WO2008015196A1

WO2008015196A1 - 5-,7-bis-substituted imidazo[1,2-a]pyridines

Info

Publication number: WO2008015196A1
Application number: PCT/EP2007/057849
Authority: WO
Inventors: Christof Brehm; Peter Jan Zimmermann; Wilm Buhr; Andreas Palmer; Maria Vittoria Chiesa; Martin Feth; Hans Christof Holst; Wolfgang-Alexander Simon; Stefan Postius; Wolfgang Kromer
Original assignee: Nycomed Gmbh
Priority date: 2006-07-31
Filing date: 2007-07-30
Publication date: 2008-02-07

Abstract

The invention provides compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.

Description

Title

5-,7-BIS-SU BSTITUTED IMIDAZO[1 ,2-A]PYRIDINES

Technical field

The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.

Background Art

In the US patent US 4,450,164 (corresponding to EP0068378), imidazo[1 ,2-a]pyridiπes having a broad variety of substituents are disclosed, which are said to be active as anti-ulcer agents. In the US patent US 4,358,453, 1,2,4-triazolo[4,3-a]pyridines are disclosed, which are said to be active as anti-ulcer agents.

In the international patent application WO 02/080911, 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.

In the international patent application WO 01/38326, 3-phenylimidazo[1,2-a]pyridine derivatives are disclosed as selective ligands for GABA_A receptors.

In the international patent application WO 04/076452, 5,8-difluoroimidazo[1 ,2-a]pyridine derivatives are disclosed as GABA_A ligands.

In the international patent applications WO2005/077947, WO2005/070927 and WO2006/061380, compounds are provided that inhibit the secretion of gastric acid.

In the international patent application WO2004/046144, 8-substituted imidazopyridines are described that have gastric secretion inhibiting and gastric and intestinal protective action properties. In the international patent application WO99/055706, imidazo pyridine derivatives are disclosed 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.

In the international patent application WO2005/089763, imidazopyridinβ and imidazopyrimidine derivatives as well as pharmaceutically acceptable compositions comprising them are disclosed which can be used in a variety of applications including use as antibacterial agents. Disclosure of invention

Technical problem

A whole series of compounds are known from the prior art which inhibit gastric acid secretion by blockade of the H+/K+-ATPase. The compounds designated as proton pump inhibitors (PPI^'s), for example omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, bind irreversibly to the H+/K+-ATPase. PPI^'s are available as therapeutics for a long time already. A new class of compounds designated as reversible proton pump inhibitors (rPPI^'s), as acid pump antagonists (APA^'s) or as potassium competitive acid blockers (P-CAB^'s) bind reversibly to the H+/K+- ATPase. Although rPPI^'s, APA^'s and P-CAB^'s are known for more than 20 years and many companies are engaged in their development, rPPIs, APAs or P-CABs are at present only very limited available for therapy. The technical problem underlying the present invention is therefore to provide acid pump antagonists which can be used in therapy.

Technical solution

The invention relates to compounds of the formula 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-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-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, 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-1-4C-alkoxy, fluoro-1-4C- alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy, cyano, the group -CO-NR31 R32, the group SO₂- 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, halogen, fluoro-1-4C-alkyl or hydroxy, 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,

Y has either the meaning -CH₂-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

wherein

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 and

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 di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,

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-alkylamino-I^C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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.

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. Thus, 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 (-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 (CH₃O-C(O)-) and the ethoxycarbonyl group (CH₃CH₂O-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 (CH₃-O-CH₂-CH₂-O-) and 2-(ethoxy)ethoxy (CH₃-CH₂-O-CH₂-CH₂-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 (CH₃-O-CH₂-CH₂-O-CH₂-) and the 2- (ethoxy)ethoxymethyl (CH₃-CH₂-O-CH₂-CH₂-O-CH₂-) 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 (CH₃-O-CH₂-CH₂-O-CH₂-O-) and the 2- (ethoxy)ethoxymethoxy (CH₃-CH₂-O-CH₂-CH₂-O-CH₂-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. Examples of 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. Examples of 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. Examples of 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-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. 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 (C₃H₇C(O)NH-) and the acetylamino group (acetamido group) (CH₃C(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 [C₃H₇C(O)N(CH₃)-] or methyl-acetylamino [CH₃C(O)N(CH₃)-] 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 [C₂H₅O-C(O)-N(CH₃)-] or methyl- methoxycarbonylamino [CH₃O-C(O)-N(CH₃)-] 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 (CH₃-O-CH₂CH₂-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH₃CH₂-O-CH₂CH₂- 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 (CH₃CO-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 (CH₃CO-O-CH₂).

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. Examples of 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.

Examples of 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), methanesulfonic acid (forming mesilate salts), benzenesulfonic acid (forming besilate salts), laurylsulfonic acid, or (4) other acids like ascorbic acid. In the salt preparation, the acids are employed in an equimolar ratio or in a ratio differing therefrom, depending on whether the acid is a mono- or polybasic acid and on which salt is desired.

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. 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. In this manner, 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.

It is known to the person skilled in the art that the compounds according to the invention and their salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents. 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.

If specific compounds have one, two or more centres of chirality, 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. Preferably, 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. For enantiomeric mixtures 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. Alternatively, derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group. Further- more, 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

X is O (oxygen),

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,

Among the compounds of the formula 1 , 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, and

Y has either the meaning -CH₂-Ar wherein

(9P)

wherein

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,

R6 is hydrogen, 1-4C-alkyl or halogen and

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 di-I^C-alkylamino-I^C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy,

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-alkylamino-1-4C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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.

In one aspect (aspect a), 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-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, 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-1-4C-alkoxy, fluoro-1-4C- alkoxy, fluoro-1-4C-alkoxy-1-4C-alkoxy, cyano, the group -CO-NR31 R32, the group SO₂- 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

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, halogen, fluoro-1-4C-alkyl or hydroxy,

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, and

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

R6 is hydrogen, 1-4C-alkyl or halogen and

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.

