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
  • C07D471/10—Spiro-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
• • 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.
• U.S. Patent 4,468,400 describes tricyclic imidazo[1 ,2-a]pyridines having different ring systems fused to the imidazopyridine skeleton, which compounds are said to be suitable for treating peptide ulcer disorders.
• the International Patent Applications WO98/42707 (which corresponds to US patent 6,197,783), WO98/54188 (which corresponds to US patent 6,160,1 19), WO00/17200 (which corresponds to US patent 6,436,953 and 6,696,460), WO00/26217 (which corresponds to US patent 6,384,048), WO 00/6321 1 (which corresponds to US patent 6,503,923), WO 01/72756, WO 01/72754 (which corresponds to US patent 6,916,825), WO 01/72755 (which corresponds to US patent 6,936,623), WO 01/72757 (which corresponds to US patent 6,696,461 ), WO 02/34749 (which corresponds to US patent 6,869,949), WO 03
• PPI ' s proton pump inhibitors
• rPPI ' s reversible proton pump inhibitors
• APA ' s acid pump antagonists
• P-CAB ' s potassium competitive acid blockers
• the invention relates to compounds of the formula 1
• 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, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 1 -4C-alkoxy- carbonyl, hydroxy-1-4C-alkyl, halogen, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C- alkynyl, fluoro-1 -4C-alkyl, mono- or di-1 -4C-alkylamino-1 -4C-alkyl or cyanomethyl,
• R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, 1 -4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkoxy-1 -4C-alkyl, fluoro-1 -4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy- 1-4C-alkyl or 1-4C-alkylcarbonyl-1-4C-alkyl, 1 -4C-alkylcarbonyl or 1 -4C-alkoxycarbonyl and
• R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, or 1-4C-alkoxy-1-4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-4C-alkylpiperazino or morpholino group,
• R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, trifluoromethyl, halo-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alk- ylcarbonylamino, 1 -4C-alkoxycarbonylamino, 1 -4C-alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl
• 1 -4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
• 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
• 3-7C-Cycloalkyl-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclo- hexylethyl group.
• 1 -4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.
• 1 -4C-Alkoxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by one of the aforementioned 1 -4C-alkoxy groups.
• Examples which may be mentioned are the methoxymethyl group, the methoxyethyl group, in particular the 2-methoxyethyl group, the ethoxyethyl group, in particular the 2-ethoxyethyl group, and the butoxyethyl group, in particular the 2-butoxyethyl group.
• 1 -4C-Alkoxycarbonyl (-CO-1 -4C-alkoxy) represents a carbonyl group, to which one of the aforementioned 1 -4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH 3 O-C(O)-) and the ethoxycarbonyl group (CH 3 CH 2 O-C(O)-) .
• 2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1 -propenyl and the 2- propenyl group (allyl group).
• 2-4C-Alkynyl represents straight-chain or branched alkynyl groups having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).
• Fluoro-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by one or more fluorine atoms. Examples which may be mentioned are the trifluoromethyl group, the difluoromethyl, the 2-fluoroethyl, the 2,2-difluoroethyl or the 2,2,2-trifluoroethyl group.
• Hydroxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxy methyl, the 2-hy- droxyethyl, the 3-hydroxypropyl, the (2S)-2-hydroxypropyl and the (2R)-2-hydroxypropyl group. Hydroxy-1 -4C-alkyl within the scope of the invention is understood to include 1 -4C-alkyl groups substituted by two or more hydroxy groups. Examples which may be mentioned are the 3,4-di- hydroxybutyl and in particular the 2,3-dihydroxypropyl groups.
• Halogen within the meaning of the invention is bromo, chloro and fluoro.
• Mono- or di-1 -4C-alkylamino radicals contain, in addition to the nitrogen atom, one or two of the abovementioned 1 -4C-alkyl radicals. Preference is given to di-1 -4C-alkylamino and in particular to dimethyl-, diethyl- or diisopropylamino.
