WO2008151927A2 - 6-n-substituted benz imidazole derivatives as acid pump antagonists - Google Patents

6-n-substituted benz imidazole derivatives as acid pump antagonists Download PDF

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Publication number
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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French (fr)
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WO2008151927A3 (en
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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/en
Publication of WO2008151927A3 publication Critical patent/WO2008151927A3/en

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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.

Abstract

The invention provides compounds of the formula (0), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.

Description

Description Title
PHARMACEUTICALLY ACTIVE 6-N-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES
Technical field
The invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments.
Background Art
In European patent application 266326 (which corresponds to US Patent 5,106,862), benzimidazole derivatives having a very broad variety of substituents are disclosed, which are said to be active as anti-ulcer agents. In the International Patent Application WO 97/47603 (Astra AB) benzimidazoles with a specific benzyloxy or benzylamino substitution are described.
The International Patent Applications WO 04/054984 and WO 06/100254 disclose substituted, bicyclic benzimidazole derivatives which compounds are useful for treating gastrointestinal diseases.
The International Patent Application WO 04/087701 , WO 06/100255 and WO 06/136552 disclose tricyclic benzimidazole derivatives having different substituents in 5-position of the benzimidazole moiety which compounds are likewise useful for treating gastrointestinal diseases.
The International Patent Applications WO 05/058893, WO 05/103057 and WO 06/037748 disclose tricyclic benzimidazole derivatives having substituents in 6- and 7-position of the tricyclic ring system which compounds are likewise useful for treating gastrointestinal diseases.
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.
The International Patent Application WO 07/031860 (Pfizer Japan Inc.) discloses indane substituted benzimidazole derivatives having substituents in 6-position of the benzimidazole moiety which compounds are likewise useful for treating gastrointestinal diseases.
The International Patent Application WO 07/003386 (GlaxoSmithKline) discloses 6-heterocyclic substituted imidazo[1 ,2-a]pyridine derivatives which compounds are likewise useful for treating gastrointestinal diseases.
Disclosure of Invention
Technical problem
A whole series of compounds are known from the prior art which inhibit gastric acid secretion by blockade of the H+/K+-ATPase. The compounds designated as proton pump inhibitors (PPI 's), for example omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, bind irreversibly to the H+/K+- ATPase. PPI 's are available as therapeutics for a long time already. A new class of compounds designated as reversible proton pump inhibitors (rPPI's), as acid pump antagonists (APA 's) or as potassium competitive acid blockers (P-CAB 's) bind reversibly to the H+/K+-ATPase. Although rPPI's, APA's and P-CAB's are known for more than 20 years and many companies are engaged in their development, rPPIs, APAs or P-CABs are at present only very limited available for therapy. The technical problem underlying the present invention is therefore to provide acid pump antagonists which can be used in therapy.
Technical solution
The invention relates to compounds of the formula 0
Figure imgf000003_0001
where either
- A and B together form a CH2-CH2 group and C and D together form a group G1 , )
Figure imgf000004_0001
or where
- A, B and C are each hydrogen and D is a group G2,
Figure imgf000004_0002
or where
- A and B are each hydrogen and C and D together form a group G3,
Figure imgf000004_0003
or where
- A and B together form a CH2-CH2 group, C is hydrogen and D is a group G4,
Figure imgf000004_0004
and whereby
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 -
alkoxy-1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-alkoxycarbonyl, car- boxy-1-4C-alkyl, I^C-alkoxycarbonyl-I^C-alkyl, halogen, hydroxyl, trifluoromethyl, halo-1-4C- alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C- alkoxycarbonylamino, I^C-alkoxy-I^C-alkoxycarbonylamino or sulfonyl,
X is NH or O, and their salts.
The invention relates in a first embodiment (embodiment 1 ) to compounds of the formula 1
)
Figure imgf000005_0001
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C- alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, 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
Figure imgf000006_0001
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, 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
Figure imgf000007_0001
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
R3a
Figure imgf000007_0002
in which 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 (CH3O-C(O)-), the ethoxycarbonyl group (CH3CH2O-C(O)-) and the 2,2-dimethylethoxycarbonyl (tert- butoxycarbonyl) group ((CH3)3CO-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 (CH3-O-CH2-CH2-O-) and 2-(ethoxy)ethoxy (CH3-CH2-O-CH2-CH2 -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. Examples of 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 ,1 ,1-trifluoro-2-propoxy, the perfluoro-fert-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 difluoro- methoxy group.
Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.
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 (C3H7C(O)NH-) and the acetylamino group (acetamido group) (CH3C(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 (CH3-O-CH2CH2-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH3CH2-O-CH2CH2-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. Those suitable are 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-2-naphthoic acid, where the acids are used in salt preparation - depending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an equi- molar quantitative ratio or one differing therefrom.
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. The acid can be employed in salt preparation, depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained for example by evaporating the solvent or by precipitating upon cooling, by re-precipitating, or by precipitating with a non-solvent for the salt and separation, for example by filtration, of the salt after precipitation.
Pharmacologically intolerable salts, which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula (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 ):
Figure imgf000012_0001
One aspect (aspect 3-1 ) of embodiment 3 of the invention, which is to be mentioned relates to compounds of the formula (3-1 ). )
Figure imgf000013_0001
in which the substituents R1 , R2, R3, X, R4 and R5 have the meanings as indicated in the outset.
Further aspects of 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):
Figure imgf000013_0002
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):
Figure imgf000014_0001
Moreover, 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):
Figure imgf000015_0001
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. Preferably, 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. Preferably, the mixtures are separated by chromatography or (fractional) crystallization. For enantiomeric mixtures 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. Alternatively, derivatization with chiral auxiliary reagents can be made, followed by diastereomer separation and removal of the chiral auxiliary group. Furthermore, enantiomeric mixtures can be separated using chiral separating columns in chromatography. Another suitable method for the separation of enantiomeric mixtures is the enzymatic separation.
Compounds of the formula 0, which are preferred are those, where either
- A and B together form a CH2-CH2 group and C and D together form a group G1 ,
(G1 )
Figure imgf000015_0002
or where
- A, B and C are each hydrogen and D is a group G2,
Figure imgf000016_0001
or where
- A and B are each hydrogen and C and D together form a group G3,
Figure imgf000016_0002
or where
- A and B together form a CH2-CH2 group, C is hydrogen and D is a group G4,
Figure imgf000016_0003
and whereby
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.