In another aspect (aspect b), the invention relates to compounds of the formula 1-2

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-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-alkylcarbonylamino, 1-4C- alkoxycarbonylamino or (1-4C-alkyl)-1-4C-alkoxycarbonylamino,

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 SO₂- NR31 R32 or the group Het, 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

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, and

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 di-I^C-alkylamino-I^C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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-alkylamino-1-4C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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.

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.

Among the compounds of the formula 1-1 , preferred compounds are those of formula 1-1-1

)

in which 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

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, and

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.

Among the compounds of the formula 1-2, preferred compounds are those of formula 1-2-1

)

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and

R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen or 1-4C-alkyl,

X is O (oxygen) or NH, and

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-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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.

Among the compounds of the formula 1-1 , particularly preferred compounds are those of formula 1-1-1 , in which

R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

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, and the salts of these compounds.

Among the compounds of the formula 1-2, particularly preferred compounds are those of formula 1-2-1 , in which

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 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, and

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.

Among the compounds of the formula 1-2-1 , particularly preferred compounds are optically pure compounds of formula 1-2-1-a,

(1 -2-1 -a) 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

R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen,

X is O (oxygen) or NH, and

Emphasis is given to compounds of the formula 1-1-1 , in which

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, and the salts of these compounds.

Preference is given to aspect a according to the invention. Particularly preferred compounds are those of the formula 1-1-1.

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.

Table A:

)

Abbreviations: Me = CH₃, Et = C₂H₅

Further exemplary preferred compounds according to the invention are those compounds of the formula 1-2-1-a, wherein R1 , R2, R3 and X have the meanings as given in Table B, and the salts of these compounds. Further exemplary preferred compounds according to the invention are those compounds of the formula 1-2-1-b, wherein R1 , R2, R3 and X have the meanings as given in Table B, 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.

Table B:

(1 -2-1 -a) (1-2-1-b) with R8 = hydroxy and with R8 = hydroxy and with R4 = R5 = H with R4 = R5 = H

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 .

Scheme 1

Ru-catalyst

Y-XH (base)

(1 )

Compounds of the formula 2, wherein Lg is a suitable leaving group, for example a halogen atom like chlorine, can react with α-halogen substituted carbonyl compounds of the general formula 3 (Hal is chlorine or bromine) under conditions known to the expert forming imidazo[1 ,2-a]pyridines of the formula 4, as described for example in CW. Rees, D.I. Smith, J. Chem. Soc. Perkin Trans. 1 , 1987; 1159- 1164. Alternatively, it is possible to obtain imidazo[1 ,2-a]pyridines of the formula 4 starting with 2- aminopyridines of the formula 2 by reaction with 1 ,2-dihydroxy compounds of the general formula 3a in the presence of a ruthenium-catalyst in analogy as described for example in T. Kondo, S. Kotachi, S. Ogino, Y. Watanabe, Chem. Lett., 1993, 1317-1320. The group Lg in compounds of the general formula 4 can be replaced by a group Y-X by nucleophilic aromatic substitution reactions using amino compounds Y-NH2 (X=NH) or alcohols Y-OH (X=O (oxygen)) in the presence of a base (e.g. sodium hydride or potassium hydroxide). The compounds of the general formula 1-1 with X = NH (1a-1 ) can be obtained alternatively according to the reaction sequence as shown in scheme 2.

Scheme 2

Starting with 2,6-diaminopyridines of the formula 5, 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. The reaction of compounds of the general formula 6 with α-halogen substituted carbonyl compounds of the general formula 3 leads to the desired imidazo[1 ,2- a]pyridines of the formula 1a-1.

The 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 α-halogen substituted carbonyl compounds of the general formula 3 and subsequent alkylation delivers the desired compounds of the formula 1a-1 as well.

Compounds of the formula 6 can also be synthesized by a reaction sequence as shown in scheme 3. Starting with 2,6-dichloropyridine derivatives of the formula 8, arylmethyl-substituted monoaminopyri- dine derivatives of formula 9 can be synthesized in analogy, for example as described in patent application DE 2459051. Compounds of the formula 9 subsequently can be transformed to compounds of formula 6 by methods known to a person skilled in the art, for example by using aqueous ammonia in the presence of a metal, like for example copper. Scheme 3

(8) (9) (6)

In the same way as illustrated in schemes 2 and 3, it is possible to synthesize imidazo[1 ,2-a]pyridines of the formula 1-1 with X = O (oxygen) (1 b-1 ). Scheme 4 summarizes this synthetic pathway. Starting with 2,6-dihalogenesubstituted (Hal = chloro or bromo) pyridine derivatives of formula 10 (preferably with dichloropyridine derivatives of formula 8), the two halogene atoms can be substituted stepwise, first by an arylmethyloxy group (by reaction with the corresponding alcohol in the presence of a base, as for example sodium hydride or potassium carbonate) and finally by an amino group (for example by reaction with aqueous ammonia in the presence of copper). Reaction of the resulting compounds of the formula 12 with α-halogen substituted carbonyl compounds of the general formula 3 delivers the desired imidazo[1 ,2-a]pyridines of the formula 1-1 with X = O (oxygen) (1 b-1 ).

Scheme 4

o

Ar

(1 b-1 )

The compounds of the general formula 1-2-1 can be obtained for example by reacting substituted imi- dazo[1 ,2-a]pyridines of the general formula 13 (in case of X = NH, compounds of the general formula 13 are identical with compounds of the general formula 7) with epoxyindanes or 1a,2,3,7b-te- trahydronaphtho[1 ,2-b]oxirenes. In scheme 5, the reaction mode is exemplified for optically pure ep- oxyindanes of the formula 14 carrying any desired substituent R4 and R5, which leads to the preferred compounds of the formula 1-2-1 -a with R8 = hydroxy.

(13) (14) (1-2-1 -a) with R8 = hydroxy

Starting from the corresponding optically pure epoxide stereoisomer of 14, the corresponding stereoisomers of the formula 1-2-1-b can be obtained.

