EP1756067A1 - Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique - Google Patents

Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique

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Publication number
EP1756067A1
EP1756067A1 EP05747188A EP05747188A EP1756067A1 EP 1756067 A1 EP1756067 A1 EP 1756067A1 EP 05747188 A EP05747188 A EP 05747188A EP 05747188 A EP05747188 A EP 05747188A EP 1756067 A1 EP1756067 A1 EP 1756067A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
hydrogen
hydroxy
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05747188A
Other languages
German (de)
English (en)
Inventor
Peter Jan Zimmermann
Wilm Buhr
M. Vittoria Chiesa
Andreas Palmer
Christof Brehm
Wolfgang-Alexander Simon
Stefan Postius
Wolfgang Kromer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Altana Pharma AG
Nycomed GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Altana Pharma AG, Nycomed GmbH filed Critical Altana Pharma AG
Priority to EP05747188A priority Critical patent/EP1756067A1/fr
Publication of EP1756067A1 publication Critical patent/EP1756067A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
  • US Patent 6,083,961 describes benzimidazole compounds which have activities as bradykinin antagonists and are said to be useful for treating several diseases such as allergy, inflammation, autoimmune disease, shock, pain or the like.
  • PPI's proton pump inhibitors
  • rPPI's reversible proton pump inhibitors
  • APA's acid pump antagonists
  • rPPI's or APA's are known for more than 20 years and many companies are engaged in their development, no rPPI or APA is at present available for therapy.
  • the technical problem underlying the present invention is therefore to provide acid pump antagonists which can be used in therapy.
  • the invention relates to compounds of the formula 1
  • H R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy- 1-4C-alkyl, 1-4C-alkoxycarb ⁇ nyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu- oro-2-4C-alkyl,
  • R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-a!kyl, 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, trifluoromethyl, nitro, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • 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, isoxa- zolyl, 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, 1-4C-alkyl, hydroxy-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, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1- 4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1- 4C-alkoxycarbonylamino or sul
  • 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-Cycloalkyl-1-4C-alkyl 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-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 methoxymethyl, the methoxyethyl group and the butoxyethyl group.
  • 1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) 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 0-C(0)-) and the ethoxycarbonyl group (CH 3 CH 2 0-C(0)-) .
  • 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.
  • An example which may be mentioned is the trifluoromethyl group.
  • Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl 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-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl group.
  • Fluoro-2-4C-alkyl represents a 2-4C-alkyl groups, which is substituted by one or more fluorine atoms.
  • An example which may be mentioned is the 2,2,2-trifluoroethyl group.
  • Aryl-1-4C-alkoxy denotes 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 -0-CH 2 -CH z -0-) and 2-(ethoxy)ethoxy (CH 3 -CH 2 -0-CH 2 -CH 2 -0-).
  • 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.
  • An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH 3 -0-CH 2 -CH 2 -0-CH 2 -).
  • 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 completely or mainly substituted by fluorine.
  • Examples of completely or mainly fluoro-substituted 1-4C-alkoxy groups which may be mentioned are the 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-l-butoxy, the 4,4,4- trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroeth- oxy, 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, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifluoroethoxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluorometh- oxyethyl radicals.
  • 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 abovementioned 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 Methoxycarbonylmethyl and the ethoxycarbonylmethyl group.
  • Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical.
  • An example which may be mentioned is the benzyl radical.
  • 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(0)NH-) and the acetylamino group (acetamido group) (CH 3 C(0)NH-) .
  • 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-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 -0-CH 2 CH 2 -0-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH 3 CH 2 -0-CH 2 CH 2 -0-CO-).
  • 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.
  • 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 cycloheptyloxy, 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.
  • 1-4C-Alkoxy-1-4C-aIkoxy-1-4C-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 cyclohexy- loxyethoxy 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 cyclobu- tylmethoxyethoxy 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-0-CH 2 ).
  • 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 l 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
  • Mono- or di-1-4C-alkylamino-1-4C-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.
  • 1-4C-Alkoxy-1-4C-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.
  • Suitable salts of compounds of the formula 1 are - depending on the substitution - in particular all acid addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D- gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, em- bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in the salt preparation in an
  • Pharmacologically unacceptable salts which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • the compounds according to the invention and their salts can, for example when they are isolated in crystalline form, comprise varying amounts of solvents.