Compounds of the formula 1 , which are preferred are those, in which
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.
Compounds of the formula 2, which are preferred are those, in which
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.
Compounds of the formula 3, which are preferred are those, in which
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.
Compounds of the formula 4, which are preferred are those, in which
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.
Compounds of the formula 0, which are to be emphasized are those, where either
- A and B together form a CH2-CH2 group and C and D together form a group G1 , )
Figure imgf000018_0001
or where
- A, B and C are each hydrogen and D is a group G2,
Figure imgf000018_0002
or where
- A and B are each hydrogen and C and D together form a group G3,
Figure imgf000018_0003
or where
- A and B together form a CH2-CH2 group, C is hydrogen and D is a group G4,
Figure imgf000018_0004
and whereby
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.
Compounds of the formula 1 , which are to be emphasized are those, in which
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.
Compounds of the formula 2, which are to be emphasized are those, in which
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.
Compounds of the formula 3, which are to be emphasized are those, in which
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.
Compounds of the formula 4, which are to be emphasized are those, in which
R1 is 1-4C-alkyl,
R2 is hydrogen or 1-4C-alkyl,
R3a is hydrogen, and
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.
Compounds of the formula 0, which are to be particularly emphasized are those, where either
- A and B together form a CH2-CH2 group and C and D together form a group G1 , )
Figure imgf000020_0001
or where
- A, B and C are each hydrogen and D is a group G2,
Figure imgf000020_0002
or where
- A and B are each hydrogen and C and D together form a group G3,
Figure imgf000021_0001
or where
- A and B together form a CH2-CH2 group, C is hydrogen and D is a group G4,
Figure imgf000021_0002
and whereby
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.
Compounds of the formula 1 , which are to be particularly emphasized are those, in which
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.
Compounds of the formula 2, which are to be particularly emphasized are those, in which
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.
Compounds of the formula 3, which are to be particularly emphasized are those, in which
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.
Compounds of the formula 4, which are to be particularly emphasized are those, in which
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
2-azetidinone group, 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:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
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. Svnthesis of compounds of the formula (1 )
As outlined in scheme 1 , 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. a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 3-oxazolidin-2-one group, 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). Preferentially, the leaving group LG is bromo or chloro. Subsequent treatment of compound (7) with 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. Perkin Trans. 1 1990, 277) or potassium fert-butoxide in N,N-dimethylformamide or fert-butanol (e.g. US patent appl. 2005/203078, or 2005/197330) provides the final compound (1 ).
Scheme 1.
Figure imgf000030_0001
Route B
Figure imgf000030_0002
LG = Leaving group, or CH9-CH9-O-CH,, 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.
Scheme 2.
Figure imgf000031_0001
Starting carboxylic acids of the formula (8) where X=NH can be prepared for example as described in WO 06/134111.
Starting carboxylic acids of the formula (8) where X=O can be prepared as outlined in Scheme 3. Al- dol addition of ketones of the formula (10) (whose synthesis is described for example in the International Patent application WO 05/121139) (with R = H or an alkyl group) to aldehydes of the formula (11 ) (the group gp comprises a protecting group, particularly a trisubstituted silyl protecting group e.g. the triethylsilyl protecting group) leads to aldol adducts of the formula (12) in which the group gp can either be the protecting group as outlined before, or after cleavage during the aldol addition, a hydrogen atom. If the 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. 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ) or chloranile) of aldol adducts of the formula (12) (with gp = hydrogen) leads to unsaturated compounds of the formula (13). Hydrogenation and saponification using methodologies known to persons skilled in the art (e.g. using hydrogen and palladium on charcoal for the hydrogenation step or bases like lithium hydroxide in aqueous media for the saponification step) delivers carboxylic acids of formula (8) with X = O. Scheme 3.
Figure imgf000032_0001
cyclization / aromatization
Figure imgf000032_0002
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.
Scheme 4.
Figure imgf000032_0003
Synthesis of compounds of the formula (2)
As outlined in scheme 5, 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. a 2-pyrrolidinone, 2-piperidinone, 2-azetidinone, 3-morpholinone or 3-oxazolid intone group, the reaction can be carried out following route B via compound (18) as it has been already described for compounds of the formula (1 ). More conveniently, 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. 1999, 2035), or tris(dibenzylideneacetone)dipalladium(0) and 2,2'-bis(diphenylphosphino)-1 ,1'- binaphthyl (e.g. Lipshutz et al., Org. Lett. 2004, 2305), or copper(l) iodide and N, N'- dimethylethylenediamine as described for example by Buchwald et al. in J. Am. Chem. Soc. 2004, 3529-3533. The starting bromides (19) can be prepared as described in WO 04/054984.
Scheme 5.
Figure imgf000034_0001
Route B
Figure imgf000034_0002
Route C
Figure imgf000034_0003
LG = Leaving group,
A = CH2-CH2, or CH2-CH2-CH2, or CH2-CH2-CH2-CH or CH2-CH2-O-CH2,
Analogously as described in Scheme 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). Alternatively, the starting amines of the formula 16 (e.g. those wherein X is NH) can also be obtained as already described in WO 04/054984. The starting carboxylic acids (20) can be prepared as described in WO 04/054984. Scheme 6.
Figure imgf000035_0001
Synthesis of compounds of the formula (3)
As outlined in Scheme 7, 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).
Scheme 7.
Figure imgf000036_0001
Route B
Figure imgf000036_0002
Route C
Figure imgf000036_0003
LG = Leaving group,
A = CH2-CH2, or CH2-CH2-CH2, or CH2-CH2-CH2-CH2, or CH2-CH2-O-CH2,
It has to be emphasized, that the 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). Scheme 8.
Figure imgf000037_0001
(26) (27) (22)
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. The required chromanes of formula (29), wherein LG = chloro, are also known, for example from WO 00/078751 or they can be prepared in an analogous manner, e.g. as described in WO 06/064339 or WO06/134460. The 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.
Scheme 9.
