WO2008084067A2

WO2008084067A2 - Pharmaceutically active dihydrobenzofurane-substituted benzimidazole derivatives

Info

Publication number: WO2008084067A2
Application number: PCT/EP2008/050212
Authority: WO
Inventors: Christof Brehm; Peter Jan Zimmermann; Saskia Zemolka; Andreas Palmer; Wilm Buhr; Stefan Postius; Wolfgang-Alexander Simon; Michael Herrmann
Original assignee: Nycomed Gmbh
Priority date: 2007-01-12
Filing date: 2008-01-10
Publication date: 2008-07-17
Also published as: WO2008084067A3

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

Description Title

PHARMACEUTICALLY ACTIVE DIHYDROBENZOFURANE-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES

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 European patent application 266326 (which corresponds to US Patent 5,106,862), benzimidazole derivatives having a very broad variety of substituents are disclosed, which are said to be active as anti-ulcer agents. In the International Patent Application WO 97/47603 (Astra AB) benzimidazoles with a specific benzyloxy or benzylamino substitution are described.

The International Patent Applications WO 2004-054984 and WO 2006-100254 disclose substituted, bicyclic benzimidazole derivatives which compounds are useful for treating gastrointestinal diseases.

The International Patent Application WO 2004-087701 discloses tricyclic benzimidazole derivatives having different substituents in 5-position of the benzimidazole moiety which compounds are likewise useful for treating gastrointestinal diseases.

The International Patent Applications WO 2005-058893 and WO 2005-103057 disclose tricyclic benzimidazole derivatives having substituents in 6- and 7-position of the tricyclic ring system which compounds are likewise useful for treating gastrointestinal diseases.

The International Patent Application WO 2005-121 139 discloses tricyclic benzimidazole derivatives having substituents in 5-, 6- and 7-position of the tricyclic ring system which compounds are likewise useful for treating gastrointestinal diseases.

The International Patent Applications WO 2006-037748, WO 2006-037759 and WO 2006-100255 disclose further tricyclic benzimidazole derivatives which compounds are likewise useful for treating gastrointestinal disorders.

The International Patent Application WO 2006-134111 discloses spiro-substituted tricyclic benzimidazole derivatives which compounds are likewise useful for treating gastrointestinal disorders. The International Patent Application WO 2006-136552 discloses a process for the synthesis of tricyclic benzimidazole derivatives and furthermore new derivatives of this type of compounds, which are likewise useful for treating gastrointestinal disorders.

The International Patent Applications WO 2006-134460 and WO 2007-072146 disclose chromane- substituted benzimidazole compounds, which are likewise useful for the treatment of gastrointestinal diseases. The International Patent Applications WO 2006-064339, WO 2007-026218 and WO 2007-107827 disclose chromane substituted imidazopyridine derivatives, which are likewise useful for the treatment of gastrointestinal diseases.

The International Patent Application WO 2007-031860 discloses indane-substituted benzimidazole derivatives, which are said to have acid pump antagonistic activity.

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 re- versibly 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, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C- alkyl, 1 -4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1 -4C-alkyl or hydroxy-1 -

4C-alkyl, R2 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, hydroxy-1 -4C-alkyl or fluoro-1 -4C-alkyl, R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, 1 -4C-alkoxycarbonyl, cyano, 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 or the group -CO-NR31 R32 where R31 is hydrogen, hydroxyl, 1 -7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -

4C-alkyl, 1 -4C-alkylcarbonyl-1 -4C-alkyl, 1 -4C-alkylcarbonyl or 1 -4C-alkoxycarbonyl 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 attached, are a pyr- rolidino, 2-hydroxypyrrolidino, 3-hydroxypyrrolidino, piperidino, piperazino, azetidino, 3- hydroxyazetidino, aziridino, N-1 -4C-alkylpiperazino, morpholino, 3-fluoroazetidino, 3,3- difluoroazetidino or 3-(1 -4C-alkoxy)-azetidino group, R4 is hydrogen, halogen, fluoro-1 -4C-alkoxy, cyano, nitro, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-

