WO2006100255A1 - Benzimidazoles tricycliques substitués par des groupements thioamide utilisés dans le traitement de maladies gastro-intestinales - Google Patents

Benzimidazoles tricycliques substitués par des groupements thioamide utilisés dans le traitement de maladies gastro-intestinales Download PDF

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Publication number
WO2006100255A1
WO2006100255A1 PCT/EP2006/060936 EP2006060936W WO2006100255A1 WO 2006100255 A1 WO2006100255 A1 WO 2006100255A1 EP 2006060936 W EP2006060936 W EP 2006060936W WO 2006100255 A1 WO2006100255 A1 WO 2006100255A1
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Prior art keywords
alkyl
hydrogen
alkoxy
hydroxy
cycloalkyl
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PCT/EP2006/060936
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English (en)
Inventor
Maria Vittoria Chiesa
Peter Jan Zimmermann
Wilm Buhr
Christof Brehm
Andreas Palmer
Wolfgang-Alexander Simon
Wolfgang Kromer
Stefan Postius
Hans Christof Holst
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Nycomed Gmbh
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Application filed by Nycomed Gmbh filed Critical Nycomed Gmbh
Priority to AU2006226352A priority Critical patent/AU2006226352A1/en
Priority to EP06725220A priority patent/EP1863820A1/fr
Priority to JP2008502403A priority patent/JP2008534476A/ja
Priority to CA002601388A priority patent/CA2601388A1/fr
Publication of WO2006100255A1 publication Critical patent/WO2006100255A1/fr

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments.
  • the International Patent Application WO 04/054984 discloses substituted, bicyclic benzimidazole derivatives which compounds are useful for treating gastrointestinal diseases.
  • the International Patent Application WO 04/087701 discloses tricyclic benzimidazole derivatives having different substituents in 5-position of the benzimidazole moiety which compounds are likewise useful for treating gastrointestinal diseases.
  • 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 tricyclic benzimidazoles of the formula 1
  • R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C- alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C- alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C- cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1 -4C-alkyl, fluoro-
  • R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C- alkyl, and
  • R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • X is O (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, wherein
  • R4 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R6 is hydrogen, 1-4C-alkyl or halogen
  • R7 is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
  • Halogen within the meaning of the invention is bromo, chloro and fluoro.
  • 1-4C-Alkyl represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
  • 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
  • 3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclo-propylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.
  • 1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.
  • 1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.
  • 1-4C-Alkoxycarbonyl (1-4C-alkoxy-CO-) represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (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. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group).
  • 2-4C-Alkynyl represents a straight-chain or branched alkynyl group having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).
  • Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms.
  • An example which may be mentioned is the trifluoromethyl group.
  • Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl group. Hydroxy-1-4C-alkyl within the scope of the invention is understood to include 1-4C-alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-di- hydroxybutyl and in particular the 2,3-dihydroxypropyl group.
  • Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.
  • Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl group.
  • Fluoro-2-4C-alkyl represents a 2-4C-alkyl group, which is substituted by one or more fluorine atoms.
  • An example which may be mentioned is the 2,2,2-trifluoroethyl group.
  • 1-7C-Alkyl represents a straight-chain or branched alkyl group having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
  • Groups Ar which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,5-bis(trifluoro- methyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6- fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3-(4- chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 2,4-dihydroxyphenyl, 2,6-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 aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group.
  • 1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)- ethoxy (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-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 addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxy- benzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are used in salt preparation - depending on whether a mono-
  • 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 compounds according to invention and their salts if, for example, they are isolated in crystalline form, can contain various amounts of solvents.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
  • the compounds of the formula 1 have a centre of chirality in the 8-position. The invention thus relates to both enantiomers in any desired mixing ratio to another, including the pure enantiomers, which are a preferred subject of the invention.
  • the thioamide substituent R31 R32N-C(S)- may give rise to an additional centre of chirality due to a hindered rotation of that residue around the bond, by which it is connected to the basic skeleton.
  • the invention thus also relates to all rotamers which occur due to that hindered rotation, including the pure rotamers, which are a preferred subject matter of the invention.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl
  • R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • X is O (oxygen) or NH
  • Ar is a phenyl group, substituted by R4, R5, R6 and R7, wherein
  • R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo- nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkyl- carbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy
  • R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, and the salts of these compounds.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • R4 is hydrogen, halogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino
  • R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R6 is hydrogen, halogen, 1-4C-alkyl and X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,
  • 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
  • R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,
  • R4 is hydrogen, halogen, 1-4C-alkyl
  • R5 is hydrogen
  • R6 is hydrogen, halogen and
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,
  • R4 is hydrogen, halogen or 1-4C-alkyl
  • R5 is hydrogen
  • R6 is hydrogen or halogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a azetidino group
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is 1-4C-alkyl
  • R31 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R32 is hydrogen or 1-4C-alkyl
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • Preferred subject of the invention are compounds of the formula 1a-1
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,
  • R4 is hydrogen, methyl, chloro or fluoro
  • R5 is hydrogen
  • R6 is hydrogen or fluoro
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino or morpholino group,
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a azetidino group
  • R4 is hydrogen, methyl, chloro or fluoro
  • R5 is hydrogen
  • R6 is hydrogen or fluoro
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a azetidino group
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is 1-4C-alkyl
  • R31 is 1-4C-alkyl or 3-7C-cycloalkyl
  • R32 is hydrogen or 1-4C-alkyl
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen) or NH, and the salts of these compounds.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R31 is 1-4C-alkyl
  • R32 is hydrogen or 1-4C-alkyl, or where
  • R31 and R32 together, including the nitrogen atom to which both are bonded, are a azetidino group
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen), and the salts of these compounds.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R31 is 1-4C-alkyl
  • R32 is 1-4C-alkyl
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen
  • X is O (oxygen), and the salts of these compounds.
  • the compounds according to the invention can be synthesised from corresponding starting compounds, for example according to the reaction scheme 1 given below, which shows in an exemplary manner the synthesis of compounds of the general formula 1 and of the general formula 1a-1.
  • the synthesis is carried out in a manner known to the expert, for example as described in more detail in the examples which follow the scheme 1.
  • Scheme 1 shows in an exemplary manner the synthesis of compounds of the general formula 1 and of the general formula 1a-1.
  • the compounds according to the invention can be synthesised from corresponding amide starting compounds of the formula 2, 2a or 2a-1 , for example according to the reaction scheme 1 given above.
  • the synthesis is carried out in a manner known to the expert, for example by treatment of appropriate starting compounds with a reagent which transfers sulphur to an amide functionality, like for example phosphorus pentasulfide (P2S5), 0,0-diethyldithio-phosphonic acid, boron sulfide, silicon disulfide, elemental sulfur or in particular Lawesson's reagent [2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1 ,3,2,4- dithiadiphosphetane] which is described for example in M. P. Cava, M. I. Levinson, Tetrahedron 1985, 41, 5061-5087, or by any other method known to replace the carbonyl oxygen in amide functionalities by sulphur.
  • the starting compounds are known, for example, from WO 04/087701 or they can be prepared as outlined in a general way in that patent application or they can be prepared using analogous process steps or they can be prepared as outlined in the following examples from known starting materials.
  • 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 compounds of the formulae 1 , 1a and 1a-1 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.