Figure imgf000037_0002
(25)
An alternative procedure, which is particularly useful if enantiomeric pure compounds of the formula (3) are desired, is outlined in Scheme 10. Carboxylic acids of the formula (26) where X = NH can be obtained by reacting bromo- or chloro-substituted benzimidazoles of the general formula (28) (Y = Br or Cl, R = 1-4-C-alkyl) with substituted 4-aminochromanes (X = NH) of the formula (31 ) in a Buchwald- Hartwig reaction in analogy as described for example by Lopez-Rodriguez et al., Tetrahedron 2000, 3245 and subsequent hydrolysis of the ester group. Analogously, if compounds of the formula (26) where X = O are desired, benzimidazoles of the formula (30) (Y = Br or Cl, R = 1-4-C-alkyl) can be reacted with substituted 4-chromanoles (X = O) of the formula (31 ) in analogy as described for example by S. L. Buchwald et al., J. Am. Chem. Soc. 2005, 8146.
Scheme 10.
Figure imgf000038_0001
(30) (31) (26)
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. Enantiomeric pure compounds of the formula (31 ) where X = O are known from literature, for example from G. L. D. Krupadanam et al., Indian J. Chem. B 1997, 1 119 or they can be prepared in an analogous manner as described therein. Analogously, enanatiomeric pure compounds of the formula (31 ) where X = NH are also known from literature, for example from N. Anand et al., Indian J. Chem. B 1981 , 1063 or from US Patent Application 2004/0157739 or they can be prepared in an analogous manner as described in any of these references.
Synthesis of compounds of the formula (4)
A preferred method for the synthesis of the target compounds of the formula (4) employs carboxylic acids of the formula (33) as starting material. Carboxylic acids of the formula (33), where X=O can be obtained by hydrolysis of enantiomerically pure carboxamides of the formula (32) (Scheme 11 ), which can be accomplished by heating the corresponding derivative of the formula (32) in a high-boiling solvent in the presence of a strong base. Carboxylic acids of the formula (33), where X=NH can be prepared from racemic 6-bromobenzimidazoles of the formula (34) by Palladium-catalysed carbonyla- tion in alcoholic solvents and cleavage of the obtained carboxylic ester as described e. g. in WO 2004/087701. Resolution of the racemic mixture can be accomplished at any stage of the synthesis applying methods known to the person skilled in art, e. g. crystallization in the presence of chiral acids or HPLC chromatography using a chiral stationary phase. Compounds of the formula (32) and (34) are known from WO 2004/087701 and WO 2006/136552. The resulting carboxylic acids of the formula (33) are then subjected to rearrangement reactions. Suitable transformations comprise the Curtius reaction or the Schmidt reaction and are described in more detail in M. B. Smith, J. March, March's advanced organic chemistry: Reactions, mechanisms, and structure, 5th edition, John Wiley & Sons, New York, 2001 , 1411-1415. 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. Alternatively, 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].
Scheme 11.
Figure imgf000039_0001
(32) (33) (34)
Figure imgf000039_0002
Arom Arom Arom (35) (36) (37)
Figure imgf000039_0003
Arom Arom (38) (39)
If the rearrangement reactions are performed in an alcoholic solvent, 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.
Figure imgf000040_0001
Arom Arom (42) (43)
Compounds of the formula (4) can be obtained by reductive amination of reagent (40) with amines of the formula (39) (Scheme 1 1 ). Sodium triacetoxyborohydride (acetic acid, dichloromethane) and Ra- ney nickel / hydrogen (sodium acetate, ethanol) constitute useful reducing agents for this transformation. The residue X depicted in formula (40) represents a functional group that could be used in a direct manner for an amide coupling reaction or that could be transformed into the corresponding car- boxylic acid (e. g. X = alkoxy). In the latter case, coupling reagents like CDI, EDC, or TBTU can be used for intramolecular amide formation of the intermediates of the formula 42. Alternatively, 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. a halide atom) and X a functional group with low reactivity (e. g. alkoxy), the reaction order can also be reversed: 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). Target compounds of the formula (4) are then obtained by intramolecular amide formation of the resulting intermediates of the formula (43) as described above.
The derivatization, if any, of the compounds obtained according to the schemes above is likewise carried out in a manner known per se.
The 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.
Advantageous effects
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 (0), (1 ), (2) and (3) 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.
Testing of the secretion-inhibiting action on the perfused rat stomach
In Table A which follows, the influence of the compounds of the formula (1 )-(3) according to the invention on the pentagastrin-stimulated acid secretion of the perfused rat stomach after intraduodenal administration in vivo is shown.
Table A
Figure imgf000041_0001
Methodology
The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m. urethane) was opened after tracheotomy by a median upper abdominal incision and a PVC catheter was fixed transorally in the esophagus and another via the pylorus such that the ends of the tubes just projected into the gastric lumen. The catheter leading from the pylorus led outward into the right abdominal wall through a side opening.
After thorough rinsing (about 50-100 ml), warm (370C) physiological NaCI solution was continuously passed through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glass electrode EA 147; φ = 5 mm, Metrohm) and, by titration with a freshly prepared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI were determined in the effluent in each case collected at an interval of 15 minutes.
The gastric secretion was stimulated by continuous infusion of 1 μg/kg (= 1.65 ml/h) of i.v. pentagas- trin (left femoral vein) about 30 min after the end of the operation (i.e. after determination of 2 preliminary fractions). 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 37.8-380C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
Mode(s) for Carrying Out the Invention
The following examples serve to illustrate the invention in greater detail without restricting it. Likewise, further compounds of the formula (0), (1 ), (2), (3) and (4) whose preparation is not described explicitly can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques. The abbreviation min stands for minute(s), h for hour(s) and m.p. for melting point. The following examples are named by using ACD/Name (ACD/Labs release 9.00 / product version 9.04).
