EP1863820A1

EP1863820A1 - Thioamide-substituted tricyclic benzimidazoles useful for the treatment of gastrointestinal diseases

Info

Publication number: EP1863820A1
Application number: EP06725220A
Authority: EP
Inventors: Maria Vittoria Chiesa; Peter Jan Zimmermann; Wilm Buhr; Christof Brehm; Andreas Palmer; Wolfgang-Alexander Simon; Wolfgang Kromer; Stefan Postius; Hans Christof Holst
Original assignee: Nycomed GmbH
Current assignee: Takeda GmbH
Priority date: 2005-03-24
Filing date: 2006-03-22
Publication date: 2007-12-12
Also published as: JP2008534476A; AU2006226352A1; CA2601388A1; WO2006100255A1

Abstract

The invention relates to cyclic benzimidazoles of formula (I), in which the substituents and symbols have the meanings indicated in the description. The compounds have gastric secretion inhibiting and excellent gastric and intestinal protective action properties.

Description

Title

THIOAMIDE-SUBSTITUTED TRICYCLIC BENZIMIDAZOLES USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISEASES .

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 Application WO 04/054984 discloses substituted, bicyclic benzimidazole derivatives which compounds are useful for treating gastrointestinal diseases.

The International Patent Application WO 04/087701 discloses tricyclic benzimidazole derivatives having different substituents in 5-position of the benzimidazole moiety which compounds are likewise useful for treating gastrointestinal diseases.

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, no rPPI, APA or P-CAB is at present available for therapy. The technical problem underlying the present invention is therefore to provide acid pump antagonists which can be used in therapy. Technical solution

The invention relates to tricyclic benzimidazoles of the formula 1

in which

R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C- alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C- cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1 -4C-alkyl, fluoro-2-4C-alkyl,

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

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 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, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

X is O (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

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

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

R7 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.

Halogen within the meaning of the invention is bromo, chloro and fluoro.

1-4C-Alkyl represents a straight-chain or branched alkyl group 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 cyclo-propylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.

1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.

1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.

1-4C-Alkoxycarbonyl (1-4C-alkoxy-CO-) 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 a straight-chain or branched alkenyl group 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 a straight-chain or branched alkynyl group having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).

Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned is the trifluoromethyl group. - A -

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 and the 3-hydroxypropyl group. Hydroxy-1-4C-alkyl within the scope of the invention is understood to include 1-4C-alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-di- hydroxybutyl and in particular the 2,3-dihydroxypropyl group.

Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.

Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl group.

Fluoro-2-4C-alkyl represents a 2-4C-alkyl group, which is substituted by one or more fluorine atoms. An example which may be mentioned is the 2,2,2-trifluoroethyl group.

1-7C-Alkyl represents a straight-chain or branched alkyl group 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.

Groups Ar which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,5-bis(trifluoro- methyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6- fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3-(4- chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 2,4-dihydroxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxy-5-hydroxyphenyl, 2,5-dimethylphenyl, 3-ethoxy-4-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, 3-methoxy-2-nitrophenyl, 3-nitrophenyl, 2,3,5-trichlorophenyl, 2,4,6-trihydroxyphenyl, 2,3,4-trimethoxyphenyl, 2-hydroxy-1- naphthyl, 2-methoxy-1-naphthyl, 4-methoxy-1-naphthyl, 1-methyl-2-pyrrolyl, 2-pyrrolyl, 3-methyl-2- pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 4-(2-methoxycarbonylethyl)-3-methyl-2-pyrrolyl, 5-ethoxycarbonyl-2,4- dimethyl-3-pyrrolyl, 3,4-dibromo-5-methyl-2-pyrrolyl, 2,5-dimethyl-1 -phenyl-3-pyrrolyl, 5-carboxy-3- ethyl-4-methyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 2,5-dimethyl-1-(4-trifluoromethylphenyl)-3-pyrrolyl, 1 -(2,6-dichloro-4-trifluoromethylphenyl)-2-pyrrolyl, 1 -(2-nitrobenzyl)-2-pyrrolyl, 1 -(2-fluorophenyl)-2- pyrrolyl, 1 -(4-trifluoromethoxyphenyl)-2-pyrrolyl, 1 -(2-nitrobenzyl)-2-pyrrolyl, 1 -(4-ethoxycarbonyl)-2,5- dimethyl-3-pyrrolyl, 5-chloro-1 ,3-dimethyl-4-pyrazolyl, 5-chloro-1 -methyl-3-trifluoromethyl-4-pyrazolyl, 1 -(4-chlorobenzyl)-5-pyrazolyl, 1 ,3-dimethyl-5-(4-chlorphenoxy)-4-pyrazolyl, 1 -methyl-3-trifluomethyl- 5-(3-trifluoromethylphenoxy)-4-pyrazolyl, 4-methoxycarbonyl-1-(2,6-dichlorophenyl)-5-pyrazolyl, 5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3,5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyl-1 ,2,3- triazol-4-yl, 3-indolyl, 4-indolyl, 7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3- indolyl, 2-(4-chlorophenyl)-3-indolyl, 7-benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3- indolyl, 4,5,6,7-tetrafluoro-3-indolyl, 1-(3,5-difluorobenzyl)-3-indolyl, 1-methyl-2-(4-trifluorophenoxy)-3- indolyl, 1-methyl-2-benzimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl, 5-(2-nitro- 4-trifluoromethylphenyl)-2-furyl, 4-ethoxycarbonyl-5-methyl-2-furyl, 5-(2-trifluoromethoxyphenyl)-2- furyl, 5-(4-methoxy-2-nitrophenyl)-2-furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuryl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2- thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl, 5-(4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3- phenoxy-2-thienyl, 5-carboxy-2-thienyl, 2,5-dichloro-3-thienyl, 3-methoxy-2-thienyl, 2-benzothienyl, 3- methyl-2-benzothienyl, 2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2,4- dichloro-5-thiazolyl, 2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2,6-dichloro-4-pyridyl, 3- chloro-5-trifluoromethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 4-(4-chlorophenyl)-3-pyridyl, 2-chloro-5- methoxycarbonyl-6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6-(3-trifluoromethylphenoxy)-3-pyri- dyl, 2-(4-chlorophenoxy)-3-pyridyl, 2,4-dimethoxy-5-pyrimidinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chloro-3-quinolinyl, 2-chloro-6-methoxy-3-quinolinyl, 8-hydroxy-2-quinolinyl and 4-isoquinolinyl.