7C-cycloalkyl-1 -4C-alkyl, 3-7C-cycloalkoxy, 1 -4C-alkoxy, 1 -4C-alkoxy- 1 -4C-alkyl, 1 -4C- alkoxycarbonyl, fluoro-1 -4C-alkyl or hydroxy-1 -4C-alkyl, R5 is hydrogen, halogen, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 3-7C- cycloalkoxy, 1 -4C-alkoxy, 1 -4C-alkoxy-1 -4C-alkyl, 1 -4C-alkoxycarbonyl or hydroxy-1 -

4C-alkyl, and their salts.

1 -4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

3-7C-Cycloalkyl-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclo- hexylethyl group.

1 -4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.

1 -4C-Alkoxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by one of the aforementioned 1 -4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl group, 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 group, the difluoromethyl, the 2-fluoroethyl, the 2,2-difluoroethyl or 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 hydroxymethyl, the 2- hydroxyethyl, the 3-hydroxypropyl, 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 substituted by two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutyl and in particular the 2,3-dihydroxypropyl groups.

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. An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH₃-O-CH₂-CH₂-O-CH₂-).

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 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 trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluoromethoxyethyl radicals.

1 -7C-Alkyl represents straight-chain or branched alkyl groups having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.

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.

1 -4C-Alkylcarbonyl-1 -4C-alkyl represents aforementioned 1 -4C-alkyl groups which are substituted by 1 -4C-alkylcarbonyl group. Examples which may be mentioned are the 2-oxo-propyl, the 2-oxo-butyl, the 2-oxo-pentyl, the 3-oxo-butyl or the 3-oxo-pentyl radicals.

N-1 -4C-alkylpiperazino represents a piperazino group, in which one of the piperazino nitrogen atoms is substituted by one of the aforementioned 1 -4-C-alkyl groups. Examples which may be mentioned are the 4-methylpiperazino, the 4-ethylpiperazino and the 4-iso-propylpiperazino groups.

Fluoro-1 -4C-alkoxy represents one of the aforementioned 1 -4C-alkoxy groups, which is substituted by one or more fluorine atoms. Examples of fluoro-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.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

Possible salts of compounds of the formula 1 - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water- soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, malonic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid, trifluoracetic acid, ascorbic acid, lactic acid, D-glucuronic acid, lactobionic acid (4-O-beta-D-Galactopyranosyl-D-gluconic acid), galactaric acid, benzenesulfonic acid, laurylsulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are used in salt preparation - depending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.

Salts of the compounds of formula I according to the invention can be obtained by dissolving, the free compound in a suitable solvent (for example a ketone such as acetone, methylethylke- tone 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 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 or by precipitating upon cooling, by re-precipitating, or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation.

Pharmacologically intolerable salts, which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable 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 .

One embodiment (embodiment a) of the invention, which is to be mentioned relates to compounds of the formula 1 -1

)

in which the substituents R1 , R2, R3, R4 and R5 have the meanings as indicated in the outset.

Further embodiments of the invention relate to compounds of the formula 1 -2 (embodiment b), 1 -3 (embodiment c), 1 -4 (embodiment d), 1 -5 (embodiment e) and 1 -6 (embodiment f),

in each of which embodiments b - f, the substituents R1 , R2, R3, R4 and R5 have the meanings as indicated in the outset.

Compounds of the formula 1 , which are to be mentioned are those, wherein

R1 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl or hydroxy-1 -4C-alkyl,

R2 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl or hydroxy-1 -4C-alkyl,

R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, 1 -4C-alkoxycarbonyl, cyano, hydroxy-

R31 and R32 together, including the nitrogen atom to which both are attached, are a pyr- rolidino, 2-hydroxypyrrolidino, 3-hydroxypyrrolidino, piperidino, piperazino, azetidino, 3- hydroxyazetidino, aziridino, N-1 -4C-alkylpiperazino, morpholino, 3-fluoroazetidino, 3,3- difluoroazetidino or 3-(1 -4C-alkoxy)-azetidino group, R4 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, R5 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, and the salts of these compounds. Compounds of the formula 1 , which are to be particularly mentioned, are those, wherein