I. Final Compounds
1. 1-{4-[(2,6-Dimethylbenzyl)amino]-1,2-dimethyl-1H-benzimidazol-6-yl}azetidin-2-one
To a mixture of 6-bromo-N-(2,6-dimethylbenzyl)-1 ,2-dimethyl-1/-/-benzimidazol-4-amine (1.76 g, 4.9 mmol) and azetidin-2-one (0.35 g, 4.9 mmol) in dioxane (55 ml) was added copper(l) iodide (0.37 g, 1.96 mmol), N,N'-dimethylethylenediamine (0.21 ml, 1.96 mmol) and potassium carbonate (3.18 g, 23 mmol). After 16 h at reflux, additional azetidin-2-one (0.1 g, 1.4 mmol) was added and stirring was continued for 4 h. The mixture was cooled down and poured into water (200 ml). The resulting precipitate was collected and washed with water. Purification of the crude product by column chromatography (silica gel, ethyl acetate/petroleum ether/triethylamine 5:4:1 ) and crystallization from ethyl acetate/n- heptane yielded the title compound as a colourless solid (1.02 g, 60 %). 1H-NMR (CDCI3): δ (ppm) 7.02-7.13 (m, 3 H), 6.80 (s, 1 H), 6.46 (s, 1 H), 4.57 (br t, 1 H, NH), 4.38 (d, 4.4 Hz, 2 H), 3.72 (t, J = 4.4 Hz, 2 H), 3.64 (s, 3 H), 3.12 (t, J = 4.4 Hz, 2 H), 2.49 (s, 3 H), 2.39 (s, 6 H).
2. 1-{4-[(2,6-Dimethylbenzyl)amino]-1,2-dimethyl-1H-benzimidazol-6-yl}pyrrolidin-2-one
To a mixture of 6-bromo-N-(2,6-dimethylbenzyl)-1 ,2-dimethyl-1/-/-benzimidazol-4-amine (2.16 g, 6.0 mmol) and pyrrolidin-2-one (0.55 ml, 7.2 mmol) in dried toluene (70 ml) was added tris(dibenzylidene- acetone)dipalladium(O) (0.27 g, 0.3 mmol), 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (0.57 g, 0.9 mmol) and sodium fert-butoxide (0.81 g, 8.4 mmol). After 16 h at reflux, the mixture was poured into saturated aqueous NH4CI and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by column chromatography (first: silica gel, toluene/dioxane/methanol 16:3:1 , second: silica gel, ethyl acetate/triethylamine 9:1 ) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (0.22 g, 10 %). 1H-NMR (CDCI3): δ (ppm) 6.99-7.13 (m, 4 H), 6.60 (s, 1 H), 4.52 (br t, 1 H, NH), 4.36 (d, 4.1 Hz, 2 H), 3.98 (t, J = 7.0 Hz, 2 H), 3.65 (s, 3 H), 2.65 (t, J = 8.1 Hz, 2 H), 2.50 (s, 3 H), 2.38 (s, 6 H), 2.15-2.25 (m, 2 H). 3. 1-[4-(3,4-Dihydro-2H-chromen-4-ylamino)-1,2-dimethyl-1H-benzimidazol-6-yl]azetidin-2-one
To a mixture of 6-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-1 ,2-dimethyl-1/-/-benzimidazol-4-amine (1.12 g, 3.0 mmol) and azetidin-2-one (0.34 g, 4.8 mmol) in dioxane (25 ml) was added copper(l) iodide (0.23 g, 1.2 mmol), N,N'-dimethylethylenediamine (0.13 ml, 1.2 mmol) and potassium carbonate (1.95 g, 14.1 mmol). After 16 h at reflux, additional azetidin-2-one (0.1 g, 1.4 mmol) was added and stirring was continued for 24 h. The mixture was cooled down and partitioned between saturated aqueous NH4CI and dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, ethyl acetate/triethylamine 9:1 ) and crystallization from ethyl acetate/n-heptane/diethyl ether yielded the title compound as a colourless solid (0.1 g, 9 %). 1H-NMR (CDCI3): δ (ppm) 7.31-7.33 (m, 1 H), 7.14-7.20 (m, 1 H), 6.83-6.89 (m, 2 H), 6.77 (s, 1 H), 6.53 (s, 1 H), 5.14 (br d, 1 H, NH), 4.79-4.86 (m, 1 H), 4.23- 4.34 (m, 2 H), 3.65-3.69 (m, 5 H), 3.12 (t, J = 4.4 Hz, 2 H), 2.51 (s, 3 H), 2.14-2.30 (m, 2 H).
4. 1-[4-(3,4-Dihydro-2H-chromen-4-ylamino)-1,2-dimethyl-1H-benzimidazol-6-yl]pyrrolidin-2- one
To a mixture of 6-bromo-N-(3,4-dihydro-2/-/-chromen-4-yl)-1 ,2-dimethyl-1/-/-benzimidazol-4-amine (0.74 g, 2.0 mmol) and pyrrolidin-2-one (0.14 ml, 2.4 mmol) in dioxane (20 ml) was added copper(l) iodide (0.15 g, 0.8 mmol), N,N'-dimethylethylenediamine (0.09 ml, 0.8 mmol) and potassium carbonate (1.3 g, 9.4 mmol). After 16 h at reflux, additional pyrrolidin-2-one (0.14 ml, 2.4 mmol) was added and stirring was continued for 3 d. The mixture was cooled down and partitioned between saturated aqueous NH4CI and dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, ethyl acetate/triethylamine 9:1 ) and crystallization from ethyl acetate/n-heptane/diethyl ether yielded the title compound as a colourless solid (0.2 g, 26 %). 1H-NMR (CDCI3): δ (ppm) 7.32-7.35 (m, 1 H), 7.14-7.20 (m, 1 H), 6.93 (s, 1 H), 6.82-6.89 (m, 2 H), 6.69 (s, 1 H), 5.09 (br d, 1 H, NH), 4.77-4.82 (m, 1 H), 4.20- 4.34 (m, 2 H), 3.93 (t, J = 7.2 Hz, 2 H), 3.65 (s, 3 H), 2.64 (t, J = 8.1 Hz, 2 H), 2.52 (s, 3 H), 2.13-2.33 (m, 4 H).
5. 1-(2,3-Dimethyl-1',3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5- yl)azetidin-2-one
To a solution of 4-bromo-N-(2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'- inden]-5-yl)propanamide (0.5 g, 1.1 mmol) in N,N-dimethylformamide (2.5 ml) was added sodium hydride (0.047 g, 1.15 mmol, 60% suspension in mineral oil) at 0 0C. After 1 h at 0 0C and 1 h at room temperature, the mixture was poured into water. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Purification of the residue by column chromatography (first: silica gel, toluene/dioxane/methanol 12:7:1 , second: dichloromethane/methanol 100:3) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (0.2 g, 51 %). 1H-NMR (Cl6-DMSO): δ (ppm) 7.13-7.23 (m, 4 H), 6.69 (s, 1 H), 5.61 (br s, 1 H, NH), 3.69 (t, J = 4.3 Hz, 2 H), 3.60 (s, 3 H), 2.92-3.10 (m, 6 H), 2.80 (t, J = 6.5 Hz, 2 H), 2.42 (s, 3 H), 1.83 (t, J = 6.5 Hz, 2 H).