2-4C-Alkenyloxy represents a group, which in addition to the oxygen atom contains one of the above- mentioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the 2-butenyloxy, 3-butenyl- oxy, 1-propenyloxy and the 2-propenyloxy group (allyloxy group).

1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the abovementioned 1-4C-alkyl groups. An example which may be mentioned is the acetyl group.

Carboxy-1-4C-alkyl represents a 1-4C-alkyl group which is substituted by a carboxyl group. Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group.

1-4C-Alkoxycarbonyl-1-4C-alkyl represents a 1-4C-alkyl group, which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxy- carbonylmethyl and the ethoxycarbonylmethyl group.

Aryl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the abovementioned aryl groups. An exemplary preferred aryl-1-4C-alkyl group is the benzyl group.

Aryl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the abovementioned aryl groups. An exemplary preferred aryl-1-4C-alkoxy group is the benzyloxy group. 1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C₃H₇C(O)NH-) and the acetylamino group (acetamido group) (CH₃C(O)NH-) .

1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group.

1-4C-Alkoxy-1-4C-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-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1- 4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy)eth- oxycarbonyl (CH₃-O-CH₂CH₂-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH₃CH₂-O-CH₂CH₂-O- CO-).

1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group.

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, D-gluconic acid, benzoic acid, 2-(4-hydroxy- benzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic 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.

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 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. The compounds of the formula 1 have a centre of chirality in the 8-position. The invention thus relates to both enantiomers in any desired mixing ratio to another, including the pure enantiomers, which are a preferred subject of the invention.

Additionally, the thioamide substituent R31 R32N-C(S)- may give rise to an additional centre of chirality due to a hindered rotation of that residue around the bond, by which it is connected to the basic skeleton. The invention thus also relates to all rotamers which occur due to that hindered rotation, including the pure rotamers, which are a preferred subject matter of the invention.

Compounds to be mentioned are those of formula 1 , in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen or 1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

X is O (oxygen) or NH and

Ar is a phenyl group, substituted by R4, R5, R6 and R7, wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyl- carbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, and the salts of these compounds.

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

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

R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy R6 is hydrogen, halogen, 1-4C-alkyl and X is O (oxygen) or NH, and the salts of these compounds.

Among the compounds of formula 1 , those of the formula 1a are also preferred in which

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

R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or

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

R6 is hydrogen,

X is O (oxygen) or NH, and the salts of these compounds.

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

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

R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,

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

R5 is hydrogen,

R6 is hydrogen, halogen and

X is O (oxygen) or NH, and the salts of these compounds.

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

R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen, and

X is O (oxygen) or NH, and the salts of these compounds.

Compounds of formula 1a which are to be particularly mentioned are those in which

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

R2 is hydrogen or 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

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

R5 is hydrogen,

R6 is hydrogen or halogen and

X is O (oxygen) or NH, and the salts of these compounds.

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

R2 is hydrogen or 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen

R5 is hydrogen,

R6 is hydrogen,

X is O (oxygen) or NH, and the salts of these compounds.

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

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

R2 is hydrogen or 1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a azetidino group,

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen, and

X is O (oxygen) or NH, and the salts of these compounds.