R1 is 1 -4C-alkyl,

R2 is hydrogen or 1 -4C-alkyl,

R3 is carboxyl, 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32 where

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

R31 and R32 together, including the nitrogen atom to which both are attached, are a pyr- rolidino, 2-hydroxypyrrolidino, 3-hydroxypyrrolidino, piperidino, piperazino, azetidino, 3- hydroxyazetidino, aziridino, N-1 -4C-alkylpiperazino, morpholino, 3-fluoroazetidino, 3,3- difluoroazetidino or 3-(methoxy)-azetidino group, R4 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, R5 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, and the salts of these compounds.

Compounds of the formula 1 , which are to be emphasized, are those, wherein

R1 is 1 -4C-alkyl,

R2 is 1 -4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1 -7C-alkyl and

R32 is 1 -7C-alkyl,

R4 is hydrogen or fluoro,

R5 is hydrogen, fluoro or 1 -4C-alkyl, and the salts of these compounds.

Compounds of the formula 1 , which are to be particularly emphasized, are those, wherein

R1 is 1 -4C-alkyl,

R2 is 1 -4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1 -7C-alkyl and

R32 is 1 -7C-alkyl,

R4 is hydrogen or fluoro,

R5 is hydrogen or fluoro, and the salts of these compounds.

The compounds of the formula 1 , 1 -1 , 1-2, 1-3, 1-4, 1-5 and 1 -6 have a center of chirality. The invention thus relates to all feasible stereoisomers in any desired mixing ratio to another, including the pure stereoisomers, which are a preferred subject of the invention.

The invention therefore particularly relates to all of the following stereoisomers of the formula 1-a, 1-b, 1-1 -a, 1-1 -b, 1-2-a, 1-2-b, 1-3-a, 1-3-b, 1-4-a, 1-4-b, 1-5-a, 1-5-b, 1-6-a and 1-6-b:

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 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. Furthermore, enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.

Exemplary preferred compounds according to the invention are those compounds of the formulae 1 , 1 -1 , 1 -2, 1 -3, 1 -4, 1 -5, 1 -6, 1 -a, 1 -b, 1 -2-a, 1 -2-b, 1 -3-a, 1 -3-b, 1 -4-a, 1 -4-b, 1 -5-a, 1 - 5-b, 1 -6-a and 1 -6-b, and in particular of the formulae 1 -1 -a and 1 -1 -b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), 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.

The invention therefore relates to compounds of the formula 1 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -1 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -2 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -3 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds. The invention therefore also relates to compounds of the formula 1 -4 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -5 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -6 wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -1 -a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -1 -b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -2-a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -2-b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds. The invention therefore also relates to compounds of the formula 1 -3-a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -3-b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -4-a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -4-b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -5-a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -5-b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -6-a wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

The invention therefore also relates to compounds of the formula 1 -6-b wherein R1 , R2, R3, R4 and R5 have the meanings as given in the following Table A (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

Table A:

Exemplary particularly preferred compounds according to the invention are those 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.

As shown in scheme 1 , the compounds of the general formula 1 can be obtained by reacting substituted benzimidazoles of formula 2 with (substituted) 1 -benzofuran-3(2H)-ones of formula 3. The reaction shown in scheme 1 is carried out in a manner known per se, for example in the presence of a reducing agent and an acid, for example using a reducing agent like sodium cyanoborohydride and an acid like acetic acid in methanol. Depending on the nucleophilicity of the NH₂-group of benzimidazoles of the formula 2 or of the carbonyl reactivity of 1 -benzofuran- 3(2H)-ones of formula 3, the coupling reaction can likewise be performed as a two-step process: first forming of an imine- or enamine intermediate, which transformation is known to a person skilled in the art, which then in a second step can be reduced to the desired compounds of the formula 1 , e.g. using a reducing agent like sodium borohydride in methanol. Scheme 1 :

An alternative procedure, which is particularly useful if enantiomeric pure compounds of the formula 1 are desired, is outlined in scheme 2. Compounds of the formula 1 can be obtained by reacting bromo- or chloro-substituted benzimidazoles of the general formula 4 (Y = Br or Cl) with (substituted) 2,3-dihydro-1 -benzofuran-3-amines of the formula 5 in a Buchwald-Hartwig reaction in analogy as described for example by Lopez-Rodriguez et al., Tetrahedron 2000, 56, 3245-3253.