6. 1-(2,3-Dimethyl-1>,3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2'-inden]-5-yl)- pyrrolidin-2-one
To a suspension of 4-chloro-N-(2,3-dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'- inden]-5-yl)butanamide (0.50 g, 1.18 mmol) in tetrahydrofuran (7.5 ml) was added a solution of potassium ferf-butoxide (0.32 g, 2.8 mmol) in tetrahydrofuran (2.5 ml) at 0 0C. After 1 h at 0 0C, saturated aqueous NH4CI was added, and the mixture was partitioned between water and dichloromethane. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, toluene/dioxane/methanol 30:19:1 ) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (0.28 g, 61 %). 1H-NMR (d6-DMSO): δ (ppm) 7.13-7.23 (m, 4 H), 6.58 (s, 1 H), 5.57 (br s, 1 H, NH), 3.68 (t, J = 6.9 Hz, 2 H), 3.60 (s, 3 H), 2.90-3.09 (m, 4 H), 2.62 (t, J = 6.4 Hz, 2 H), 2.43 (s, 3 H), 2.40 (t, J = 8.2 Hz, 2 H), 2.07-2.17 (m, 2 H), 1.82 (t, J = 6.5 Hz, 2 H).
7. 1-(2,3-Dimethyl-1',3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5-yl)- piperidin-2-one
To a suspension of 5-chloro-N-(2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'- inden]-5-yl)pentanamide (1.0 g, 2.3 mmol) in tetrahydrofuran (15 ml) was added a solution of potassium ferf-butoxide (0.26 g, 2.3 mmol) in tetrahydrofuran (5 ml) at 0 0C. After 1 h at 0 0C and 3 h at room temperature, the mixture was poured into water. The mixture was extracted with dichloromethane, and the organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, toluene/dioxane/methanol 12:7:1 ) and crystallization from ethyl acetate/n- heptane yielded the title compound as a colourless solid (0.46 g, 50 %). 1H-NMR (d6-DMSO): δ (ppm) 7.13-7.22 (m, 4 H), 6.53 (s, 1 H), 5.50 (br s, 1 H, NH), 3.52-3.64 (m, 4 H), 3.31-3.44 (m, 1 H), 2.87- 3.10 (m, 4 H), 2.57 (m, 2 H), 2.43 (s, 3 H), 2.30-2.40 (m, 2 H), 1.78-1.95 (m, 6 H).
8. 3-(2,3-Dimethyl-1',3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5-yl)-1,3- oxazolidin-2-one
To a suspension of 2-chloroethyl (2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline- 8,2'-inden]-5-yl)carbamate (1.0 g, 2.4 mmol) in tetrahydrofuran (15 ml) was added a solution of potassium fert-butoxide (0.29 g, 2.6 mmol) in tetrahydrofuran (5 ml) at 0 0C. After 1 h at room temperature, saturated aqueous NH4CI was added, and the mixture was partitioned between water and dichloromethane. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, tolu- ene/dioxane/methanol 30:19:1 ) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (0.62 g, 68 %). 1H-NMR (d6-DMSO): δ (ppm) 7.13-7.27 (m, 4 H), 6.72 (s, 1 H), 5.64 (br s, 1 H, NH), 4.46 (t, J = 7.9 Hz, 2 H), 3.93 (t, J = 7.9 Hz, 2 H), 3.61 (s, 3 H), 2.92-3.10 (m, 4 H), 2.72 (t, J = 6.5 Hz, 2 H), 2.44 (s, 3 H), 1.85 (t, J = 6.5 Hz, 2 H).
9. 4-(2,3-Dimethyl-1>,3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2'-inden]-5-yl)- morpholin-3-one
To a suspension of 2-(2-chloroethoxy)-Λ/-(2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]qui- noline-8,2'-inden]-5-yl)acetamide (0.9 g, 2.1 mmol) in tetrahydrofuran (10 ml) was added a solution of potassium fert-butoxide (0.26 g, 2.3 mmol) in tetrahydrofuran (5 ml) at 0 0C. After 1 h at room temperature, saturated aqueous NH4CI was added, and the mixture was partitioned between water and dichloromethane. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, tolu- ene/dioxane/methanol 30:19:1 ) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (0.76 g, 92 %). 1H-NMR (d6-DMSO): δ (ppm) 7.13-7.22 (m, 4 H), 6.63 (s, 1 H), 5.59 (s, 1 H, NH), 4.13-4.24 (m, 2 H), 3.93-4.03 (m, 2 H), 3.67-3.73 (m, 1 H), 3.61 (s, 3 H), 3.43- 3.52 ( m, 1 H), 2.89-3.11 (m, 4 H), 2.56-2.68 (m, 2 H), 2.43 (s, 3 H), 1.84 (t, J = 6.5 Hz, 2 H).
10. I^.S-Dimethyl-i'.S'.ej-tetrahydro-SH-spirotchromenoty.δ-cflimidazole-δ^'-indenl-S-yl)- pyrrolidin-2-one
4-Bromobutyryl chloride (54 μl, 0.47 mmol) was added carefully at 10 0C to a suspension of 2,3-di- methyl-1',3',6,7-tetrahydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-inden]-5-amine (0.15 g, 0.47 mmol) and triethylamine (65 μl, 0.47 mmol) in tetrahydrofuran (5 ml). The suspension was stirred at 10 0C for 2 h, cooled to 0 0C, and a solution of potassium fert-butoxide in tetrahydrofuran (1.1 ml, 1 M) was added. The solution was stirred 1 h at 0 0C, 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 (MgSO4) and concentrated in vacuo. After crystallization using diisopropyl ether, the title compound resulted as a pale brown solid (0.12 g, 63 %). 1H-NMR (d6-DMSO): δ (ppm) 7.29-7.12 (m, 4 H), 6.96 (s, 1 H), 3.73 (t, 2 H), 3.62 (s, 3 H), 3.12 (dd, 4 H), 2.70 (t, 2 H), 2.56-2.33 (m, 5 H + DMSO), 2.21-2.01 (m, 4 H).
