Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments.
• Kaminski et. al. describe in J. Med. Chem. 1989, 32, 1686 the synthesis and configurations of imidazo[1 ,2-a]pyridines and their anti-ulcer activity. In a latter publication by Kaminski et. al. (J. Med Chem., 1991 , 34, 533), the inhibition of gastric H+/K+-ATPase by certain substituted imidazo[1 ,2- a]pyridines is described.
• the invention relates to condensed benzimidazoles of the formula 1 in which
• R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C- alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, aryl,
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
• R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, dihydroxy-1-4C-alkyl, or 1-4C- alkoxy-1-4C-alkyl and
• R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, dihydroxy-1-4C-alkyl or 1-4C- alkoxy-1-4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, azetidino, aziridino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkylamino-1-4C- alkylcarbonyl
• Ar is a mono- or bicyclic aromatic residue, substituted by R5, R6, R7 and R8, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,
• R5 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl
• R6 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen,
• R7 is hydrogen, 1-4C-alkyl or halogen and R8 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
• Halogen within the meaning of the invention is bromo, chloro and fluoro.
• 1-4C-Alkyl represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
• 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
• 3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is sub ⁇ stituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.
• 1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforemen ⁇ tioned 1-4C-alkyl groups. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.
• 1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.
• 1-4C-Alkoxycarbonyl (1-4C-alkoxy-CO-) represents a carbonyl group, to which one of the aforemen ⁇ tioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH 3 O-C(O)-) and the ethoxycarbonyl group (CH 3 CH 2 O-C(O)-) .
• 2-4C-Alkenyl represents a straight-chain or branched alkenyl group having 2 to 4 carbon atoms. Ex ⁇ amples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group). - A -
• 2-4C-Alkynyl represents a straight-chain or branched alkynyl group having 2 to 4 carbon atoms. Ex ⁇ amples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).
• Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms. Examples which may be mentioned are the trifluoromethyl, the difluoromethyl, the 2-fluoroethyl, the 2,2-difluoroethyl or the 2,2,2-trifluoroethyl group.
• Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl group. Hydroxy-1-4C-alkyl within the scope of the invention is understood to include 1-4C-alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-di- hydroxybutyl and in particular the 2,3-dihydroxypropyl group.
• Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.
• Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino group. Examples, which may be mentioned, are the dimethylamino-methyl-carbonyl and the diethylamino-methylcarbonyl group.
• Fluoro-2-4C-alkyl represents a 2-4C-alkyl group, which is substituted by one or more fluorine atoms.
• An example which may be mentioned is the 2,2,2-trifluoroethyl group.
• Aryl-2-4C-alkinyl represents a 2-4C-alkynyl group, which is substituted by one aryl group.
• Preferred groups of this type are aryl-ethinyl groups. Examples which may be mentioned are the phenyl-ethinyl, 4-methylphenyl-ethinyl, 2-fluorophenyl-ethinyl or the 4-fluorophenyl-ethinyl group.
• Aryl-2-4C-alkenyl represents a 2-4C-alkenyl group, which is substituted by one aryl group.
• Preferred groups of this type are 2-aryl-vinyl groups. Examples which may be mentioned are the 2-phenyl-vinyl, 2-(4-methylphenyl)-vinyl, 2-(2-fluorophenyl)-vinyl or the 2-(4-fluorophenyl)-vinyl group.
• Cyano-1-4C-alkyl represents a 1-4C-alkyl group, which is substituted by one cyano group. Examples which may be mentioned are the cyanomethyl, the 2-cyanoethyl and the 3-cyanopropyl group.
• NR31 R32-carbonyl-1-4C-alkyl represents a 1-4C-alkyl group, which is substituted by a carbonyl to which is bonded the nitrogen containing residue NR31 R32 via its nitrogen atom.
• R31 and R32 are defined as described above.
• Preferred groups of this type are NR31 R32-carbonyl-CH 2 - groups.
