WO2008151927A2 - Dérivés de benzimidazole à substitution 6-n pharmaceutiquement actifs - Google Patents

Dérivés de benzimidazole à substitution 6-n pharmaceutiquement actifs Download PDF

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WO2008151927A2
WO2008151927A2 PCT/EP2008/056478 EP2008056478W WO2008151927A2 WO 2008151927 A2 WO2008151927 A2 WO 2008151927A2 EP 2008056478 W EP2008056478 W EP 2008056478W WO 2008151927 A2 WO2008151927 A2 WO 2008151927A2
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alkyl
alkoxy
group
hydrogen
hydroxy
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PCT/EP2008/056478
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WO2008151927A3 (fr
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Peter Jan Zimmermann
Christof Brehm
Andreas Palmer
Wilm Buhr
Jörg Senn-Bilfinger
Wolfgang-Alexander Simon
Michael Herrmann
Stefan Postius
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Nycomed Gmbh
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Publication of WO2008151927A2 publication Critical patent/WO2008151927A2/fr
Publication of WO2008151927A3 publication Critical patent/WO2008151927A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • 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
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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 05/121 139 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.
  • the International Patent Application WO 06/037759 discloses tricyclic benzimidazole derivatives having substituents in 5- or in 5- and 6-position of the tricyclic ring system which compounds are likewise useful for treating gastrointestinal diseases.
  • the International Patent Application WO 06/1341 11 discloses spiro-benzimidazole derivatives having substituents in 6-position of the pentacyclic ring system which compounds are likewise useful for treating gastrointestinal diseases.
  • the International Patent Application WO 06/134460 (Pfizer Japan Inc.) discloses chromane substituted benzimidazole derivatives having substituents in 6-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 compounds of the formula 0
  • 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, 1-4C-alkoxy, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or fluoro-1-4C-alkyl,
  • R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2- pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group, provided that, if D is a group G4 and R3a is hydrogen or 1-4C-alkyl, R3b is not 1-4C-alkylcarbonyl,
  • 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- - A -
  • X is NH or O, and their salts.
  • the invention relates in a first embodiment (embodiment 1 ) 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, 1-4C-alkoxy, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy- 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or fluoro-1-4C-alkyl,
  • R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one 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- alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • X is NH or O, and their salts.
  • the invention further relates in a second embodiment (embodiment 2) to compounds of the formula 2
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, S-TC-cycloalkyl-I ⁇ C-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, 1-4C-alkoxy, 3-7C-cycloalkyl, S-TC-cycloalkyl-I ⁇ C-alkyl, hydroxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or fluoro-1-4C-alkyl,
  • R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2- pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one 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, carbo- xy-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-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • X is NH or O, and their salts.
  • the invention further relates in a third embodiment (embodiment 3) to compounds of the formula 3 in which
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, S-TC-cycloalkyl-I ⁇ C-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, 1-4C-alkoxy, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or fluoro-1-4C-alkyl,
  • R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one 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, car- boxy-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-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • X is NH or O, and their salts.
  • the invention relates in a fourth embodiment (embodiment 4) to compounds of the formula 1
  • R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, S ⁇ C-cycloalkyl-I ⁇ C-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, 1-4C-alkoxy, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl or fluoro-1-4C-alkyl,
  • R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2- pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group, provided that, if R3a is hydrogen or 1-4C-alkyl, R3b is not 1-4C-alkylcarbonyl,
  • 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, car- boxy-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-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
  • X is NH or O, and their salts.
  • 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, fert-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, isobutoxy, sec-butoxy, fert-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.
  • 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)-), the ethoxycarbonyl group (CH 3 CH 2 O-C(O)-) and the 2,2-dimethylethoxycarbonyl (tert- butoxycarbonyl) group ((CH 3 ) 3 CO-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 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.
  • 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.
  • 3-7C-Cycloalkyl-carbonyl represents a group, which in addition to the carbonyl group contains one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropyl- carbonyl, the cyclobutyl-carbonyl, cyclopentyl-carbonyl and the cyclohexyl-carbonyl groups.
  • 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.
  • 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-).
  • 2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the above- mentioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the 2-butenyloxy, 3- butenyloxy 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 Methoxy- carbonyl methyl 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-, bromo- and/or in particular fluoro-substituted 1-4C-alkoxy groups.