11. Λ/-{4-[(2,6-Dimethylbenzyl)amino]-1,2-dimethyl-1H-benzimidazol-6-yl}-N-methylacetamide
To a solution of Λ/4-(2,6-dimethylbenzyl)-Λ/6,1 ,2-trimethyl-1/-/-benzimidazole-4,6-diamine (0.49 g, 1.6 mmol) in dichloromethane (10 ml) was added 4-dimethylaminopyridine (50 mg) and acetic anhydride (0.16 ml, 1.65 mmol). After 2 h at room temperature, the mixture was partitioned between saturated aqueous NH4CI and dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and evaporated. Purification of the residue by column chromatography (silica gel, first: ethyl acetate/- petroleum ether 7:3, second: ethyl acetate/triethylamine 9:1 ) and crystallization from ethyl acetate yielded the title compound as a colourless solid (0.21 g, 37 %). 1H-NMR (CDCI3): δ (ppm) 7.03-7.15 (m, 3 H), 6.47 (s, 1 H), 6.29 (s, 1 H), 4.63 (br t, 1 H, NH), 4.34 (d, J = 4.3 Hz, 2 H), 3.66 (s, 3 H), 3.35 (s, 3 H), 2.53 (s, 3 H), 2.39 (s, 6 H), 1.97 (s, 3 H).
12. I^.S-Dimethyl-i'.S'.ej-tetrahydro-SH-spirotchromenoty.δ-cdimidazole-δ^'-indenl-S-yl)- piperidin-2-one
5-Bromopentanoyl chloride (63 μl, 0.47 mmol) was added carefully at O0C to a suspension of 2,3-di- methyl-1',3',6,7-tetrahydro-3H-spiro[chromeno[7,8-d]imidazole-8,2'-inden]-5-amine (0.15 g, 0.47 mmol) and triethylamine (65 μl, 0.47 mmol) in THF (5 ml). The suspension was stirred at room temperature for 1 h, cooled to O0C, and a solution of potassium tert-butylate in THF (1.13 ml, 1 M) was added. The solution was stirred 2 h at O0C and 18 h at room temperature. Water (50 ml) was added at O0C and the aqueous mixture was extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the residue by preparative HPLC using a 75 x 30 mm Phenomenex Gemini C18, 5 μm column (mobile phase: A - acetonitrile + 4 % water + 30 ml/l ammonium formate puffer pH 3.75, B - water + 4 % acetonitrile + 30 ml/l ammonium formate puffer pH 3.75; flow rate: 40 ml/min; gradient: 1.5 min: 10 % A, 90 % B; 0.5 min: 40% A, 60 % B; 5 min: 70 % A, 30 % B; 2 min: 100 % A, 0 % B) and, finally, by flash column chromatography (silica gel, dichloromethane/methanol 15:1 ) gave the title compound as white solid (0.01 g, 5 %). 1 H-NMR (d6- DMSO): δ (ppm) 7.28-7.12 (m, 4H), 6.90 (s, 1 H), 3.69-3.57 (m, 4H), 3.46-3.35 (m, 1 H), 3.14 (d, 2H), 3.08 (d, 2H), 2.79-2.69 (m, 2H), 2.45-2.33 (m, 5H), 2.09 (t, 2H), 1.97-1.81 (m, 4H).
13. 1-[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazol-5-yl]- pyrrolidin-2-one
At a temperature of 0 0C, 4-bromobutanoyl chloride (151 μl, 242 mg, 1.30 mmol) was added to a suspension of (δS^.S-dimethyl-δ^-methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazol-S-amine (400 mg, 1.30 mmol) in THF (15 ml) and triethylamine (160 μl, 131 mg, 1.30 mmol). The reaction mixture was stirred for 2 h at 10 0C. Another portion of triethylamine (1δO μl, 131 mg, 1.30 mmol) and 4- bromobutanoyl chloride (151 μl, 242 mg, 1.30 mmol) was added and the reaction was continued for 1 h at 50 0C. At room temperature, a solution of potassium tert-butylate (675 mg, 7.80 mmol) in THF (7 ml) was added dropwise to the yellow suspension and stirring was continued for 16 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography [50 g of silica gel, eluant: dichloromethane / methanol = 30:1 (v/v)]. The title compound (200 mg, 41 % yield) was isolated as mixture with N-[(8S)-2,3-dimethyl-8-(2-methylphenyl)- 3,6,7,8-tetrahydrochromeno[7,8-c/]imidazol-5-yl]cyclopropane-carboxamide (25-mol %) and was ob- tained in analytically pure form after purification by preparative HPLC: 46 mg of a colourless solid, m. p. 130-131 0C. - 1H NMR (DMSOd6, 300 MHz): δ = 1.92 (mc, 1 H), 2.17 (mc, 3 H), 2.38, 2.42, 2.46 (s, mc, s, 8 H), 2.61 (mc, 1 H), 2.86 (mc, 1 H), 3.63, 3.66 (mc, s, 4 H), 3.81 (mc, 1 H), 5.25 (dd, 1 H), 6.99 (s, 1 H), 7.27 (mc, 3 H), 7.48 (mc, 1 H), 8.15 (s, 1 H).
14. 1-[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-o(]imidazol-5-yl]- piperidin-2-one
4-Bromopentanoyl chloride (87 μl, 130 mg, 0.65 mmol) was added to a suspension of (8S)-2,3-dimeth- yl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-c/]imidazol-5-amine (200 mg, 0.65 mmol) in THF (5 ml) and triethylamine (91 μl, 66 mg, 0.65 mmol). The reaction mixture was briefly heated to 50 0C and the stirred for 1 h at room temperature. At 0 0C, a solution of potassium tert-butylate (146 mg, 1.30 mmol) in THF (1 ml) was added dropwise. After a period of 1.5 h, another portion of potassium tert-butylate (146 mg, 1.30 mmol) in THF (1 ml) was added. The reaction was continued for 0.5 h. The reaction mixture was quenched with water (10 ml) and extracted with dichloromethane (3 x 10 ml). The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by column chromatography [50 g of silica gel, eluant: dichloromethane / methanol = 30:1 (v/v)] and washed with diethyl ether. The title compound (100 mg of a colourless solid) was obtained in 40 % yield, m.p. 247 0C. - 1H NMR (DMSOd6, 300 MHz): δ = 1.91 (mc, 5 H), 2.22 (mc, 1 H), 2.38 (s, mc, 5 H), 2.46 (s, 3 H), 2.58 (mc, 1 H), 2.78 (mc, 1 H), 3.52, 3.66 (mc, s, 5 H), 5.20, 5.26 (2 dd, 1 H), 6.91 , 6.97 (2 s, 1 H), 7.27 (mc, 3 H), 7.48 (mc, 1 H). Due to the hindered rotation of the piperidin-2-one residue, signals of two diastereomers are visible in the 1H NMR spectrum.