• Examples which may be mentioned are the carbamoyl (H 2 N-C(O)-CH 2 -), the CH 3 N(H)-C(O)-CH 2 -, the (CHa) 2 N-C(O)-CH 2 -, the CH 3 OCH 2 CH 2 -N(H)-C(O)-CH 2 -, the CH 3 OCH 2 CH 2 -N(CH 3 )-C(O)-CH 2 -, the HOCH 2 CH 2 -N(H)-C(O)-CH 2 - or the HOCH 2 CH 2 -N(CH 3 )-C(O)-CH 2 - group.
• 1-7C-Alkyl represents a straight-chain or branched alkyl group having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
• Dihydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by two hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutyl and in particular the 2,3-dihydroxypropyl group.
• 1-4C-Alkoxy-1-4C-alkyl-carbonyl represents a carbonyl group, to which one of the aforementioned 1- 4C-alkoxy-1-4C-alkyl groups is bonded. Examples which may be mentioned are the methoxy-methyl- carbonyl (CH 3 -O-CH 2 -CO-) and the ethoxy-methyl-carbonyl group (CH 3 CH 2 -O-CH 2 -CO-).
• Groups Ar which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,5-bis(trifluoro- methyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6- fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3-(4- chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 2,4-dihydroxyphenyl, 2,6-dimethoxy
• 2-4C-Alkenyloxy represents a group, which in addition to the oxygen atom contains one of the above- mentioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the 2-butenyloxy, 3-butenyl- oxy, 1-propenyloxy and the 2-propenyloxy group (allyloxy group).
• 1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the abovementioned 1-4C-alkyl groups.
• An example which may be mentioned is the acetyl group.
• Carboxy-1-4C-alkyl represents a 1-4C-alkyl group which is substituted by a carboxyl group. Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group.
• 1-4C-Alkoxycarbonyl-1-4C-alkyl represents a 1-4C-alkyl group, which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxy- carbonylmethyl and the ethoxycarbonylmethyl group.
• Aryl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the abovementioned aryl groups.
• An exemplary preferred aryl-1-4C-alkyl group is the benzyl group.
• Aryl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the abovementioned aryl groups.
• An exemplary preferred aryl-1-4C-alkoxy group is the benzyloxy group.
• 1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C 3 H 7 C(O)NH-) and the acetylamino group (acetamido group) (CH 3 C(O)NH-) .
• 1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementio ⁇ ned 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)eth- oxycarbonyl (CH 3 -O-CH 2 CH 2 -O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH 3 CH 2 -O-CH 2 CH 2 -O- CO-).
• 1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group.
• Possible salts of compounds of the formula 1 - depending on substitution - are especially all acid addi ⁇ tion salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxy- benzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are used in salt preparation - depending on whether
• 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.
• 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.
• the compounds of the formula 1 have at least three centers of chirality in the skeleton.
• the invention thus provides all feasible stereoisomers in any mixing ratio, including the pure stereoisomers, which are a preferred subject matter of the invention.
• Compounds which are to be mentioned are those of the formula 1 , where
• R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
• R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
• R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen or 1-7C-alkyl or where
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl or thiazolyl residue, substituted by R5, R6, R7 and R8, wherein
• R5 is hydrogen, 1-4C-alkyl or halogen
• R6 is hydrogen, 1-4C-alkyl or halogen
• R7 is hydrogen, 1-4C-alkyl or halogen
• R8 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
• R1 is 1-4C-alkyl or 3-7C-cycloalkyl
• R2 is hydrogen, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or 3-7C-cycloalkyl
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl, 2-
• R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, halogen or trifluoromethyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
• R3 is 1 -4C-alkyl, fluoro-1 -4C-alkyl, 3-7C-cycloalkyl, 1 -4C-alkoxy-1 -4C-alkyl, 2-4C-alkinyl, aryl-2-4C- alkinyl, cyano-1-4C-alkyl or a NR31 R32-carbonyl-1-4C-alkyl group, where
• R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, fluoro-1 -4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, halogen or trifluoromethyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, aryl-2-4C-alkinyl, cyano-1-4C-alkyl or a NR31 R32- carbonyl-1-4C-alkyl group, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and wherein aryl is phenyl and the salts of these compounds.