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

R1 is 1-4C-alkyl or 3-7C-cycloalkyl, R2 is 1-4C-alkyl,

R31 is 1-4C-alkyl or 3-7C-cycloalkyl,

R32 is hydrogen or 1-4C-alkyl,

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen, and

X is O (oxygen) or NH, and the salts of these compounds.

Preferred subject of the invention are compounds of the formula 1a-1

Compounds of formula 1a which are to be particularly mentioned are those compounds of the formula

1a-1 , in which

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

R2 is hydrogen or 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen, methyl, chloro or fluoro,

R5 is hydrogen,

R6 is hydrogen or fluoro and

X is O (oxygen) or NH, and the salts of these compounds.

Compounds of formula 1a which are also to be particularly mentioned are those compounds of the formula 1a-1 , in which R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is hydrogen or 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen and

X is O (oxygen) or NH, and the salts of these compounds.

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

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

R2 is hydrogen or 1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen, methyl, chloro or fluoro,

R5 is hydrogen,

R6 is hydrogen or fluoro and

X is O (oxygen) or NH, and the salts of these compounds.

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

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

R2 is hydrogen or 1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen and

X is O (oxygen) or NH, and the salts of these compounds. Emphasis is also given to compounds of the formula 1a-1 , in which

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

R2 is 1-4C-alkyl,

R31 is 1-4C-alkyl or 3-7C-cycloalkyl,

R32 is hydrogen or 1-4C-alkyl,

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen and

X is O (oxygen) or NH, and the salts of these compounds.

Particular emphasis is given to compounds of the formula 1a-1 , in which

R1 is 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

R31 is 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen,

X is O (oxygen), and the salts of these compounds.

Particular emphasis is also given to compounds of the formula 1a-1 , in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R31 is 1-4C-alkyl,

R32 is 1-4C-alkyl,

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen,

X is O (oxygen), and the salts of these compounds.

Exemplary preferred compounds are those of the formula 1a, in which R1 , R2, R31 , R32, R4, R5 and X have the meanings given in the following table 1 (Me = CH₃, Et = C₂H₅), and the salts of these compounds. Exemplary particularly preferred compounds are those of the formula 1a-1 , in which R1 , R2, R31 , R32, R4, R5 and X have the meanings given in the following table 1 (Me = CH₃, Et = C₂H₅), and the salts of these compounds.

Table 1

Particularly preferred are the compounds given as final products of formula 1 in the examples, and the salts of these compounds.

The compounds according to the invention can be synthesised from corresponding starting compounds, for example according to the reaction scheme 1 given below, which shows in an exemplary manner the synthesis of compounds of the general formula 1 and of the general formula 1a-1. The synthesis is carried out in a manner known to the expert, for example as described in more detail in the examples which follow the scheme 1. Scheme 1 :

Lawesson^'s reagent

The compounds according to the invention can be synthesised from corresponding amide starting compounds of the formula 2, 2a or 2a-1 , for example according to the reaction scheme 1 given above. The synthesis is carried out in a manner known to the expert, for example by treatment of appropriate starting compounds with a reagent which transfers sulphur to an amide functionality, like for example phosphorus pentasulfide (P2S5), 0,0-diethyldithio-phosphonic acid, boron sulfide, silicon disulfide, elemental sulfur or in particular Lawesson's reagent [2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1 ,3,2,4- dithiadiphosphetane] which is described for example in M. P. Cava, M. I. Levinson, Tetrahedron 1985, 41, 5061-5087, or by any other method known to replace the carbonyl oxygen in amide functionalities by sulphur.

The starting compounds are known, for example, from WO 04/087701 or they can be prepared as outlined in a general way in that patent application or they can be prepared using analogous process steps or they can be prepared as outlined in the following examples from known starting materials.

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 A 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 A

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. pentagastrin (left femoral vein) about 30 min after the end of the operation (i.e. after determination of 2 preliminary fractions). The substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.

The body temperature of the animals was kept at a constant 37.8-38°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 examples below serve to illustrate the invention in more detail without limiting it. Further compounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary process techniques. The compounds named expressly as examples, and the salts of these compounds, are preferred subject matter of the invention. The abbreviation min stands for minute(s), h stands for hour(s), m.p. stands for melting point and ee for enantiomeric excess.