(1-2-1-b) with R8 = hydroxy and with R4 = R5 = H

Starting compounds of the formula 2 are known, for example from Temple et al., J. Heterocycl. Chem. 1970, 7, 451 or can be prepared in an analogous manner. α-Halogen substituted carbonyl compounds are commercially available or can be prepared (e.g. for 3- bromo-4-phenyl-butane-2-one) as described in T. Aoyama, T. Takido, M. Kodomari, Tetrahedron Lett. 2004, 45, 9, 1873 - 1876.

2,6-Diaminopyridines of the formula 5 are known, for example from B. Brodbeck, B. Pϋllmann, 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. In general, substituted epoxyindanes can be prepared from the corresponding substituted indenes by methods known from the literature (e.g. epoxidation). Compounds of the general formula 13-2 - with X = O (oxygen) - can be prepared as illustrated in scheme 6.

Scheme 6

(4) (15)

deprotection

(13-2)

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.

The 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) is likewise carried out in a manner known per se. If for example compounds of the formula 1 where R3 = -CO-1-4C-alkoxy or R3 = -CO-NR31 R32 are desired, an appropriate derivatization can be performed in a manner known per se (e. g. metal catalyzed carbonylation of the corresponding halogen, for example chloro, compound or conversion of an ester or a carboxylic acid into an amide) for example at the stage of compounds of the formula 4, 6 or 7 or preferably at the stage of compounds of the formula 1-1 or 1-2 respectively (scheme 1 , 2, 4 and scheme 5). If compounds of the formula 1 are desired where 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 person skilled in the art knows on the basis of his/her knowledge and on the basis of those synthesis routes, which are shown and described within the description of this invention, how to find other possible synthesis routes for compounds according to this invention. All synthesis routes described herein as well as all other possible synthesis routes are also part of this invention.

The present invention thus further relates to a process for preparation of compounds of formula 1a-1 ,

comprising a reaction of a compound of the general formula 6 with a α-halogen substituted carbonyl compound of the general formula 3, wherein Hal is chloro or bromo,

with the substituents R1 , R2, R3 and Ar having the meanings as defined for the compounds according to the invention.

The present invention further relates to a process for conversion of a compound of formula 1 into another compound of formula 1 ,

comprising either

(a) converting a compound of formula 1 , wherein R3 is 1-4C-alkoxycarbonyl or carboxyl, into another compound of formula 1 , wherein R3 is -CO-NR31 R32, with the substituents R1 , R2, R31 , R32, X and Y having the meanings as defined for the compounds according to the invention, or

(b) converting a compound of formula 1 , wherein R1 and/or R2 is hydrogen, into another compound of formula 1 , wherein R1 and/or R2 are different from hydrogen but have the meanings as as defined for the compounds according to the invention, by an aromatic substitution reaction optionally followed by further derivatizations, with the substituents R3, X and Y having the meanings as defined for the compounds according to the invention.

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.

(6) (12)

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.

(13) Advantageous effects

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.

Testing of the secretion-inhibiting action on the perfused rat stomach

In Table C which follows, the influence of the compounds of the formula 1 according to the invention on the pentagastrin-stimulated acid secretion of the perfused rat stomach after intraduodenal administration in vivo is shown.

Table C

Methodology

The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m. urethane) was opened after tracheotomy by a median upper abdominal incision and a PVC catheter was fixed transorally in the esophagus and another via the pylorus such that the ends of the tubes just projected into the gastric lumen. The catheter leading from the pylorus led outward into the right abdominal wall through a side opening.

After thorough rinsing (about 50-100 ml), warm (37⁰C) physiological NaCI solution was continuously passed through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glass electrode EA 147; φ = 5 mm, Metrohm) and, by titration with a freshly prepared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI were determined in the effluent in each case collected at an interval of 15 minutes.

The gastric secretion was stimulated by continuous infusion of 1 μg/kg (= 1.65 ml/h) of i.v. pentagastrin (left femoral vein) about 30 min after the end of the operation (i.e. after determination of 2 preliminary fractions). 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 37.8-38⁰C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).

Mode(s) for Carrying Out the Invention

The examples below serve to illustrate the invention in more detail without limiting it. Further compounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary process techniques. The compounds named expressly as examples, and the salts of these compounds, are preferred subject matter of the invention. The abbreviation min stands for minute(s), h stands for hour(s), m.p. stands for melting point and ee for enantiomeric excess.

1. Final Compounds of the formula 1

2. Methyl 5-[(2,6-dimethylbenzyl)amino]-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate hydrochloride

Chloroacetone (0.46 ml, 5.40 mmol) was added to a solution of methyl 2-amino-6-[(2,6-dimethyl- benzyl)amino]isonicotinate (515 mg, 1.80 mmol) in methanol (30 ml). The reaction mixture was re- fluxed for 3 days. The solvent was removed and the residue was recrystallized from diisopropylether / dichloromethane to afford 0.57 g (90%) of the title compound as a beige solid, m.p. 230-234⁰C (decomposition).

3. Methyl 5-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1 ,2-a]pyridine-7-carboxylate

3-Bromo-2-butanone (4.50 ml, 42.0 mmol) was added to a solution of methyl 2-amino-6-[(2,6-dimethyl- benzyl)amino]isonicotinate (3.43 g, 12.0 mmol) in methanol (175 ml). The reaction mixture was re- fluxed for 5 days. The solvent was removed and the residue was purified by column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) yielding a brown solid which was recrystallized from diisopropylether to afford 1.88 g (46%) of the title compound as a beige solid. 1H-NMR (200 MHz, d₆-DMSO): δ = 7.48 (s, 1 H), 7.20-7.00 (m, 3H), 6.59 (s, 1 H), 6.04 (t, 1 H), 4.32 (d, 2H), 3.90 (s, 3H), 2.64 (s, 3H), 2.41 (s, 6H), 2.30 (s, 3H).

