ZA200503910B

ZA200503910B - 4-substituted benzimidazoles and their use as inhibitors of gastric secretion

Info

Publication number: ZA200503910B
Application number: ZA200503910A
Authority: ZA
Inventors: Vittoria Chiesa; Christof Brehm; Joerg Senn-Bilfinger; Stefan Postius; Peter J Zimmermann; Andreas Palmer; Gerhard Grundler; Wolfgang-Alexander Simon; Wolfgang Kromer
Original assignee: Altana Pharma Ag
Priority date: 2002-12-13
Filing date: 2005-05-16
Publication date: 2006-07-26
Also published as: UA79843C2; CN1720236A

Description

4- SUBSTITUTED BENZIMIDAZOLES AND THEIR USE AS INHIBITORS OF GASTRIC SECRETION

Technical field

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

Prior art

In the 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. The international patent application WO 97/47603 (which corresponds to US Patent 6,465,505) discloses benzimidazole derivatives substituted by a 2,8-dialkyl phenyl moiety, which are effective as inhibitors of the H' K'-ATPase.

Summary of the invention ~The invention relates to compounds of the formula 1 rz

R3 N )—R1 vx in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyt, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4GC-alky!

R2 Is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkyicarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy

R3 is hydrogen, halogen, fiuoro-1 -4C-alkyl, carboxyl, -CO-1 -4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1 -4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO-NR31 R32 or the group Het, where ‘

R31is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, amino and

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

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

Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist- ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where

R33 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,

R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy,

R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy,

X is O (oxygen) or NH and

Y has either the meaning —-CHz-Ar wherein

Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazoly), fury, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp

R4 wk (9p) z wherein

Z has the meaning ~CHR8- or -CHR8-CHRS- where in, Ar and/or in the group gp

R4 is hydrogen, 1-4C-alkyi, 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, halo- gen, hydroxy, aryl, aryl-1-4C-alkyi, 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-alkoxycarbonyi, halogen, trifluoromethyl or hy- droxy,

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

R7 is hydrogen, 1-4C-alkyl or halogen,

RS is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-

alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1 -4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-alkoxy-1 4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy

R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- of di-1-4C- alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-alkoxy-1 -4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy, : and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes —CH-Ar and

R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, and the salts of these compounds. 1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group. 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which . cyclopropyl, cyclobutyl and cyclopentyl are preferred. 3-7C-Cycloalkyl-1-4C-alkyi represents one of the aforementioned 1-4C-alky! groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be men- tioned 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 bran- ched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group. 1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxy- methyl, the methoxyethyl group and the butoxyethyl group. 1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) represents a carbonyl group, to which one of the aforemen- tioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH30-C(O)-) and the ethoxycarbonyl group (CHsCH.0-C(O)-) .

2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 4 carbon atoms. Exam- ples 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. Exam- ples which may be mentioned are the 2-butynyl, 3-butynyi, and preferably the 2-propynyl, group (propargyl group).

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

Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl group. 1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the afo- rementioned 1-4C-alkyl groups. An example which may be mentioned Is the acetyl group.

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

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

Fluoro-2-4C-alkyl represents a 2-4C-alkyl groups, which is substituted by one or more fluorine atoms.

An example which may be mentioned is the 2,2,2-trifluoroethyl group.

Aryl-1-4C-alkoxy denotes an aryl-substituted 1-4C-alkoxy radical. An example which may be mentioned is the benzyloxy radical.

Aryl-1-4C-alkoxy-1-4C-alkyl denotes one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned aryl-1-4C-alkoxy radicals. An example which may be mentioned is the benzyloxymethyl radical.

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

1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substi- tuted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH3s-0-CHCHZO-) and 2-(ethoxy)ethoxy (CH3-CHzO-CH2-CH: -0-). 1-4C-Alkoxy-1 -4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkoxy-1 -4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example which may be mentioned is the group 2-{methoxy)ethoxymethy! (CHs-O-CHz-CH,-O-CHy).

Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substi- tuted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case represents one of the aforemen- tioned 1-4C-alkoxy groups, which is completely or mainly substituted by fluorine. Examples of com- pletely or mainly fluoro-substituted 1-4C-alkoxy groups which may be mentioned are the 1,1,1,3,3,3- hexafluoro-2-propoxy, the 2.trifluoromethyl-2-propoxy, the 1,1 ,1-trifluoro-2-propoxy, the perfiuoro-tert- butoxy, the 2,2,3,3,4,4,4-heptaflucro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2.2,3,3,3-penta- fluoropropoxy, the perfiuoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-triflucroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group. 1-7C-Alkyl represents straight-chain or branched alkyl! groups having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neo- hexy! (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobu- tyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group. 2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the abovemen- tioned 2-4C-alkenyi groups. Examples, which may be mentioned, are the 2-butenyloxy, 3-butenyloxy, 1- propenyloxy and the 2-propenyloxy group (altyloxy group).

Carboxy-1-4C-alkyl represents 1-4C-alkyl groups which are substituted by a carboxyl group. Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group. 1-4C-Alkoxycarbonyl-1-4C-alkyl represents 1-4C-alky! groups, which are substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxy- carbonylmethyl and the ethoxycarbonylmethyt group.

Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example which may be mentioned is the benzyl radical. 1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded.

Examples which may be mentioned are the propionylamino (CsH;C(O)NH-) and the acetylamino group (acetamido group) (CHaC(O)NH-) .

1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforemen- tioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group. 1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy)- ethoxycarbonyl (CH3-O-CH,CH,-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CHsCH2-O-CH,CHz- 0-CO-). 1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyt groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group. 2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon atoms. Exam- ples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred. 2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon atoms. Exam- ples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkeny! groups are preferred.

Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy group, which instead of a methylene group con- tains a carbonyt group. An example which may be mentioned is the 2-oxopropoxy group. 3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred. 3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is sub- stituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylimethoxy, the cyclobutylmethoxy and the cyclohexylethoxy group.

Hydroxy-1-4C-alkoxy represents aforementioned 1-4C-alkoxy groups, which are substituted by a hy- droxy group. A preferred example which may be mentioned is the 2-hydroxyethoxy group. 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups. A preferred exam- ple which may be mentioned is the methoxyethoxyethoxy group. 3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups. Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexyloxyethoxy group.

, 3-7C-Cycloalkyl-1 -4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1 -4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyciobutyimethoxyethoxy and the cyclohexy- lethoxyethoxy group. 1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy group (CH5CO-0-). 1-4C-Alkylcarbonyloxy-1-4C-alky! represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkylcarbonyloxy groups. An example which may be mentioned is the acetoxymethyl group (CH3CO-0-CHy).

Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halo- gen. "Mainly" in this connection means that more than haif of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms. Halo-1-4C-alkoxy groups are primarily chloro- and/or in particu- lar fluoro-substituted 1-4C-alkoxy groups. Examples of halogen-substituted 1-4C-alkoxy groups which may be mentioned are the 2,2 2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1,1,1-trichloro-2-methyl-2-propoxy, the 1,1,1-trichloro-2- propoxy, the 3-bromo-1 ,1,1-trifluoro-2-propoxy, the 3-bromo-1, 1, 1-trifluoro-2-butoxy, the 4-bromo- 3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1,1,1 ,3,3,3-hexafluoro-2-propoxy, the 2- trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfiuoro-tert-butoxy, the 2,2,3,3,4,44- heptafluoro-1-butoxy, the 4,4 A-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-triflucroethoxy, the trifluo- romethoxy and preferably the difluoromethoxy group.

Mono- or di-1-4C-alkylamino-1 -4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy ~~ group. 1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C-alkylcarbonyloxy radi- cals which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example, which may be mentioned, is the methoxymethylcarbonyloxy group.

Possible salts of compounds of the formula 1 or 2 - 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- hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fu- maric 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 - de- pending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an equimo- lar 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 inven- tion 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) comprises compounds of the formula 1, in which

R1 is mono- or di-1-4C-alkylamino

R2, R3, X and Y have the meanings given above in the summary of the invention with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes ~CHz-Ar and

R2 denotes hydrogen, 1-4C-alky! or 3-7C-cycloalkyl-1-4C-alkyl, and the salts of these compounds.

One embodiment (embodiment b) comprises compounds of the formula 1, in which

R1 is 1-4C-alkylcarbonyloxy-1-4C-alkyl and

R2, R3, X and Y have the meanings given above in the summary of the invention and the salts of these compounds.

Another embodiment (embodiment ¢) comprises compounds of the formula 1, in which

R2 is hydroxy or 1-4C-alkoxy and

R1, R3, X and Y have the meanings given above in the summary of the invention and the salts of these compounds.

Another embodiment (embodiment d) comprises compounds of the formula 1, in which

R3 is cyano, the group SO-NR31R32 or the group Het and where

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

R32 is hydrogen, 1-7C-alky!, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where

Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where

R33 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,

R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy, where

R1, R2, X and Y have the meanings given above in the summary of the invention and the salts of these compounds.