Furthermore the following abbreviations are used for the chemical substances indicated:

Lawesson's reagent [2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1 ,3,2,4-dithiadiphosphetane]

(S)-Xyl-P-Phos (S)-4,4'-bis-[bis-(3,5-dimethyl-phenyl)-phosphanyl]-2,6,2',6'-tetramethoxy-

[3,3']bipyridinyl

(S)-DAIPEN (2S)-(+)-1 ,1-bis(4-methoxyphenyl)-3-methyl-1 ,2-butanediamine

DIAD diisopropyl azodicarboxylate

THF tetrahydrofuran

DMF dimethylformamide

Et20 diethylether

DIPEA diisopropylethylamine

TBTU O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate

I. Final compounds of the formula 1

1. (S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid Dimethylamide

A solution of 1.1 g (3.7 mmol) (S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole- 5-carboxylic acid dimethylamide in 30 ml toluene was treated with 1.6 g (4.1 mmol) Lawesson^'s reagent and the reaction mixture was heated to 100° C overnight. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (100 ml) and washed with 50 ml saturated sodium bicarbonate solution. The layers were separated, the organic layer was dried over anhydrous magnesium sulphate and evaporated. After purification by column chromatography on silica gel (Dichloromethane / Methanol = 98:2) and crystallization from diethyl ether of the residue, were isolated 0.8 g (62%) of the title compound as a yellow solid, m.p. 246°-250° C.

2. 2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic acid cyclopropylamide A mixture of 0.18 g (0.49 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole- 5-carboxylic acid cyclopropylamide and 0.12 g (0.28 mmol) Lawesson^'s reagent in toluene (30 ml) was heated to 90° C for 2 h. After cooling to room temperature, the reaction was washed with saturated sodium bicarbonate solution and the water layer was extracted with dichloromethane (3 x 20 ml). The organic layers were dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 15:1) and crystallized from diethyl ether to afford 0.12 g (63%) of the title compound as a white solid, m.p. 183°- 185° C.

3. 2-Cyclopropyl-3-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5- carbothioic acid dimethylamide

A mixture of 0.18 g (0.48 mmol) 2-Cyclopropyl-3-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazole-5-carboxylic acid dimethylamide and 0.11 g (0.26 mmol) Lawesson^'s reagent in toluene (30 ml) was heated to 90° C for 2 h. After cooling to room temperature, the reaction was washed with saturated sodium bicarbonate solution and the water layer was extracted with dichloromethane (3 x 20 ml). The organic layers were dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 15:1) and crystallized from diethyl ether to afford 0.1 g (53%) of the title compound as a white solid, m.p. 272°- 274° C.

4. 2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carbothioic Acid Dimethylamide

A solution of 0.2 g (0.57 mmol) 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5- carboxylic acid dimethylamide in 5 ml 1 ,2-dimethoxyethane was treated with 0.3 g (0.74 mmol) Lawesson^'s reagent and the reaction mixture was heated to 50 ⁰C overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The layers were separated, the organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification by column chromatography on silica gel (ethyl acetate) and crystallization from diethyl ether/acetone yielded 0.1 g (48%) of the title compound as a solid, m.p. 178-180 ⁰C.

5. (S)-2-Methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid Dimethylamide

To a suspension of 150 mg (0.44 mmol) (S)-2-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazole-5-carboxylic acid dimethylamide in toluene (10 ml) were added 90 mg (0.22 mmol) Lawesson^'s reagent and the reaction was refluxed for 8 h. After cooling to room temperature, the reaction mixture was treated with saturated sodium bicarbonate solution and extracted with chloroform (3 x 20 ml). The organic layers were dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 15:1) to afford 107 mg (63%) of the title compound as a yellow solid, m.p. 178°-183° C.

6. (S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid Methylamide

A mixture of 0.2 g (0.59 mmol) (S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazole-5-carboxylic acid methylamide and 0.12 g (0.3 mmol) Lawesson^'s reagent in toluene (30 ml) was heated to 95° C for 2 h. After cooling to room temperature, the reaction was washed with saturated sodium bicarbonate solution and the water layer was extracted with dichloromethane (3 x 20 ml). The organic layers were dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 15:1) and crystallized from diethyl ether to afford 0.13 g (70%) of the title compound as a white solid, m.p. 179°- 183° C.

7. 1-Azetidin-1-yl-1-((S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol- 5-yl)-methanethione

A mixture of 0.15 g (0.42 mmol) (1-azetidin-1-yl-1-((S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro- chromeno[7,8-d]imidazol-5-yl)-methanone and 0.08 g (0.21 mmol) Lawesson^'s reagent in toluene (30 ml) was heated to 95° C for 5 h. After cooling to room temperature, the reaction was washed with saturated sodium bicarbonate solution and the water layer was extracted with dichloromethane (3 x 20 ml). The organic layers were dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 15:1) and crystallized from diethyl ether to afford 0.06 g (46%) of the title compound as a white solid, m.p. 242°- 245° C.