  • halogen-substituted 1-4C-alkoxy groups which may be mentioned are the 2-chloroethoxy, the 2,2,2-trichloroethoxy, the hexachloroiso- propoxy, the pentachloroisopropoxy, the 1 ,1 ,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1 ,1 ,1-trichloro-2- methyl-2-propoxy, the 1 ,1 ,1-trichloro-2-propoxy, the 3-bromo-1 ,1 ,1-trifluoro-2-propoxy, the 3-bromo- 1 ,1 ,1-trifluoro-2-butoxy, the 4-bromo-3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1 ,
  • 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 ethoxycarbonyl- amino and the methoxycarbonylamino group.
  • 1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1- 4C-alkoxy-1-4C-alkoxy groups is bonded.
  • Examples which may be mentioned are the 2-(methoxy)eth- oxycarbonyl (CH 3 -O-CH 2 CH 2 -O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH 3 CH 2 -O-CH 2 CH 2 -O- CO-).
  • 'MC-Alkoxy-'MC-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 (0), (1 ), (2), (3) and (4) - 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.
  • water- soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hy- drobromic 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, tolue- nesulfonic acid, methanesulfonic acid, trifluoracetic acid, ascorbic acid, lactic acid, D-glucuronic acid, lactobionic acid (4-O-beta-D-Galactopyranosyl-D-gluconic acid), galactaric acid, benzenesulfonic acid, laurylsulfonic acid or 3-hydroxy
  • Salts of the compounds of formula (0), (1 ), (2), (3) and (4) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, me- thylethylketone 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, me- thylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chlor
  • 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.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula (0), (1 ), (2), (3) and (4), and also all solvates and in particular all hydrates of the salts of the compounds of the formula (0), (1 ), (2), (3) and (4).
  • 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, or when R4 and R5 are identical in case of the compounds of the formula 1-a, 1-b, 1-c and 1-d.
  • 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 ):
  • embodiment 3 of the invention relate to compounds of the formula (3-2) (aspect 3- 2), (3-3) (aspect 3-3), (3-4) (aspect 3-4), (3-5) (aspect 3-5) and (3-6) (aspect 3-6):
  • the compounds of the formula (3), (3-1 ), (3-2), (3-3), (3-4), (3-5) and (3-6) have a center of chirality.
  • 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 (3-a), (3-b), (3-1 -a), (3-1 -b), (3-2-a), (3-2-b), (3-3-a), (3-3-b), (3-4-a), (3-4-b), (3-5-a), (3-5-b), (3-6-a) and (3- 6-b):
  • the invention particularly relates to all of the following stereoisomers of the formula (4-a), (4-b), (4-c), (4-d), (4-e), (4-f), (4-g), (4-h):
  • the pure stereoisomers of the compounds of the formula (1 ), (3) or (4) 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 ), (3) or (4) are obtained by using chiral starting compounds.
  • Stereoisomeric mixtures of compounds of the formula (1 ), (3) or (4) can be split up into the pure stereoisomers by methods known to a person skilled in the art.
  • 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.
  • R1 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2- pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group, provided that, if D is a group G4 and R3a is hydrogen or 1-4C-alkyl, R3b is not 1-4C-alkylcarbonyl,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group, provided that, if R3a is hydrogen or 1-4C-alkyl, R3b is not 1-4C-alkylcarbonyl,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen or 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or S-TC-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group, provided that, if D is a group G4 and R3a is hydrogen or 1-4C-alkyl, R3b is not 1-4C- alkylcarbonyl,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen or 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are each hydrogen
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen or 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen or 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or S-TC-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is hydrogen or 1-4C-alkyl
  • R3a is hydrogen
  • R3b is 3-7C-cycloalkylcarbonyl or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, 1-4C- alkyl or halogen,
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3a is hydrogen or 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2- pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group, provided that, if D is a group G4 and R3a is hydrogen or 1-4C-alkyl, R3b is not 1-4C-alkylcarbonyl,
  • R4 and R5 are identical or different substituents selected from the group consisting of hydrogen, halogen and 1-4C-alkyl,
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3a is hydrogen or 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl or 3-7C-cycloalkylcarbonyl, or R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 1 ,3-oxazolidin-2-one group,
  • R4 and R5 are each hydrogen
  • X is NH or O, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3a is 1-4C-alkyl
  • R3b is 1-4C-alkylcarbonyl, or where R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2- pyrrolidinone or 2-azetidinone group
  • R4 and R5 are each 1-4C-alkyl
  • X is NH, and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone, 2- piperidinone, or 2-azetidinone group
  • R4 and R5 are each hydrogen or halogen
  • X is NH or O and their salts.