  • the invention therefore also embraces all solvates and, in particular, all hydrates of the compounds of the formula 1, and all solvates and, in particular, all hydrates of the salts of the compounds of the formula 1.
  • One embodiment (embodiment 1) of the invention relates to compounds of the formula 1, in which X is O (oxygen)
  • R1 , R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
  • X is NH
  • R1, R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
  • Another embodiment (embodiment 3) of the invention relates to compounds of the formula 1 , in which
  • R3 is hydrogen
  • R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds.
  • Still another embodiment (embodiment 4) of the invention relates to compounds of the formula 1 , in which R3 does not have the meaning hydrogen, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds.
  • Still another embodiment (embodiment 5) of the invention relates to compounds of the formula 1, in which
  • R3 is halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1 -4C-alkyl, 1 -4C-alkoxy-1 - C-alkoxy-1 -4C-alkyl, fluoro-1 -4C-alkoxy-1 -4C-alkyl, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi- soxazol, pyrazol 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-a!kyl, 1-4C-alkoxycarbonyl-1-4C- alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyIcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R34 is hydrogen, 1 ⁇ C-alkyl, 1-4C-aIkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds
  • the invention also relates to compounds of the formula 1, in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 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, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, 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, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, mo ⁇ holino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi- soxazol, pyrazol 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, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • X is O (oxygen) or NH
  • Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyciic 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, isoxa- zolyl, 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, 1-4C-aIkyl, hydroxy-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, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1- 4C-alkoxy, trifluoromethyl, fluoro-1 -4C-alkoxy, nitro, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1- 4C-alkoxycarbonylamino or
  • the invention also relates to compounds of the formula 1, in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 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, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-aIkyl, flu- oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
  • R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, -CO-1-4C-alkoxy, 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, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi- soxazol, pyrazol 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, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • X is O (oxygen) or NH
  • Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyciic 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, isoxa- zolyl, 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, 1-4C-alkyl, hydroxy-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, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1- 4C-alkoxy, trifluoromethyl, fluoro-1 -4C-alkoxy, nitro, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1- 4C-alkoxycarbonylamino or
  • the invention relates to compounds of the formula 1a
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-aIkyl, 1-4C-alkoxy, 1-4C- alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1 -4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
  • R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, -CO-1-4C-alkoxy, 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, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi- soxazol, pyrazol and tetrazol
  • 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, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-
  • R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • X is O (oxygen) or NH
  • Ar is a mono- or bicyciic 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, isoxa- zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
  • R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1- C-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, trifluoromethyl, fluoro-1-4C-alkoxy, 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, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R6 is hydrogen, 1 ⁇ 4C-alkyl or halogen
  • R7 is hydrogen, 1-4C : alkyl or halogen
  • 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, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
  • the invention relates to compounds of the formula 1a, in which
  • R1 is hydrogen, 1- C-alkyl, 3-7C-cycloalkyl, 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, hydroxy-1-4C-alkyl, mono- ordi-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu- oro-2-4C-alkyl, aryl-1 ⁇ 4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
  • R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, -CO-1-4C-alkoxy, 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, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi- soxazol, pyrazol 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, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • X is O (oxygen) or NH
  • Ar is a mono- or bicyciic aromatic residue, substituted by R4, R5, R6 and R7, which is se- lected from the group consisting of phenyl, naphthyl, pyrrolyl,. pyrazolyl, imidazolyl, 1 ,2,3- triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa- zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
  • R4 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, trifluoromethyl, fluoro-1 -4C-alkoxy, 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, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R6 is hydrogen, 1-4C-alkyl or halogen
  • R7 is hydrogen, 1-4C-alkyl or halogen
