determined.
  • the active compounds according to the invention are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine and/or upper digestive tract, particularly of the abovementioned diseases.
  • a further subject of the invention are therefore the active compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention likewise includes the use of the active compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
  • a further subject of the invention are medicaments which comprise one or more active compounds according to the invention.
  • the active compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical excipients in the form of tablets, coated tablets (e.g. film-coated tablets), multi unit particulate system tablets, capsules, suppositories, granules, powders (e.g. lyophilized compounds), pellets, patches (e.g. as TTS [transdermal therapeutic system]), emulsions, suspensions or solutions.
  • the content of the active compound is advantageously being between 0.1 and 95wt% (weight percent in the final dosage form), preferably between 1 and 60wt%.
  • the active compounds according to the invention can be administered orally, parenterally (e.g. intravenously), rectally or percutaneously. Oral or intravenous administration is preferred.
  • excipients or combinations of excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge and are composed of one or more accessory ingredients.
  • solvents antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins)
  • excipients may be mentioned as examples:
  • gelling agents antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g.
  • a further subject of the invention is therefore a substance according to the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof, for treating or preventing the abovementioned diseases.
  • a further subject of the invention is a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment, the maintenance treatment and/or prophylaxis of gastrointestinal diseases.
  • a further subject of the invention is a pharmaceutical composition, comprising a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment, the maintenance treatment and/or prophylaxis of gastrointestinal diseases.
  • a daily dose (given continuously or on-demand) of approximately 0.01 to approximately 20, preferably 0.02 to 5, in particular 0.02 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 2, individual doses to achieve the desired result.
  • a parenteral treatment similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses can be used.
  • the frequency of administration can be adapted to intermittent, weekly, monthly, even more infrequent (e.g. implant) dosing.
  • the establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
  • the medicaments may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical science. All methods include the step of bringing the active compounds according to the invention into association with the excipients or a combination of excipients. In general the formulations are prepared by uniformly and intimately bringing into association the active compounds according to the invention with liquid excipients or finely divided solid excipients or both and then, if necessary, formulating the product into the desired medicament.
  • the active compounds according to the invention or their pharmaceutical preparations can also be used in combination with one or more pharmacologically active constituents from other groups of drugs [combination partner(s)].
  • “Combination” is understood to be the supply of both the active compound(s) according to the invention and the combination partner(s) for separate, sequential, simultaneous or chronologically staggered use.
  • a combination is usually designed with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or decreasing the side effects of the combination partner(s), or with the aim to obtain a more rapid onset of action and a fast symptom relief.
  • the drug release profile of the components can be exactly adapted to the desired effect, e.g.
  • a combination can be, for example, a composition containing all active compounds (for example a fixed combination) or a kit-of-parts comprising separate preparations of all active compounds.
  • a "fixed combination” is defined as a combination wherein a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture of simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a “kit-of-parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.
  • “Other groups of drugs” are understood to include, for example: tranquillizers (for example from the group of the benzodiazepines, like diazepam), spasmolytics (for example butylscopolaminium bromide [Buscopan®]), anticholinergics (for example atropine sulfate, pirenzepine, tolterodine), pain perception reducing or normalizing agents (for example, paracetamol, tetracaine or procaine or especially oxeta- cain), and, if appropriate, also enzymes, vitamins, trace elements or amino acids.
  • tranquillizers for example from the group of the benzodiazepines, like diazepam
  • spasmolytics for example butylscopolaminium bromide [Buscopan®]
  • anticholinergics for example atropine sulfate, pirenzepine, tolterodine
  • pain perception reducing or normalizing agents for example, paraceta
  • histamine-H 2 blockers e.g. cimetidine, ranitidine
  • peripheral anticholinergics e.g. pirenzepine
  • gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists).
  • antibacterially active substances and especially substances with a bactericidal effect, or combinations thereof.
  • These combination partners are especially useful for the control of Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases.
  • suitable antibacterially active combination partner(s) may be mentioned, for example:
  • cephalosporins such as, for example, cifuroximaxetil
  • penicillines such as, for example, amoxicillin, ampicillin (C) tetracyclines, such as, for example, tetracyline itself, doxycycline
  • (E) macrolide antibiotics such as, for example, erythromycin, clarithromycin, azithromycin
  • glycoside antibiotics such as, for example, gentamicin, streptomycin
  • gyrase inhibitors such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin
  • I oxazolidines, such as, for example, linezolid
  • nitrofuranes or nitroimidazoles such as, for example, metronidazole, tinidazole, nitrofurantoin
  • K bismuth salts, such as, for example, bismuth subcitrat (L) other antibacterially active substances and combinations of substances selected from (A) to (L), for example clarithromycin + metronidazole.
  • Preferred is the use of two combination partners. Preferred is the use of two combination partners selected from amoxicillin, clarithromycin and metronidazole. A preferred example is the use of amoxicillin and clarithromycin.
  • the active compounds according to the invention are especially suited for a free or fixed combination with drugs, which are known to cause "drug-induced dyspepsia" or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirheumatics, such as NSAIDs (non-steroidal antiinflammatory drugs, e.g. etofenamate, diclofenac, indometacin, ibuprofen, piroxicam, naproxen, meloxicam), oral steroids, bisphosponates (e.g. alendronate), or even NO- releasing NSAIDs, COX-2 inhibitors (e.g. celecoxib, lumiracoxib).
  • drugs which are known to cause "drug-induced dyspepsia” or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirhe
  • the active compounds according to the invention are suited for a free or fixed combination with motility-modifying or -regulating drugs (e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid), and especially with pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR), such as, for example, pharmaceuticals modulating (activating) directly or indirectly the GABA-B receptor, such as, for example, GABA-B receptor agonists (e.g. baclofen, (2R)-3-amino-2-fluoropropylphosphinic acid), GABA-B receptor positive allosteric modulators (e.g.
  • motility-modifying or -regulating drugs e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid
  • GABA-B receptor positive allosteric modulators in combination with GABA-B receptor agonists, or substances that enhance the endogenous GABA tone such as GABA re-uptake inhibitors (e.g. tiagabine), pharmaceuticals antagonising the metabotropic glutamate receptor type 5 (mGluR5), such as metabotropic glutamate receptor type 5 (mGluR5) antagonists (e.g.
  • composition partners used for the treatment of IBS or IBD are also suitable combination partner(s), such as, for example: 5-HT4 receptor agonists like mosapride, tegaserod; 5-HT3 receptor antagonists like alosetron, cilansetron; NK2 antagonists like saredutant, nepadutant; ⁇ -opiate agonists like fedotozine.
  • 5-HT4 receptor agonists like mosapride, tegaserod
  • 5-HT3 receptor antagonists like alosetron, cilansetron
  • NK2 antagonists like saredutant, nepadutant
  • ⁇ -opiate agonists like fedotozine.
  • Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis.
  • a hypnotic aid such as, for example, Zolpidem [Bikalm®]
  • combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