8. 2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid Dimethylamide

A suspension of 1.6 g (4.5 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole- 5-carboxylic acid dimethylamide in 10 ml toluene and 2 ml tetrahydrofuran was treated with 960 mg (2.3 mmol) Lawesson^'s reagent and the reaction was heated to 90° C overnight. After cooling to room temperature, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution and extracted with dichloromethane (3 x). The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. After purification by column chromatography on silica gel (Dichloromethane / Methanol = 20:1) and crystallization from hot ethyl acetate of the residue, 0.55 g (34%) of the title compound were isolated as a white solid, m.p. 229°-231° C. II. Starting Materials

A. Preparation of the catalyst RuCI2[(S)-Xyl-P-Phos][(S)-DAIPEN]:

(Benzene)dichlororuthenium dimer (CAS 37366-09-9, 1 equivalent) and (S)-Xyl-P-Phos (CAS 443347- 10-2, commercially available from Strem Chemicals and Alfa Aesar, 1.03 equivalents) were placed in a Schlenk flask that was evacuated and filled with argon. Anhydrous, degassed DMF (2 ml per mmol) was added and the flask was placed in an oil bath pre-heated to 105 ⁰C. The reaction was stirred at 105 ⁰C for 1.5 hours. (S)-DAIPEN (CAS 148369-91-9, commercially available from Strem Chemicals, 1.1 equivalents) was added and the reaction was stirred at room temperature for 3 hours. At this stage, a sample of the reaction mixture was diluted in chloroform-d and analysed by 31 P-NMR spectroscopy. Only the two doublets of the desired complex + the small excess of free ligand were visible. The DMF was evaporated under vacuum (heating necessary) and the residue was dissolved in anhydrous degassed dichloromethane (5-10 ml per mmol) and placed on top of a silica gel column in a Schlenk filter under argon. The product was eluted with dichloromethane / methyl tert-butyl ether = 1 :1 (v/v). The clear yellow solution was collected in a Schlenk flask and the solvent was evaporated to give a yellow/green solid that was further dried under vacuum overnight. The isolated yield was 90% (Adaptation of a general procedure described by Noyori in Angew. Chem. 1998, 110, 1792-1796).

B. 4-Benzyloxy-6-bromo-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole

To a suspension of 36.5 g (115 mmol) 4-benzyloxy-6-bromo-2-methyl-1 H-benzoimidazole and 17.7 ml (138 mmol) triethylamine in a dimethylformamide-dichloromethane mixture (10:1) were slowly dropped 24.5 ml (138 mmol) (2-chloromethoxy-ethyl)-trimethylsilane and the suspension was stirred for 5h at room temperature. The reaction was poured into water and extracted 3 x with dichloromethane. The collected organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Toluene / Dioxane = 9:1) to afford 19.5 g (39%) of the title compound as a white solid, m.p. 94°-95° C.

C. 7-Benzyloxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5- carboxylic Acid Dimethylamide

19.5 g (43.6 mmol) 4-Benzyloxy-6-bromo-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H- benzoimidazole, 4.6 g (17.9 mmol) triphenylphosphine, 1.5 g (6.5 mmol) palladium(ll) acetate and 218 ml (436 mmol) dimethylamine (2M in THF) were transferred to an autoclave and carbonylated (6 bar CO2) for 6Oh at 120° C. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Toluene / Dioxane = 2:1) to afford 13.8 g (72%) of the title compound as a white solid, m.p. 118°-120° C. D. y-Hydroxy^-methyl-S^-trimethylsilanyl-ethoxymethyO-SH-benzoimidazole-δ-carboxylic Acid Dimethylamide

A solution of 13.7 g (31.1 mmol) 7-benzyloxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H- benzoimidazole-5-carboxylic acid dimethylamide in 1.2 L ethanol was hydrogenated over 1.4 g 10% Pd/C in autoclave (5 bar H2) for 16h at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from diisopropyl ether to afford 10.1 g (93%) of the title compound as a white solid, m.p. 154°-156° C.

E. 7-Hydroxy-2-methyl-6-(3-oxo-3-phenyl-propyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H- benzoimidazole-5-carboxylic Acid Dimethylamide

A solution of 10 g (28.6 mmol) 7-hydroxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H- benzoimidazole-5-carboxylic acid dimethylamide in 600 ml dichloromethane was treated with 6.4 g (34.3 mmol) N,N-dimethylenimmonium iodide and the reaction was stirred for 3h at room temperature. The reaction mixture was poured into a sat. sodium hydrogencarbonate solution and extracted twice with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue (11.3 g; 98%) was suspended in toluene (250 ml) and 7.2 g (41.6 mmol) acetophenone pyrrolidine were added. The suspension was refluxed for 3h and after cooling to room temperature, the solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Ethyl acetate / Petroleum ether = 5:1) to afford 10.6 g of a beige solid which was dissolved in acetone and treated with fumaric acid. The precipitate was filtered, dissolved in dichloromethane-methanol and the solution was neutralized with 1 M NaOH solution. The layers were separated, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue afforded 9.7 g (73%) of the title compound as a brown solid, m.p. 192°-194° C.