4. 5-[(2,6-Dimethylbenzyl)amino]-Λ/,2,3-trimethylimidazo[1,2-a]pyridine-7-carboxamide

S-^.θ-DimethylbenzyOaminol^.S-dimethylimidazoti ^-alpyridine^-carboxylic acid: An aqueous solution of lithium hydroxide (6N) (2.50 ml, 15 mmol) was added to the suspension of methyl 5-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1 ,2-a]pyridine-7-carboxylate (1.69 g, 5.00 mmol) in the solvent mixture of dioxane (70 ml) and water (20 ml). The reaction mixture was stirred at a temperature of 100⁰C for 2.5 h and at room temperature for 18 h. By adding an aqueous solution of hydrochloric acid (6N), the reaction mixture was neutralized (pH 5-6) and concentrated in vacuo. The obtained white solid (2.39 g) was a mixture of the desired carboxylic acid and inorganic salts, e.g. sodium chloride. It was used in the next step without further purification.

5-[(2,6-Dimethylbenzyl)amino]-N,2,3-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide: The crude product of the saponification step described above (0.72 g, 1.50 mmol) was suspended in the solvent mixture of dichloromethane (25 ml) and dimethylformamide (4 ml). O-(1 H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (0.73 g, 2.25 mmol) was added and the reaction mixture was stirred at a temperature of 45⁰C (oil bath) for 90 min, a brown suspension resulted. A solution of methyl amine in tetrahydrofuran (2M) (3.00 ml, 6.00 mmol) was added and the resulting suspension was stirred at a temperature of 45⁰C (oil bath) for 2 h. The reaction mixture was poured onto ice-cold water (150 ml), a small amount of a saturated sodium bicarbonate solution was added (pH 4), and the aqueous phase was extracted with dichloromethane. The collected organic layers were washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethylacetate:methanol:ammonia (20:1 :3%, v/v/v) yielding a brown solid which was dissolved in hot isopropanol, cleared by addition of charcoal, and after filtration and removing of the solvent recrystallized from dichloro- methane/diisopropanol to afford 0.10 g (20%) of the title compound as a beige solid. 1 H-NMR (200 MHz, d6-DMSO): δ = 8.44 (d, 1 H), 7.37 (s, 1 H), 7.18-7.01 (m, 3H), 6.45 (s, 1 H), 5.59 (t, 1 H), 4.25 (d, 2H), 2.80 (d, 3H), 2.59 (s, 3H), 2.40 (s, 6H), 2.21 (s, 3H).

5. 5-[(2,6-Dimethylbenzyl)amino]-N,2-dimethylimidazo[1,2-a]pyridine-7-carboxamide

S-^θ-Dimethylbenzy^aminol^-methylimidazoti ^-alpyridine^-carboxylic acid: An aqueous solution of lithium hydroxide (6N) (7.51 ml, 45 mmol) was added to the suspension of methyl 5-[(2,6-dimethylbenzyl)amino]-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate hydrochloride (4.80 g, 13.34 mmol) in the solvent mixture of dioxane (125 ml) and water (40 ml). The reaction mixture was stirred at a temperature of 100⁰C for 2.5 h and at room temperature for 18 h. By adding an aqueous solution of hydrochloric acid (6N), the reaction mixture was neutralized (pH 5-6) and concentrated in vacuo. The obtained white solid (7.85 g) was a mixture of the desired carboxylic acid and inorganic salts, e.g. sodium chloride. It was used in the next step without further purification.

5-[(2,6-Dimethylbenzyl)amino]-Λ/,2-dimethylimidazo[1 ,2-a]pyridine-7-carboxamide: The crude product of the saponification step described above (1.30 g, 2.21 mmol) was suspended in the solvent mixture of dichloromethane (45 ml) and dimethylformamide (7 ml). O-(1 H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (1.22 g, 3.75 mmol) was added and the reaction mixture was stirred at a temperature of 45⁰C (oil bath) for 90 min, a brown solution resulted. A solution of methyl amine in tetrahydrofuran (2M) (5.00 ml, 10.00 mmol) was added and the resulting suspension was stirred at a temperature of 45⁰C (oil bath) for 1 h and at room temperature for 18 h. The reaction mixture was poured onto ice-cold water (400 ml), a small amount of a saturated sodium bicarbonate solution was added (pH 4), and the aqueous phase was extracted with dichloromethane. The collected organic layers were washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) yielding a brown solid which was recrystallized from dichloro- methane/methanol to afford 0.48 g (67%) of the title compound as a beige solid. 1H-NMR (200 MHz, d₆-DMSO): δ = 8.48 (s, 1 H), 7.90 (s, 1 H), 7.36 (s, 1 H), 7.18-7.04 (m, 3H), 6.49 (t, 1 H), 6.46 (s, 1 H), 4.41 (d, 2H), 2.82 (d, 3H), 2.36 (s, 6H), 2.30 (s, 3H).

Starting from methyl 5-[(2,6-dimethylbenzyl)amino]-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate hydrochloride, the following compounds were synthesized following the procedure as described above for the synthesis of 5-[(2,6-dimethylbenzyl)amino]-Λ/,2-dimethylimidazo[1 ,2-a]pyridine-7-carboxamide: 6. 5-[(2,6-Dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2-methylimidazo[1,2-a]pyridine-7- carboxamide

Using pure 2-hydroxyethyl amin instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) and recrystallization from diisopropyl ether, 0.42 g (54%) of the title compound were obtained as pale brown solid. 1H-NMR (200 MHz, d₆-DMSO): δ = 8.48 (t, 1 H), 7.89 (s, 1 H), 7.39 (s, 1 H), 7.25-7.03 (m, 3H), 6.54-6.41 (m, 2H), 4.73 (t, 1 H), 4.41 (d, 2H), 3.61-3.46 (m, 2H), 3.40-3.24 (m, 2H), 2.36 (s, 6H), 2.30 (s, 3H).

7. 5-[(2,6-Dimethylbenzyl)amino]-2-methylimidazo[1,2-a]pyridine-7 -carboxamide

Using an aqueous solution of ammonia (25%) instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) and re- crystallization from dichloromethane/methanol, 0.50 g (73%) of the title compound were obtained as pale red solid.