• Mono- or di-1 -4C-alkylamino-1 -4C-alkyl denotes one of the abovementioned 1 -4C-alkyl radicals which is substituted by one of the abovementioned mono- or di-1 -4C-alkylamino radicals.
• Preferred mono- or di-1 -4C-alkylamino-1 -4C-alkyl radicals are the mono- or di-1 -4C- alkylaminomethyl radicals.
• An Example which may be mentioned is the dimethylaminomethyl (CH3) 2 N-CH 2 radical.
• 1 -4C-Alkoxy-1 -4C-alkoxy represents one of the aforementioned 1 -4C-alkoxy groups, which is substituted by a further 1 -4C-alkoxy group.
• Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH 3 -O-CH 2 -CH 2 -O-) and 2-(ethoxy)ethoxy (CH 3 -CH 2 -O-CH 2 -CH 2 -O-).
• 1 -4C-Alkoxy-1 -4C-alkoxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkoxy1 -4C- alkyl groups, which is substituted by one of the aforementioned 1 -4C-alkoxy groups.
• An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH 3 -O-CH 2 -CH 2 -O-CH 2 -).
• Fluoro-1 -4C-alkoxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl groups, which is substituted by a fluoro-1 -4C-alkoxy group.
• Fluoro-1 -4C-alkoxy in this case represents one of the aforementioned 1 -4C-alkoxy groups, which substituted by one or more fluorine atoms.
• fluoro-substituted 1 -4C-alkoxy groups which may be mentioned are the 2-fluoro- ethoxy, 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,1 ,1 -trifluoro-2- propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1 -butoxy, the 4,4,4-trifluoro-1 - butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and prefera- bly the difluoromethoxy group.
• fluoro-1 -4C-alkoxy-1 -4C-alkyl radicals which may be mentioned are, 1 ,1 ,2,2-tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluo- romethoxymethyl, 2-fluoroethoxyethyl, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifluoroeth- oxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluoro- methoxyethyl radicals.
• 1 -4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the aforementioned 1 -4C-alkyl groups.
• An example which may be mentioned is the acetyl group.
• 1 -4C-Alkylcarbonyl-1 -4C-alkyl represents aforementioned 1 -4C-alkyl groups which are substituted by 1 -4C-alkylcarbonyl group. Examples which may be mentioned are the 2-oxo-propyl, the 2-oxo-butyl, the 2-oxo-pentyl, the 3-oxo-butyl or the 3-oxo-pentyl radicals.
• Hydroxy-1 -4C-alkoxy represents aforementioned 1 -4C-alkoxy groups, which are substituted by a hydroxy group.
• a preferred example which may be mentioned is the 2-hydroxyethoxy group.
• 2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the abovementioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the 2-butenyl- oxy, 3-butenyloxy, 1 -propenyloxy and the 2-propenyloxy group (allyloxy 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-alkyl groups, which are substituted by one of the abovementioned 1 -4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxycarbonylmethyl and the ethoxycarbonylmethyl group.
• Halo-1 -4C-alkoxy represents 1 -4C-alkoxy groups which are completely or mainly substituted by halogen. "Mainly” in this connection means that more than half 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 particular fluoro-substituted 1 -4C-alkoxy groups.
• halogen-substituted 1 -4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexa- chloroisopropoxy, the pentachloroisopropoxy, the 1 ,1 ,1 -trichloro-3,3,3-trifluoro-2-propoxy, the 1 ,1 ,1 -trichloro ⁇ -methyl ⁇ -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
• 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.
• 1 -4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the aforementioned 1 -4C-alkyl groups.
• An example which may be mentioned is the acetyl group.
• 1 -4C-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 aforementioned 1 -4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the eth- oxycarbonylamino 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 (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.
• Hydroxypyrrolidino represents a pyrrolidino group, which is substituted by a hydroxy group. Examples which may be mentioned are the 2-hydroxypyrrolidino and the 3-hydroxypyrrolidino groups.
• Hydroxyazetidino represents an azetidino group, which is substituted by a hydroxy group.