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Abstract

La présente invention a pour objet des composés de formule (1), les substituants et les symboles étant tels que définis dans la description. Les composés inhibent la sécrétion d'acide gastrique.
PCT/EP2007/057849 2006-07-31 2007-07-30 Imidazo[1,2-a]pyridines 5,7-bis-substituées WO2008015196A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal
EP2320907A1 (fr) * 2008-08-05 2011-05-18 Merck & Co., Inc. Composés thérapeutiques
JPWO2014021383A1 (ja) * 2012-07-31 2016-07-21 協和発酵キリン株式会社 縮環複素環化合物
US10696671B2 (en) 2016-07-05 2020-06-30 Jeil Pharmaceutical Co., Ltd. Imidazo[1,2-A]pyridine derivatives, methods for preparing the same and use thereof
KR102496869B1 (ko) * 2022-07-29 2023-02-07 제일약품주식회사 이미다조[1,2-a]피리딘 화합물의 신규 염, 이의 결정형 및 제조방법

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WO2005077947A1 (fr) * 2004-02-18 2005-08-25 Altana Pharma Ag 1,2,4-triazolo[4,3-a]pyridines convenant au traitement de troubles gastrointestinaux
WO2005089763A1 (fr) * 2004-03-19 2005-09-29 Warner-Lambert Company Llc Derives d'imidazopyridine et d'imidazopyrimidine en tant qu'agents antibacteriens
WO2006061380A2 (fr) * 2004-12-09 2006-06-15 Altana Pharma Ag Imidazo[4,5-b]pyridines substitues

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EP0068378A1 (fr) * 1981-06-26 1983-01-05 Schering Corporation Imidazo(1,2-a)pyridines et pyrazines, procédés pour leur préparation et composés pharmaceutiques les contenant
WO2005070927A2 (fr) * 2004-01-26 2005-08-04 Altana Pharma Ag 1,2,4-triazolo[1,5-a]pyridines
WO2005077947A1 (fr) * 2004-02-18 2005-08-25 Altana Pharma Ag 1,2,4-triazolo[4,3-a]pyridines convenant au traitement de troubles gastrointestinaux
WO2005089763A1 (fr) * 2004-03-19 2005-09-29 Warner-Lambert Company Llc Derives d'imidazopyridine et d'imidazopyrimidine en tant qu'agents antibacteriens
WO2006061380A2 (fr) * 2004-12-09 2006-06-15 Altana Pharma Ag Imidazo[4,5-b]pyridines substitues

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2320907A1 (fr) * 2008-08-05 2011-05-18 Merck & Co., Inc. Composés thérapeutiques
JP2011530511A (ja) * 2008-08-05 2011-12-22 メルク・シャープ・エンド・ドーム・コーポレイション 治療用化合物
EP2320907A4 (fr) * 2008-08-05 2012-09-05 Merck Sharp & Dohme Composés thérapeutiques
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal
JPWO2014021383A1 (ja) * 2012-07-31 2016-07-21 協和発酵キリン株式会社 縮環複素環化合物
US10696671B2 (en) 2016-07-05 2020-06-30 Jeil Pharmaceutical Co., Ltd. Imidazo[1,2-A]pyridine derivatives, methods for preparing the same and use thereof
KR102496869B1 (ko) * 2022-07-29 2023-02-07 제일약품주식회사 이미다조[1,2-a]피리딘 화합물의 신규 염, 이의 결정형 및 제조방법
WO2024025393A1 (fr) * 2022-07-29 2024-02-01 제일약품주식회사 Nouveau sel de composé imidazo[1,2-a]pyridine, forme cristalline de celui-ci et procédé de préparation

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