  • R1 is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3a and R3b together, including the nitrogen atom to which both are bonded, are a 2-pyrrolidinone or
  • R4 is 1-4C-alkyl and R5 is hydrogen, X is O, and their salts.
  • Exemplary preferred compounds according to the invention are those compounds depicted in the following table 1 and the salts of these compounds. Table 1:
  • 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 formula 1 can be obtained by different synthetic routes. If compounds of the formula (1 ) are desired, where one of the substituent R3a or R3b is acyl and the other substituted alkyl, the synthesis follows route A. The starting amine (5) is alkylated to give compound (6) and subsequently acylated to give the final compound (1 ). The reaction sequence in general, i.e. alkylation of an amine and subsequent acylation is known to a person skilled in the art. If compounds of the formula (1 ) are desired, where R3a and R3b together, including the nitrogen atom to which both are bonded, are e.g.
  • the reaction sequence follows route B.
  • the amine (5) is first acylated with an appropriate carboxylic acid derivative LG-A-CO(HaI), for example a carboxylic acid chloride LG-A- CO(CI), to give the compound (7).
  • the leaving group LG is bromo or chloro.
  • a base for example with sodium hydride in N,N-dimethylformamide (see e.g. Abe et al., J. Med. Chem. 1998, 4053 or Easton et al., J. Chem. Soc.
  • the starting amine (5) can be obtained from the corresponding carboxylic acid (8) by methods known to a person skilled in the art, for example the Curtius rearrangement or any other reaction for the conversion of a carboxylic acid to an amine (Scheme 2). Most conveniently, the reaction is carried out with diphenyl phosphoryl azide (DPPA) in fert-butanol to give the fert-butoxycarbonyl-protected amine (9) according to procedures known in literature (e.g. Hisashi et al., Chem. Pharm. Bull. 1993, 163 or Brickwood et al., J. Med. Chem. 1998, 2960). The carbamate (9) is then hydrolyzed to the corresponding amine (5) by treatment with acid, e.g. hydrochloric acid or trifluoroacetic acid.
  • acid e.g. hydrochloric acid or trifluoroacetic acid.
  • cleavage of the group pg does not take place during the aldol addition, it has to be removed under standard conditions (e.g. using tetrabutylammonium fluoride for the cleavage of silyl ethers; suitable reaction conditions can be defined by the person skilled in art and can be based on the suggestions compiled in T. W. Greene / P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, J. Wiley & sons, New York, 1999). Cyclization (under acidic or Lewis acidic conditions) and aromatization (using standard aromatization reagents, e.g.
  • Aldehydes of the formula (1 1 ) can be prepared as outlined in the following Scheme 4.
  • the hydroxyl group of hydroxyesters of the formula (14) can be protected by a group gp (e.g. silyl groups, particularly the triethylsilyl group or the fert-butyldimethylsilyl group) by several methodologies known to the expert (e.g. using silyl triflate in the presence of imidazole) to give compounds of the formula (15).
  • Selective reduction of the ester group in compounds of the formula (15) to give aldehydes of the formula (11 ) can be performed by methods known to the expert (e.g. using diisobutylaluminium hydride).
  • Hydroxyesters of the formula (14) can be prepared as described in the literature or in an analogous manner, for example the synthesis of ethyl (2-hydroxy-2,3-dihydro-1/-/-inden-2-yl)acetate is described by H. Ahmed, N. Campbell, J. Chem. Soc. 1960, 41 15-4120.
  • the compounds of the formula (2) can be obtained by different synthetic routes. If compounds of the formula (2) are desired, where one of the substituent R3a or R3b is acyl and the other substituted alkyl, the synthesis follows route A. The starting amine (16) is alkylated to give compound (17) and subsequently acylated to give the final compound (2). If compounds of the formula (2) are desired, where R3a and R3b together, including the nitrogen atom to which both are bonded, are e.g.
  • reaction can be carried out following route B via compound (18) as it has been already described for compounds of the formula (1 ).
  • compounds of the formula (2) are obtained from the 6-bromine-substituted benzimidazoles of the formula (19) by palladium- or copper- catalyzed C-N coupling of (19) with the corresponding amides.