• An which may be mentioned is the 3-hydroxyazetidino group.
• Fluorazetidino represents an azetidino group, which is substituted by a fluoro atom. Examples which may be mentioned are the (2S)-and the (2R)-fluoroazetidino and in particular the 3-fluo- roazetidino group.
• N-1 -4C-alkylpiperazino represents a piperazino group, in which one of the piperazino nitrogen atoms is substituted by one of the aforementioned 1 -4-C-alkyl groups. Examples which may be mentioned are the 4-methylpiperazino, the 4-ethylpiperazino and the 4-iso-propylpiperazino groups.
• Possible salts of compounds of the formula 1 - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water- soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D- gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, malonic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy- 2-naphthoic acid, where the acids are used in salt preparation - depending on
• Salts of the compounds of formula I according to the invention can be obtained by dissolving, the free compound in a suitable solvent (for example a ketone such as acetone, methylethylke- tone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or to which the desired acid is then added, if necessary upon heating.
• a suitable solvent for example a ketone such as acetone, methylethylke- tone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight alipha
• the acid can be employed in salt preparation, depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
• the salts are obtained for example by evaporating the solvent or by precipitating upon cooling, by re-precipitating, or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation.
• Pharmacologically intolerable salts which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art. It is known to the person skilled in the art that the compounds according to the invention and their salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents.
• the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1 .
• the compounds of the formula 1 can have a center of chirality at the spiro carbon atom in 8- postion of the basic skeleton.
• the occurance of such a center of chirality depends on the nature and the position of the substituents R4 and R5.
• a center of chirality arises for example if R4 is different from R5.
• the invention thus relates to all feasible stereoisomers in any desired mixing ratio to another, including the pure stereoisomers, which are a preferred subject of the invention.
• the invention therefore relates to all of the following stereoisomers of the formula 1 :
• the pure stereoisomers of the compounds of the formula 1 and salts according to the present invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up stereoisomeric mixtures obtained in synthesis.
• the pure stereoisomers of the compounds of the formula 1 are obtained by using chiral starting compounds.
• Stereoisomeric mixtures of compounds of the formula 1 can be split up into the pure stereoisomers by methods known to a person skilled in the art. Preferably, the mixtures are separated by chromatography or (fractional) crystallization.
• the split up is preferably done by forming diastereomeric salts by adding chiral additives like chiral acids, subsequent resolution of the salts and release of the desired compound from the salt.
• derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group.
• enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
• One embodiment of the invention are compounds of the formula 1 , in which R3 is hydrogen, and their salts.
• R3 is the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1 -7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-
• 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 pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluoraze- tidino, aziridino, N-1 -4C-alkylpiperazino or morpholino group, and their salts.
• R3 is halogen, fluoro-1 -4C-alkyl, 1 -4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1 -4C-alk- oxycarbonyl, 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 and their salts.
• R4 and R5 are each hydrogen, and their salts.
• Another embodiment of the invention (embodiment 5) are compounds of the formula 1 , in which
• R1 is 1 -4C-alkyl and their salts.
• R2 is hydrogen or 1 -4C-alkyl, and their salts.
• R1 is methyl and their salts.
• R2 is hydrogen or methyl, and their salts.
• An embodiment of the invention (embodiment 9) to be emphasized are compounds of the formula 1 , in which R1 is methyl, R2 is hydrogen or methyl, and their salts.