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  • Organic Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des benzimidazoles cycliques de formule (I), où les substituants et les symboles ont les significations indiquées dans la description de l'invention. Ces composés présentent des propriétés d'inhibition de sécrétion gastrique ainsi qu'une excellente activité protectrice gastrique et intestinale.
PCT/EP2006/060936 2005-03-24 2006-03-22 Benzimidazoles tricycliques substitués par des groupements thioamide utilisés dans le traitement de maladies gastro-intestinales WO2006100255A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2006226352A AU2006226352A1 (en) 2005-03-24 2006-03-22 Thioamide-substituted tricyclic benzimidazoles useful for the treatment of gastrointestinal diseases
EP06725220A EP1863820A1 (fr) 2005-03-24 2006-03-22 Benzimidazoles tricycliques substitués par des groupements thioamide utilisés dans le traitement de maladies gastro-intestinales
JP2008502403A JP2008534476A (ja) 2005-03-24 2006-03-22 胃腸疾病の治療のために有用なチオアミド置換された三環式のベンゾイミダゾール
CA002601388A CA2601388A1 (fr) 2005-03-24 2006-03-22 Benzimidazoles tricycliques substitues par des groupements thioamide utilises dans le traitement de maladies gastro-intestinales

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP05102407 2005-03-24
EP05102407.3 2005-03-24
EP05107518 2005-08-16
EP05107518.2 2005-08-16

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WO2006100255A1 true WO2006100255A1 (fr) 2006-09-28

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AU (1) AU2006226352A1 (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035195A1 (fr) * 2006-09-21 2008-03-27 Raqualia Pharma Inc. Composés tricycliques
WO2008074858A1 (fr) * 2006-12-21 2008-06-26 Nycomed Gmbh Intermédiaires et procédé pour la production de benzimidazoles tricycliques substitués en position 5
WO2008114123A1 (fr) * 2007-03-21 2008-09-25 Raqualia Pharma Inc. Dérivés de spiro benzimidazole comme inhibiteurs de pompe à acide
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087701A1 (fr) * 2003-04-04 2004-10-14 Altana Pharma Ag Benzimidazoles cycliques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087701A1 (fr) * 2003-04-04 2004-10-14 Altana Pharma Ag Benzimidazoles cycliques

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035195A1 (fr) * 2006-09-21 2008-03-27 Raqualia Pharma Inc. Composés tricycliques
JP2010504317A (ja) * 2006-09-21 2010-02-12 ラクオリア創薬株式会社 選択的アシッドポンプ阻害剤としてのベンゾイミダゾール誘導体
US8466166B2 (en) 2006-09-21 2013-06-18 Raqualia Pharma Inc. Benzimidazole derivatives as selective acid pump inhibitors
WO2008074858A1 (fr) * 2006-12-21 2008-06-26 Nycomed Gmbh Intermédiaires et procédé pour la production de benzimidazoles tricycliques substitués en position 5
WO2008114123A1 (fr) * 2007-03-21 2008-09-25 Raqualia Pharma Inc. Dérivés de spiro benzimidazole comme inhibiteurs de pompe à acide
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal

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CA2601388A1 (fr) 2006-09-28
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JP2008534476A (ja) 2008-08-28

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