WO2008017466A1 - Pharmaceutically active tetrahydroisoquinoline-substituted benzimidazole derivatives - Google Patents

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

PHARMACEUTICALLY ACTIVE TETRAHYDROISOQUINOLINE-SUBSTITUTED BENZIMIDA- ZOLE 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 WO9747603 (Astra AB) benzimidazoles with a specific benzyloxy or benzylamino substitution are described.

The International Patent Application WO2004/054984 and WO2006/100254 disclose substituted, bi- cyclic benzimidazole derivatives which compounds are useful for treating gastrointestinal diseases.

The International Patent Applications WO2004/087701 , WO2006/100255 and WO2006/136552 disclose 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 WO2005/058893 and WO2005/103057 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 WO2005/121139 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 WO2006/037748 and WO2006/037759 disclose further tricyclic benzimidazole derivatives which compounds are likewise useful for treating gastrointestinal disorders.

The International Patent Application WO2006/134111 discloses spiro-substituted benzimidazole derivatives which compounds are likewise useful for treating gastrointestinal diseases. - -

The International Patent Applications WO2006/134460 and W 02007/072146 disclose chromane- substituted benzimidazoles and their use as acid pump inhibitors or acid pump antagonists.

The International Patent Application WO2007/031860 discloses indane-substituted benzimidazole derivatives and their use as acid pump inhibitors.

The International Patent Application WO2007/072142 discloses benzimidazole 5-carboxamide derivatives and the use of these compounds in the treatment of conditions mediated by acid pump antagonist activity.

The International Patent Applications WO2006/025714, WO2006/025715, WO2006/025716 and WO2006/038773 disclose different pyrrolo-pyridine derivatives which are inter alia substituted by a tetrahydroisoquinolinyl group. The compounds are said to have excellent proton pump inhibition effects and possess the ability to attain a reversible proton pump inhibitory effect.

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, 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 fluo- ro-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 bonded, are a pyrrolidino, hy- droxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino,

N-1-4C-alkylpiperazino or morpholino group, R4 is hydrogen, 1-4C-alkyl or cyclopropyl, R5 is hydrogen, halogen, fluoro-1-4C-alkoxy, cyano, nitro, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cyclo- alkyl-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, R6 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 cyclohexylethyl group.

1-4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, iso- butoxy, 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 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 (pro- pargyl 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 di- fluoromethyl, 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-1-4Calkyl 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-trifIuoroethoxyethyl, the trifluorometh- oxyethyl 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.

Hydroxypyrrolidino represents a pyrrolidino group, which is substituted by a hydroxy group. Examples which may be mentioned are the 2-hydroxypyrrolidino and the 3-hydroxypyrrolidino groups.

Hydroxyazetidino represents an azetidino group, which is substituted by a hydroxy group. An example which may be mentioned is the 3-hydroxyazetidino group. Fluorazetidino represents an azetidino group, which is substituted by a fluoro atom. Examples which may be mentioned are the (2S)-and the (2R)-fluoroazetidino and in particular the 3-fluoroazetidino group.

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 di- fluoromethoxy group.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo- heptyloxy, 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, methylethylketone or methyli- sobutylketone, 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, R5 and R6 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-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-4C-alkylpiperazino or morpholino group,

R4 is hydrogen, 1-4C-alkyl or cyclopropyl,

R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R6 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-1-4C-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-

1-4C-alkylpiperazino or morpholino group, R4 is hydrogen, 1-4C-alkyl or cyclopropyl, R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R6 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 hydrogen or 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is hydrogen or 1-7C-alkyl and

R32 is 1-7C-alkyl,

R4 is hydrogen, 1-4C-alkyl or cyclopropyl,

R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R6 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 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 1-4C-alkyl,

R5 is hydrogen,

R6 is hydrogen, 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,

R5 is hydrogen,

R6 is hydrogen, and the salts of these compounds.

The compounds of the formula 1 and 1-1 can have a center of chirality at the carbon atom substituted by R4 in the case when R4 is different from hydrogen. 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 and 1-1-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-a, 1-b, and in particular of the formulae 1-1 -a and 1-1 -b wherein R1 , R2, R3, R4, R5 and R6 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.

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.