F. (3R)-7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2-methyl-3-(2-trimethylsilanyl- ethoxymethyl)-3H-benzoimidazole-5-carboxylic Acid Dimethylamide

In a flask filled with argon, 6.4 g (13.2 mmol) 7-hydroxy-2-methyl-6-(3-oxo-3-phenyl-propyl)-3-(2- trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid dimethylamide were dissolved in 9.3 ml isopropanol, 2.7 ml water, 10 ml tert-butanol and 14.6 ml 1 M tert-butylate solution. 33 mg of the Hydrogenation catalyst RuCI2[(S)-Xyl-P-Phos][(S)-DAIPEN] were added and the mixture was transferred into an autoclave and hydrogenated at 65° C and 80 bar pressure for 2Oh. After cooling to room temperature and releasing of the hydrogen pressure, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Dichloromethane / Methanol = 15:1) to afford 4.9 g (77%; ee 94%) of the title compound as a white solid, m.p. 142°-143° C.

G. (δS)-2-Methyl-δ-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3,6,7,δ-tetrahydro- chromeno[7,8-d]imidazole-5-carboxylic Acid Dimethylamide

To a solution of 3.3 g (6.8 mmol) (3R)-7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2-methyl-3-(2- trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid dimethylamide in 100 ml tetrahydrofuran were added 5.2 g (19.7 mmol) triphenylphosphine and 4 ml (20.5 mmol) DIAD and the mixture was stirred for 90 min. at room temperature. The reaction was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 250 ml sat. ammonium chloride solution. After separation of the phases, the aqueous layer was extracted twice with ethyl acetate. The collected organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Toluene / Ethyl acetate = 1 :1) to afford 3.0 g (98%) of the title compound as a beige solid.

1 H-NMR (DMSO-d6, 200 MHz): δ = - 0.1 (s, 9H, 3 Me), 0.8 (t, 2H, CH2SiMe3), 2.0-2.3 (m, 2H), 2.5 (s, 3H, Me), 2.78 (s, 3H, NMe), 3.03 (s, 3H, NMe), 3.3 (s, 3H, Me), 3.52 (t, 2H, OCH2), 5.21 (dd, 1 H), 5.51 (s, 2H, NCH2O), 7.02 (s, 1 H), 7.31-7.70 (m, 5H, Ph).

H. (S)-2-Methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic Acid Dimethylamide Oxalic Acid

A solution of 3.6 g (7.7 mmol) (8S)-2-methyl-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3,6,7,8- tetrahydro-chromenop.δ-dJimidazole-S-carboxylic acid dimethylamide in 30 ml dichloromethane was cooled to 0° C and then treated with 3.9 ml (30.9 mmol) BF3. Et20. The reaction mixture was stirred at room temperature for 2Oh. The solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 10:1) and crystallized by treatment with oxalic acid (1.0 eq) in acetone to afford 930 mg (28%) of the title compound as oxalate, m.p. 216° C

I. δ-Methoxy-2,3-dimethyl-δ-phenyl-3,6,7,δ-tetrahydro-chromeno[7,δ-d]imidazole-5- carboxylic Acid Ethyl Ester

70 ml (570 mmol) 2,2-Dimethoxypropane were added to a solution of 13.9 g (37.9 mmol) 7-hydroxy- 2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzoimidazole-5-carboxylic acid ethyl ester in dichloromethane (170 ml). After slow adding of 3.2 ml (49.3 mmol) methanesulfonic acid, the obtained red solution was refluxed for 16h. After cooling to room temperature, the reaction mixture was poured into a mixture of 170 ml sat. sodium hydrogencarbonate solution and 140 ml dichloromethane. The phases were separated and the aqueous layer was extracted with dichloromethane (2 x 50 ml). The collected organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diisopropyl ether to afford 13.2 g (92%) of the title compound as a beige solid, m.p. 176°-178° C.

J. δ-Methoxy-2,3-dimethyl-δ-phenyl-3,6,7,δ-tetrahydro-chromeno[7,δ-d]imidazole-5- carboxylic Acid

To a suspension of 13.1 g (34.4 mmol) 8-methoxy-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro- chromeno[7,8-d]imidazole-5-carboxylic acid ethyl ester in methanol (290 ml) were added 35 ml potassium hydroxide (2M in water) and the mixture was heated to 55° C for 16h. After cooling to room temperature, the solvent was removed in vauo and the residue was suspended in 300 ml water. The suspension was adjusted to pH 5-6 by adding 2M aq. HCI solution and the solution was stirred for 1h at room temperature. The precipitate was isolated by filtration and dried in vacuo to afford 12 g (99%) of the title compound as a beige solid, m.p. 288°-289° C.