Another embodiment (embodiment e) comprises compounds of the formula 1, in which

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

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkyicarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl

R3 is hydrogen, halogen, fiuoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where

R31is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl and

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

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

X is O (oxygen) or NH and

Y has either the meaning —CH,-Ar wherein

Ar is a mono- or bicyclic aromatic residue, substituted by R4, RS, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, fury], benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,

or Y denotes the group gp

R4 wk (gp)

Zz wherein

Z has the meaning -CHR8- or —CHR8-CHRO9- where in Ar and/or in the group gp

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo- gen, 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,

RS is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy,

R6is hydrogen, 1-4C-alkyl or halogen and

R7is hydrogen, 1-4C-alkyl or halogen,

RS is hydrogen, 1-7C-alkyl, 2-7G-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkyicarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonyiamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy

R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloatkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-~cycloalkyi-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 4-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy, . and wherein aryl is phenyl! or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CHz-Ar, and the salts of these compounds.

Another embodiment (embodiment f) comprises compounds of the formula 1, in which

R1 Is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyi, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fiuoro-1-4C-alkyl or hydroxy-1-4C- alkyl,

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyi,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, . -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where

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

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

X is O (oxygen) or NH and

Y has either the meaning —CHzx-Ar wherein

Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyt, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp

R4 wk (9p) z wherein

Z has the meaning -CHR8- or -CHR8-CHR9- where in Ar and/or in the group gp

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo- gen, 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 hy- droxy,

R6 is hydrogen, 1-4C-alky! or halogen and

R7 is hydrogen, 1-4C-alkyl or halogen,

RS is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C~cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloaikoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-14C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy or 1-4C-alkoxy-1-4C-alkoxycarbonylamino,

RS is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyt-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoXxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1 -4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkyicarbonyloxy or 1-4C-alkoxy-1-4C-alkoxycarbonylamino 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, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes ~CH-Ar, and the salts of these compounds.

In one aspect, the invention relates to compounds of the formula 1a

R3 J

N oh (1a)

Ar in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-aikoxy-1-4C-alkoxy-1 -4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO,-NR31 R32 or the group Het, where

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

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

or where

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

R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyt or hy- droxy,

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, ben- zimidazolyl, furyl, benzofuryl, thienyl, benzothienyt, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, 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, halo- gen, hydroxy, aryl, aryl-1-4C-alkyi, aryl-oxy, aryl-1-4C-alkoxy, trifiuoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyicarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, .1-4C-alkoxycarbonyi, halogen, trifluoromethyl or hy- droxy,

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, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes —CHz-Ar and

R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, : and the salts of these compounds

In another aspect, the invention relates to compounds of the formula 1a in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkyny!, fiuoro-1-4C-alkyl or hydroxy-1-4C- alkyl,

R2 is hydrogen, 1-4C-alkyl, aryi, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl

R3 is fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alky!, 1- 4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1 -4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where

X is O (oxygen) or NH and

Ar is a mono- or bicyclic aromatic residue, substituted by R4, RS, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, ben- zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyicarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo- gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyicarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

RS5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy,

R6is hydrogen, 1-4C-alkyl or halogen and

R7is 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.

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyi, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C- alkyl,

R2 is hydrogen, 1-4C-alkyl, aryl, 3.7C-cycloalkyl, 3-7C-cycloatkyt-1 -4C-alkyl,’ 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1 -4C-alkylcarbonyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alky!

R3 is fluoro-1-4C-alkyl, carboxyl, -CO-1 -4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1 -4C-alkyl, 1-

AC-alkoxy-1-4C-alkoxy-1 AC-alkyl, fluoro-1-4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where

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

X is O (oxygen) or NH and

Ar is a mono- or bicyclic aromatic residue, substituted by R4, RS, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyi, ben- zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyicarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1 -4C-alkyl, halo- gen, 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 of hy- droxy,

RB 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, trifiuoromethyi, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.

In another aspect, the invention relates to compounds of the formula 1b

R3 J )—R1

R4 jg wk J (1b) r4 in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C<cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7Ccycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbony!, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1 -4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, , the group SO,-NR31R32 or the group Het, where

R31is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, amino and

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

R33 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-alkyi, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryt-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,

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyicarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyi, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy- droxy, 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,

X is O (oxygen) or NH and

Z has the meaning ~CHR8- or -CHR8-CHR9- where

R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-

alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamine, 1-4C-alkoxycarbonylamino, mono- of di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy,

R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkyicarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- of di-14C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.

In another aspect, the invention relates to compounds of the formula 1b in which

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

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycioatkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, filuoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alky!

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, '1-4C-alkoxy-1-4C-alkoxy-1-4C-alky, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where

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

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

R4 is hydrogen, 1-4C-alkyi, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy- droxy, aryl, aryl-1-4C-alkyt, 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,

X is O (oxygen) or NH and

Zz has the meaning -CHR8- or -CHR8-CHR®- where .

R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-, alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonyliamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy,

R9 is hydrogen, 1-7C-alky}, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyi, fiuoro-1-4C-alky! or hydroxy-1-4C- alkyl,

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alky! or fluoro-2-4C-alkyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group —CO-NR31R32, where

R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-atkyl 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-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy-

droxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifiuoromethyi, nitro, amino, mono- or di-1- 4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or sulfonyl,

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

X is O (oxygen) or NH and

Z has the meaning —~CHR8- or -CHR8-CHRS- where

RS is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1 -4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1 -4C-alkoxy, amino, mono- or di-1-4C~ alkylamino, 1-4C-alkyicarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy or 1-4C-alkoxy-1-4C-alkoxycarbonylamino,

RQ is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycioalkoxy, 3-7C-cycloalkyl-1 -4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloatkoxy-1-4C-alkoxy, 3-7C-cycloalkyt-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1 -4AC- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy or 1-4C-alkoxy-1-4C-alkoxycarbonytamino, and wherein aryl is phenyl or substituted phenyt with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.

The compounds of the formula 1b have up to three chiral centers in the parent structure. The invention thus relates to all conceivable stereoisomers in any desired mixing ratio to one another, including the pure enantiomers, which are a preferred subject of the invention.

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

R3 J

Rt joe

X (1a-1)

A in which

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

R2 is hydrogen, 1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1 -AC-alkoxy-1-4C-alkyl

R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-

NR31R32, the group SO.-NR31R32 or the group Het, where

R31is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and

R32 is hydrogen or 1-7C-alkyl, or where

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

Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist- ing of oxadiazol, dihydrooxazol and dihydroimidazol, where

R33 is hydrogen or 1-4C-alkyl,

R34 is hydrogen or 1-4C-alkyl

R35 is hydrogen or 1-4C-alkyl

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

AC-alkoxy-1-4C-alkoxycarbonylamino,

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

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

Among the compounds of the formula 1a, particularly preferred compounds are those of the formula 1a-1 : where

R1 Is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group -CO-

NR31R32, where

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

R32 is hydrogen or 1-7C-alkyl, or where

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,

RS is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and

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

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

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

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

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

R32 is hydrogen or 1-4C-alkyl,

R4 is 1-4C-alkyl or 1-4C-alkyicarbonylamino,

R5 is 1-4C-alkyl,

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

Among the compounds of the formula 1b, compounds of the formula 1b-1

R3 5 )—Ri

R4 N ot Oy (1b-1)

R8 are preferred.

Preferred exemplary compounds of the formula 1b-1 are those, in which

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

R2 is hydrogen or 1-4C-alkyl,

R3 Is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1 -4C-alkoxy-1-4C-aikyl or the group -CO-NR31R32, where

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

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

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

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

R5 is hydrogen or 1-4C-alkyl,

R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3- 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycioalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyicarbonylamino, 1-4C- alkoxycarbonylamino, mono- of di-1-4C-alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkyicarbonyloxy

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

Particularly preferred exemplary compounds of the formula 1b-1 are those, in which

R1 is 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

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

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

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

R5 is hydrogen or alkyl,

R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3- 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-14C-alkoxy, amino, mono- or di-1 -4C-alkyltamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy

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

Still particularly preferred exemplary compounds of the formula 1b-1 are those, in which

R1 is 1-4C-alkyl,

R2 is hydrogen or 1-4C-alkyl,

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

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

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

R5 is hydrogen,

R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3- 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy

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

Preferred compounds are those of the formula 12-1.

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 com- pounds, 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 starting compounds are known, for example from M. W. Lovell, 8. G. Schulman, Anal. Chem. 1983, 55, 963-965 (e. g. 4-bromo-6-nitro-1,2-phenylenediamine). 6-Halo,4-nitro-substituted benzimida- zoles are known in literature, for example 6-chloro-2-methyl-4-nitro-1 (3)H-benzimidazole (Gillespie et al., J. Org. Chem. 1960, 25, 942) or they can be prepared using analogous process steps. 1,2-

Epoxyindan is described for example in W. F. Whitmore, A. |. Gebhart, J. Am. Chem. Soc. 1942, 64, 912. In general, substituted alkyl-, alkoxy- or halogeno-epoxyindanes can be prepared from the corre- sponding substituted indenes by methods known from literature (e.g. epoxidation). The compounds of the general formula 1a can be obtained by reacting substituted benzimidazoles of formula | with com- pounds of formula It as depicted in scheme 1. ‘

Scheme 1:

R2 R2 >r + — )—R1

N Ar N

XH o

I, X=0, NH n Ar 1a, X=0, NH

Analogously, compounds of the general formula 1b are obtained by reacting substituted benzimidazoles of formula | with epoxyindanes il, carrying any desired substituent R4 and RS (cf. scheme 2 for a com- pound 1b-1).