15. N-(2,3-Dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5-yl)-N- methylacetamide
A solution of N,2,3-trimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'-inden]-5-amine (0.50 g, 1.5 mmol), acetic anhydride (150 μl, 1.58 mmol) and DMAP (50 mg) in dichloromethane (10 ml) was stirred for 5 h at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 ml) and extracted with dichloromethane (2 x). The combined organic phases were washed with water and evaporated to dryness. The residue was purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:38:2 (v/v/v)] and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration and dried: 0.44 g of a colourless solid, 78 % yield.
1 H NMR (300 MHz, DMSO-d6): = 1.70 (s, 3 H), 1.88 (mc, 2 H), 2.43 (s, 3 H), 2.60 (mc, 2 H), 2.96 (mc, 2 H), 3.08, 3.09 (mc, s, 5 H), 3.62 (s, 3 H), 5.69 (s, 1 H), 6.64 (s, 1 H), 7.18 (mc, 4 H). 16. N-(2,3-Dimethyl-1>,3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2'-inden]-5-yl)-N- methylpropanamide
A solution of N,2,3-trimethyl-1\3,3\6,7,9-hexahydrospiro[imidazo[4,5-/7]quinoline-8,2'-inden]-5-amine (0.50 g, 1.5 mmol), propionic anhydride (203 μl, 1.58 mmol) and DMAP (50 mg) in dichloromethane (10 ml) was stirred for 1.5 h at room temperature. The reaction mixture was quenched with water and extracted with dichloromethane (2 x). The combined organic phases were evaporated to dryness. The residue was purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:38:2 (v/v/v)] and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration and dried: 0.48 g of a colourless solid, 82 % yield.
1 H NMR (300 MHz, DMSO-d6): = 0.92 (t, 3 H), 1.88 (me, 3 H), 2.06 (me, 1 H), 2.43 (s, 3 H), 2.59 (me, 2 H), 2.95 (me, 2 H), 3.08, 3.10 (me, s, 5 H), 3.61 (s, 3 H), 5.68 (s, 1 H), 6.63 (s, 1 H), 7.18 (me, 4 H).
17. N^.S-Dimethyl-i'.S'.δJ-tetrahydro-SH-spirotchromeno^.δ-cflimidazole-δ^'-indenl-S-yl)- cyclopropanecarboxamide
Cyclopropylcarbonyl chloride (9 μl, 0.10 mmol) was added to a suspension of 2,3-dimethyl-1',3',6,7-te- trahydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-inden]-5-amine (30 mg, 0.09 mmol) and ethyldiiso- propylamine (23 μl, 0.14 mmol) in dimethoxyethane (1.5 ml). After a period of 2 hours at room temperature, the reaction mixture was treated with water (20 ml) and extracted with dichloromethane (3 x 10 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure. This afforded the title compound in 66 % yield (23 mg of an off-white solid).
1 H NMR (300 MHz, DMSO-d6): = 0.79 (me, 4 H), 1.24 (me, 1 H), 2.12 (me, 2 H), 2.50 (s, 3 H), 2.79 (me, 2 H), 3.12 (me, 4 H), 3.61 (s, 3 H), 7.17 (me, 5 H), 9.49 (s, 1 H).
18. 1-(4-{[5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl]oxy}-1,2-dimethyl-1H-benzimidazol-6-yl)- azetidin-2-one
At a temperature of 60 0C, sodium hydride (60 weight-% in mineral oil, 18 mg, 0.45 mmol) was added to a solution of 1-(4-hydroxy-1 ,2-dimethyl-1/-/-benzimidazol-6-yl)azetidin-2-one (93 mg, 0.40 mmol) and 4-chloro-5,7-difluorochromane (180 mg, 0.88 mmol) in DMF (4 ml). The reaction mixture was stirred for 1 day at 60 0C, diluted with saturated ammonium chloride solution, and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography (silica gel, eluant: ethyl acetate) and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration, washed with petroleum ether, and dried (19 mg of a colourless solid, 12 % yield).
1 H NMR (300 MHz, CDCI3): = 2.11 (me, 1 H), 2.42 (me, 1 H), 2.56 (s, 3 H), 3.14 (me, 2 H), 3.67 (s, me, 5 H), 4.30 (me, 1 H), 4.47 (me, 1 H), 6.39 (me, 2 H), 6.82 (d, 1 H), 7.08 (d, 1 H).
19. 1-(4-{[5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl]oxy}-1,2-dimethyl-1H-benzimidazol-6-yl)- pyrrolidin-2-one
At a temperature of 60 0C, sodium hydride (60 weight-% in mineral oil, 66 mg, 1.65 mmol) was added to a solution of 1-(4-hydroxy-1 ,2-dimethyl-1/-/-benzimidazol-6-yl)pyrrolidin-2-one (368 mg, 1.5 mmol) and 4-chloro-5,7-difluorochromane (670 mg, 3.3 mmol) in DMF (6 ml). The reaction mixture was stirred for 1 day at 60 0C, diluted with saturated ammonium chloride solution, and extracted with dichlo- romethane. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:35:5 (v/v/v)] and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration, washed with petroleum ether, and dried (194 mg of a colourless solid, 31 % yield).
1 H NMR (300 MHz, CDCI3): = 2.08 (me, 1 H), 2.20 (me, 2 H), 2.45 (me, 1 H), 2.56 (s, 3 H), 2.64 (me, 2 H), 3.68 (s, 3 H), 3.92 (me, 2 H), 4.29 (me, 1 H), 4.48 (me, 1 H), 6.13 (me, 1 H), 6.40 (me, 2 H), 7.02 (d, 1 H), 7.36 (d, 1 H).