Scheme 2:

Y = suitable leaving

group, e.g. Br, Cl

The starting amino-substituted benzimidazoles of the formula 2 are known, for example from WO 2004-054984 or they can be prepared using analogous process steps.

The required dihydrobenzofuranes of formula 3 are commercial available, are known from the literature, e.g. from N. Diedrichs, J. P. Ragot, K. Thede, Eur. J. Org. Chem. 2005, 9, 1731 - 1735, or can be prepared according to scheme 3 from commercial available o- hydroxyacetophenones of formula 6 via bromination (preferably using CuBr₂ or tetrabutylam- monium tribromide) and cyclization using bases (e.g. K₂CO₃ or sodium acetate) or alternatively from aryloxyacetic acid chlorides of formula 8 (whose preparation is described in the literature e.g. in Patent US4479900 (Chevron Research Company) for example for the synthesis of 2-(p- fluorophenoxyaceticacetyl chloride) via intramolecular Friedel-Crafts-acylation using Lewis acids as for example AICI₃ or Bronsted acids as for example trifluoromethanesulfonic acid.

Scheme 3:

cyclization

Friedel-Crafts- acylation

Some compounds of the formula 4 are known, for example from Parker et. al., Tetrahedron Letters, 1998, 39, 2797 or from Hartmann, Chem. Ber. 1890, 23, 1050 or from US Patent Application 2006/0116383, they can be prepared in an analogous manner as described in any of these references, or compounds of the formula 4 can be prepared starting from amino substituted benzimidazoles of the formula 2 applying the Sandmeyer reaction (e.g. using sodium ni- trite in acidic solvents like hydrochloric acid or hydrobromic acid followed by the addition of copper(l) chlorides or copper(l) bromides) as illustrated in the following scheme 4.

Compounds of the formula 5 are also known from literature, for example from G. Turan-Zitouni et al. Farmaco, Edizione Scientifica 1988, 43, 7-8, 643-655 or they can be prepared in an analogous manner as described therein. Furthermore, many of these derivatives are commercially available.

The derivatization, if any, of the compounds obtained according to the schemes above (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-NR31 R32 are desired, an appropriate derivatization can be performed in a manner known per se (e. g. conversion of an ester or a carboxylic acid into an amide), preferably at the stage of compounds of the formula 1 or at the stage of any intermediate thereof.

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 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 invention particularly further relates to the processes as shown in scheme 1 and in scheme 2 for the synthesis of compounds of the formula 1 , wherein R1 , R2, R3, R4 and R5 are as defined in the outset.

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 B, 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 in- traduodenal administration in vivo is shown. Table B

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 (37O) 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. pen- tagastrin (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 37.8-38O by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor). Mode(s) for Carrying Out the Invention

The following examples serve to illustrate the invention in greater detail without restricting it. Likewise, further compounds of the formula 1 whose preparation is not described explicitly can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques. The abbreviation min stands for minute(s), h for hour(s) and m.p. for melting point.