  • the reaction conditions and catalysts are known from literature, for example palladium(ll) acetate and dppf (e.g. Shakespeare, Tetrahedron Lett.
  • A CH 2 -CH 2 , or CH 2 -CH 2 -CH 2 , or CH 2 -CH 2 -CH 2 -CH or CH 2 -CH 2 -O-CH 2 ,
  • the starting amine (16) can be obtained from the corresponding carboxylic acid (20) by reaction with DPPA and subsequent acidic hydrolysis of the intermediate fert-butoxycarbonyl-protected amine (21 ) (Scheme 6).
  • the starting amines of the formula 16 e.g. those wherein X is NH
  • the starting carboxylic acids (20) can be prepared as described in WO 04/054984.
  • the compounds of the formula (3) can be obtained in analogy to the compounds of the formula (2) by different synthetic routes as described above: Route A and B starting from the corresponding amine (22) and route C starting from the corresponding bromide (25).
  • A CH 2 -CH 2 , or CH 2 -CH 2 -CH 2 , or CH 2 -CH 2 -CH 2 , or CH 2 -CH 2 -O-CH 2 ,
  • reaction order for those reactions outlined above in particular that reaction order as detailed for route C (attachment of the chromane substituent vs. attachment of NR3aR3b by C,N-coupling) can also be reversed.
  • the starting amines and bromides of the general formula (22) and (25) can be prepared as shown in Scheme 8 and Scheme 9, respectively.
  • the carboxylic acids (26) are known for example from WO 06/134460 or they can be prepared using analogous steps.
  • the conversion of the carboxylic acids (26) to the corresponding amines (22) is accomplished for example by the aforementioned method with DPPA and subsequent hydrolysis of the intermediate fert-butoxycarbonyl-protected amine (27).
  • the bromides of the general formula (25) are preferably obtained by reacting 6-bromine-substituted benzimidazoles of formula (28) with substituted chromanes of formula (29) wherein LG is a suitable leaving group, like for example a halogen radical, preferably a chloro radical.
  • the starting benzimidazoles of the formula (28) are known, for example from WO 04/054984 or they can be prepared using analogous process steps.
  • reaction shown in Scheme 9 is carried out in a manner known per se, for example in analogy to the procedure as described in WO 06/134460, preferably in the presence of a base and in the presence of a suitable solvent, for example using a base like potassium carbonate in acetone or acetonitrile, or sodium hydride in N,N-dimethylformamide.
  • a base like potassium carbonate in acetone or acetonitrile, or sodium hydride in N,N-dimethylformamide.
  • Some compounds of the formula (30) are known, for example from Parker et. al., Tetrahedron Lett. 1998, 2797 or from Hartmann, Chem. Ber. 1890, 1050 or from US Patent Application 2006/0116383 or they can be prepared in an analogous manner as described in any of these references.
  • a preferred method for the synthesis of the target compounds of the formula (4) employs carboxylic acids of the formula (33) as starting material.
  • Diphenylphosphoryl azide is a particularly convenient reagent, which allows the use of carboxylic acids of the formula (33) rather than acyl azides of the formula (35) as starting materials for the Curtius rearrangement.
  • the carboxylic acids of the formula (33) can be transformed into derivatives suitable for rearrangement reactions, like e. g. acyl azides of the formula (35), carboxamides of the formula (36), or O-acyl derivatives of hydroxamic acids of the formula (37). These derivatives can then be subjected to other rearrangement reactions, like e. g. the Curtius reaction, the Hofmann reaction, the Lossen reaction, or the method described in Z. Natur- forsch. 2003, 58b, 843 [(diacetoxyiodo)benzene, potassium hydroxide, methanol].
  • carbamates of the formula (38) are isolated. Conversion of carbamates of the formula (38) into amines of the formula (39) can be accomplished by using suitable deprotection methods (see e. g. T. W. Greene, P. G. M. Wuts, Protective groups in organic synthesis, 3rd edition, John Wiley & Sons, New York, 1999). The following specific examples might be mentioned: If methanol is used as a solvent for the rearrangement reaction, methyl carbamates are obtained, which can be cleaved under basic conditions (e. g. sodium hydroxide, dioxane, water). If tert-butanol is used as a solvent for the rearrangement reaction, tert-butyl carbamates are isolated, which can be cleaved under acidic conditions (e. g. trifluoroacetic acid). Scheme 12.