Scheme 2:

R3 Fe

R3 J Ré4 N )—R1

JR + — R N

N

R5

XH rac. RS KX

I, X=0, NH in OH 1b-1, X=0, NH

The reaction steps outlined above are carried out in a manner known per se, €. g. as described in more detail in the examples. The derivatization, if any, of the compounds obtained according to the above

Scheme 1 and 2 (e.g. conversion of a group R3 into another group R3, or of R2 = H into another group

R2, or conversion of the hydroxyl group into an alkoxy or ester group) is likewise carried out in a man- ner known per se. if compounds where R3 = -CO-1-4C-alkoxy or R3 = -CO-NR31R32 are desired, an appropriate derivatization can be performed in a manner known per se (e. g. metal catalysed carbonyla- tion of the corresponding bromo compound or conversion of an ester into an amide) at the stage of the benzimidazoles of formula | (scheme 1 and 2) or more conveniently at a later point in time.

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 proc- ess techniques. The abbreviation min stands for minute(s), h for hour(s) and m.p. for melting point.

Examples 1.Starting materials

A, 2-Benzyloxy-4-bromo-6-nitro-aniline

To a suspension of 50 g (325 mmol) 2-amino-3-nitrophenol, 45 g (325 mmol) potassium carbonate and 2 g (13 mmol) sodium iodide in 400 mi ethanol were added 47 mi (408 mmol) benzyl! chloride and the mixture was heated to 80 °C. After 2 b, the reaction mixture was cooled down and the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Coevaporation with dichloromethane led to a dark brown oily residue which was dissolved in 400 ml acetonitrile. After addition of 63.4 g (356 mmol)

N-bromosuccinimide, the reaction mixture was refluxed for 1 h. After cooling down, 400 g of silica gel were added and the mixture was evaporated to dryness. The resulting solid was purified by column chromatography on silica gel using ethyl acetate: light petroleum ether (4:1). Evaporation of the eluent left a solid which was recrystallized from ethyl acetate/n-heptane to give 62 g (59 %) of the title com- pound as a red solid (m.p. 90 °C).

B. N-Acetyl-N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-acetamide

A suspension of 20 g (62 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in 120 ml acetic anhydride and 2 mi methanesulphonic acid was heated to 120 °C. After complete reaction (15 min), excess acetic anhy- dride was evaporated. The residue was dissolved in dichloromethanel/water and neutralized with 6N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous magnesium sul- phate and evaporated. Crystaliization of the residue from ethy! acetate/n-heptane yielded 23.2 g (92 %) of the title compound as a beige solid (m.p. 148 °C).

C. N-{2-Amino-6-benzyloxy-4-bromo-phenyl)-acetamide

A suspension of 23 g (56 mmot) N-acetyl-N-(2-benzyloxy-4-bromo-6-hitro-phenyl)-acetamide, 55g(34 mmol) iron(lll) chloride and 13.8 g activated charcoal in 600 m! methanol was heated to reflux. To the reaction mixture were added 28 ml hydrazine hydrate (95 %) to maintain gentle reflux. After complete reaction (2 h), the mixture was cooled down and filtered through celite. The filter cake was washed thoroughly with dichloromethane/methanol and the filtrate was evaporated to dryness. The residue was partitioned between dichloromethane/methanol and water. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and evaporated. The residue was recrystallized from boiling ethyl acetate/n-heptane to give 12.3 g (65 %) of the tittle compound as a colourless solid (m.p. 185 °C).

D. N-(2-Benzyloxy-4-bromo-8-dimethylamino-phenyl)-acetamide

A suspension of 5.0 g (15 mmol) N-(2-amino-6-benzyloxy-4-bromo-phenyl)-acetamide in 80 ml metha- nol and 34 ml formaldehyde (37 %) was acidified with saturated methanolic hydrogen chloride to give a clear yellow solution. To the solution were added 1.5 g (24 mmol) sodium cyanoborohydride in small portions. After complete reaction (15 min), the mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous magne- sium sulphate and evaporated. Crystallization of the residue from ethyl acetate/n-heptane yielded 4.39 (79 %) of the title compound as a colourless solid (m.p. 177 °C).

E. 4-Benzyloxy-6-bromo-1,2-dimethyl-1 H-benzimidazole

A suspension of 26.2 g (72 mmol) N-(2-benzyloxy-4-bromo-6-dimethylamino-phenyl)-acetamide in 180 mi phosphoryl chloride was heated to 70 °C for 24 h. After the reaction was complete, excess phos- phoryl chloride was evaporated. The residue was suspended in dichloromethane and carefully neutral- ized with 6N aqueous potassium hydroxide and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Crystallization of the residue from ethyl acetate yielded 15.1 g (63 %) of the title compound as a colourless solid (m.p. 177-178 °C).

F. Ethyl 4-hydroxy-1,2-dimethy)-1 H-benzimidazole-8-carboxylate

A suspension of 12.0 g (37 mmol) ethy! 4-benzyloxy-1 2-dimethyl-1H-benzimidazole-6-carboxylate in 100 ml ethanol was hydrogenated over 1 g 10% Pd/C (50 °C, 5 bar Hy) for 16 h. The catalyst was fil- tered off and the filtrate was evaporated. The residue was crystallized from ethanol/diethyl ether to give 5.91 g (69 %) of the title compound as a colourless solid (m.p. 272-273 °C).

G. Methyl 4-hydroxy-1 ,2-dimethyl-1H-benzimidazole-6-carboxylate

A suspension of 8.5 g (27 mmol) methyl 4-benzyloxy-1,2-dimethyl-1 H-benzimidazole-6-carboxylate in 100 mi methanol was hydrogenated over 0.7 g 10% Pd/C (30 °C, 1 bar H,) for 2 h. The catalyst was filtered off, washed several times with hot methanol and the filtrate was evaporated. The residue was crystallized from methanol/diethy! ether to give 8 g (89 %) of the title compound as a colourless solid (m.p. 286 °C).

H. 4-Hydroxy-6-methoxymethyi-1 ,2-dimethyl-1H-benzimidazole

A solution of 1.2 g (4.1 mmol) 4-benzyloxy-6-methoxymethyi-1,2-dimethyl-1H-benzimidazole in12 ml methanol was hydrogenated over 0.12 g 10% Pd/C (1 bar Hy) for 16 h. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate/light petroleum ether to give 0.83 g (99 %) of the title compound as a colourless solid (m.p. 219-220 °C).

IR 6-(N,N-Dimethylaminocarbonyl)-4-hydroxy-1 ,2-dimethyl-1H-benzimidazole

A solution of 2.3 g (7.1 mmol) 4-benzyloxy-6-(N,N-dimethylaminocarbony)}-1 ,2-dimethyl-1H- benzimidazole in 80 ml methanol was hydrogenated over 0.3 g 10% Pd/C (1 bar Hy) for 16 h. The cata- lyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetone to give 1.2 g (71 %) of the title compound as a colourless solid (m.p. 248 °C).

J. 6-Bromo-2-methyl-4-nitro-1 (3)H-benzimidazole

To a suspension of 65 g (0.28 mol) 5-bromo-3-nitro-1,2-phenylenediamine in 600 mi ethanol were added 140 ml 5N hydrochloric acid. The reaction mixture was hetaed to reflux and 58 ml (0.56 mol) 2,4- pentanedione were added in one portion. After 1 h, the mixture was cooled down, poured into 500 mi water and neutralized with conc. ammonia. The precipitate was collected, washed thoroughly with water and dried over phosphorus pentoxide to give 70.8 g (99 %) of the title compound (m.p. 229-231 °C).

K. 6-Bromo-4-nitro-1(3)H-benzimidazole

To a suspension of 14.25 g (61.4 mmol) 5-bromo-3-hitro-1,2-phenylenediamine in 120 ml 4N hydro- chloric acid were added 4.65 mi (123 mmol) formic acid. The reaction mixture was heated to 120 °C.

After 1.5 h, the mixture was cooled down and neutralized with conc. ammonia. The precipitate was collected, washed with water and dried over phosphorus pentoxide. Recrystallization from ethanol and activated charcoal yielded 9.79 g (66 %) of the title compound (m.p. 249 °C).

L. 6-Bromo-2-methoxymethyl-4-nitro-1 (3)H-benzimidazole

A suspension of 1 g (4.3 mmol) 5-bromo-3-nitro-1,2-phenylenediamine in 4 mi methoxyacetic acid was heated to 110 °C for 16 h. The mixture was poured into icewater, neutralized with 6N aqueous sodium hydroxide and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate and activated charcoal yielded 0.9 g (73 %) of the title compound as a colourless solid (m.p. 173 °C).

M. 6-Bromo-1-methyl-4-nitro-1H-benzimidazole

A suspension of 5.12 g (21.2 mmol) 6-bromo-4-nitro-1(3)H-benzimidazole and 4.6 9 (33.3 mmol) po- tassium carbonate in 200 mi acetone was stirred 30 min and 1.54 ml (24.7 mmol) methyl! iodide were then added. After stirring 18 h at ambient temperature, excess solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over an- hydrous magnesium sulphate and evaporated. Purification of the residue by crystaliization from ethyl acetate yielded 2.7 g (50 %) of the title compound as a colourless solid (m.p. 198 °C).