  • 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, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Ar is phenyl or a phenyl substituted by a 1-4C-alkoxy radical, and the salts of these compounds.
  • the invention relates to compounds of the formula 1a, in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 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, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu- oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, 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, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi- soxazol, pyrazol 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, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,
  • X is O (oxygen) or NH
  • Ar is a mono- or bicyciic 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, isoxa- zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,
  • R4 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-alkoxycart)onyl-1-4C- alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1 -4C-alkoxy, 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, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R6 is hydrogen, 1-4C-alkyl or halogen
  • R7 is hydrogen, 1-4C-alkyl or halogen
  • 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, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when R1 denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-alkyl or 3-7C- cycloalkyl-1-4C ⁇ alkyl, and the salts of these compounds.
  • the invention relates to compounds of the formula 1b
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 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-alky I, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, 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, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihy- droisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C- alkylcarbony
  • the compounds of the formula 1 b have up to three chiral centers in the parent structure.
  • the invention thus relates to all conceivable stereoisomers in any desired mixing ration to one another, including the pure enantiomers, which are a preferred subject of the invention.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R2 is hydrogen,1-4C-alkyl, hydroxy, 1 ⁇ 4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1 ⁇ 4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino 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 pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol and dihydroimidazol, where
  • R33 is hydrogen or 1-4C-alkyl
  • R34 is hydrogen or 1-4C-alkyl
  • R35 is hydrogen or 1-4C-alkyl
  • R4 is hydrogen, 1 ⁇ 4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, fluoro-1 -4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C- alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group - CO-NR31R32, 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 or 1-7C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group,
  • R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino,
  • R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1 ⁇ 4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is O (oxygen) or NH, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1- C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is O (oxygen) or NH, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R31 is 1-4C-alkyl
  • R32 is 1-4C-alkyl, or where
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl.
  • R31 is 1-4C-alkyl
  • R32 is 1-4C-alkyl
  • R4 is 1-4C-alkyl
  • R5 is 1-4C-alkyl
  • X is NH, and their salts.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alky I, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group S0 2 -NR31R32 or the group Het, where
  • R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino 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, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and
  • Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol and dihydroimidazol, where
  • R33 is hydrogen or 1-4C-alkyl
  • R34 is hydrogen or 1-4C-alkyl
  • R35 is hydrogen or 1-4C-alkyI
  • R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen
  • R5 is hydrogen or 1-4C-alkyl
  • 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-alkylcart)onyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C- alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- ordi-1-4C-alkylamino-1-4C- alkylcarbonyloxy, 1-4C-alkoxy-1-4C
  • X is O (oxygen) or NH, and their salts.
  • Particularly preferred compounds of the formula 1b-1 are those, in which
  • R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group - CO-NR31R32, 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 or 1-7C-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,
  • R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen
  • R5 is hydrogen or alkyl
  • 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- alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C- alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxy
  • X is O (oxygen) or NH, and their salts.
  • Still particularly preferred compounds of the formula 1b-1 are those, in which
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and
  • R32 is hydrogen or 1-4C-alkyl
  • R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen
  • R5 is hydrogen
  • 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- alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C- alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxy
  • X is O (oxygen) or NH, and their salts.
  • Still particularly preferred compounds of the formula 1b-1 are those, in which
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl or 1-4C-alkoxy X is O (oxygen) or NH, and their salts.
  • R1 is 1-4C-alkyl.
  • R2 is 1-4C-alkyl
  • R3 is the group -CO-NR31 R32, where
  • R31 is 1-4C-alkyl.
  • R32 is 1-4C-alkyl
  • R4 is hydrogen
  • R5 is hydrogen
  • R8 is hydroxyl
  • X is O (oxygen) and their salts.
  • the compounds of the general formula 1a can be obtained as depicted in scheme 1 by reacting substituted benzimidazole compounds of formula 2 with compounds of formula 3, wherein L is a suitable leaving group like for example a suitable halogen atom, like for example chlorine.
  • Scheme 1 : 1a, X 0, NH