I. Final Compounds of the formula 1

1. 4-(2,3-dihydro-1-benzofuran-3-ylamino)-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide

Benzofuran-3(2H)-one (0.29 g, 2.15 mmol) was added to a solution of 4-amino-N,N,1 ,2-tetramethyl- 1 H-benzimidazole-6-carboxamide (0.50 g, 2.15 mmol) in a mixture of methanol (19.4 ml) and acetic acid (0.6 ml). After stirring for one hour at reflux, sodium cyanoborohydride (0.20 g, 3.23 mmol) was added and the reaction mixture was refluxed two days. The reaction mixture was cooled down, diato- maceous earth was added and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, ethyl acetate/methanol 15:1 ) and, finally, by preparative HPLC using a 250 x 21 mm Gemini C18 column (mobile phase: A - ammonium formate puffer pH 3.75, B - acetonitrile) to afford 0.10 g (13 %) of the title compound as a colorless solid. ¹H NMR (d₆-DMSO, 400 MHz): δ = 7.28 (d, 1 H), 7.22 (t, 1 H), 6.90-6.78 (m, 3H), 6.46 (s, 1 H), 5.87-5.76 (m, 1 H), 5.70 (d, 1 H), 4.76 (dd, 1 H), 4.37 (dd, 1 H), 3.68 (s, 3H), 2.95 (s, 6H), 2.48 (s, 3H).

2. 4-[(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)amino]-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide

6-Fluoro-1 -benzofuran-3(2H)-one (1.20 g, 7.89 mmol) was added to a solution of 4-amino-N,N,1 ,2- tetramethyl-1 H-benzimidazole-6-carboxamide (1.80 g, 7.89 mmol) in a mixture of methanol (38.8 ml) and acetic acid (1.2 ml). After stirring for one hour at reflux, sodium cyanoborohydride (0.74 g, 11.84 mmol) was added and the reaction mixture was refluxed three days. The reaction mixture was cooled down, diatomaceous earth was added and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, toluene/dioxane 1 :1 ) and, finally, by a second column chromatography (silica gel, ethyl acetate then ethyl acetate/methanol 9:1 ). Crystallization with diiso- propyl ether afforded 0.44 g (15 %) of the title compound as a yellow solid. ¹H NMR (CDCI₃, 300 MHz): δ = 7.32 (dd, 1 H), 6.81 (s, 1 H), 6.66-6.53 (m, 2H), 6.42 (s, 1 H), 5.42-5.32 (m, 1 H), 5.08 (d, 1 H), 4.80 (dd, 1 H), 4.52 (dd, 1 H), 3.71 (s, 3H), 3.08 (br s, 6H), 2.55 (s, 3H).

3. 4-[(4,6-difluoro-2,3-dihydro-1-benzofuran-3-yl)amino]-N,N,1 ,2-tetramethyl-1 H- benzimidazole-6-carboxamide 4,6-difluoro-1 -benzofuran-3(2H)-one (0.55 g, 3.23 mmol) was added to a solution of 4-amino-N,N,1 ,2- tetramethyl-1 H-benzimidazole-6-carboxamide (0.75 g, 3.23 mmol) in a mixture of methanol (20.0 ml) and acetic acid (0.6 ml). After stirring for two hours at reflux, sodium cyanoborohydride (0.31 g, 4.94 mmol) was added and the reaction mixture was refluxed for 18 h. Further sodium cyanborohydride (0.31 g, 4.94 mmol) was added and stirring at reflux was continued for three days. The reaction mixture was cooled down, silica gel was added and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, ethyl acetate/methanol 9:1 ) to afford a white solid. A further aqueous workup (dissolve in ethyl acetate, washing with an aqueous saturated solution of sodium bicarbonate, drying and removal of solvent) gave after crystallization with diisopropyl ether 0.21 g (17 %) of the title compound as a colorless solid. ¹H NMR (d₆-DMSO, 300 MHz): δ = 6.81 (s, 1 H), 6.71 (s, 1 H), 6.68 (s, 1 H), 6.40 (s, 1 H), 6.08-5.90 (m, 2H), 4.84 (dd, 1 H), 4.48 (dd, 1 H), 3.69 (s, 3H), 2.95 (S, 6H), 2.48 (s, 3H).