¹H-NMR (200 MHz, d₆-DMSO): δ = 8.02 (s, 1 H), 7.90 (s, 1 H), 7.42 (s, 1 H), 7.37 (s, 1 H), 7.22-7.05 (m, 3H), 6.50-6.40 (m, 2H), 4.41 (d, 2H), 2.36 (s, 6H), 2.30 (s, 3H).

8. 5-[(2,6-Dimethylbenzyl)amino]-N-(2-hydroxypropyl)-2-methylimidazo[1,2-a]pyridine-7- carboxamide

Using pure 2-hydroxypropyl amine instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) and recrystallization from dichloromethane/diisopropyl ether, 0.47 g (58%) of the title compound were obtained as beige solid.

¹H-NMR (200 MHz, d₆-DMSO): δ = 8.45 (t, 1 H), 7.90 (s, 1 H), 7.40 (s, 1 H), 7.22-7.03 (m, 3H), 6.54-6.40 (m, 2H), 4.74 (d, 1 H), 4.42 (d, 2H), 3.97-3.70 (m, 1 H), 3.23 (t, 2H), 2.36 (s, 6H), 2.30 (s, 3H), 1.09 (d, 3H).

9. 5-[(2,6-Dimethylbenzyl)amino]-N,N,2-trimethylimidazo[1,2-a]pyridine-7 -carboxamide

Using a solution of dimethyl amine in tetrahydrofuran (2M) instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) and recrystallization from ethyl acetate/diisopropyl ether, 0.11 g (71 %) of the title compound were obtained as pale brown-red solid.

¹H-NMR (200 MHz, CDCI₃): δ = 7.25-7.00 (m, 5H), 6.17 (s, 1 H), 4.44 (d, 2H), 3.79 (t, 1 H), 3.13 (s, 6H), 2.42 (s, 3H), 2.41 (s, 6H).

10. 7-(Azetidin-1-ylcarbonyl)-N-(2,6-dimethylbenzyl)-2-methylimidazo[1,2-a]pyridin-5-amine

Using pure azetidine instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using toluene:dioxane:methanol (12:7:1 , v/v/v) and recrystallization from dichloromethane/diisopropyl ether, 0.11 g (47%) of the title compound were obtained as pale brown solid. ¹H-NMR (200 MHz, CDCI₃): δ = 7.25-7.03 (m, 5H), 6.51 (s, 1 H), 4.52-4.38 (m, 4H), 4.30-4.21 (m, 2H), 3.81-3.73 (m, 1 H), 2.44 (s, 3H), 2.40-2.31 (m, 8H).

11. N-(2,6-Dimethylbenzyl)-2-methyl-7-(morpholin-4-ylcarbonyl)imidazo[1 ,2-a]pyridin-5- amine

Using pure morpholine instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using dichloromethan:methanol (20:1 , v/v) and recrystallization from diisopro- pyl ether, 0.66 g (65%) of the title compound were obtained as pale brown solid. 1H-NMR (200 MHz, CDCI₃): δ = 7.23-7.01 (m, 5H), 6.17 (s, 1 H), 4.45 (d, 2H), 3.88 (t, 1 H), 3.85-3.55 (m, 8H), 2.43 (s, 3H), 2.41 (s, 6H).

12. N-(2,6-Dimethylbenzyl)-2-methyl-7-(pyrrolidin-1-ylcarbonyl)imidazo[1 ,2-a]pyridin-5- amine

Using pure pyrrolidine instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using dichloromethan:methanol (20:1 , v/v) and recrystallization from diisopro- pyl ether, 0.59 g (60%) of the title compound were obtained as pale brown solid. 1H-NMR (200 MHz, CDCI₃): δ = 7.24-7.01 (m, 5H), 6.31 (s, 1 H), 4.46 (d, 2H), 3.88 (t, 1 H), 3.73-3.48 (m, 4H), 2.43 (s, 3H), 2.40 (s, 6H), 2.08-1.80 (m, 4H).

13. N-cyclopropyl-5-[(2,6-dimethylbenzyl)amino]-2-methylimidazo[1,2-a]pyridine-7- carboxamide

14. 5-[(2,6-dimethylbenzyl)amino]-N,2-dimethyl-N-(2-hydroxyethyl)- imidazo[1,2-a]pyridine-7- carboxamide

Using pure 2-(methylamino)ethanol instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using dichloromethan:methanol (15:1 , v/v) and recrystallization from isopropanol/diisopropyl ether, 0.47 g (48%) of the title compound were obtained as pale brown solid.

¹H-NMR (200 MHz, CDCI₃): δ = 7.28-7.01 (m, 5H), 6.20 (s, 1 H), 4.44 (d, 2H), 4.08-3.53 (m, 5H), 3.17

(s, 3H), 2.40 (s, 9H), 2.33-2.14 (m, 1 H). 15. 5-[(2,6-dimethylbenzyl)amino]-N,2-dimethyl-N-(2-hydroxypropyl)- imidazo[1,2-a]pyridine- 7-carboxamide

Using pure 1-(methylannino)propan-2-ol instead of a solution of methyl amine in tetrahydrofuran and after column chromatography on silica gel using dichloromethan:methanol (20:1 , v/v) and recrystalliza- tion from diisopropyl ether, 0.68 g (67%) of the title compound were obtained as pale brown solid. ¹H-NMR (200 MHz, CDCI₃): δ = 7.27-7.01 (m, 5H), 6.20 (s, 1 H), 4.45 (d, 2H), 4.32-4.08 (m, 1 H), 3.97- 3.85 (m, 1 H), 3.72-3.55 (m, 1 H), 3.44-3.28 (m, 1 H), 3.18 (s, 3H), 2.42 (s, 3H), 2.41 (s, 6H), 1.97 (br s, 1 H), 1.36-1.15 (m, 3H).