  • Scheme 2 :
  • compounds of the general formula 1b are obtained by reacting substituted ben- zimidazoles of formula 2 with 1,2-epoxyindanes of the formula 5, carrying any desired sub- stituent R4 and R5 (cf. scheme 3 for a compound 1b-1).
  • 1 ,2-Epoxyindan is described for example in W. F. Whitmore; A. I. Gebhart, J. Am. Chem. Soc. 1942, 64, 912.
  • substituted alkyl-, alkoxy- or halogeno-epoxyindanes can be prepared from the corresponding substituted indenes by methods known from literature (e.g. epoxidation).
  • 3-Nitro-2-aminophenol can be reacted in a first step with a suitable benzyl derivative, for example benzylchloride, to form the reaction product of the formula 9 which is known for example from J. Heterocyclic Chem. (1983), 20, 1525).
  • a sub- stituent R3 can be introduced, for example a bromine substituent can be introduced by a bro- mination reaction using a suitable bromination reagent, like for example N-bromosuccinimide.
  • reaction with primary amines of the formula 14 leads to compounds of the formula 15 (L. A. Summers, Austr. J. Chem. 1965, 18, 1695-1698) that are reduced to phenylenediamines of the formula 16 by methods known to the expert.
  • the benzimidazoles of the formula 2 are then obtained by a cyclization reaction of compounds of the formula 16, for example with a diketone of the formula 12 to give compounds of the formula 17, and subsequent reduction of the N0 2 -group by catalytic hydrogenation or any other method known from literature (scheme 6).
  • 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 intraduode- nally 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°C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
  • the precipitate was collected and suspended in 30 ml methanol and 10 ml water. To the mixture were added 0.96 g (40 mmol) lithium hydroxide and the suspension was heated to 70 °C. After 30 min, the pH of the reaction mixture was adjusted to pH ⁇ 6 by adding 4N hydrochloric acid. Excess methanol was removed and the precipitate was collected and washed with water to yield 0.8 g (21 %) of the title compound as a colourless solid (m.p. 303-305 °C).
  • the compounds of the formula 1 and their 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 action in warm-blooded animals, in particular humans.
  • the compounds according to the invention are distinguished by a high selectivity of action, an advantageous duration of action, a particularly good enteral activity, the absence of significant side effects and a large therapeutic range.
  • Gastric and intestinal protection in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations.
  • gastroesophageal reflux disease GGID
  • the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation include, but are not limited to, heartburn and/or acid regurgitation.
  • the 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 antiul- cerogenic and the antisecretory properties are determined.
  • the compounds of the formula 1 and their pharmacologically acceptable salts are out ⁇ tandingly 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.
  • a further subject of the invention are therefore the 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 compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the above- mentioned diseases.
  • the invention furthermore includes the use of the 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 compounds of the formula 1 and/or their pharmacologically acceptable salts.
  • the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
  • suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as
  • auxiliaries and 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.
  • solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor cor- rigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex- ing agents (e.g. cyclodextrins).
  • the active compounds can be administered orally, parenterally or percutaneously.
  • the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, preferably 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 4, 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 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 pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, for example: tranquillizers (for example from the group of the benzodiazepines, for example diazepam), spasmolytics (for example, bietamiverine or camylofine), anticholinergics (for example, oxyphencyclimine or phencar- bamide), local anesthetics, (for example, tetracaine or procaine), and, if appropriate, also enzymes, vitamins or amino acids.
  • tranquillizers for example from the group of the benzodiazepines, for example diazepam
  • spasmolytics for example, bietamiverine or camylofine
  • anticholinergics for example, oxyphencyclimine or phencar- bamide
  • local anesthetics for example, tetracaine or procaine
  • enzymes for example, tetracaine or procaine
  • H 2 Mockers e.g. cimetidine, ranitidine
  • H ⁇ K* ATPase inhibitors e.g. omeprazole, pantoprazole
  • peripheral anticholinergics e.g.
  • pirenzepine pirenzepine, telenzepine
  • gastrin antago- nists with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or of decreasing the side effects, or further the combination with antibacterially active substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimi- dazoles or alternatively bismuth salts) for the control of Helicobacter pylori.
  • antibacterially active substances such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimi- dazoles or alternatively bismuth salts
  • Suitable antibacterial co-components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefa- lothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, met- ronidazole, clarithromycin, azithromycin and combinations thereof (for example clarithromycin + metronidazole).
  • the compounds of formula 1 are suited for a free or fixed combination with those medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs), which are known to have a certain ulcerogenic potency.
  • those medicaments e.g. certain antiinflammatories and antirheumatics, such as NSAIDs
  • the compounds of formula 1 are suited for a free or fixed combination with motility-modifying drugs.