4. 4-[(4-fluoro-2,3-dihydro-1-benzofuran-3-yl)amino]-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide

4,6-difluoro-1 -benzofuran-3(2H)-one (0.55 g, 3.23 mmol) was added to a solution of 4-amino-N,N,1 ,2- tetramethyl-1 H-benzimidazole-6-carboxamide (0.75 g, 3.23 mmol) in a mixture of methanol (20.0 ml) and acetic acid (0.6 ml). After stirring for two hours at reflux, sodium cyanoborohydride (0.31 g, 4.94 mmol) was added and the reaction mixture was refluxed for 18 h. Further sodium cyanborohydride (0.31 g, 4.94 mmol) was added and stirring at reflux was continued for three days. The reaction mixture was cooled down, silica gel was added and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, ethyl acetate/methanol 9:1 ) to afford 0.27 g (23 %) of the title compound as a white solid. ¹H NMR (d₆-DMSO, 300 MHz): δ = 7.28 (dt, 1 H), 6.81 (s, 1 H), 6.74 (d, 1 H), 6.69 (t, 1 H), 6.41 (s, 1 H), 6.04-5.91 (m, 1 H), 5.89 (d, 1 H), 4.78 (dd, 1 H), 4.43 (dd, 1 H), 3.67 (s, 3H), 2.94 (s, 6H), 2.51 (s, 3H).

II. Starting materials

A. 6-Fluoro-1-benzofuran-3(2H)-one

(i) 2-Bromo-1-(4-fluoro-2-hydroxyphenyl)ethanone:

The solution of 1 -(4-fluoro-2-hydroxyphenyl)ethanone (5.00 g, 32.44 mmol) in chloroform (25 ml) was added to a suspension of copper(ll) bromide (10.90 g, 48.66 mmol) in ethyl acetate (25 ml). The reaction mixture was refluxed for 18 h, cooled down to room temperature and filtered off. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, tolu- ene/dioxane 12:1 ) to give 4.70 g of a brown oil which was used as such without analytical characterization in the next step.

(H) 6-Fluoro-1 -benzofuran-3(2H)-one The solution of 2-bromo-1 -(4-fluoro-2-hydroxyphenyl)ethanone (4.70 g, 21.46 mmol) in acetone (200 ml) was treated with solid potassium carbonate (5.90 g, 42.92 mmol). The reaction mixture was stirred at room temperature for 18 h, poured onto water, and the aqueous phase was extracted with dichloro- methane. The combined extracts were washed with water, dried (MgSO₄) and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, toluene/dioxane 20:1 ) gave the title compound (1 .23 g, 37%) as an orange solid. ¹H NMR (d₆-DMSO, 300 MHz): δ = 7.72 (dd, 1 H), 7.23 (dd 1 H), 7.01 (ddd, 1 H), 4.86 (s, 2H).

B. 4-Fluoro-1-benzofuran-3(2H)-one

(i) 2-Bromo-1-(2-fluoro-6-hydroxyphenyl)ethanone:

The solution of 1 -(4-fluoro-2-hydroxyphenyl)ethanone (5.00 g, 32.44 mmol) in chloroform (25 ml) was added to a suspension of copper(ll) bromide (10.90 g, 48.66 mmol) in ethyl acetate (25 ml). The reaction mixture was refluxed for 18 h, cooled down to room temperature and filtered off. The filtrate was concentrated in vacuo to give 7.20 g of a yellowish solid which was used as such without analytical characterization in the next step.

(H) 4-Fluoro-1 -benzofuran-3(2H)-one

The solution of 2-bromo-1 -(2-fluoro-2-hydroxyphenyl)ethanone (7.20 g, 30.90 mmol) in acetone (250 ml) was treated with solid potassium carbonate (8.60 g, 62.23 mmol). The reaction mixture was stirred at room temperature for 18 h and poured onto a mixture of water and dichloromethane. Using 2N HCI, the mixture was neutralized, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined extracts were washed with water, dried (MgSO₄) and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, hexane/ethyl acetate 4:1 ) gave the title compound (1 .50 g, 32 %) as a yellow solid. ¹H NMR (CDCI₃, 300 MHz): δ = 7.56 (ddd, 1 H), 6.93 (d, 1 H), 6.71 (t, 1 H), 4.65 (s, 2H).