16. 5-(Benzylamino)-N,N,2-trimethylimidazo[1,2-a]pyridine-7-carboxamide oxalate

To the solution of 5-chloro-N,N,2-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide (480 mg, 2.00 mmol) in N-methyl-2-pyrrolidinone (12 ml) were added potassium carbonate (1.40 g, 10 mmol) and benzylamine (1.12 ml, 10 mmol). The reaction mixture was heated to 200⁰C for 18 h and, after cooling down to room temperature, poured onto ice water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water, dried (MgSO4), and the solvent was removed in vacuo. The residue, still containing N-methyl-2-pyrrolidinone, was purified by column chromatography on silica gel using dichloromethane:methanol (15:1 , v/v) to afford 370 mg of a brown oil as crude product. The oil was dissolved in acetone (10 ml) and by adding a solution of oxalic acid (110 mg, 1.2 mmol) in acetone (2 ml) the title compound was precipitated as pale yellow crystals. Stirring at O⁰C for 30 min, filtering off and drying at 4O⁰C in vacuo delivered 290 mg (36%) of the title compound. ¹H-NMR (200 MHz, d₆-DMSO): δ = 7.91 (s, 1 H), 7.77 (t, 1 H), 7.50-7.22 (m, 5H), 7.0-5.5 (br s, 2H, oxalate), 6.83 (s, 1 H), 5.87 (s, 1 H), 4.58 (d, 2H), 2.90 (br s, 3H), 2.77 (br s, 3H), 2.39 (s, 3H).

17. N,N,2-Trimethyl-5-[(2-methylbenzyl)amino]-imidazo[1,2-a]pyridine-7-carboxamide oxalate

To the solution of 5-chloro-N,N,2-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide (600 mg, 2.50 mmol) in N-methyl-2-pyrrolidinone (25 ml) were added potassium carbonate (1.75 g, 12.5 mmol) and benzylamine (1.62 ml, 12.5 mmol). The reaction mixture was heated to 200⁰C for 18 h and, after cooling down to room temperature, poured onto ice water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water, dried (MgSO4), and the solvent was removed in vacuo. The residue, still containing N-methyl-2-pyrrolidinone, was purified by column chromatography on silica gel using dichloromethane:methanol (15:1 , v/v) to afford 300 mg of a brown oil as crude product. The oil was dissolved in hot isopropanol (5 ml), a solution of oxalic acid (85 mg, 1.2 mmol) in hot isopropanol (3 ml) was added, and by adding diisopropyl ether the title compound was precipitated as pale brown crystals. Stirring at O⁰C for 30 min, filtering off and drying at 4O⁰C in vacuo delivered 230 mg (22%) of the title compound.

¹H-NMR (200 MHz, d₆-DMSO): δ = 8.00 (s, 1 H), 7.70 (t, 1 H), 7.30-7.06 (m, 4H), 6.89 (s, 1 H), 5.99 (s, 1 H), 4.55 (d, 2H), 2.92 (br s, 3H), 2.83 (br s, 3H), 2.41 (s, 3H), 2.36 (s, 3H). (Oxalate protons not observed.) I. Starting Compounds

A. Methyl 5-amino-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate

To the solution of methyl 2,6-diaminoisonicotinate (168 mg, 1.00 mmol) in methanol (12 ml) was added chloroacetone (252 μl, 3 mmmol). The reaction mixture was heated to reflux for 4 days. The solvent was removed, the obtained residue was dissolved in water, and the aqueous solution was neutralized using a saturated aqueous solution of sodium bicarbonate (pH 8). The resulting precipitate was filtered off, washed with water, and dried at 4O⁰C in vacuo for 18 h to obtain 170 mg (83%) of the title compound as white crystals, m.p. 175-178⁰C.

B. Methyl 5-amino-2,3-dimethylimidazo[1 ,2-a]pyridine-7-carboxylate

To the solution of methyl 2,6-diaminoisonicotinate (1.01 g, 6.00 mmol) in methanol (105 ml) was added 3-bromobutan-2-one (0.96 ml, 9 mmmol). The reaction mixture was heated to reflux for 20 h. Further 3- bromobutan-2-one (0.96 ml, 9 mmmol) were added and stirring at reflux temperature was continued for 3 days. The solvent was removed, the obtained residue was dissolved in water, the aqueous solution was neutralized using a saturated aqueous solution of sodium bicarbonate (pH 8) and extracted with dichloromethane. The combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate and water, dried (MgSO₄), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using toluene:dioxane (2:1 , v/v) to afford 0.82 g (63%) of the title compound as a pale brown solid, m.p. 208-212°C.

C. Methyl 2-amino-6-[(2,6-dimethylbenzyl)amino]isonicotinate

Sodium carbonate (13.8 g, 129 mmol) and sodium iodide (19.5 g, 129 mmol) were added to the solution of methyl 2,6-diaminoisonicotinate (14.4 g, 86 mmol) in acetone (1100 ml). After stirring for 15 min, the solution of 2-(chloromethyl)-1 ,3-dimethylbenzene (16.3 g, 103 mmol) in acetone (50 ml) was added slowly (about 30 min). The resulting suspension was stirred at room temperature for 1 h and at reflux temperature for 4 h. Most of the solvent was removed, the residue poured onto water, and the aqueous mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried (MgSO₄), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using toluene:dioxane (10:1 , v/v) to afford 6.65 g (27%) of the title compound as a pale brown solid, m.p. 138-141⁰C.

D. Methyl 5-chloro-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate hydrobromide

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. After stirring at reflux for 20 h, 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.

¹H-NMR (200 MHz, d₆-DMSO): δ = 8.29 (s, 1 H), 8.25 (s, 1 H), 7.83 (s, 1 H), 6.14 (br s), 3.95 (s, 3H), 2.53 (s, 3H). E. 5-chloro-N,N,2-trimethylimidazo[1,2-a]pyridine-7-carboxamide

5-chloro-2-nnethylinnidazo[1 ,2-a]pyridine-7-carboxylic acid:

An aqueous solution of lithium hydroxide (6N) (22.10 ml, 133 mmol) was added to the suspension of methyl 5-chloro-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate hydrobromide D (13.50 g, 44.2 mmol) in the solvent mixture of dioxane (400 ml) and water (135 ml). The reaction mixture was stirred at a temperature of 100⁰C for 1.5 h and at room temperature for 18 h. By adding an aqueous solution of hydrochloric acid (6N), the reaction mixture was neutralized (pH 5-6) and concentrated in vacuo. The obtained white solid (17.40 g) was a mixture of the desired carboxylic acid and inorganic salts, e.g. sodium chloride. It was used in the next step without further purification.