N. 8-Bromo-2-methoxymethyl-1 -methyl-4-nitro-1H-benzimidazole

To a suspension of 13 g (45.4 mmol) 6-bromo-2-methoxymethyl4-nitro-1(3)H-benzimidazole and 12.6 g (90.9 mmol) potassium carbonate in 130 ml acetone were added 6.8 g (47.7 mmol) methyl iodide and the mixture was stirred for 18 h at ambient temperature. The thick suspension was poured into 200 ml water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from diisopropyl ether yielded 13.6 g (99 %) of the title compound as a yellow solid (m.p. 145-147 °C).

0. 1-Benzyloxymethy}-8-bromo-2-methyl-4-nitro-1 H-benzimidazole

To a suspension of 0.26 g (6.4 mmol) sodium hydride (60 % dispersion in mineral oil) in 10 mi N,N- dimethylformamide was slowly added a solution of 1.5 g (5.9 mmol) 6-bromo-2-methyl-4-nitro-1(3)H- benzimidazole in 5 mi N,N-dimethylformamide at 0 °C. After 1 hat 0°C, 2.299 (8.8 mmol) benzyloxy- methyichloride (60 %) were added over 20 min. When the reaction was finished (1 h), 10 mi water were carefully added and the mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:triethylamine (95:5) gave an oil which was crystallized from diisopropyl ether to yield 1.16 g (53 %) of the title compound as a yellow solid (m.p. 106-1 09°C).

P. 6-Bromo-1 ,2-dimethyl-4-nitro-1H-benzimidazole

To a suspension of 4.3 g (107 mmol) sodium hydride (60 % dispersion in mineral oil) in 25 ml N,N- dimethylformamide was slowly added a solution of 25 g (98 mmol) 6-bromo-2-methyl-4-nitro-1(3)H- benzimidazole in 100 mi N,N-dimethylformamide at 0 °C. After 30 min at 0 °C, 15.2 g (107 mmol) methyl iodide were added over 20 min. When the reaction was finished (45 min), 200 ml water were carefully added and the mixture was stirred 1 h at ambient temperature. The precipitate was collected, washed thoroughly with water and dried over phosphorus pentoxide. Recrystallization from methanol yielded 19.6 g (74 %) of the title compound as a colourless solid (m.p. 193-195 °C).

Q. 4-Amino-8-bromo-1-methyl-1 H-benzimidazole

To a suspension of 10 g (39 mmol) 6-bromo-1-methyl-4-nitro-1H-benzimidazole in 100 mil methanol were added 7.6 g (46.9 mmol) iron(lll) chloride and 2.5 g activated charcoal. The reaction mixture was heated to 80 °C and 9.5 ml hydrazine hydrate (95 %) were slowly added. After refluxing 2 h, a further amount of 2 m! hydrazine hydrate (95 %) was added. After 5 h, the hot reaction mixture was filtered through celite and the filter cake was washed with methanol and dichloromethane. The filtrate was evaporated to leave a solid, which was purified by column chromatography on silica gel using tolu- ene:dioxane:methanol (6:3.6:0.4). Crystallization from diisopropyl ether yielded 6.8 g (77 %) of the title compound as a light yellow solid (m.p. 170 °C).

R. 4-Amino-8-bromo-2-methoxymethyl-1-methyl-1 H-benzimidazole

To a suspension of 8.5 g (28.3 mmol) 8-bromo-2-methoxymethyl-1 -methyl-4-nitro-1H-benzimidazole in 150 mi methanol were added 5.51 g (34 mmol) iron(!ll) chloride, 2.5 g activated charcoal and 6.9 ml hydrazine hydrate (85 %). After refiuxing 2 h, a further amount of 4 mi hydrazine hydrate (95 %) was added. After 4 h, the hot reaction mixture was filtered through celite and the filter cake was washed with methanol and dichloromethane. The filtrate was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane:methanol (20:1). Crystallization from diisopropyl ether yielded 5.5 g (72 %) of the title compound as a colourless solid (m.p. 138-140 °C).

S. 4-Amino-1-benzyloxymethyl-6-bromo-2-methyi-1 H-benzimidazole

To a suspension of 10 9 (26.6 mmol) 4-benzyloxymethyl-6-bromo-2-methyl-4-nitro-1 H-benzimidazole and 1 g activated charcoal in 150 mi methanol were added 5.2 g (31 © mmol) iron(lil) chloride and 6.5 ml hydrazine hydrate (95 %). After refluxing 1 h, a further amount of 3 mi hydrazine hydrate (85 %) was added. After 6 h, the hot reaction mixture was filtered through celite and the filter cake was washed with hot methanol. The filtrate was evaporated to leave a yellow solid which was purified by column chroma- tography on silica gel using dichloromethane:methanol (9:1). Crystallization from diisopropyl ether yielded 6.68 g (73 %) of the title compound as a light yellow solid (m.p. 142 °C).

T. 4-Amino-6-bromo-1,2-dimethyl-1 H-benzimidazole

To a solution of 19 g (70 mmol) 6-bromo-1 2-dimethyl-4-nitro-1H-benzimidazole in 250 mi methanol were added 13.7 g (84 mmol) iron(llf) chloride and 6 g activated charcoal. The reaction mixture was heated to 80 °C and 17 mi hydrazine hydrate (95 9%) were slowly added. After refluxing 3 h, the hot re- action mixture was filtered through celite and the filter cake was washed with methanol and dichloro- methane. The filtrate was evaporated to leave a suspension, which was treated with n-heptane. The precipitate was collected, washed with n-heptane and dried to give 13.39 (79 %) of the title compound as a solid (m.p. 206-209 °C). u. 6-Bromo-4-(2-ethyl-6-methyl-benzylamino)-1 ,2-dimethy1 H-benzimidazole

To a suspension of 12 g (50 mmol) A-amino-6-bromo-1,2-dimethyl-1 H-benzimidazole and 8.8 g (52 mmol) 2-ethyl-6-methyl-benzyl chloride in 220 mi acetone were added 5.5 g (52 mmol) sodium carbon- ate and 1.5 g (10 mmol) sodium iodide. After 3 h stirring at 45 °C, the reaction mixture was poured into 400 ml water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:3) and crystallization with n-heptane yielded 15.6 g (84 %) of the title compound as a colourless solid (m.p. 145-147 °C).

V. 6-Bromo-4-(2,6-dimethyl-benzylamino)-1 ,2-dimethyl-1 H-benzimidazole

To a suspension of 0.97 g (4 mmol) 4-amino-6-bromo-1 2-dimethyi-1 H-benzimidazole and 0.66 g (4.2 mmol) 2,6-dimethyl-benzyl chioride in 25 mi acetonitrile were added 0.56 g (4 mmol) potassium carbo- nate and 70 mg (0.4 mmol) potassium iodide. After 1 h stirring at 65 °C, 2 ml 1N aqueous ammonia were added and the reaction mixture was evaporated. The residue was partitioned between dichloro- methane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from ethyl acetate/n-heptane yielded 0.93 g (64 %) of the title compound as a colourless solid (m.p. 185 °C).

W. 4-Benzyloxymethyl-6-bromo-4-{2-ethyl-6-methyl-benzylamino)-2-methyl-1 H-benzimidazole

To a suspension of 8.59 (18.8 mmo!) 4-amino-1-benzyloxymethyl-6-bromo-2-methyl-1H-benzimidazole and 3.32 g (19.7 mmol) 2-ethyl-6-methyl-benzyl chloride in 120 mi acetonitrile were added 3.0 g (28.2 mmol) sodium carbonate and 0.56 g (3.75 mmol) sodium iodide. After 3 h reflux, the reaction mixture was poured into 300 mi water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro- matography on silica gel using ethyl acetate:light petroleum ether (2:3) and crystallization from diisopro- pyl ether yielded 6.88 g (77 %) of the title compound as a colourless solid (m.p. 117-119 °C).

X. 6-Bromo-4-(2-athyl-6-methyl-benzylamino)-1-methyl-1 H-benzimidazole

To a suspension of 2.0 g (8.9 mmol) 4-amino-6-bromo-1-methyl-1H-benzimidazole and 1.6 g (9.5 mmol) 2-ethyl-6-methyl-benzyl chioride in 40 mi acetonitrile were added 1.4 g (13.1 mmol) sodium car- bonate and 0.3 g (2 mmol) sodium iodide. After 1 h at 70 °C, the mixture was partitioned between di- chloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro- methane:methanol (100:1) yielded 2.0 g (63 %) of the title compound as a colourless solid (m.p. 132- 134 °C).

Y. 6-Bromo-4-(2-ethyl-8-methyl-benzylamino)-2-methoxymethyi-1 -methyl-1H-benzimldazole

To a suspension of 6.8 g (25.2 mmol) 4-amino-6-bromo-2-methoxymethyl-1-methyt-1 H-benzimidazole and 4.46 g (26.4 mmol) 2-ethy-6-methyl-benzylchloride in 70 ml acetonitrile were added 7.0 g (50.3 mmol) potassium carbonate and a catalytic amount of potassium iodide. After 5 h at 70 °C, the reaction mixture was poured into 200 ml water and extracted with dichloromethane. The organic layer was sepa- rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from diisopropyl ether yielded 5.46 g (54 %) of the tite compound as a colourless solid (m.p. 110-112 °C).