C. 4,6-Dif luoro-1 -benzofuran-3(2H)-one

The suspension of (3,5-difluorophenoxy)acetic acid (2.3 g, 12.23 mmol) in toluene (20 ml) was treated with thionyl chloride (7.20 g, 60.52 mmol). The reaction mixture was refluxed for 2 h and, after cooling down to room temperature, concentrated in vacuo. The oily residue was suspended in dichloromethane (25 ml), treated with a suspension of AICI₃ (1 .63 g, 12.22 mmol) in dichloromethane (20 ml) and stirred at 40O for 18 h. The reaction mixture was poured onto ice water and the aqueous phase was extracted with dichloromethane. The combined extracts were washed with water, dried (Na₂SO₄) and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, hexane/ethyl acetate 4:1 ) gave the title compound (0.55 g, 27 %) as a pale yellow solid. ¹H NMR (CDCI₃, 300 MHz): δ = 6.64 (d, 1 H), 6.46 (t, 1 H), 4.69 (s, 2H). lndustrial applicability

The compounds of the formulae 1 , 1 -1 , 1 -2, 1 -3, 1 -4, 1 -5, 1 -6, 1 -a, 1 -b, 1 -1 -a, 1 -1 -b, 1 -2-a, 1 -2-b, 1 -3- a, 1 -3-b, 1 -4-a, 1 -4-b, 1 -5-a, 1 -5-b, 1 -6-a an 1 -6-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. Compared to compounds known from the prior art, the active compounds according to the present invention are particularly distinguished by an excellent efficacy with regard to inhibition of gastric acid secretion and/or by a low potential to cause side effects for example due to a low affinity to one or more other enzymes whose inhibition is related to these side effects and/or by a low potential of drug-drug interactions.

"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 admini- stration, 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.

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, rabepra- zole, tenatoprazole, ilaprazole, leminoprazole, all including their salts and enantiomers] or

(III) other potassium-competitive acid blockers [e.g. soraprazan and its stereoisomers, linaprazan, revaprazan, 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, ibupro- fen, 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, GABA-B agonists (e.g. baclofen, (2R)-3-amino-2-fluoropropylphosphinic acid) or allosteric GABA-B agonists (e.g. 3,5-bis(1 ,1 - dimethylethyl)-4-hydroxy-β,β-dimethylbenzenepropanol), GABA re-uptake inhibitors (e.g. tiagabine), metabotropic glutamate receptor type 5 (mGluRδ) antagonists (e.g. 2-methyl-6-(phenylethynyl)pyridine hydrochloride), CB1 (cannabinoid 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 mesylate). 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, cilanse- tron; 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

We claim:

1. A compound of the formula 1

in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, S^C-cycloalkyl-I^C-alkyl, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1 -

4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluoro-1-4C-alkyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, cyano, 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 or the group -CO-NR31 R32 where R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-

4C-alkyl, 1-4C-alkylcarbonyl-1-4C-alkyl, 1 -4C-alkylcarbonyl or 1 -4C-alkoxycarbonyl 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 attached, are a pyr- rolidino, 2-hydroxypyrrolidino, 3-hydroxypyrrolidino, piperidino, piperazino, azetidino, 3- hydroxyazetidino, aziridino, N-1-4C-alkylpiperazino, morpholino, 3-fluoroazetidino, 3,3- difluoroazetidino or 3-(1-4C-alkoxy)-azetidino group, R4 is hydrogen, halogen, fluoro-1-4C-alkoxy, cyano, nitro, 1-4C-alkyl, 3-7C-cycloalkyl, 3-

7C-cycloalkyl-1-4C-alkyl, 3-7C-cycloalkoxy, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C- alkoxycarbonyl, fluoro-1-4C-alkyl or hydroxy-1 -4C-alkyl, R5 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 3-7C- cycloalkoxy, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1 -4C-alkoxycarbonyl or hydroxy-1 -

4C-alkyl, and its salts.

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

in which R1 , R2, R3, R4, R5 and R6 are as defined in claim 1.