• the invention also relates to compounds of the formula 1 , in which
• R1 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 1 -4C-alkoxy, 1 -4C- alkoxy- 1 -4C-alkyl, 1 -4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1 -4C-alkyl or hydroxy-1 -4C-alkyl,
• R2 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 1 -4C- alkoxycarbonyl, hydroxy-1 -4C-alkyl, halogen, 1 -4C-alkoxy-1 -4C-alkyl, 2-4C-alkenyl, 2- 4C-alkynyl, fluoro-1 -4C-alkyl, mono- or di-1 -4C-alkylamino-1 -4C-alkyl or cyanomethyl,
• R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, 1 -4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1 -4C-alkoxycarbonyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C- alkoxy-1 -4C-alkyl, fluoro-1 -4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1 -7C-alkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alkyl or 1 -4C-alkylcarbonyl-1 -4C-alkyl, 1 -4C-alkylcarbonyl or 1 -4C-alkoxycarbonyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, or 1-4C-alkoxy-1-4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, aziridino,
• R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, trifluoromethyl, halo-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyl- carbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, and their salts
• R1 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C- alkyl or hydroxyl-1-4C-alkyl,
• R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, halogen, 1-4C-alkoxy-1- 4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl orfluoro-1-4C-alkyl,
• R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, 1 -4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alk- oxy-1 -4C-alkyl, fluoro-1 -4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy- 1-4C-alkyl or 1-4C-alkylcarbonyl-1-4C-alkyl, 1-4C-alkylcarbonyl or 1 -4C-alkoxycarbonyl and
• R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluoraze- tidino, aziridino, N-1-4C-alkylpiperazino or morpholino group,
• R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C-alkyl or halogen, and their salts.
• R1 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C- alkyl or hydroxyl-1 -4C-alkyl,
• R2 is hydrogen, 1 -4C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl, halogen, 1 -4C-alkoxy-1 - 4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or fluoro-1 -4C-alkyl,
• R3 is hydrogen, halogen, fluoro-1 -4C-alkyl, 1 -4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, 1 -4C-alkoxycarbonyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alk- oxy-1 -4C-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, 1 -4C-alkoxy-1 -4C-alkyl or 1 -4C-alkylcarbonyl-1 -4C-alkyl, 1 -4C-alkylcarbonyl or 1 -4C-alkoxycarbonyl and R32 is hydrogen, 1 -7C-alkyl, hydroxy-1 -4C-alkyl or 1 -4C-alkoxy-1 -4C-alkyl, or where
• R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, aziridino, N-1 -4C-alkylpiperazino or morpholino group,
• R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1 -4C-alkyl or halogen, and their salts.
• R1 is hydrogen, 1 -4C-alkyl or hydroxy-1 -4C-alkyl
• R2 is hydrogen, 1 -4C-alkyl, hydroxy-1 -4C-alkyl or halogen
• R3 is hydrogen, carboxyl, 1 -4C-alkoxycarbonyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1 -7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-
• 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 pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluoraze- tidino, aziridino, N-1 -4C-alkylpiperazino or morpholino group,
• R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1 -4C-alkyl or halogen, and their salts.
• R1 is hydrogen, 1 -4C-alkyl or hydroxy-1 -4C-alkyl
• R2 is hydrogen, 1 -4C-alkyl, hydroxy-1 -4C-alkyl or halogen
• R3 is hydrogen, carboxyl, 1 -4C-alkoxycarbonyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1 -7C-alkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-1 -4C-alkyl or
• 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 pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, aziridino,
• R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1 -4C-alkyl or halogen, and their salts.
• R1 is 1 -4C-alkyl
• R2 is hydrogen or 1 -4C-alkyl
• R3 is hydrogen, carboxyl, 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32, where
• R31 is hydrogen, hydroxyl, 1 -7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl, 1 -4C-alkoxy-
• 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 pyr- rolidino, hydroxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluoraze- tidino, aziridino, N-1 -4C-alkylpiperazino or morpholino group
• R4 and R5 are each hydrogen, and their salts.
• R1 is 1 -4C-alkyl
• R2 is 1 -4C-alkyl
• R3 is hydrogen, carboxyl, 1 -4C-alkoxycarbonyl or the group -CO-NR31 R32 where
• R31 is 1 -7C-alkyl and R32 is hydrogen, R4 and R5 are each hydrogen, and their salts.
• R1 is 1 -4C-alkyl
• R2 is 1 -4C-alkyl
• R3 is hydrogen
• R4 and R5 are each hydrogen, and their salts.