Z 6-Bromo-4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-1 -methyl-1H-benzimidazole

To a suspension of 2.5 g (8.25 mmol) A-amino-6-bromo-2-methoxymethyl-1-methyl-1H-benzimidazole and 1.52 g (9.72 mmol) 2,6-dimethyl-benzyl chloride in 50 ml acetonitrile were added 2.56 g (18.5 mmol) potassium carbonate and a catalytic amount of potassium iodide. After 3 h at 70 °C, the reaction mixture was poured into 150 mi water and extracted with dichloromethane. The organic layer was sepa- rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:1) and crystallization from diisopro- pyl ether yielded 0.84 g (23 %) of the title compound as a colourless solid (m.p. 143-145 °C).

AA. 4-Amino-8-(N,N-dimethylaminocarbonyl)-1 ,2-dimethyl-1H-benzimidazole

To a suspension of 3 g (12.5 mmol) 4-amino-6-bromo-1 ,2-dimethyl-1H-benzimidazole in 100 ml di- methylamine (2M in tetrahydrofuran) were added 280 mg (1.25 mmol) palladium(ll) acetate and29(7.5 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 120 °C) for 16 h. The reaction mixture was cooled down, poured into 200 ml water and 100 mi saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated.

Purification of the residue by column chromatography on silica gel using ethyl acetate/methanol (4:1)

and crystallization from diisopropyl ether yielded 0.7 g (24 %) of the title compound as a colourless solid (m.p. 230-234 °C).

BB. Cyclopropanecarboxylic acid (2-benzyloxy-4-bromo-6-nitro-phenyl)-amide

A suspension of 20.0 g (61.9 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline and 11.2 ml (123.4 mmol) cyclopropanecarbonyl chloride in 130 ml dioxane was heated to 100 °C. After 5 h, the flask was im- mersed in an ice bath, the precipitate was collected, washed with toluene and dried in vacuo to give 21.2 g (87 %) of the title compound as a yellow solid (m.p. 191 °C).

CC. Cyclopropanecarboxylic acld (2-amino-6-benzyloxy-4-bromo-phenyl)-amide

A suspension of 11.0 g (28.1 mmol) cyclopropanecarboxylic acid (2-benzyloxy-4-bromo-8-nitro-phenyl)- amide, 3.0 g (18.5 mmol) iron(lil) chloride and 7.4 g activated charcoal in 140 ml methanol was heated to reflux. To the reaction mixture were added 14.7 mi hydrazine hydrate (85 %) to maintain gentie re- flux. After complete reaction (1 hy, the mixture was cooled down and filtered through celite. The filter cake was washed thoroughly with hot methanol/acetone and the filtrate was evaporated to dryness. The residue was crystallized from ethyl acetate to give 7.5 g (73 %) of the title compound as a colourless solid (m.p. 207-208 °C).

DD. 4-Benzyloxy-6-bromo-2-cyclopropyl-1 -methyl-1H-benzimidazole

A suspension of 7.5 g (20.8 mmol) cyclopropanecarboxylic acid (2-amino-6-benzyloxy-4-bromo-phenyl)- amide in 80 mi methanol and 13.3 ml formaldehyde (37 %) was acidified with saturated methanolic hydrogen chloride to give a clear yellow solution. To the solution were added 0.75 g (11.9 mmol) so- dium cyanoborohydride in small portions. After complete reaction (4 h), the mixture was poured into water and neutralized with 40% aqueous sodium hydroxide. The precipitate was collected, washed with water and dried over phosphorus pentoxide to yield 6.3 g of a colourless solid. The solid was sus- pended in 10 mi phosphoryl chloride and the mixture was heated to 90 °C for 2 h. After the reaction was complete, the mixture was diluted with dichloromethane and neutralized with with 6N aqueous potas- sium hydroxide and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu- ene:dioxane (10:1) and crystallization from diethyl ether yielded 2.97 g (40 %) of the title compound as a colourless solid (m.p. 153-154 °C).

EE. Ethyl 2-cyclopropyl-4-hydroxy-1-methyi-1H-benzimidazole-6-carboxylate

A suspension of 2.3 g (6.6 mmol) ethyl 4-benzyloxy-2-cyclopropyl-1 -methyl-1H-benzimidazole-6- carboxylate in 23 ml methanol was hydrogenated over 0.27 g-10% Pd/C (25 °C, 1 bar Hy) for 5 h. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate to give 1.5 g (88 %) of the title compound as a colourless solid (m.p. 201-202 °C).

EF. 4-Amino-N,N-dimethy}-3,5-dinitro-benzenesulfonamide

A suspension of 5.0 g (27.3 mmol) 2,6-dinitroaniline in 40 mi chlorosulphonic acid was heated to 100 °C. After 2.5 h, the reaction mixture was cooled down and cautiously poured onto 1000 ml crushed ice.

The suspension was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in 100 mi tetrahydrofuran and a solution of 25 mi dimethylamine in 25 mi tetrahydrofuran was slowly added. After 20 min, the suspension was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethanol yielded 6.7 g (85 %) of the tite compound as an orange solid (m.p. 169-170 °C).

GG. 3,4-Diamino-N,N-dimethyl-5-nitro-benzenesulfonamide 50 ml 2N aqueous ammonia were saturated with hydrogen suifide at 0 °C. The solution was diluted with 50 mi ethanol and 5.58 g (19.2 mmol) 4-amino-N,N-dimethyl-3,5-dinitro-benzenesulfonamide were added. After 40 min at 60 °C, the mixture was diluted with water and filtered through celite. The filter cake was extracted several times with boiling dichloromethane and methanol. The combined extracts were evaporated and the residue recrystallized from ethanol/diethyl ether to yield 1.18 g (24 %) of the title compound as a red solid (m.p. 211-213 °C).

HH. 2-Methyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide

A suspension of 1.0 g (3.84 mmol) 3,4-diamino-N,N-dimethyl-5-nitro-benzenesulfonamide in 20 mi ethanol and 5 ml 5N hydrochloric acid was heated to 80 °C. To the reaction mixture were added 1.6 ml (15.4 mmol) 2,4-pentanedione in two portions over a period of 1 h. The solution was cooled down and neutralized with 6N aqueous sodium hydroxide. The precipitate was collected, washed with water and dried in vacuo over phosphorus pentoxide to give 0.99 g (90 %) of a beige solid (m.p. 254-255 °C). i. 2,3-Dimethyl-7-nitro-3H-benzimidazole-5-sulfonic acld dimethylamide

A suspension of 1.87 g (6.6 mmol) 2-methyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide, 1.82 g (13.2 mmol) potassium carbonate and 0.71 ml (11.6 mmol) methyl! iodide in 50 ml acetone was stirred 3 h at ambient temperature. The mixture was partitioned between dichloromethane and satu- rated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magne- sium sulphate and evaporated to dryness. Recrystallization of the residue from boiling ethyl acetate yielded 1.5 g (76 %) of the title compound as a beige solid (m.p. 184-196 °C). 4J. 7-Amino-2,3-dimethyi-3H-benzimidazole-8-sulfonic acid dimethylamide

A suspension of 1.2 g (4.0 mmol) 2,3-dimethyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide in 15 ml methanol and 5 ml acetic acid was heated to 60 °C and 1.1 g (20 mmol) iron filings were added. After 1.5 h, the solids were filtered off and extracted several times with boiling dichloromethane.

The combined extracts were evaporated and the residue was crystallized from ethyl acetate/n-heptane to yield 0.99 g (92 %) of the title compound as a beige solid (m.p. 2556-258 °C).

KK. N-(4-Bromo-2,6-dinitro-phenyl)-acetamide

A suspension of 5.0 g (19.1 mmol) 4-bromo-2,6-dinitroaniline in 50 ml acetic anhydride and 1 mi methanesulphonic acid was stirred 3 h at 30 °C. The precipitate was collected, washed with diethyl ether and dried to yield 4.8 g (83 %) of the title compound as a colourless solid (m.p. 238-239 °C).

LL. 4-Amino-6-bromo-1-hydroxy-2-methyi-1 H-benzimidazole

To a suspension of 2.0 g (6.6 mmol) N-(4-bromo-2,6-dinitro-phenyl)-acetamide and 0.4 g ruthenium on charcoal (5 %) in 80 mi ethanol were added 1.2 ml (24.7 mmol) hydrazine hydrate (95 %) over a period of 1.5 h at 60 °C. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was extracted with boiling ethyl acetate to leave 1.23 g (77 %) of the title compound as a light grey solid (m.p. 257-258 °C).

MM. N-{5-Bromo-2-{2-chloro-acetylamino)-3-nitro-phenyf}-2-chloro-acetamide

To a solution of 46.4 g (200 mmol) 4-bromo-2,6-dinitroaniline in 500 ml N,N-dimethyiformamide and 20 mi pyridine were slowly added 80 mi (1000 mmol) chloroacetyl chloride. After 3 h, the reaction mixture was poured into 600 ml ice water and the resulting suspension was neutralized with 6N aqueous so- dium hydroxide. The precipitate was collected, washed with water and dried in vacuo to yield 74.1 g (96 %) of the title compound as a beige solid (m.p. 172-173 °C).