K. δ-Methoxy-2,3-dimethyl-δ-phenyl-3,6,7,δ-tetrahydro-chromeno[7,δ-d]imidazole-5- carboxylic Acid Methylamide

A solution of 6 g (17 mmol) 8-methoxy-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazole-5-carboxylic acid in dimethylformamide (60 ml) was treated with 6.5 g (20.4 mmol) TBTU, 7.3 ml (42.6 mmol) DIPEA and was stirred for 1 h at room temperature. 11.5 ml (29 mmol) Methylamine (2M in THF) were added and the reaction mixture was stirred for 2h at room temperature. The mixture was poured into water (400 ml), the precipitate was filtered and dried in vacuo to afford 5.2 g (84%) of the title compound as a white solid, m.p. 237°-239° C.

L. 7-Hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzoimidazole-5-carboxylic Acid Methylamide

A suspension of 5.1 g (14 mmol) 8-methoxy-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazole-5-carboxylic acid methylamide in THF (75 ml) was treated with 1 N hydrochloric acid (30 ml) and the mixture was heated to 50° C for 3h. After cooling to 5° C, the reaction mixture was cautiously poured into water (100 ml) and neutralized with 2M NaOH. The precipitate was filtered and dried in vacuo to afford 4.4 g (90%) of the title compound as a white solid, m.p. 284°-285° C. M. (3R)-7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzoimidazole-5- carboxylic Acid Methylamide

In a flask filled with argon, 4.4 g (12.5 mmol) 7-hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H- benzoimidazole-5-carboxylic acid methylamide were suspended in isopropanol (30 ml), water (5 ml), and 15 ml 1 M tert-butylate solution. 31 mg of the Hydrogenation catalyst RuCI2[(S)-Xyl-P-Phos][(S)- DAIPEN] were added and the suspension was transferred into an autoclave and hydrogenated at 65° C and 80 bar pressure for 3d. After cooling to room temperature and releasing of the hydrogen pressure, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Dichloromethane / Methanol = 10:1) to afford 2.2 g (52%) of the title compound as a light green solid, m.p. 247°-249° C.

N. (8S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic Acid Methylamide

To a suspension of 1 g (2.8 mmol) (3R)-7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H- benzoimidazole-5-carboxylic acid methylamide and 2.1 g (8.1 mmol) triphenyl-phosphine in 50 ml tetrahydrofuran were added 1.6 ml (8.4 mmol) DIAD and the suspension was stirred overnight at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (Dichloromethane / Methanol = 10:1) to afford 0.7 g (75%; ee 75%) of the title compound as a white solid, m.p. 290°-291° C

O. i-Azetidin-i-yl-i-tδ-methoxy^.S-dimethyl-δ-phenyl-S.GJ.δ-tetrahydro-chromeno^.δ- d]imidazol-5-yl)-methanone

A solution of 6 g (17 mmol) 8-methoxy-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazole-5-carboxylic acid in dimethylformamide (60 ml) was treated with 6.5 g (20.4 mmol) TBTU, 7.3 ml (42.6 mmol) DIPEA and was stirred for 1h at room temperature. 2 ml (29 mmol) Azetidine were added and the reaction mixture was stirred for 2h at room temperature. The mixture was poured into water (400 ml), the precipitate was filtered and dried in vacuo to afford 4.8 g (72%) of the title compound as a beige solid, m.p. 147°-150° C.

P. 3-[6-(1 -Azetidin-1 -yl-methanoyl)-4-hydroxy-1 ,2-dimethyl-1 H-benzoimidazol-5-yl]-1 - phenyl-propan-1 -one A suspension of 4.7 g (12 mmol) 1 -azetidin-1 -yl-1 -(8-methoxy-2,3-dimethyl-8-phenyl-3,6,7,8- tetrahydro-chromeno[7,8-d]imidazol-5-yl)-methanone in THF (75 ml) was treated with 1 N hydrochloric acid (30 ml) and the mixture was heated to 50° C for 2h. After cooling to room temperature, the reaction mixture was cautiously poured into water (100 ml) and neutralized with 2M NaOH. The precipitate was filtered and dried in vacuo to afford 2.9 g (65%) of the title compound as a white solid, m.p. 242°-243° C.

Q. (3R)-1 -Azetidin-1 -yl-1 -[7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H- benzoimidazol-5-yl]-methanone

In a flask filled with argon, 2.8 g (7.6 mmol) 3-[6-(1 -azetidin-1 -yl-methanoyl)-4-hydroxy-1 , 2-dimethyl- 1 H-benzoimidazol-5-yl]-1-phenyl-propan-1-one were suspended in isopropanol (18.2 ml), water (3 ml), and 9.1 ml 1 M tert-butylate solution. 22 mg of the Hydrogenation catalyst RuCI2[(S)-Xyl-P-Phos][(S)- DAIPEN] were added and the mixture was transferred into an autoclave and hydrogenated at 65° C and 80 bar pressure for 2d. After cooling to room temperature and releasing of the hydrogen pressure, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Dichloromethane / Methanol = 10:1) to afford 0.93 g (32%; ee 92%) of the title compound as a beige solid, m.p. 265°-266° C.