  • title compounds of the formula (4) can be prepared by alkylation of amines of the formula (39) with reagents of the formula (41 ). If both residues X and Y represent a good leaving group, e. g. a halide atom, amide coupling can be accomplished by condensation of (39) and (41 ) in the presence of a base. In a second step, title compounds of the formula (4) are secured by intramolecular nucleophilic substitution of intermediates of the formula (43) in the presence of a base. If Y represents a good leaving group (e. g.
  • nucleophilic substitution can be accomplished by heating amines of the formula (39) in the presence of a base (e. g. potassium carbonate) with reagents of the formula (41 ) in a dipolar aprotic solvent (e. g. DMSO).
  • a base e. g. potassium carbonate
  • reagents of the formula (41 ) in a dipolar aprotic solvent (e. g. DMSO).
  • Target compounds of the formula (4) are then obtained by intramolecular amide formation of the resulting intermediates of the formula (43) as described above.
  • reaction steps outlined above are carried out in a manner known per se, e.g. as described in more detail in the examples.
  • the person skilled in the art knows on the basis of his/her knowledge and on the basis of those synthesis routes, which are shown and described within the description of this invention, how to find other possible synthesis routes for compounds according to this invention. All synthesis routes described herein as well as all other possible synthesis routes are also part of this invention.
  • 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 0 C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
  • the suspension was stirred at 10 0 C for 2 h, cooled to 0 0 C, and a solution of potassium fert-butoxide in tetrahydrofuran (1.1 ml, 1 M) was added.
  • the solution was stirred 1 h at 0 0 C, further potassium fert-butoxide solution in tetrahydrofuran (2.2 ml, 1 M) was added in two portions, and stirring was continued for 18 h.
  • Water (50 ml) was added and the aqueous mixture was extracted with dichloromethane. The combined organic phases were dried (MgSO 4 ) and concentrated in vacuo.
  • Trifluoroacetic acid (4 ml) was added carefully to an ice-cold solution of fert-butyl (2,3-dimethyl- 1',3',6,7-tetrahydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-inden]-5-yl)carbamate (0.25 g, 0.60 mmol) in dichloromethane (4 ml). The solution was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated in vacuo, co-evaporated with toluene (3 x), and the remaining dark oil was dissolved in dichloromethane.
  • the reaction mixture was stirred for 2 h at 0 0 C and poured on a mixture of water (100 ml) and dichloromethane (300 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 50 ml). The combined organic phases were dried over sodium sulfate.
  • the phases were separated and the aqueous phase was extracted with dichloromethane (2 x 10 ml). The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo.
  • the crude title compound was purified by crystallization from a mixture of acetone (0.5 ml) and diethyl ether (20 ml) and was isolated in the form of a pale-yellow solid (210 mg, 60 % yield, m.p. 265-266 0 C).
  • sodium methylate solution (30 weight-% in methanol, 20 ml) was added to a suspension of 2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline- ⁇ ,2'-inden]-5- amine (4.0 g, 12.6 mmol) and paraformaldehyde (1.5 g, 50.2 mmol) in methanol (400 ml).
  • the suspension was heated to reflux for 4 hours and gradually a solution was obtained.
  • Sodium borohydride (1.3 g, 34.5 mmol) was added portion-wise and stirring was continued for 18 hours at room temperature.
  • the Celite pad was washed with dichloromethane. The filtrates were combined and the phases were separated. The aqueous phase was extracted with dichloromethane (3 x 150 ml). The combined organic phases were washed with saturated ammonium chloride solution, dried over magnesium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and n-heptane. The title compound was isolated by filtration, washed with petroleum ether, and dried. This afforded 6.60 g of a slightly yellow solid (69 % yield).
  • the catalyst was removed by filtration over Celite.
  • the Celite pad was washed with a mixture of dichloromethane / methanol (1 I).
  • the combined filtrates were evaporated to dryness.
  • the residue was crystallized from a mixture of ethyl acetate and n- heptane.
  • the title compound was isolated by filtration, washed with n-heptane, and dried. This afforded 195 mg of an off-white solid (8 % yield).
  • Activated charcoal was added at ambient temperature. The mixture was refluxed for 30 minutes, cooled, and filtered over Celite. The Celite pad was washed with ethanol. The combined filtrates were treated with palladium on charcoal (3.0 g) and 1 ,4-cyclohexadiene (10 ml). The reaction mixture was refluxed for 1 d, cooled, and diluted with dichloromethane (200 ml). The catalyst was removed by filtration over Celite and the filtrate was concentrated. The residue was crystallized from a mixture of ethyl acetate and n-heptane. The title compound was isolated by filtration, washed with n-heptane, and dried. This afforded 1.21 g of an off-white solid (49 % yield).