NN. 8-Bromo-2-chloromethyl-4-nitro-1H-benzimidazole

A suspension of 1.0 g (2.59 mmol) N-[5-bromo-2-(2-chloro-acetylamino)-3-nitro-phenyl]-2-chloro- acetamide in 25 ml 4N hydrochloric acid and 20 ml ethanol was heated to reflux. After 4 h, the reaction mixture was poured into 75 ml water and neutralized with saturated aqueous sodium hydrogen carbon- ate. The precipitate was collected, washed with water and dried over phosphorus pentoxide to give 0.65 g (86 %) of the title compound as an orange solid (m.p. 148-150 °C). 00. 6-Bromo-2-chloromethyl-1-methyl-4-nitro-1H-benzimidazole

To a solution of 39.3 g (135.3 mmol) 6-bromo-2-chloromethyl-4-nitro-1 H-benzimidazole in 500 ml ace- tone were added 26.0 g (206.1 mmol) dimethyl sulphate and 50.0 g (362 mmol) potassium carbonate.

After 1.25 h stirring at room temperature, the reaction mixture was poured into 1000 mi water. The pre- cipitate was collected, washed with water and recrystallized from methanol to give 32.5 g (63 %) of the title compound as a beige solid (m.p. 154-155 °C).

PP. 2-Acetoxymethyi-6-bromo-1-methyl-4-nitro-1 H-benzimidazole

To a solution of 30.0 g (98.5 mmol) 6-bromo-2-chloromethyl-1-methyl-4-nitro-1 H-benzimidazole in 200 mi acetone were added 16.4 g (98.5 mmol) potassium iodide. The resulting suspension was stirred 1 h at ambient temperature and 14.5 g (147.8 mmol) potassium acetate were added. After 2 h at 40 °C, the reaction mixture was poured into 500 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to dryness. Recrystallization of the residue from boiling ethanol yielded 23.9 g (74 %) of the title compound as an orange solid (m.p. 143-145 °C).

QQ. 2-Acetoxymethyl-4-amino-8-bromo-1 -methyl-1H-benzimidazole

To a suspension of 10.0 g (30.5 mmol) 2-acetoxymethyl-6-bromo-1-methyt-4-nitro-1 H-benzimidazole in 40 ml acetic acid were added 6.8 g (122 mmol) iron filings and the reaction mixture was heated to 60 °C. After 4 h, a further amountof 1.09 (18 mmol) iron filings were added and heating was continued for 1.25 h. The precipitate was collected, dissolved in dichloromethane and extracted with water. The or- ganic layer was separated, dried over anhydrous magnesium sulphate and evaporated to dryness. Puri- fication of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (7:3) and crystallization from ethyl acetate/n-heptane yielded 4.6 g (51 %) of the tite compound as a beige solid (m.p. 104-106 °C).

RR. 4-Amino-6-bromo-2-hydroxymethyl-1-methy}-1 H-benzimidazole

A suspension of 7.5 g (22.9 mmol) 2-acetoxymethyl-6-bromo-1 -methyi4-nitro-1H-benzimidazole in 180 ml methanol was hydrogenated over Raney nickel (25 °C, 1 bar Hy) for2.5 h. The catalyst was filtered off and the filtrate was partitioned between water and dichloromethane. The organic layer was sepa- rated, dried over anhydrous magnesium sulphate and evaporated. The residue was crystallized from - ethanol/diisopropyl ether to give 1.329 (22 %) of the title compound as a solid (m.p. 216-218 °C).

SS. 2,6-Dibromo-1-methyl-4-nitro-1H-benzimidazole

To a solution of 1.0 g (3.9 mmol) 6-bromo-1 -methyl-4-nitro-1H-benzimidazole in 25 ml dichloroethane were added 5 g silica gel and 0.94 g (5.3 mmol) N-bromosuccinimide. After 2.5 h at 85 °C, the mixture was cooled down and filtered. The filtrate was extracted with saturated aqueous sodium hydrogen car- bonate, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by col- umn chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from ethyl acetate/n-heptane yielded 0.745 g (57 %) of the title compound as a yellow solid (m.p. 235- 236 °C).

TT. 6-Bromo-2-{N,N-dimethylamino)-1-methyi-4-nitro-1 H-benzimidazole

To a solution of 3.0 g (11.7 mmol) 6-bromo-1-methyl-4-nitro-1H-benzimidazole in 75 ml dichloroethane were added 25 g silica gel and 2.5 g (14.1 mmol) N-bromosuccinimide. After 3 h at 85 °C, the mixture was cooled down and filtered. The filtrate was evaporated and the residue was dissolved in 100 mi tetrahydrofuran. A solution of 10 ml dimethylamine in 20 ml tetrahydrofuran was slowly added and the mixture was stirred for 4 h. The mixture was evaporated to 1/4 of its volume and partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was sepa- rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystal- lization from ethyl acetate yielded 1.6 g (46 %) of the title compound as an orange coloured solid (m.p. 206-207 °C).

UU. 4-Amino-6-bromo-2-(N,N-dimethylamino)-1 -methyl-1H-benzimidazole

To a suspension of 1.0 g (3.3 mmol) 6-bromo-2-(N,N-dimethylamino)-1 -methyl-4-nitro-1H- benzimidazole in 25 ml methanol and 8 ml acetic acid were added 0.85 g (15.2 mmol) iron powder at 65

°C. After 2 h, the solids were filtered off and washed with dichloromethane. The filtrate was extracted with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from diethyl ether yielded 0.2 g (22 %) of the title compound as a colourless solid (m.p. 137 °C).

VV. 6-Bromo-1,2-dimethyl-4-(2-methyl-benzylamino)-1H-benzimidazole

To a solution of 0.9 ml (6.4 mmol) 2-methyl-benzy! chloride in 20 ml acetone were added 1.19 (6.6 mmol) sodium iodide and the mixture was stirred 1.5 h at room temperature. The solid was filtered off and 1.5 g (4.4 mmol) 4-amino-6-bromo-1 ,2-dimethyl-1H-benzimidazole and 1.3 g (9.4 mmol) potassium carbonate were added to the filtrate. After 3 h at reflux, the mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro- methane:methanol (30:1) and crystallization from ethyl acetate/n-heptane yielded 1.28 g (61 %) of the title compound as a colourless solid (m.p. 128-129 °C).

WW. 6-Bromo-4-(2,4-dimethyl-furan-3-yl-methylamino)-1 ,2-dimethy}-1H-benzimidazole

To a suspension of 1.95 g (4.6 mmol) Dess-Martin-periodinane in 10 ml dichloromethane and 0.5 ml . pyridine was dropwise added a solution of 0.5 g (4.0 mmol) (2,4-dimethyl-furan-3-yl)-methanol in5 mi dichloromethane at room temperature. After 30 min, water and 1 ml saturated aqueous sodium sulfite were added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was filtered through silica gel using ethyl acetate:light petroleum ether (9:1) to leave a colourless oil after evaporation. The crude product was dissolved in 10 ml methanol and 0.5 mi acetic acid. After addition of 0.48 g (2 mmol) 4- amino-6-bromo-1,2-dimethyl-1H-benzimidazole, 0.3 g (4.8 mmol) sodium cyanoborohydride were added in three portions over a period of 2.5 h. After 2 h, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The organic layer was dried over an- hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl acetate/n-heptane yielded 0.45 g (65 %) of the title compound as a colourless solid (m.p. 207-208 °C).

XX. 6-Bromo-4-(2-hydroxymethyl-8-methyl-benzylamino)-1 ,2-dimethyl-1 H-benzimidazole

To a solution of 0.8 g (5.4 mmol) 7-methyl-3H-isobenzofuran-1-one in 15 ml dried toluene were slowly added 4.3 mi (6.5 mmol) diisobutylaluminium hydride (1.5M in toluene) at -78 °C. After 1 h, the reaction mixture was quenched with 1 ml methanol and allowed to warm to room temperature. The mixture was partitioned between saturated aqueous potassium sodium tartrate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The oil thus obtained was dissolved in 20 ml methanol and 1 ml acetic acid. After the addition of excess sodium cyanoboro- hydride, the mixture was stirred 4 h at 45 °C. The mixture was partitioned between water and dichloro- methane and neutralized with 6N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog-

raphy on silica gel using ethyl acetate and crystallization from ethyl acetate/n-heptane yielded 0.35 g (24 %) of the title compound as a colourless solid (m.p. 215-218 °C).

YY. 6-Bromo-4-(2-ethyl-6-methyl-benzylamino)-2-hydroxymethy-1 -methyl-1H-benzimidazole

A suspension of 1.25 g (4.88 mmol) 4-amino-6-bromo-2-hydroxymethyk-1 -methyl-1H-benzimidazole, 0.86 g (5.12 mmol) 2-ethyl-6-methyl-benzyl chioride, 1.35 g (9.76 mmol) potassium carbonate and a catalytic amount of potassium iodide in 15 ml acetonitrile was heated to 70 °C. After 6 h, the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro- matography on silica gel using dichloromethane:methanol (100:3) and crystallization from diisopropyl ether yielded 0.54 g (29 %) of the title compound as a colourless solid (m.p. 206-208 °C).

ZZ. 6-Bromo-2-{N,N-dimethylamino)-4-(2,6-dimethyl-benzylamino)-1 -methyl-1H-benzimidazole

To a solution of 0.46 g (1.7 mmol) 4A-amino-6-bromo-2-(N,N-dimethylamino)-1-methyt-1 H-benzimidazole and 0.3 g (2.2 mmol) 2,6-dimethyl-benzaldehyde in 10 mi dichloromethane and 2.5 ml acetic acid were added 0.6 g (2.8 mmol) sodium triacetoxyborohydride. After 1 h at ambient temperature, saturated aqueous sodium hydrogen carbonate was added and stirring was continued for 30 min. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl ace- tate/n-heptane yielded 0.46 g (70 %) of the title compound as a colourless solid (m.p. 157-158 °C).