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Abstract

La présente invention concerne des composés représentés par la formule (1), dans laquelle les substituants et les symboles sont tels que définis dans le descriptif. Ces composés inhibent la sécrétion d'acide gastrique. Formule (1)
EP05747188A 2004-05-18 2005-05-13 Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique Withdrawn EP1756067A1 (fr)

Priority Applications (1)

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EP05747188A EP1756067A1 (fr) 2004-05-18 2005-05-13 Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique

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EP04102191 2004-05-18
EP05747188A EP1756067A1 (fr) 2004-05-18 2005-05-13 Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique
PCT/EP2005/052196 WO2005111000A1 (fr) 2004-05-18 2005-05-13 Benzimidazoles a substitution 7 et utilisation de ces derniers en tant qu'inhibiteurs de la secretion d'acide gastrique

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CA2619518A1 (fr) * 2005-08-22 2007-03-01 Nycomed Gmbh Derives de benzimidazole a substitution isotopique
WO2007031860A1 (fr) * 2005-09-15 2007-03-22 Pfizer Japan Inc. Benzimidazoles substitués par un indane et leur emploi en tant qu’inhibiteurs de la pompe à acide
WO2007072142A2 (fr) * 2005-12-19 2007-06-28 Pfizer Japan Inc. Dérivés de benzimidazole-5-carboxamide
EP1963311B1 (fr) 2005-12-19 2010-06-16 RaQualia Pharma Inc Benzimidazoles substitues par des chromanes et leur utilisation en tant qu'inhibiteurs de la pompe a protons
KR20190057569A (ko) * 2017-11-20 2019-05-29 제일약품주식회사 7-아미노-1h-인돌-5-카르복사미드 유도체 및 이의 용도
WO2024087155A1 (fr) * 2022-10-28 2024-05-02 深圳市华先医药科技有限公司 Procédé de synthèse de 4-hydroxy-n, n, 2-triméthylbenzimidazole-6-carboxamide

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SE8604566D0 (sv) * 1986-10-27 1986-10-27 Haessle Ab Novel compunds
IL108520A (en) * 1993-02-15 1997-09-30 Byk Gulden Lomberg Chem Fab 2, 3, 8-TRISUBSTITUTED IMIDAZO £1, 2-a| PYRIDINE DERIVATIVES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP0774462A4 (fr) * 1994-08-03 1997-10-29 Fujisawa Pharmaceutical Co Compose heterocyclique
SE9602286D0 (sv) * 1996-06-10 1996-06-10 Astra Ab New compounds
AR043063A1 (es) * 2002-12-13 2005-07-13 Altana Pharma Ag Bencimidazoles 6-sustituidos y su uso como inhibidores de secreciones gastricas

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WO2005111000A1 (fr) 2005-11-24
AR049168A1 (es) 2006-07-05

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