• Exemplary particularly preferred compounds according to the invention are those described by way of example and the salts of these compounds.
• the compounds according to the invention can be synthesized from corresponding starting compounds, for example according to the reaction schemes given below. The synthesis is carried out in a manner known to the expert, for example as described in more detail in the following examples.
• Scheme 1 .
• Compounds of the formula 2 can be prepared for example as outlined in scheme 2.
• ketones of the formula 3 are reacted with spiro-amino acid derivatives of the formula 4 (wherein Y is a suitable leaving group, for example an 1 -4C-alkoxy group, e.g. an ethoxy group) to give compounds of the formula 5.
• Y is a suitable leaving group, for example an 1 -4C-alkoxy group, e.g. an ethoxy group
• compounds of the formula 5 are oxidized by standard procedures using a suitable oxidizing agent (e.g. chloranil or 2,3-dichloro- 5,6-dicyanobenzoquinone) to give compounds of the formula 2.
• a suitable oxidizing agent e.g. chloranil or 2,3-dichloro- 5,6-dicyanobenzoquinone
• Ketones of the formula 3 are known to a person skilled in the art (inter alia from the International Patent Applications WO 02/34749, WO 01 /72748, WO 01 /72757 or from Angew. Chem. Int. Ed. Engl. 1996, 35, 545), or they can be prepared using analogous process steps which are known to a person skilled in the art.
• the required ⁇ -amino acid derivatives of the general formula 4 can be prepared from the corresponding ⁇ -hydroxy acids of the formula 5, wherein Y is a suitable leaving group, for example an 1 -4C-alkoxy group, e.g. an ethoxy group, by methods familiar to a person skilled in the art, like for example the Ritter reaction in analogy to the procedure described for example in Org. React. 1969, 17, 213.
• Y is a suitable leaving group, for example an 1 -4C-alkoxy group, e.g. an ethoxy group
• reaction steps outlined above are carried out in a manner known per se, e.g. as described in more detail in the examples.
• the present invention further relates to compounds of the formula 2 and 5 shown above, which are intermediates in the process of producing the compounds of the formula 1 according to the present invention.
• R1 , R2, R3, R4, R5 are thereby defined as for compounds of the formula 1 .
• the excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models.
• the compounds of the formula 1 according to the invention investigated in the model mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples.
• 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).
• reaction mixture was cooled to room temperature and diluted with 80 ml tetrahydrofuran.
• 25 ml (25 mmol) of lithium bis(trimethylsilylamide) (1 M in tetrahydrofuran) were added dropwise during 5 min and the mixture was allowed to warm to room temperature.
• the reaction mixture was hydrolyzed with 60 ml saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was separated and dried over anhydrous sodium sulphate. On concentration in vacuo, a precipitate formed which was collected and rinsed with xylene and heptane to yield 3.0 g (55 %) of the title compound as a yellow solid, m.p. 232-233 0 C.
• the compounds of the formula 1 and their pharmaceutically 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 or curative action in warm-blooded animals, in particular humans.
• the active compounds according to the invention are distinguished by a high selectivity of action, a fast onset of action, an advantageous duration of action, efficient control of the duration of action by the dosage, a particularly good antisecretory efficacy, the absence of significant side effects and a large therapeutic range.
• Gastric and intestinal protection or cure in this connection is understood to include, according to general knowledge, the prevention, the treatment and the maintenance treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duodenal ulcer]), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, drugs (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. ethanol), gastric acid or stress situations.
• gastrointestinal inflammatory diseases and lesions such as, for example, reflux esophagitis, gastritis, hyperacidic or drug-related functional dyspepsia, and peptic ulcer disease [including peptic ulcer bleeding, gastric ulcer, duo
• gastrointestinal diseases is understood to include, according to general knowledge,
• GSD gastroesophageal reflux disease
• GERD extra-esophageal manifestations of GERD that include, but are not limited to, acid-related asthma, bronchitis, laryngitis and sleep disorders.