AAA. 4-Benzyloxymethyl-6-bromo-4-(2,6-dimethyl-benzylamino)-2-methyl-1H-benzimidazole

To a suspension of 7.6 g (22 mmol) 4-amino-1-benzyloxymethyl-8-bromo-2-methyl-1 H-benzimidazole and 3.56 g (23.0 mmol) 2,6-dimethyl-benzyl chloride in 140 ml acetonitrile were added 3.5 g (32.7 mmol) sodium carbonate and 0.66 g (4.4 mmol) sodium iodide. After 3.5 h reflux, the reaction mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over an- hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (2:3) and crystallization from ethyl acetate/n-heptane yielded 6.8 g (64 %) of the title compound as a colourless solid (m.p. 147-148 °C).

I1.Final products of the formula 1 1. Methyl! 4-(2-ethyl-6-methyl-benzyloxy)-1 ,2-dimethyi-1 H-benzimidazole-6-carboxylate

To a solution of 2.0 g (9.1 mmol) methyl 4-hydroxy-1 ,2-dimethy!-1H-benzimidazole-6-carboxylate and 1.7 g (10.1 mmol) 2-ethyl-6-methyl-benzyi chloride in 56 ml N,N-dimethylformamide were slowly added 0.7 g (17.5 mmol) sodium hydride (60 % dispersion in mineral oil). After 1 h, a further amount of 0.3 g (1.8 mmol) 2-ethyl-6-methyl-benzyl chloride was added and the mixture was stirred for 4 h. The mixture was carefully hydrolyzed with saturated aqueous ammonium chloride and partitioned between di-

. a7 chloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from water/acetone yielded 2.7 g (84 %) of the title compound as a solid (m.p. 157 °C). 2. 4-(2-Ethyl-6-methyl-benzyloxy)-1 2-dimethyl-tH-benzimidazole-8-carboxylic Acid

To a suspension of 2.6 g (7.4 mmol) methyl 4-(2-thyl-6-methyl-benzyloxy)-1 ,2-dimethyl-1H- benzimidazole-6-carboxylate in 75 mi dioxane were added 15 mi 2N aqueous sodium hydroxide. After 3 h at 80 °C, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the resi- due was purified by column chromatography on silica gel using dichloromethane: methanol (4:1)

Evaporation of the solvent left a solid, which was crystallized from diethyl ether to give 2.67 g (quant) of the title compound (crude product, contained silica gel) which was used without further purification for the next step. 3. Methyl 4-(2,6-dimethyl-benzyloxy)-1 ,2-dimethyl-1 H-benzimidazole-8-carboxylate

To a solution of 3.6 g (16.4 mmol) methyl 4-hydroxy-1,2-dimethyl-1 H-benzimidazole-6-carboxylate and 2.8 g (18.1 mmol) 2,6-dimethyl-benzyl chloride in 100 mi N,N-dimethylformamide were slowly added 1.3 g (32.5 mmol) sodium hydride (60 % dispersion in mineral oil) over a period of 2 h. After complete reac- tion, the mixture was carefully hydrolyzed with saturated aqueous ammonium chloride and diluted with 500 ml water. The precipitate was collected, washed thoroughly with water and dried over phosphorus pentoxide to give 4.04 g (73 %) of the title compound (m.p. 165-168 °C). 4. 4-(2,6-Dimethyl-benzyloxy)-1 ,2-dimethy}-1H-benzimidazole-8-carboxylic Acid

To a suspension of 3.5 g (10.3 mmol) methyl 4-(2,6-dimethyl-benzyloxy)-1 ,2-dimethyl-1H- benzimidazole-6-carboxylate in 100 mi dioxane were added 20 ml 2N aqueous sodium hydroxide. After 2 h at 80 °C, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the resi- due was put on a column and eluted with dichloromethane: methanol (4:1). Evaporation of the solvent left a solid, which was crystallized from ethyl acetate/diethyl ether to give 2.33 g (70 %) of the title com- pound (m.p. 285-286 °C). 5. 4-Benzyloxy-8-hydroxymethyl-1 ,2-dimethyl-1H-benzimidazole

To a suspension of 0.7 g (18.4 mmo!) lithium aluminium hydride in 40 mi tetrahydrofuran was slowly added a solution of 3 g (9.7 mmol) methyl 4-benzyloxy-1 ,2-dimethyl-1H-benzimidazole-6-carboxylate in mi tetrahydrofuran. After complete addition, the reaction mixture was carefully hydrolyzed with 0.13 mil water, 0.25 ml 6N aqueous potassium hydroxide and 0.13 ml water. Anhydrous magnesium sulphate was added and the mixture was stirred 1 h. After filtration of the suspension through celite, the filtrate was evaporated and the residue was crystallized from acetone to yield 1.99 g (74 %) of the title com- pound as a colourless solid (m.p. 213-214 °C).

3s 6. 4-Benzyloxy-8-methoxymethyi-1 ,2-dimethyl-1H-benzimidazole

To a solution of 1.5 g (6.3 mmol) 4-benzyloxy-8-hydroxymethyl-1 ,2-dimethyl-1H-benzimidazole in 122ml

N,N-dimethytformamide were slowly added 0.4 g (10 mmol) sodium hydride (60 % dispersion in mineral oil) and the mixture was warmed to 50 °C. After 1 h, the reaction mixture was cooled to -10°C and 0.4 ml (6.4 mmol) methyl iodide were added over a period of 30 min. The reaction mixture was stirred 3 h and then carefully hydrolyzed with saturated aqueous ammonium chloride. The mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magne- sium sulphate and evaporated. Purification of the residue by crystallization from light petroleum ether yielded 1.25 g (80 %) of the title compound as a solid (m.p. 113 °C). 7. 4-Benzyloxy-8-(N,N-dimethylaminocarbonyl)}-1 ,2-dimethyl-1H-benzimidazole

To a solution of 3.0 g (9.1 mmol) 4-benzyloxy-8-bromo-1 2-dimethy}-1H-benzimidazole in 100 ml di- methylamine (3.2M in tetrahydrofuran) were added 0.3 g (1.3 mmol) palladium(ll) acetate and 1.4 g (5.3 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 120 °C) for 16 h. The reaction mixture was cooled down, evaporated and the resi- due was dissolved in dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate yielded 2.3 g (78 %) of the title compound as a colourless solid (m.p. 159-160 °C). 8. 6-(N,N-Dimethylaminocarbonyl)-4-(2-sthyl-6-methyl-benzyloxy)-1 ,2-dimethyl-1H-benzimidazole

To a suspension of 0.35 g (1.5 mmol) 8-(N,N-dimethylaminocarbonyl)-4-hydroxy-1 ,2-dimethyl-1H- benzimidazole and 0.32 g (3 mmol) sodium carbonate in 5 ml acetone were added 0.5 g (3 mmol) 2- ethyl-6-methyi-benzyl chloride and the mixture was stirred 20 h at ambient temperature. The mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over an- hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate yielded 0.38 g (68 %) of the title compound as a colourless solid (m.p. 161- 162 °C). 9. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1 H-benzimidazole

To a suspension of 1.0 g (3.08 mmol) 4-(2,6-dimethyl-benzyloxy)-1,2-dimethy!-1 H-benzimidazole-6- carboxylic acid in 40 ml dichloromethane and 10 mi N,N-dimethylformamide were added 1.7 g (5.3 mmol) O-(1H-benzotriazol-1-yl)-N,N,N’,N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mix- ture was heated to 40 °C. After 1 h, 3.7 ml (18.5 mmol) of dimethylamine (5M in tetrahydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous mag- nesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichioromethane:methanol (13:1) gave an oil which was crystallized from ethyl acetatel/light petro- leumn ether to yield 1.0 g (91 %) of the title compound as a yellow solid (m.p. 180 °C).