5-chloro-N,N,2-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide:

The crude product of the saponification step described above (17.40 g, 44.2 mmol) was suspended in the solvent mixture of dichloromethane (600 ml) and dimethylformamide (75 ml). O-(1 H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (21.4 g, 66.0 mmol) was added and the reaction mixture was stirred at a temperature of 45⁰C (oil bath) for 2.5 h. The reaction was cooled down to room temperature and a solution of dimethyl amine in tetrahydrofuran (2M) (88 ml, 176 mmol) was added. The resulting pale brown suspension was stirred at a temperature of 45⁰C (oil bath) for 1.5 h and at room temperature for 18 h. The reaction mixture was poured onto ice- cold water (2.3 I), a small amount of a saturated sodium bicarbonate solution was added (pH 8-9), and the aqueous phase was extracted with dichloromethane. The collected organic layers were washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (15:1 , v/v) yielding 7.56 g (72%) of the title compound as a yellow oil. 1H-NMR (200 MHz, CDCI₃): δ = 7.59 (s, 1 H), 7.53 (s, 1 H), 7.00 (s, 1 H), 3.11 (s, 6H), 2.51 (s, 3H).

Commercial utility

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 (= active compounds according to the invention) 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. In this connection, 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. The term "gastrointestinal diseases" is understood to include, according to general knowledge,

A) gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation and/or non-acid regurgitation.

B) other 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).

D) Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases.

E) Furthermore, "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).

In their excellent properties, 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. On account of these properties, 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.

As medicaments, 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%. By means of the appropriate selection of the excipients, it is possible to obtain a pharmaceutical administration form adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained release form or a delayed release form).

The active compounds according to the invention can be administered orally, parenterally (e.g. intravenously), rectally or percutaneously. Oral or intravenous administration is preferred.

The 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. In addition to solvents, antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins), the following excipients may be mentioned as examples: For oral administration, gelling agents, antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g. carriers, fillers, binders, disintegrating agents, lubricants, coating agents); for intravenous administration, dispersants, emulsifiers, preservatives, solubilizers, buffer substances and/or isotonic adjusting substances. For percutaneous administration, the person skilled in the art may choose as excipients, for example: solvents, gelling agents, polymers, permeation promoters, adhesives, matrix substances and/or wetting agents. 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.

In general, it has been proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in 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. In the case of 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. Furthermore, 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. By choosing the appropriate pharmaceutical formulation of the drugs contained in the combination, the drug release profile of the components can be exactly adapted to the desired effect, e.g. the release of one compound and its onset of action is chronologically previous to the release of the other compound. 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. One example of 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. A "kit-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. One example of 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.

To be emphasized in this connection is in particular the combination of the active compounds according to the invention with pharmaceuticals which buffer or neutralize gastric acid (such as, for example, magaldrat, aluminium hydroxide, magnesium carbonate, magnesium hydroxide or other antacids), or especially with pharmaceuticals which inhibit or reduce acid secretion, such as, for example:

(I) histamine-H₂ blockers [e.g. cimetidine, ranitidine], or

(II) proton pump inhibitors [e.g. omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, tenatoprazole, ilaprazole, leminoprazole, all including their salts and enantiomers] or

(III) other potassium-competitive acid blockers [e.g. soraprazan and its stereoisomers, linaprazan, re- vaprazan, all including their salts]), or

(IV) so-called peripheral anticholinergics (e.g. pirenzepine), with gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists).

An important combination to be mentioned is the combination with 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. As suitable antibacterially active combination partner(s) may be mentioned, for example:

(A) cephalosporins, such as, for example, cifuroximaxetil

(B) penicillines, such as, for example, amoxicillin, ampicillin (C) tetracyclines, such as, for example, tetracyline itself, doxycycline

(D) β-lactamase inhibitors, such as, for example, clavulanic acid

(E) macrolide antibiotics, such as, for example, erythromycin, clarithromycin, azithromycin

(F) rifamycines, such as, for example, rifamycine itself

(G) glycoside antibiotics, such as, for example, gentamicin, streptomycin

(H) gyrase inhibitors, such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin (I) oxazolidines, such as, for example, linezolid

(J) 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.

In view of their excellent activity regarding gastric and intestinal protection or cure, 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).

In addition, 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. 3,5-bis(1 ,1-dimethylethyl)-4-hydroxy-β,β-dimethylbenzenepropanol (CGP7930), N, N- dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783)), 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. 2-methyl-6-(phenylethynyl)pyridine hydrochloride), pharmaceuticals modulating (activating) directly or indirectly the cannabinoid (CB) receptor, in particularly the cannabi- noid receptor type 1 (CB1 ), such as, for example, cannabinoid (CB) receptor agonists (e.g. [(3R)-2,3- dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1 ,2,3,de]-1 ,4-benzoxazin-6-yl]-1-naphthalenyl- methanone (WIN55, 212-2), or pharmaceuticals acting as selective cholecystokinin subtype 1 (CCK1 ) receptor antagonists (e.g. loxiglumide).

Pharmaceuticals 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; κ-opiate agonists like fedotozine.

Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis. In some cases, the use of a hypnotic aid (such as, for example, Zolpidem [Bikalm®]) as combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

Claims

ClaimsWe claim:

1. A compound of the formula 1

in which

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, halogen, fluoro-1-4C-alkyl or hydroxy,

X is O (oxygen) or NH,

Y has either the meaning -CH₂-Ar wherein

wherein

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, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or sulfonyl,

R6 is hydrogen, 1-4C-alkyl or halogen and

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 di-I^C-alkylamino-I^C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 'MC-alkoxy-'MC-alkylcarbonyloxy, 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-alkylamino-I^C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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 its salts.