The compounds of the general formula 1 , wherein R4 is hydrogen can be obtained by reacting substituted benzimidazoles of formula 2 with dibromides of formula 3 as depicted in scheme 1. The starting amino-substituted benzimidazoles of the formula 2 are known, for example from WO2004054984 or they can be prepared using process steps, as described for example in WO2007023135 or in an analogous manner thereto. The required dibromides of formula 3 are also known from literature or can be prepared in an analogous manner, e.g. as described in US Patent 5,364,876. Alternatively, compounds of the formula 3 can be prepared from the corresponding diols using triphenylphosphine and carbon tetrabromide in analogy for example as described by A. Solladie-Cavallo et al. in Tetrahedron: Asymmetry 2001 , 12, 967-970. The reaction shown in Scheme 1 is carried out in a manner known per se, for example using a base like potassium carbonate in a suitable solvent in analogy as described for example by Holliman and Mann, J. Chem. Soc. 1945, 45 or by M. Yus et al., Tetrahedron 1996, 52, 8545-8564. - -

Scheme 1 :

If compounds of the formula 1 with R4 = hydrogen or other than hydrogen are desired, the reaction outlined in scheme 2 can be followed to obtain compounds of the formula 1. Bromo- or chloro-substi- tuted benzimidazoles of the general formula 4 (X = Br or Cl) are reacted with substituted tetrahydroi- soquinolines of the formula 5 in a Buchwald-Hartwig reaction for example in analogy as described by Lopez-Rodriguez et al., Tetrahedron 2000, 56, 3245-3253 or Giorgi-Renault et al., Synth. Commun. 2001, 987-992 to give the desired compounds of the formula 1.

Scheme 2:

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 nitrite 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 3.

Scheme 3:

2 Y = Br, Cl

Compounds of the formula 5 are known, for example from WO2006025716 or they can be prepared in an analogous manner as described therein. Furthermore, a large number of these derivatives is 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 present invention further relates to compounds of the formula 4 shown above, which are intermediates in the process of producing the compounds of the formula 1 according to the present invention. R1 , R2, R3, R4, R5 and R6 are thereby defined as for compounds of the formula 1.

In particular the present invention further relates to compounds of the formula 4, 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-1-4C-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-

4C-alkylpiperazino or morpholino group, and X is bromo or chloro. The invention further relates to the use of a compound of the formula 4 in the synthesis of compounds of the formula 1 , wherein R1 , R2, R3, R4, R5 and R6 are as defined in the outset and where X is bromo or chloro..

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 scheme 2 for the synthesis of compounds of the formula 1 , wherein R1 , R2, R3, R4, R5 and R6 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 intraduodenal 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 (37°C) 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. pentagas- trin (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 37.8-38°C 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-(3,4-Dihydroisoquinolin-2(1 H)-yl)-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide

Method Scheme 1 :

To a suspension of 1.0 g (4.3 mmol) 4-amino-N, N, 1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide and 1.4 g (10.1 mmol) potassium carbonate in 5 ml ethanol were added 1.4 g (5.1 mmol) 1-(2-bromo- ethyl)-2-(bromomethyl)benzene. After 2 h stirring at 80 ⁰C, an additional amount of 0.6 g (4.4 mmol) potassium carbonate and 0.6 g (2.2 mmol) 1-(2-bromoethyl)-2-(bromomethyl)benzene were added and stirring was continued overnight at room temperature and 3 h at 80 ⁰C. The reaction mixture was cooled down and partitioned between water and dichloromethane. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography (silica gel, di- chloromethane/methanol 13:1) and crystallization from ethyl acetate yielded 0.2 g (13 %) of the title compound as a solid. ¹H-NMR (CDCI₃): δ (ppm) = 2.60 (s, 3 H, CH₃), 3.03 (t, 2 H), 2.9-3.2 (bs, 6 H, 2 CH₃), 3.69 (s, 3 H, CH₃), 4.00 (t, 2 H), 4.71 (s, 2 H), 6.68 (s, 1 H), 6.96 (s, 1 H), 7.12-7.16 (m, 4 H).

Method Scheme 2

A mixture of 0.5 g (1.68 mmol) 4-bromo-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide, 20 mg (0.084 mmol) palladium(ll) acetate, 58 mg (0.092 mmol) 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl, 0.27 g (2.35 mmol) potassium tert-butoxide and 0.28 g (2.02 mmol) 1 ,2,3,4-tetrahydroisoquinoline in 4 ml dried toluene was stirred 45 min at 100 ⁰C. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate, filtered through Celite and evaporated. Purification of the residue by column chromatography (silica gel, toluene/dioxane/methanol 6:3.8:0.2) and crystallization from diisopropyl ether yielded 0.22 g (37 %) of the title compound as a colourless solid.