3. A compound of the formula 1 as claimed in claim 1 or a compound of the formula 1 -1 as claimed in claim 2, in which

R1 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl or hydroxy-1 -4C-alkyl, R2 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl or hydroxy-1 -4C-alkyl, R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, 1 -4C-alkoxycarbonyl, cyano, hydroxy-

R31 and R32 together, including the nitrogen atom to which both are attached, are a pyr- rolidino, 2-hydroxypyrrolidino, 3-hydroxypyrrolidino, piperidino, piperazino, azetidino, 3- hydroxyazetidino, aziridino, N-1 -4C-alkylpiperazino, morpholino, 3-fluoroazetidino, 3,3- difluoroazetidino or 3-(1 -4C-alkoxy)-azetidino group, R4 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, R5 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, and its salts.

4. A compound of the formula 1 as claimed in claim 1 or a compound of the formula 1 -1 as claimed in claim 2, in which R1 is 1 -4C-alkyl, R2 is hydrogen or 1 -4C-alkyl,

R3 is carboxyl, 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32 where R31 is hydrogen, hydroxyl, 1 -7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -

R31 and R32 together, including the nitrogen atom to which both are attached, are a pyr- rolidino, 2-hydroxypyrrolidino, 3-hydroxypyrrolidino, piperidino, piperazino, azetidino, 3- hydroxyazetidino, aziridino, N-1 -4C-alkylpiperazino, morpholino, 3-fluoroazetidino, 3,3- difluoroazetidino or 3-(methoxy)-azetidino group, R4 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, R5 is hydrogen, halogen, 1 -4C-alkyl or 1 -4C-alkoxy, and its salts.

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

R1 is 1 -4C-alkyl, R2 is 1 -4C-alkyl, R3 is the group -CO-NR31 R32 where

R31 is 1 -7C-alkyl and R32 is 1 -7C-alkyl, R4 is hydrogen or fluoro, R5 is hydrogen, fluoro or 1 -4C-alkyl, and its salts.

6. A compound of the formula 1 as claimed in claim 1 or a compound of the formula 1 -1 as claimed in claim 2, in which

R1 is 1 -4C-alkyl, R2 is 1 -4C-alkyl, R3 is the group -CO-NR31 R32 where

R31 is 1 -7C-alkyl and R32 is 1 -7C-alkyl, R4 is hydrogen or fluoro, R5 is hydrogen or fluoro, and its salts.

7. A compound of the formula 1 as claimed in claim 1 which is selected from the group consisting of

4-(2,3-dihydro-1 -benzofuran-3-ylamino)-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide, 4-[(6-fluoro-2,3-dihydro-1 -benzofuran-3-yl)amino]-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide,

4-[(4,6-difluoro-2,3-dihydro-1 -benzofuran-3-yl)amino]-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide and 4-[(4-fluoro-2,3-dihydro-1 -benzofuran-3-yl)amino]-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6- carboxamide and its salts.

8. A process for the preparation of a compound according to any of claims 1 to 7, which comprises the reaction of a compound of the formula 2 with a compound of the formula 3

in which R1 , R2, R3, R4 and R5 have the meanings as indicated in any of claims 1 to 7.

9. A process for the preparation of a compound according to any of claims 1 to 7, which comprises the reaction of a compound of the formula 4 with a compound of the formula 5

in which R1 , R2, R3, R4 and R5 have the meanings as indicated in any of claims 1 to 7 and Y is a suitable leaving group.

10. Use of a compound according to any of claims 1 to 7 for the production of medicaments, which are employed for the treatment and/or prophylaxis of gastrointestinal disorders.

11. A medicament comprising one or more compounds according to any of claims 1 to 7 and/or a pharmaceutically acceptable salt thereof together with customary pharmaceutical excipients.

12. A compound according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis of gastrointestinal disorders.

13. The use of a compound according to any of claims 1 to 7 and its pharmaceutically acceptable salts for the prevention and/or treatment of gastrointestinal disorders.