10. 4-{trans 2,3-Dihydro-2-hydroxy-1-indenyloxy)-6-{N.N-timethylaminocarbonyl)-1,2-dimethyl- 1H-benzimidazole Oxalate ’

To a suspension of 0.5 g (2.1 mmol) 6-(N,N-dimethylaminocarbonyl)-4-hydroxy-1 ,2-dimethyi-1H- benzimidazole and 1.1 g (8.3 mmol) 1,2-epoxyindane in 5.3 ml methanol and 1.3 mi water were added 0.6 mi triethylamine and the mixture was heated to 70 °C for 30 min. The cooled solution was parti- tioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (1 3:1) gave an ofl which was dissolved in acetone and treated with a solution of 0.27 g (2.1 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone to yield 0.64 g (65 %) of the tittle compound as a colourless solid (m.p. 144-145 °C). 1. 44(15,25)-2,3-Dihydro-2-hydroxy-1-indenyloxy]-6-{N.N-dimethylaminocarbonyl)-1 ,2-dimethyl- 1H-benzimidazole Oxalate

To a suspension of 0.5 g (2.1 mmol) 6-(N,N-dimethylaminocarbonyl)-4-hydroxy-1 ,2-dimethyl-1H- benzimidazole and 0.75 g (5.7 mmol) (1R,2S)-epoxyindane in 5 ml ethanol and 1.25 mi water were added 0.6 ml triethylamine and the mixture was heated to 60 °C for 48 h. The cooled solution was parti- tioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) gave an oil which was dissolved in acetone and treated with a solution of 0.12 g (1 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone and diethylether to yield 0.14 g (14 %) of the title compound as a colourless solid (m.p. 126-127 °C, 92 % ee). 12. 4-{trans-2,3-Dihydro-2-methoxy-1-indenyloxy)-8-(N,N-dimethylaminocarbonyi)-1 »2-dimethyl- 1H-benzimidazole Oxalate

To a solution of 0.57 g (1.56 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-6-(N,N- dimethylaminocarbonyl)-1,2-dimethyh-1 H-benzimidazole in 5 mi N,N-dimethylformamide were slowly added 0.15 g (2.3 mmol) sodium hydride (60 % dispersion in mineral oil) at 0 °C. After 5 min, 0.13 ml (2 mmol) methyl iodide were added and stirring was continued for 40 min at ambient temperature. The reaction mixture was carefully hydrolyzed with 1 mi 1N aqueous ammonia and partitioned between di- chloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu- ene:dioxane:methanol (6:3:1) gave an oil which was dissolved in acetone and treated with a solution of 0.19 g (1.6 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with ace- tone and diethy! ether to yield 0.51 g (70 %) of the title compound as a colourless solid (m.p. 126-127 °C).

13. 4-jtrans-2,3-Dihydro-2-{methoxymethylcarbonyloxy)-1 -indenyloxy]-6-(N,N-dimethylamino- carbonyi)-1,2-dimethyl-1 H-benzimidazole

To a solution of 0.2 ml (1.9 mmol) methoxyacetic acic in 4 ml tetrahydrofuran were added 0.3g(1.9 mmol) N,N'-carbonyldiimidazole. After 15 min, 0.4 g (1.1 mmol) 4-{trans-2,3-dihydro-2-hydroxy-1- indenyloxy)-6-(N,N-dimethylaminocarbonyi)-1 2-dimethyi-1 H-benzimidazole and 0.3 mi (2 mmol) 1,8- diazabicyclo[5.4.0Jundec-7-ene were added and stirring was continued for 1 h. The mixture was parti- tioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using toluene:dioxane:methanol (6:3.5:0.5) and crystallization from 2-propanol/diethyl ether/n-heptane yielded 0.47 g (97 %) of the title compound as a solid (m.p. 140 °C). 14. 4-(trans-2,3-Dihydro-2-hydroxy-1-indenyloxy)-8-methoxymethyl-1 ,2-dimethyl-1H-benz- imidazole Oxalate

To a suspension of 0.8 g (3.9 mmol) 4-hydroxy-6-methoxymethyl-1 ,2-dimethyl-1H-benzimidazole and 1.03 g (7.8 mmol) 1,2-epoxyindane in 9.5 ml methanol and 2.5 ml water were added 1.08 ml triethyl- amine and the mixture was heated to 50 °C for 4 h. The cooled solution was partitioned between di- chioromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog- raphy on silica gel using dichloromethane:methanol (20:1) gave an oil which was dissolved in acetone and treated with a solution of 0.51 g (4 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone to yield 0.72 g (42 %) of the title compound as a colourless solid (purity: 93 %). "165. Ethyl 4{trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-1 ,2-dimethyl-1H-benzimidazole-6- carboxylate

To a suspension of 5.0 g (21.4 mmol) ethyl 4-hydroxy-1,2-dimethyl-1 H-benzimidazole-6-carboxylate and 5.65 g (42.8 mmol) 1,2-epoxyindane in 48 mi ethanol and 12 mi water were added 6 ml triethyl- amine and the mixture was heated to 60 °C for 4 h. The cooled solution was partitioned between di- chloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethanol/diethyl ether yielded 5.66 g (72 %) of the title compound which was used without further purifi- cation in the next step. 16. 4-{trans-2,3-Dihydro-2-hydroxy-1 -Indenyloxy)-1,2-dimethyl-1 H-benzimidazole-6-carboxylic

Acid

To a suspension of 5.6 g (15.3 mmol) ethyl 4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-1,2-dimethyl- 1H-benzimidazole-6-carboxylate in 50 ml dioxane were added 10 ml 2N aqueous sodium hydroxide.

After 2.5 h at 80 °C, the reaction mixture was cooled down and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and

Claims

Patent claims

1. A compound of the formula 1 R2 R3 N )—R1 JO N (1) vx in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-atkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, aml, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fiuoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1 -4C-alkoxy-1-4C-atkyl, fluoro-1 -4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO,-NR31R32 or the group Het, : where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist- ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 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, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy, X is O (oxygen) or NH and

Y has either the meaning —CHz-Ar © wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, RS, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryi, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl,

or Y denotes the group gp

‘ R4 ok (gp) Zz wherein

Z has the meaning ~CHR8- or -CHR8-CHR9-

where in, Ar and/or in the group gp

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo- gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C- alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

R6is hydrogen, 1-4C-alkyl or halogen and

R7is hydrogen, 1-4C-alkyl or halogen,

RS is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkyicarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy

R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-~1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy,

and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-aikyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, triftuoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes —CHz-Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyt-1-4C-alkyl, or a salt thereof.

2. A compound as claimed in claim 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyi, fluoro-1 -4C-alkyl or hydroxy-1 AC- alkyl, ~ R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl, R3 is hydrogen, halogen, fiuoro-1 -4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1 -4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1 -4C-alkylpiperazino or morpholino group, X is O (oxygen) or NH and Y has either the meaning -CHz-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyi, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R4 wk (gp) ,; : wherein Z has the meaning —CHR8- or -CHR8-CHRS- where in Ar and/or in the group gp

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo- gen, hydroxy, aryl, aryt-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 hy- droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, RS is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonytamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkyicarbonyloxy or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy or 1-4C-alkoxy-1-4C-alkoxycarbonylamino 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, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes —CH,-Avr, or a salt thereof.

3. A compound as claimed in claim 1, characterized by the formula 1a R3 J N (1a) Ar in which R1 is hydrogen, 1-4C-alkyi, 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-alkynyi, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1 -4C-alkyl

R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- ofr di-1-4C-alkylamino1-4C-alkyicarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group S0,-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 41-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3.7C- cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist- ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 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-alkoxycarbonyi-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy, 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, ben- zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, : 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, halo- gen, 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, triflucromethy! or hy- droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen,

and wherein aryl is phenyl or substituted phenyi with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-atkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifiuoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes —CHz-Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, or a salt thereof.

4. A compound as claimed in claim 1, characterized by the formula 1b R3 Je )—RI R4 : N ae or (1b) Z in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1~ 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino1-4C-alkyicarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C- alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1 -4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1 -4C-alkyl, cyano, the group ~CO-NR31R32, , the group S0,-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C- cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1 -4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist- ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 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, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifiuoromethyl or hy- droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxy, i R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy- droxy, 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- alkoxycarbonyliamino or sulfonyl, R5 is hydrogen, 1-4C-alkyi, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifiuoromethyl or hydroxy, X is O (oxygen) or NH and 4 has the meaning —-CHR8- or -CHR8-CHR9- where R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyioxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy, R9 Is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3- 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C- alkylamino, 1-4C-alkyicarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C- alkylamino-1-4C-alkyicarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1- 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, or a salt thereof.

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

R2 R3 N JQ )—R1 N X (1a-1) where Co R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryH1 -4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO- NR31R32, the group SO-NR31R32 or the group Het, where R31is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloaltkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1 -4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist- . ing of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, hydroxy-1 -AC-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonyiamino, 1-4C-alkoxycarbonylamino or 1- 4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O (oxygen) or NH, or a salt thereof.

6. A compound of formula 1b as claimed in claim 4, characterized by the formula 1b-1

R3 a )—R1 R4 N wt Oy (16-1) R8 in which R1 is 1-4C-alkyl or 3-7C-cycloalkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1 -AC-alkyl or 3-7C-cycloalkyi 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 pyrrolidine,

. piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or 1-4C-alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3- 7C-~cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 14C- alkoxycarbonytamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O (oxygen) or NH, or a salt thereof.

7. A compound of the formula 1b-1 as claimed in claim 6 in which R1 is 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyt and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alky! or 1-4C-alkoxy-1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1 -4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyi, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloatkyl-1-4C- alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3- 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1 -4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, mono- or di-1 -4C-alkylamino-1-4C-alkylcarbonyloxy, 1 -4C-alkoxy-1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1 -AC-alkylcarbonyloxy X is O (oxygen) or NH, or a salt thereof.

8. A compound of the formula 1a-1 as claimed in claim 5, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyi or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 14C-alkyl, X is O (oxygen) or NH, or a salt thereof.

9. The compound 6-(N,N-Dimethylaminocarbonyi)}-4-(2-ethyl-6-methyl-benzylamino)-1 ,2-dimethyl-1H- benzimidazole or a salt thereof.

10. The compound 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-1 ,2-dimethyl-1H- benzimidazole or a sait thereof.

11. A medicament comprising a compound as claimed in claim 1 and/or a pharmacologically accept- able salt thereof together with customary pharmaceutical auxiliaries and/or excipients.

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