2. N,N,1,2-tetramethyl-4-(1-methyl-3,4-dihydroquinolin-2(1H)-yl)-1H-benzimidazole-6- carboxamide - -

A mixture of 0.75 g (2.53 mmol) 4-bromo-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide, 23 mg (0.025 mmol) tris(dibenzylideneacetone)dipalladium(0), 15 mg (0.031 mmol) 2- (dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1 ,r-biphenyl (98%), 0.61 g (6.32 mmol) sodium tert- butoxide and 0.90 g (6.10 mmol) 1-methyl-1 ,2,3,4-tetrahydroisoquinoline in toluene (5.0 ml) and tert- butanol (1.0 ml) was stirred for 3 h at 110⁰C. The reaction mixture was poured into an ice-cold saturated ammonium chloride solution and extracted with dichloromethane two times. The combined organic layers were dried over anhydrous magnesium sulphate and concentrated in vaccum. The crude mixture was purified by column chromatography (toluene/dioxane/methanol: 6/3/1 ) to times to give 39.0 mg (0.11 mmol / 15%) of the title compound as a light brown solid. I H-NMR^OOMHZ₁CDCI₃): δ = 1.39 (d, 3 H)₇ 2.59 (s,3 H),2.75-2.78 (d, 1 H),2.90-3.17 (m, 7 H), 3.62 (dt, 1 H), 3.68 (s, 3 H),4.18 (dd,1 H),5.67-5.71 (me, 1 H), 6.63 (s, 1 H),6.95 (s, 1 H), 7.08-7.18 (m, 4 H).

II. Starting materials

A. 4-Amino-N,N-dimethyl-3,5-dinitrobenzamide

A mixture of 5.0 g (22 mmol) 4-amino-N,N-dimethyl-3,5-dinitrobenzoic acid and 30 ml thionyl chloride was stirred overnight at 50 ⁰C. After 2 h stirring at 80 ⁰C, the reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was dissolved in tetrahydrofuran and 50 ml (100 mmol) dimethylamine (2M in tetrahydrofuran) were added slowly at 0 ⁰C. After 3 h, the mixture was evaporated to dryness and the residue was suspended in water. After stirring overnight, the precipitate was collected and dried in vacuo to yield 4.4 g (79 %) of the title compound as a yellow solid (m.p. 192-193 ⁰C).

B. 3,4-Diamino-N,N-dimethyl-5-nitrobenzamide

A mixture of 2.0 g (8.6 mmol) 4-amino-N,N-dimethyl-3,5-dinitrobenzamide in 20 ml methanol was heated to reflux and 9 ml (24.5 mmol) ammonium sulphide (20% in water) were added over a period of 30 min. After 3 h, the reaction mixture was poured into 300 ml water and extracted with methyl iso- butyl ketone. The combined organic extracts were evaporated to dryness and the residue was recrys- tallized from isopropanol to yield 0.7 g (36 %) of the title compound (m.p. 144-146 ⁰C).

C. N,N,2-Trimethyl-4-nitro-1H-benzimidazole-6-carboxamide

A suspension of 20.0 g (89 mmol) 3,4-diamino-N,N-dimethyl-5-nitrobenzamide in 270 ml ethanol and 42 ml 5N hydrochloric acid was heated to reflux and 18.3 ml (178 mmol) pentane-2,4-dione were added. After 2 h, the reaction mixture was cooled down, poured onto 500 ml crushed ice and neutralized with 40% aqueous sodium hydroxide. The mixture was partitioned between water and dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evapo- - -

rated. The residue was recrystallized from ethyl acetate/n-heptane with charcoal to yield 18.4 g (83 %) of the title compound as a colourless solid (m.p. 198-200 ⁰C).

D. N, N, 1,2-Tetramethyl-4-nitro-1 H-benzimidazole-6-carboxamide

To a suspension of 6.0 g (24 mmol) N,N,2-trimethyl-4-nitro-1 H-benzimidazole-6-carboxamide and 7.2 g (52 mmol) potassium carbonate in 250 ml acetone were slowly added 4.8 ml (77 mmol) methyl iodide. After 3 h, a second amount of 4.8 ml (77 mmol) methyl iodide was added and the reaction mixture was stirred for 2 h. To the reaction mixture was added saturated aqueous ammonium chloride and the mixture was partitioned between water and dichloromethane. The combined organic phases were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from acetone/diethyl ether yielded 4.6 g (73 %) of the title compound as a yellow solid (m.p. 178- 179 ⁰C).

E. 4-Amino-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide

A mixture of 5.5 g (21 mmol) N, N, 1 ,2-tetramethyl-4-nitro-1 H-benzimidazole-6-carboxamide and 250 mg 10% palladium on charcoal in 150 ml methanol/acetic acid was hydrogenated for 72 h (1 bar hydrogen, 40 ⁰C). The catalyst was filtered off and the filtrate was evaporated. The residue was partitioned between saturated aqueous sodium hydrogencarbonate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate yielded 3.8 g (78 %) of the title compound as a yellow solid (m.p. 233-234 °C).