• C) other diseases that can be connected to undiagnosed reflux and/or aspiration include, but are not limited to, airway disorders such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease).
• gastrointestinal diseases comprise other gastrointestinal conditions that might be related to acid secretion, such as Zollinger-Ellison syndrome, acute upper gastrointestinal bleeding, nausea, vomiting due to chemotherapy or post-operative conditions, stress ulceration, IBD (inflammatory bowel disease) and particularly IBS (irritable bowel syndrome).
• 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 antiul- cerogenic 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 and/or upper digestive tract, particularly of the abovementioned diseases.
• a further subject of the invention are therefore the active compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
• the invention likewise includes the use of the active compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the above- mentioned diseases.
• the invention furthermore includes the use of the active compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
• a further subject of the invention are medicaments which comprise one or more active compounds according to the invention.
• the active compounds according to the invention are either employed as such, or preferably in combination with suitable pharmaceutical excipients in the form of tablets, coated tablets (e.g. film-coated tablets), multi unit particulate system tablets, capsules, suppositories, granules, powders (e.g. lyophilized compounds), pellets, patches (e.g. as TTS [transdermal therapeutic system]), emulsions, suspensions or solutions.
• the content of the active compound is advantageously being between 0.1 and 95wt% (weight percent in the final dosage form), preferably between 1 and 60wt%.
• the active compounds according to the invention can be administered orally, parenterally (e.g. intravenously), rectally or percutaneously. Oral or intravenous administration is preferred.
• excipients or combinations of excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge and are composed of one or more accessory ingredients.
• solvents antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins)
• excipients may be mentioned as examples:
• gelling agents antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g.
• carriers for intravenous administration, dispersants, emulsifiers, preservatives, solubilizers, buffer substances and/or isotonic adjusting substances.
• dispersants for intravenous administration, the person skilled in the art may choose as excipients, for example: solvents, gelling agents, polymers, permeation promoters, adhesives, matrix substances and/or wetting agents.
• a daily dose (given continuously or on-demand) of approximately 0.01 to approximately 20, preferably 0.02 to 5, in particular 0.02 to 1 .5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 2, individual doses to achieve the desired result.
• 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 frequency of administration can be adapted to intermittent, weekly, monthly, even more infrequent (e.g. implant) dosing.
• the establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
• the medicaments may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical science. All methods include the step of bringing the active compounds according to the invention into association with the excipients or a combination of excipients. In general the formulations are prepared by uniformly and intimately bringing into association the active compounds according to the invention with liquid excipients or finely divided solid excipients or both and then, if necessary, formulating the product into the desired medicament.
• the active compounds according to the invention or their pharmaceutical preparations can also be used in combination with one or more pharmacologically active constituents from other groups of drugs [combination partner(s)].
• “Combination” is understood to be the supply of both the active compound(s) according to the invention and the combination partner(s) for separate, sequential, simultaneous or chronologically staggered use.
• a combination is usually designed with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or decreasing the side effects of the combination partner(s), or with the aim to obtain a more rapid onset of action and a fast symptom relief.
• the drug release profile of the components can be exactly adapted to the desired effect, e.g. the release of one compound and its onset of action is chronologically previous to the release of the other compound.
• a combination can be, for example, a composition containing all active compounds (for example a fixed combination) or a kit-of-parts comprising separate preparations of all active compounds.
• a “fixed combination” is defined as a combination wherein a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity.
• a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture of simultaneous administration, such as in a formulation.
• Another example of a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
• kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
• a “kit-of-parts” is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
• the components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.
• “Other groups of drugs” are understood to include, for example: tranquillizers (for example from the group of the benzodiazepines, like diazepam), spasmolytics (for example butylscopolaminium bromide [Buscopan®]), anticholinergics (for example atropine sulfate, pirenzepine, tolterodine), pain perception reducing or normalizing agents (for example, paracetamol, tetracaine or procaine or especially oxetacain), and, if appropriate, also enzymes, vitamins, trace elements or amino acids.