R. (8S)-1 -Azetidin-1 -yl-1 -(2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8- d]imidazol-5-yl)-methanone

To a suspension of 0.8 g (2.2 mmol) (3R)-1 -azetidin-1 -yl-1 -[7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)- 2,3-dimethyl-3H-benzoimidazol-5-yl]-methanone and 1.6 g (6.3 mmol) triphenyl-phosphine in 40 ml tetrahydrofuran were added 1.3 ml (6.5 mmol) DIAD and the mixture was stirred overnight at room temperature. The precipitate was filtered and dried in vacuo at 40° C to afford 0.6 g (76%; ee 90%) of the title compound as a white solid, m.p. 241°-242° C lndustrial applicability

The compounds of the formulae 1 , 1a and 1a-1 and their pharmacologically 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 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, an advantageous duration of action, a particularly good enteral activity, the absence of significant side effects and a large therapeutic range.

"Gastric and intestinal protection" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations. "Gastric and intestinal protection" is understood to include, according to general knowledge, gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation.

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.

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 medicaments are prepared by processes which are known per se and familiar to the person skilled in the art. As medicaments, the active compounds according to the invention (= active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and it being possible to obtain a pharmaceutical administration form exactly adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained-release form or an enteric form) by means of the appropriate selection of the auxiliaries and excipients.

The auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge. In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).

The active compounds can be administered orally, parenterally or percutaneously.

In general, it has proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, preferably 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 4, individual doses to achieve the desired result. 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. 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.

If the active compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, for example: tranquillizers (for example from the group of the benzodiazepines, for example diazepam), spasmolytics (for example, bietamiverine or camylofine), anticholinergics (for example, oxyphencyclimine or phencarbamide), local anesthetics, (for example, tetracaine or procaine), and, if appropriate, also enzymes, vitamins 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 inhibit acid secretion, such as, for example, H₂ blockers (e.g. cimetidine, ranitidine), H⁺/K⁺ ATPase inhibitors (e.g. omeprazole, pantoprazole), or further with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and with gastrin antagonists with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or of decreasing the side effects, or further the combination with antibacterially active substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts) for the control of Helicobacter pylori. Suitable antibacterial co-components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and combinations thereof (for example clarithromycin + metronidazole).

In view of their excellent gastric and intestinal protection action, the active compounds according to the invention are suited for a free or fixed combination with those medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs), which are known to have a certain ulcerogenic potency. In addition, the compounds of formula 1 are suited for a free or fixed combination with motility-modifying drugs.

Claims

1. A compound of the formula 1

in which

R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C- alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C- cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl,

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

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

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

R7 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and its salts.

2. A compound of the formula 1 as claimed in claim 1 in which

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

R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

X is O (oxygen) or NH and

Ar is a phenyl group, substituted by R4, R5, R6 and R7, wherein

R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, and its salts.

3. A compound of the formula 1 as claimed in claim 1 , characterized by the formula 1 a,

in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy R6 is hydrogen, halogen, 1-4C-alkyl and X is O (oxygen) or NH, and its salts.

4. A compound of the formula 1a as claimed in claim 3, in which

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

R2 is hydrogen or 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

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

R5 is hydrogen,

R6 is hydrogen or halogen and

X is O (oxygen) or NH, and its salts.

5. A compound of the formula 1a as claimed in claim 3, in which

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

R2 is hydrogen or 1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen, and X is O (oxygen) or NH, and its salts.

6. A compound of the formula 1a as claimed in claim 3, characterized by the formula 1a-1

)

in which

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

R2 is hydrogen or 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen, methyl, chloro or fluoro,

R5 is hydrogen,

R6 is hydrogen or fluoro and

X is O (oxygen) or NH, and its salts.

7. A compound of the formula 1a-1 as claimed in claim 6,

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

R2 is hydrogen or 1-4C-alkyl,

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

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen

R5 is hydrogen,

R6 is hydrogen and

X is O (oxygen) or NH, and its salts.

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

R1 is 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

R31 is 1-4C-alkyl,

R32 is hydrogen or 1-4C-alkyl, or where

R4 is hydrogen,

R5 is hydrogen,

R6 is hydrogen,

X is O (oxygen), and its salts.

9. A compound which is selected from the group consisting of (S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid

Dimethylamide 2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic acid cyclopropylamide 2-Cyclopropyl-3-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic acid dimethylamide 2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carbothioic Acid

Dimethylamide

(S)-2-Methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid Dimethylamide (S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid

Methylamide 1-Azetidin-1-yl-1-((S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)- methanethione and

2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carbothioic Acid Dimethylamide and its salts.

10. A medicament comprising a compound as claimed in claim 1 and/or a pharmacologically acceptable salt thereof together with customary pharmaceutical auxiliaries and/or excipients.

11. The use of a compound as claimed in claim 1 and its pharmacologically acceptable salts for the prevention and treatment of gastrointestinal disorders.