2. A compound as claimed in claim 1 , characterized by 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-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-alkylcarbonylamino, 1-4C- alkoxycarbonylamino or (1-4C-alkyl)-1-4C-alkoxycarbonylamino,

R3 is fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkyl, 1-4C-al koxy- 1-4C-al koxy- 1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy, hydroxy- 1-4C-al koxy, 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 SO₂- 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

X is O (oxygen) or NH, and

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, 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,

R6 is hydrogen, 1-4C-alkyl or halogen and 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, ni- tro, fluoro-1-4C-alkoxy, hydroxy and cyano, and its salts.

3. A compound as claimed in claim 1 , characterized by the formula 1-2

in which

X is O (oxygen) or NH, and

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 di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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- alkoxy-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-alkylamino-I^C-alkylcarbonyloxy, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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 its salts.

4. A compound as claimed in claim 2, characterized by the formula 1-1-1

)

in which

R1 is hydrogen, 1-4C-alkyl, aryl-1-4C-alkyl, 3-7C-cycloalkyl, β-TC-cycloalkyl-I^C-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,

X is O (oxygen) or NH, and

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 its salts.

5. A compound as claimed in claim 3, characterized by the formula 1-2-1

)

in which

R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen or 1-4C-alkyl,

X is O (oxygen) or NH, and

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-alkyl- carbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-I^C-alkylamino-I^C-alkylcarbony- loxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, 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 its salts.

6. A compound of the formula 1-1-1 as claimed in claim 4, in which

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-NR31 R32, 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, and its salts.

7. A compound of the formula 1-2-1 as claimed in claim 5, in which

R3 is carboxyl, 1-4C-alkoxycarbonyl or the group -CO-NR31R32, where

R4 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen,

X is O (oxygen) or NH, and

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 its salts.

8. A compound of the formula 1-1-1 as claimed in claim 4, in which 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, and its salts.

9. A compound of formula 1 , selected from the group consisting of:

Methyl 5-[(2,6-dimethylbenzyl)amino]-2-methylimidazo[1 ,2-a]pyridine-7-carboxylate,

Methyl 5-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1 ,2-a]pyridine-7-carboxylate,

5-[(2,6-Dimethylbenzyl)amino]-N,2,3-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide,

5-[(2,6-Dimethylbenzyl)amino]-N,2-dimethylimidazo[1 ,2-a]pyridine-7-carboxamide,

5-[(2,6-Dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2-methylimidazo[1 ,2-a]pyridine-7-carboxamide,

5-[(2,6-Dimethylbenzyl)amino]-2-methylimidazo[1 ,2-a]pyridine-7-carboxamide,

5-[(2,6-Dimethylbenzyl)amino]-N-(2-hydroxypropyl)-2-methylimidazo[1 ,2-a]pyridine-7-carboxamide,

5-[(2,6-Dimethylbenzyl)amino]-N,N,2-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide,

7-(Azetidin-1-ylcarbonyl)-N-(2,6-dimethylbenzyl)-2-methylimidazo[1 ,2-a]pyridin-5-amine,

N-(2,6-Dimethylbenzyl)-2-methyl-7-(morpholin-4-ylcarbonyl)imidazo[1 ,2-a]pyridin-5-amine,

N-(2,6-Dimethylbenzyl)-2-methyl-7-(pyrrolidin-1-ylcarbonyl)imidazo[1 ,2-a]pyridin-5-amine,

N-cyclopropyl-S-^.θ-dimethylbenzyOaminol^-methylimidazoti ^-alpyridine^-carboxamide,

5-[(2,6-dimethylbenzyl)amino]-N,2-dimethyl-N-(2-hydroxyethyl)- imidazo[1 ,2-a]pyridine-7-carboxamide,

5-[(2,6-dimethylbenzyl)amino]-N,2-dimethyl-N-(2-hydroxypropyl)- imidazo[1 ,2-a]pyridine-7- carboxamide,

5-(Benzylamino)-N,N,2-trimethylimidazo[1 ,2-a]pyridine-7-carboxamide,

N,N,2-Trimethyl-5-[(2-methylbenzyl)amino]-imidazo[1 ,2-a]pyridine-7-carboxamide, and the salts of these compounds.

10. A process for preparation of compounds of formula 1a-1 ,

with the substituents R1 , R2, R3 and Ar having the meanings as defined in any of claims 1 , 2, 4, 6, 8 or 9.

1 1. A process for conversion of a compound of formula 1 into another compound of formula 1 ,

comprising either

(a) converting a compound of formula 1 , wherein R3 is 1-4C-alkoxycarbonyl or carboxyl, into another compound of formula 1 , wherein R3 is -CO-NR31 R32, with the substituents R1 , R2, R31 , R32, X and Y having the meanings as defined in any of claims 1 to 9, or

(b) converting a compound of formula 1 , wherein R1 and/or R2 is hydrogen, into another compound of formula 1 , wherein R1 and/or R2 are different from hydrogen but have the meanings as defined in any of claims 1 to 9, by an aromatic substitution reaction optionally followed by further derivatizations, with the substituents R3, X and Y having the meanings as defined in any of claims 1 to 9.

12. A compound of formula (6) or (12),

(6) (12) with the substituents R3 and Ar having the meanings as defined in any of claims 1 , 2, 4, 6, 8 or 9.

13. A compound of formula (13),

(13) with the substituents R1 , R2, R3 and X having the meanings as defined in any of claims 1 to 9.

14. A medicament comprising a compound as claimed in any of claims 1 to 9 and/or a pharmacologically acceptable salt thereof together with customary pharmaceutical excipients.

15. The use of a compound as claimed in any of claims 1 to 9 and its pharmacologically acceptable salts for the prevention and treatment of gastrointestinal diseases.

16. The use of a compound as claimed in any of claims 1 to 9 and its pharmacologically acceptable salts for the production of medicaments which are employed for the treatment and/or prophylaxis of gastrointestinal diseases.

17. A compound according to any of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis of gastrointestinal diseases.