• Compounds which are to be particularly emphasized are those of the formula 1 , where
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is 1-4C-alkyl, 3-7C-cycloalkyl, cyano-1-4C-alkyl or a NR31 R32-carbonyl-1-4C-alkyl group, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and the salts of these compounds.
• R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C- alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, aryl,
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
• R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, dihydroxy-1-4C-alkyl, or 1-4C- alkoxy-1-4C-alkyl and
• R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, dihydroxy-1-4C-alkyl or 1-4C- alkoxy-1-4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, azetidino, aziridino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkylamino-1-4C- alkylcarbonyl
• Ar is a mono- or bicyclic aromatic residue, substituted by R5, R6, R7 and R8, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,
• R5 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
• R6 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
• R7 is hydrogen, 1-4C-alkyl or halogen
• R8 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
• R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
• R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
• R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen or 1-7C-alkyl or where
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl or thiazolyl residue, substituted by R5, R6, R7 and R8, wherein
• R5 is hydrogen, 1-4C-alkyl or halogen
• R6 is hydrogen, 1-4C-alkyl or halogen
• R7 is hydrogen, 1-4C-alkyl or halogen
• R8 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
• R1 is 1-4C-alkyl or 3-7C-cycloalkyl
• R2 is hydrogen, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or 3-7C-cycloalkyl
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl, 2-
• R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, halogen or trifluoromethyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
• R3 is 1 -4C-alkyl, fluoro-1 -4C-alkyl, 3-7C-cycloalkyl, 1 -4C-alkoxy-1 -4C-alkyl, 2-4C-alkinyl, aryl-2-4C- alkinyl, cyano-1-4C-alkyl or a NR31 R32-carbonyl-1-4C-alkyl group, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, halogen or trifluoromethyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or aryl-2-4C-alkinyl, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and wherein aryl is phenyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is 1-4C-alkyl, 3-7C-cycloalkyl, cyano-1-4C-alkyl or a NR31 R32-carbonyl-1-4C-alkyl group, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is 1-4C-alkyl or 3-7C-cycloalkyl
• R4 is hydrogen
• Ar is a phenyl and the salts of these compounds.
• R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C- alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, aryl,
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
• R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, dihydroxy-1-4C-alkyl, or 1-4C- alkoxy-1-4C-alkyl and
• R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, dihydroxy-1-4C-alkyl or 1-4C- alkoxy-1-4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, azetidino, aziridino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkylamino-1-4C- alkylcarbonyl
• Ar is a mono- or bicyclic aromatic residue, substituted by R5, R6, R7 and R8, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,
• R5 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, ⁇ MC-alkoxycarbonylamino, ⁇ MC-alkoxy-'MC-alkoxycarbonylamino or sulfonyl,
• R6 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
• R7 is hydrogen, 1-4C-alkyl or halogen
• R8 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
• R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
• R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,
• R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen or 1-7C-alkyl or where
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl or thiazolyl residue, substituted by R5, R6, R7 and R8, wherein
• R5 is hydrogen, 1-4C-alkyl or halogen
• R6 is hydrogen, 1-4C-alkyl or halogen
• R7 is hydrogen, 1-4C-alkyl or halogen
• R8 is hydrogen, 1-4C-alkyl or halogen
• 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 1-4C-alkyl or 3-7C-cycloalkyl
• R2 is hydrogen, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or 3-7C-cycloalkyl
• R3 is hydrogen, halogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl, 2-
• R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, fluoro-1-4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, halogen or trifluoromethyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
• R3 is 1 -4C-alkyl, fluoro-1 -4C-alkyl, 3-7C-cycloalkyl, 1 -4C-alkoxy-1 -4C-alkyl, 2-4C-alkinyl, aryl-2-4C- alkinyl, cyano-1-4C-alkyl or a NR31 R32-carbonyl-1-4C-alkyl group, where
• R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
• R32 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, fluoro-1 -4C-alkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl-carbonyl or mono- or di-1-4C-alkyl-amino-1-4C- alkyl-carbonyl
• Ar is a phenyl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, halogen or trifluoromethyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, aryl-2-4C-alkinyl, cyano-1-4C-alkyl or a NR31 R32- carbonyl-1-4C-alkyl group, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and wherein aryl is phenyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is 1-4C-alkyl, 3-7C-cycloalkyl, cyano-1-4C-alkyl or a NR31 R32-carbonyl-1-4C-alkyl group, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and the salts of these compounds.