F. 4-Bromo-N,N,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide

To a solution of 25.0 g (107 mmol) 4-amino-N, N, 1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide in 125 ml hydrobromic acid (48 %) was slowly added a solution of 12.0 g (174 mmol) sodium nitrite in 125 ml water at 0-5 ⁰C. After 15 min, the resulting solution was transferred to a dropping funnel and added slowly to a solution of 13.0 g (58 mmol) copper(ll) bromide in 125 ml hydrobromic acid (60 %) at 60 ⁰C. After complete addition, the reaction mixture was stirred 1 h at 80 °C and then poured into 400 ml water. The mixture was carefully neutralized with cone, ammonia and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography (silica gel, toluene/dioxane/methanol first 6:3.8:0.2, then 6:3.5:0.5) and crystallization from diisopropyl ether yielded 14.7 g (46 %) of the title compound as a solid (m.p. 156-158 ⁰C). 1 H-NMR (d6-DMSO): δ (ppm) = 2.57 (s, 3 H, CH3), 2.98 (bs, 6 H, 2 CH3), 3.76 (s, 3 H, CH3), 7.39 (d, 1 H), 7.62 (d, 1 H). - -

lndustrial applicability

The compounds of the formulae 1 , 1-1 , 1-a, 1-b, 1-1 -a and 1-1 -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. 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 above- mentioned diseases.

The invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.

A further subject of the invention are medicaments which comprise one or more active compounds according to the invention.

The invention further relates to the active compounds according to the invention for the treatment and/or prophylaxis of gastrointestinal diseases.

The invention further relates to pharmaceutical compositions comprising an active compound according to the invention, for the treatment and/or prophylaxis of gastrointestinal diseases.

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.

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^) 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. - 7 -

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 (mGluR5) 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 partners), 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

We claim:

1. A compound of the formula 1

in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-CyClOaIKyI, 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 fluo- ro-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-

4C-alkylpiperazino or morpholino group,

R4 is hydrogen, 1-4C-alkyl or cyclopropyl, R5 is hydrogen, halogen, fluoro-1-4C-alkoxy, cyano, nitro, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cyclo- alkyl-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,

R6 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-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-

4C-alkylpiperazino or morpholino group, R4 is hydrogen, 1-4C-alkyl or cyclopropyl, R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R6 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-1-4C-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1- 4C-alkylpiperazino or morpholino group,

R4 is hydrogen, 1-4C-alkyl or cyclopropyl,

R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R6 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 hydrogen or 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is hydrogen or 1-7C-alkyl and

R32 is 1-7C-alkyl,

R4 is hydrogen, 1-4C-alkyl or cyclopropyl,

R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

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

R5 is hydrogen,

R6 is hydrogen, and its salts. - -

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

4-(3,4-Dihydroisoquinolin-2(1 H)-yl)-N,N,1 ,2-tetramethyl-i H-benzimidazole-6-carboxamide and N,N,1 ,2-tetramethyl-4-(1-methyl-3,4-dihydroquinolin-2(1 H)-yl)-1 H-benzimidazole-6-carboxamide, and its salts.

8. A compound of the formula 4

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-1-4C-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 bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-

4C-alkylpiperazino or morpholino group, and X is bromo or chloro.

9. Use of a compound of the formula 4 as claimed in claim 8 in the synthesis of compounds of the formula 1 or of the formula 1-1 as claimed in claim 4, wherein R1 , R2, R3, R4, R5 and R6 are as defined in claim 4.

10. A process for preparing a compound of the formula 1 as claimed in claim 1 , comprising the step of reacting a compound of the formula 2 with a compound of the formula 3 - -

whereby R1, R2, R3, R5 and R6 are as defined in claim 1 and R4 is hydrogen.

11. A process for preparing a compound of the formula 1 as claimed in claim 1 , comprising the step of reacting a compound of the formula 4 with a compound of the formula 5,

whereby R1 , R2, R3, R4, R5 and R6 are as defined in claim 1 and X is bromo or chloro.

12. Use of a compound according to any of claims 1 to 7 and its pharmaceutically acceptable salts for the production of medicaments which are employed for the treatment and/or prophylaxis of gastrointestinal disorders.

13. 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.

14. 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.

15. A compound according to any of claims 1 to 7and its pharmaceutically acceptable salts for the treatment and/or prophylaxis of gastrointestinal diseases.

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