  • the aqueous phase was extracted with chloroform (200 ml).
  • the combined organic phases were washed with 1 N sodium hydroxide solution (2 x 200 ml), water, and saturated sodium chloride solution, and dried over magnei- sum sulfate. Evaporation of the solvent afforded the title compound as mixture with 8-fluoro-2,3- dihydro-4/-/-chromen-4-one (16.26 g of a yellow solid, 91 % yield).
  • the compounds of the formula (0), (1 ), (2), (3) and (4) 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, A) gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartburn and/or acid regurgitation and/or non-acid regurgitation. B) other extra-esophageal manifestations of GERD that include, but are not limited to, acid-related asthma, bronchitis, laryngitis and sleep disorders.
  • GFD gastroesophageal reflux disease
  • other 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 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 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.
  • 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%.
  • ad- ministration form adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained release form or a delayed release form).
  • 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).
  • CCK2 antagonists cholestocystokinin 2 receptor antagonists.
  • 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-B re-uptake inhibitors e.g. tiagabine
  • metabotropic glutamate receptor type 5 (mGluR5) 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, cilanse- tron; NK2 antagonists like saredutant, nepadutant; ⁇ -opiate agonists like fedotozine.
  • 5- HT4 receptor agonists like mosapride, tegaserod
  • 5-HT3 receptor antagonists like alosetron, cilanse- tron
  • 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)
  • Chemical & Material Sciences (AREA)
  • 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)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (0), dans laquelle les substituants et les symboles sont tels que définis dans la description. Les composés inhibent la sécrétion de l'acide gastrique.
PCT/EP2008/056478 2007-06-15 2008-05-27 Dérivés de benzimidazole à substitution 6-n pharmaceutiquement actifs WO2008151927A2 (fr)

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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
US8486940B2 (en) 2009-09-11 2013-07-16 Probiodrug Ag Inhibitors
WO2016200148A1 (fr) * 2015-06-08 2016-12-15 씨제이헬스케어 주식회사 Utilisation de dérivé de benzimidazole pour l'acidité nocturne
WO2017023124A1 (fr) * 2015-08-04 2017-02-09 씨제이헬스케어 주식회사 Nouveau procédé de préparation d'un dérivé de chromanol
JP2020097607A (ja) * 2015-08-04 2020-06-25 エイチケー イノ．エヌ コーポレーション クロマノン誘導体の新規な製造方法

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WO2006134460A1 (fr) * 2005-06-14 2006-12-21 Pfizer Japan Inc. Dérivés de benzimidazole à substitution chromane comme antagonistes de la pompe à acide
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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
WO2004087701A1 (fr) * 2003-04-04 2004-10-14 Altana Pharma Ag Benzimidazoles cycliques
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WO2006134111A1 (fr) * 2005-06-16 2006-12-21 Nycomed Gmbh Spiro-benzimidazoles utilises comme inhibiteurs de la secretion d'acide gastrique
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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
US8486940B2 (en) 2009-09-11 2013-07-16 Probiodrug Ag Inhibitors
US9173885B2 (en) 2009-09-11 2015-11-03 Probiodrug Ag Inhibitors
US9650362B2 (en) 2009-09-11 2017-05-16 Probiodrug Ag Inhibitors
WO2016200148A1 (fr) * 2015-06-08 2016-12-15 씨제이헬스케어 주식회사 Utilisation de dérivé de benzimidazole pour l'acidité nocturne
US10512635B2 (en) 2015-06-08 2019-12-24 Cj Healthcare Corporation Uses of benzimidazole derivative for nocturnal acid breakthrough
US11033532B2 (en) 2015-06-08 2021-06-15 Hk Inno.N Corporation Uses of benzimidazole derivative for nocturnal acid breakthrough
WO2017023124A1 (fr) * 2015-08-04 2017-02-09 씨제이헬스케어 주식회사 Nouveau procédé de préparation d'un dérivé de chromanol
JP2020097607A (ja) * 2015-08-04 2020-06-25 エイチケー イノ．エヌ コーポレーション クロマノン誘導体の新規な製造方法

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