• R1 is 1-4C-alkyl
• R2 is 1-4C-alkyl
• R3 is cyano-1 -4C-alkyl or a NR31 R32-carbonyl-1 -4C-alkyl group, where
• R31 is hydrogen
• R32 is hydrogen
• R4 is hydrogen
• Ar is a phenyl and the salts of these compounds.
• 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 examples which follow the schemes.
• the synthesis of precursors described in the following schemes, for example of compounds of the formulae 2, 3, 4, 5, 6 and 7, is described inter alia in WO 05/058893 or can be performed in a similar way by a person skilled in the art.
• the compounds of the formula 1 can be obtained for example starting from compounds of the formula 2.
• the reaction sequence is shown in scheme 1.
• Oxidation of compounds of the formula 2 to compounds of the formula 3 is performed by standard procedures, for example using manganese dioxide. Protection of the hydroxyl group and of the amino group of compounds of formula 3 provides compounds of formula 4 and is performed by standard procedures and standard protection groups (P' and P"), like for example formyl, acetyl, pivaloyl or benzoyl. Reduction of the keto group of compounds of formula 4 by simultaneous or subsequent deprotection of the hydroxyl group leads to the corresponding diols of the formula 5 and can be carried out, for example, using sodium borohydride followed by treatment with potassium carbonate. Epoxid formation to yield epoxide compounds of the formula 6 is carried out, for example under Mitsunobu conditions or by other reaction conditions known to the expert.
• suitable alkylation reagents like for example Grignard reagents or organolithium compounds
• the stereochemical outcome of the title compounds of formula 1 (1a and/or 1b) depends on the alkylation condition and the alkylating reagent applied to the epoxide of the formula 6a.
• a person skilled in the art is able to adapt the reaction conditions and reagents accordingly.
• Ketones of the formula 7 are known, for example from Helvetica Chimica Acta (1979), 62, 507, or can be prepared in a manner as shown for example in scheme 3 (route A).
• 3-Nitro-2-aminophenol can be reacted in a first step with a suitable benzyl derivative, for example benzylchloride, and the amino group of the reaction product of the formula 11 (known from J. Heterocyclic Chem. (1983), 20, 1525) is converted to the di-amide of the formula 12.
• ketones of the formula 7 can be prepared from compounds of the formula 19 by a cyclization reaction in the presence of a primary amine as shown in scheme 4 (route B).
• Compounds of the formula 19 are known, for example from H. Stetter and K. Hoehne, Chem. Ber., 1958, 91 , 1123- 1128, or can be prepared in an analogous manner starting from 2-nitroresorcin as shown in scheme 4.
• Phenylisoserine derivatives of the formula 8 or 8a can be prepared in analogy to methods known in literature (see for example J. Amer. Chem. Soc. (1998), 120, 431 ) or by methods known to the expert, for example by reaction under basic conditions of the corresponding unprotected phenylisoserine derivatives of the formula 20 with suitable protection group precursor Prot-X with a suitable leaving group X, like a suitable silyl chloride, for example 4 BuMe 2 SiCI, as shown in Scheme 5.
• suitable protection group precursor Prot-X with a suitable leaving group X like a suitable silyl chloride, for example 4 BuMe 2 SiCI, as shown in Scheme 5.