• tranquillizers for example from the group of the benzodiazepines, like diazepam
• spasmolytics for example butylscopolaminium bromide [Buscopan®]
• anticholinergics for example atropine sulfate, pirenzepine, tolterodine
• pain perception reducing or normalizing agents for example, paracetamol
• histamine-H2 blockers e.g. cimetidine, ranitidine
• peripheral anticholinergics e.g. pirenzepine
• gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists).
• antibacterially active substances and especially substances with a bactericidal effect, or combinations thereof.
• These combination partner(s) are especially useful for the control of Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases.
• suitable antibacterially active combination partner(s) may be mentioned, for example:
• cephalosporins such as, for example, cifuroximaxetil
• (B) penicillines such as, for example, amoxicillin, ampicillin
• (E) macrolide antibiotics such as, for example, erythromycin, clarithromycin, azithromycin
• glycoside antibiotics such as, for example, gentamicin, streptomycin (H) gyrase inhibitors, such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin (I) oxazolidines, such as, for example, linezolid
• nitrofuranes or nitroimidazoles such as, for example, metronidazole, tinidazole, nitrofurantoin
• K bismuth salts, such as, for example, bismuth subcitrat (L) other antibacterially active substances and combinations of substances selected from (A) to (L), for example clarithromycin + metronidazole.
• Preferred is the use of two combination partners. Preferred is the use of two combination partners selected from amoxicillin, clarithromycin and metronidazole. A preferred example is the use of amoxicillin and clarithromycin.
• the active compounds according to the invention are especially suited for a free or fixed combination with drugs, which are known to cause "drug-induced dyspepsia" or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirheumatics, such as NSAIDs (non-steroidal antiinflammatory drugs, e.g. etofenamate, diclofenac, indometacin, ibuprofen, piroxicam, naproxen, meloxicam), oral steroids, bisphosponates (e.g. alendronate), or even NO-releasing NSAIDs, COX-2 inhibitors (e.g. celecoxib, lumiracoxib).
• drugs which are known to cause "drug-induced dyspepsia” or are known to have a certain ulcerogenic potency, such as, for example, acetylsalicylic acid, certain antiinflammatories and antirheu
• the active compounds according to the invention are suited for a free or fixed combination with motility-modifying or -regulating drugs (e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid), and especially with pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR), such as, for example, GABA-B agonists (e.g. baclofen, (2R)-3-amino-2-fluoropropylphosphinic acid) or allosteric GABA-B agonists (e.g.
• motility-modifying or -regulating drugs e.g. gastroprokinetics like mosapride, tegaserod, itopride, metoclopramid
• pharmaceuticals which reduce or normalize the incidence of transient lower esophageal sphincter relaxation (TLESR) such as, for example, GABA-B agonists (e.g. baclofen
• GABA-B re-uptake inhibitors e.g. tiagabine
• metabotropic glutamate receptor type 5 (mGluR ⁇ ) antagonists e.g. 2-methyl- 6-(phenylethynyl)pyridine hydrochloride
• CB2 (cannabinoid receptor) agonists e.g. [(3R)-2,3- dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1 ,2,3,de]-1 ,4-benzoxazin-6-yl]-1 -naphthalenyl- methanone mesylate).
• composition partners used for the treatment of IBS or IBD are also suitable combination partner(s), such as, for example: 5-HT4 receptor agonists like mosapride, tegaserod; 5- HT3 receptor antagonists like alosetron, cilansetron; NK2 antagonists like saredutant, nepadutant; ⁇ -opiate agonists like fedotozine.
• 5-HT4 receptor agonists like mosapride, tegaserod
• 5- HT3 receptor antagonists like alosetron, cilansetron
• NK2 antagonists like saredutant, nepadutant
• ⁇ -opiate agonists like fedotozine.
• Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis.
• a hypnotic aid such as, for example, Zolpidem [Bikalm®]
• combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

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