WO2008017466A1 - Dérivés de benzimidazole pharmaceutiquement actifs substitués par la tétrahydroisoquinoléine - Google Patents

Dérivés de benzimidazole pharmaceutiquement actifs substitués par la tétrahydroisoquinoléine Download PDF

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WO2008017466A1
WO2008017466A1 PCT/EP2007/007007 EP2007007007W WO2008017466A1 WO 2008017466 A1 WO2008017466 A1 WO 2008017466A1 EP 2007007007 W EP2007007007 W EP 2007007007W WO 2008017466 A1 WO2008017466 A1 WO 2008017466A1
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alkyl
hydrogen
alkoxy
formula
compound
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PCT/EP2007/007007
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WO2008017466A8 (fr
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Peter Jan Zimmermann
Christof Brehm
Wilm Buhr
Andreas Palmer
Saskia Zemolka
Wolfgang-Alexander Simon
Stefan Postius
Wolfgang Kromer
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Nycomed Gmbh
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Publication of WO2008017466A8 publication Critical patent/WO2008017466A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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 WO2005/121139 discloses tricyclic benzimidazole derivatives having substituents in 5-, 6- and 7-position of the tricyclic ring system 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 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-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C-alkyl or fluo- ro-1-4C-alkyl
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, cyano, 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-cycloalky
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hy- droxypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino,
  • R4 is hydrogen, 1-4C-alkyl or cyclopropyl
  • R5 is hydrogen, halogen, fluoro-1-4C-alkoxy, cyano, nitro, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cyclo- alkyl-1-4C-alkyl, 3-7C-cycloalkoxy, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkyl or hydroxy-1-4C-alkyl
  • R6 is hydrogen, halogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 3-7C-cycloalkoxy,
  • 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 cyclohexylethyl 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, iso- butoxy, 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 meth- oxymethyl 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 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 (pro- pargyl 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 di- fluoromethyl, 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, 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-dihydroxybutyl and in particular the 2,3-dihydroxypropyl groups.
  • Halogen within the meaning of the invention is bromo, chloro and fluoro.
  • 1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is 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-alkoxy-1-4Calkyl 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 preferably 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 trifluoromethoxymethyl, 2- fluoroethoxyethyl, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifIuoroethoxyethyl, the trifluorometh- oxyethyl and preferably the difluoromethoxymethyl and the difluoromethoxyethyl radicals.
  • 1-7C-Alkyl represents straight-chain or branched alkyl groups having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), 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.
  • 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.
  • 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 example 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-fluoroazetidino 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.
  • Fluoro-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one or more fluorine atoms.
  • fluoro-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 preferably the di- fluo
  • 3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
  • 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, 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, trifluoracetic acid, ascorbic acid, lactic acid, D-glucuronic acid, lactobionic acid (4-O-bet
  • 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, methylethylketone or methyli- sobutylketone, 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, methylethylketone or methyli- sobutylketone, 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 - -
  • 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 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.
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,
  • R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,
  • R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, cyano, 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,
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-4C-alkylpiperazino or morpholino group,
  • R4 is hydrogen, 1-4C-alkyl or cyclopropyl
  • R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, and the salts of these compounds.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3 is 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-1-4C-alkyl,
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-
  • R4 is hydrogen, 1-4C-alkyl or cyclopropyl
  • R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3 is the group -CO-NR31 R32 where
  • R31 is hydrogen or 1-7C-alkyl
  • R32 is 1-7C-alkyl
  • R4 is hydrogen, 1-4C-alkyl or cyclopropyl
  • R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
  • R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, and the salts of these compounds.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is the group -CO-NR31 R32 where
  • R31 is 1-7C-alkyl
  • R32 is 1-7C-alkyl
  • R4 is hydrogen or 1-4C-alkyl
  • R5 is hydrogen
  • R6 is hydrogen, and the salts of these compounds.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is the group -CO-NR31 R32 where
  • R31 is 1-7C-alkyl
  • R32 is 1-7C-alkyl
  • R4 is hydrogen
  • R5 is hydrogen
  • R6 is hydrogen, and the salts of these compounds.
  • the compounds of the formula 1 and 1-1 can have a center of chirality at the carbon atom substituted by R4 in the case when R4 is different from hydrogen.
  • 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 particularly relates to all of the following stereoisomers of the formula 1-a, 1-b, 1-1-a and 1-1-b:
  • 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.
  • 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.
  • the compounds of the general formula 1 , wherein R4 is hydrogen can be obtained by reacting substituted benzimidazoles of formula 2 with dibromides of formula 3 as depicted in scheme 1.
  • the starting amino-substituted benzimidazoles of the formula 2 are known, for example from WO2004054984 or they can be prepared using process steps, as described for example in WO2007023135 or in an analogous manner thereto.
  • the required dibromides of formula 3 are also known from literature or can be prepared in an analogous manner, e.g. as described in US Patent 5,364,876.
  • compounds of the formula 3 can be prepared from the corresponding diols using triphenylphosphine and carbon tetrabromide in analogy for example as described by A. Solladie-Cavallo et al. in Tetrahedron: Asymmetry 2001 , 12, 967-970.
  • the reaction shown in Scheme 1 is carried out in a manner known per se, for example using a base like potassium carbonate in a suitable solvent in analogy as described for example by Holliman and Mann, J. Chem. Soc. 1945, 45 or by M. Yus et al., Tetrahedron 1996, 52, 8545-8564. - -
  • Some compounds of the formula 4 are known, for example from Parker et. al., Tetrahedron Letters, 1998, 39, 2797 or from Hartmann, Chem. Ber. 1890, 23, 1050 or from US Patent Application 2006/0116383, they can be prepared in an analogous manner as described in any of these references, or compounds of the formula 4 can be prepared starting from amino substituted benzimidazoles of the formula 2 applying the Sandmeyer reaction (e.g. using sodium nitrite in acidic solvents like hydrochloric acid or hydrobromic acid followed by the addition of copper(l) chlorides or copper(l) bromides) as illustrated in the following scheme 3.
  • the Sandmeyer reaction e.g. using sodium nitrite in acidic solvents like hydrochloric acid or hydrobromic acid followed by the addition of copper(l) chlorides or copper(l) bromides
  • 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 4 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 and R6 are thereby defined as for compounds of the formula 1.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3 is 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-1-4C-alkyl,
  • R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydro- xypyrrolidino, piperidino, piperazino, azetidino, hydroxyazetidino, fluorazetidino, aziridino, N-1-
  • the invention further relates to the use of a compound of the formula 4 in the synthesis of compounds of the formula 1 , wherein R1 , R2, R3, R4, R5 and R6 are as defined in the outset and where X is bromo or chloro..
  • 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).
  • the reaction mixture was poured into an ice-cold saturated ammonium chloride solution and extracted with dichloromethane two times. The combined organic layers were dried over anhydrous magnesium sulphate and concentrated in vaccum. The crude mixture was purified by column chromatography (toluene/dioxane/methanol: 6/3/1 ) to times to give 39.0 mg (0.11 mmol / 15%) of the title compound as a light brown solid.
  • the compounds of the formulae 1 , 1-1 , 1-a, 1-b, 1-1 -a and 1-1 -b 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.
  • the active compounds according to the present invention are particularly distinguished by an excellent efficacy with regard to inhibition of gastric acid secretion and/or by a low potential to cause side effects for example due to a low affinity to one or more other enzymes whose inhibition is related to these side effects and/or by a low potential of drug-drug interactions.
  • 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).
  • IBD inflammatory bowel disease
  • 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 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 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 invention further relates to the active compounds according to the invention for the treatment and/or prophylaxis of gastrointestinal diseases.
  • the invention further relates to pharmaceutical compositions comprising an active compound according to the invention, for the treatment and/or prophylaxis of gastrointestinal diseases.
  • 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 ⁇ ) 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 oxeta- cain), 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, paraceta
  • 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 partners 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
  • 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, ibupro- fen, 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 anti
  • 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 re-uptake inhibitors e.g. tiagabine
  • metabotropic glutamate receptor type 5 (mGluR5) antagonists e.g. 2-methyl-6- (phenylethynyl)pyridine hydrochloride
  • CB1 (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).
  • compositions used for the treatment of IBS or IBD are also suitable combination partners), 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. - -
  • 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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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne des composés de formule (1) dont les substituants et symboles sont tels que définis dans la description. Les composés inhibent la sécrétion de l'acide gastrique.
PCT/EP2007/007007 2006-08-08 2007-08-08 Dérivés de benzimidazole pharmaceutiquement actifs substitués par la tétrahydroisoquinoléine WO2008017466A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054984A1 (fr) * 2002-12-13 2004-07-01 Altana Pharma Ag Benzimidazoles substitues en position 4 et leur utilisation en tant qu'inhibiteurs de la secretion gastrique
WO2006025714A1 (fr) * 2004-09-03 2006-03-09 Yuhan Corporation Derives pyrrolo[3,2-c]pyridine et procedes de preparation de ces derniers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054984A1 (fr) * 2002-12-13 2004-07-01 Altana Pharma Ag Benzimidazoles substitues en position 4 et leur utilisation en tant qu'inhibiteurs de la secretion gastrique
WO2006025714A1 (fr) * 2004-09-03 2006-03-09 Yuhan Corporation Derives pyrrolo[3,2-c]pyridine et procedes de preparation de ces derniers

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