• Route A A suspension of 2.00 g (7.93 mmol) 4-benzyloxy-1 ,2-dimethyl-1/-/-benzimidazole and 1.70 g palladium on carbon (10 %) in methanol (50 ml) is stirred in a autoclave by a hydrogen pressure of 150 bar at 70 0 C for 20 h. Afterwards the catalyst is filtered off and the methanol is removed in vacuo. The crude product is purified by column chromatography (dichloromethane / methanol: 100 / 3 to 13 / 1 ) to give 0.14 g (0.85 mmol / 11 %) of the title product with a melting point of 98.1 °C (dichloromethane / methanol).
• Route B To a stirred mixture of 29.0 g (0.17 mol) 2-acetylamino-3-hydroxy-cyclohex-2-enone in xylene (580 ml) is added acetic acid (57 ml) and dropewise 116 ml (0.23 mol) methylamine (2 M in THF). The reaction mixture is heated to 155°C for 5 h, cooled down to 25°C and stirred for further 20 h.
• the crude product is purified by column chromatography (dichloromethane / methanol: 100 / 1 to 13 / 1 ) and crystallized from acetone to give 4.70 g (15.3 mmol / 76 %) of the title product as a solid with a melting point of 235.1 0 C (acetone).
• the compounds of the formulae 1 , 1a and 2 and their pharmacologically acceptable salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals, in particular humans.
• the active compounds according to the invention are distinguished by a high selectivity of action, an advantageous duration of action, a particularly good enteral activity, the absence of significant side effects and a large therapeutic range.
• Gastric and intestinal protection in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations.
• gastroesophageal reflux disease GGID
• the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation include, but are not limited to, heartburn and/or acid regurgitation.
• the active compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcero- genic and the antisecretory properties are determined.
• the active compounds according to the invention are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine.
• a further subject of the invention are therefore the active compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
• the invention likewise includes the use of the active compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the above- mentioned diseases.
• the invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
• a further subject of the invention are medicaments which comprise one or more active compounds according to the invention.
• the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
• suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active
• auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge.
• solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).
• the active compounds can be administered orally, parenterally or percutaneously.
• the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, preferably 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 4, individual doses to achieve the desired result.
• a parenteral treatment similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses can be used.
• the establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
• the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, for example: tranquillizers (for example from the group of the benzodiazepines, for example diazepam), spasmolytics (for example, bietamiverine or camylofine), anticholinergics (for example, oxyphencyclimine or phencarbamide), local anesthetics, (for example, tetracaine or procaine), and, if appropriate, also enzymes, vitamins or amino acids.
• tranquillizers for example from the group of the benzodiazepines, for example diazepam
• spasmolytics for example, bietamiverine or camylofine
• anticholinergics for example, oxyphencyclimine or phencarbamide
• local anesthetics for example, tetracaine or procaine
• enzymes for example, tetracaine or procaine
• H 2 blockers e.g. cimetidine, ranitidine
• H + /K + ATPase inhibitors e.g. omeprazole, pantoprazole
• peripheral anticholinergics e.g.
• pirenzepine pirenzepine, telenzepine
• gastrin antagonists with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or of decreasing the side effects, or further the combination with antibacterially active substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts) for the control of Helicobacter pylori.
• antibacterially active substances such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts
• Suitable antibacterial co-components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and combinations thereof (for example clarithromycin + metronidazole).
• the active compounds according to the invention are suited for a free or fixed combination with those medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs), which are known to have a certain ulcerogenic potency.
• those medicaments e.g. certain antiinflammatories and antirheumatics, such as NSAIDs
• the compounds of formula 1 are suited for a free or fixed combination with motility-modifying drugs.
• the excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models.
• the compounds according to the invention investigated in the model mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples.
• pentagastrin left femoral vein
• pentagastrin left femoral vein
• the substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
• the body temperature of the animals was kept at a constant 37.8-38°C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).

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