20. 1-(4-{[5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl]oxy}-1,2-dimethyl-1H-benzimidazol-6-yl)- piperidin-2-one
At a temperature of 60 0C, sodium hydride (60 weight-% in mineral oil, 66 mg, 1.65 mmol) was added to a solution of 1-(4-hydroxy-1 ,2-dimethyl-1/-/-benzimidazol-6-yl)piperidin-2-one (390 mg, 1.5 mmol) and 4-chloro-5,7-difluorochromane (670 mg, 3.3 mmol) in DMF (6 ml). The reaction mixture was stirred for 1 day at 60 0C, diluted with saturated ammonium chloride solution, and extracted with dichlo- romethane. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:30:10 (v/v/v)] and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration, washed with petroleum ether, and dried (116 mg of a colourless solid, 18 % yield).
21. 1-(4-{[7-Fluoro-3,4-dihydro-2H-chromen-4-yl]oxy}-1,2-dimethyl-1H-benzimidazol-6-yl)- pyrrolidin-2-one At a temperature of 60 0C, sodium hydride (60 weight-% in mineral oil, 66 mg, 1.65 mmol) was added to a solution of 1-(4-hydroxy-1 ,2-dimethyl-1/-/-benzimidazol-6-yl)pyrrolidin-2-one (370 mg, 1.5 mmol) and 4-chloro-7-fluorochromane (620 mg, 3.3 mmol) in DMF (6 ml). The reaction mixture was stirred for 1 day at 60 0C, diluted with saturated ammonium chloride solution, and extracted with dichloro- methane. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:35:5 (v/v/v)] and subsequent crystallization from dichloromethane / diethyl ether / n-heptane. The title compound was isolated by filtration, washed with petroleum ether, and dried (155 mg of a colourless solid, 26 % yield).
1 H NMR (300 MHz, CDCI3): = 2.18 (me, 3 H), 2.37 (me, 1 H), 2.58 (s, 3 H), 2.64 (me, 2 H), 3.70 (s, 3 H), 3.87 (me, 2 H), 4.27 (me, 1 H), 4.45 (me, 1 H), 6.11 (me, 1 H), 6.56 (me, 2 H), 6.90 (d, 1 H), 7.30 (me, 1 H), 7.44 (d, 1 H).
22. 1-(4-{[7-Fluoro-3,4-dihydro-2H-chromen-4-yl]oxy}-1,2-dimethyl-1H-benzimidazol-6-yl)- piperidin-2-one
At a temperature of 60 0C, sodium hydride (60 weight-% in mineral oil, 66 mg, 1.65 mmol) was added to a solution of 1-(4-hydroxy-1 ,2-dimethyl-1/-/-benzimidazol-6-yl)piperidin-2-one (390 mg, 1.5 mmol) and 4-chloro-7-fluorochromane (620 mg, 3.3 mmol) in DMF (6 ml). The reaction mixture was stirred for 1 day at 60 0C, diluted with saturated ammonium chloride solution, and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:35:5 (v/v/v)] and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration, washed with n-heptane, and dried (160 mg of an off-white solid, 26 % yield).
1 H NMR (300 MHz, CDCI3): = 1.96 (me, 4 H), 2.17 (me, 1 H), 2.38 (me, 1 H), 2.58 (bs, 5 H), 3.63, 3.67 (me, s, 5 H), 4.25 (me, 1 H), 4.43 (me, 1 H), 5.98 (me, 1 H), 6.62 (me, 3 H), 6.88 (d, 1 H), 7.34 (me, 1 H).
II. Starting Compounds
A. fert-Butyl (2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5- yl)carbamate
A suspension of 2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-h]quinoline-8,2'-indene]-5-carb- oxylic acid (2.0 g, 5.8 mmol), N-ethyldiisopropylamine (3.0 g, 23 mmol) and diphenylphosphoryl azide (4.76 g, 17.3 mmol) in fert-butanol (20 ml) was refluxed for 2.5 d. Then, the mixture was poured into water and extracted with dichloromethane. The organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, ethyl acetate) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (1.0 g, 41 %). 1H-NMR (d6-DMSO): δ (ppm) 8.21 (s, 1 H, NH), 7.13-7.22 (m, 4 H), 6.64 (s, 1 H), 5.40 (s, 1 H, NH), 3.58 (s, 3 H), 2.90-3.06 (m, 4 H), 2.71 (t, J = 6.5 Hz, 2 H), 2.41 (s, 3 H), 1.84 (t, J = 6.5 Hz, 2 H), 1.46 (s, 9 H).
B. 2,3-Dimethyl-1>,3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2'-inden]-5-amine
To a suspension of fert-butyl (2,3-dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-in- den]-5-yl)carbamate (0.9 g, 2.2 mmol) in methanol (10 ml) was added cone, hydrochloric acid (1 ml) and the mixture was stirred overnight at room temperature. The mixture was poured into water and neutralized with saturated aqueous NaHCO3. The resulting precipitate was collected and dried over potassium hydroxide at 50 0C to yield the title compound as a colourless solid (0.67 g, 88 %). 1H-NMR (d6-DMSO): δ (ppm) 7.13-7.22 (m, 4 H), 5.93 (s, 1 H), 5.09 (s, 1 H, NH), 4.46 (br s, 1 H, NH2), 3.47 (s, 3 H), 2.91-3.00 (m, 4 H), 2.54 (t, J = 6.6 Hz, 2 H), 2.33 (s, 3 H), 1.90 (t, J = 6.5 Hz, 2 H).
C. 3-Bromo-N-(2,3-dimethyl-1',3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5- yl)propanamide
To a suspension of 2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'-inden]-5- amine (2.0 g, 6.3 mmol) and triethylamine (0.88 ml, 6.3 mmol) in chloroform (20 ml) was slowly added 3-bromopropionyl chloride (0.65 ml, 6.3 mmol) via syringe at 0-5 0C. After 1 h at 0 0C, the mixture was poured into water and saturated aqueous NaHCO3 was added. The mixture was extracted with dichlo- romethane and the organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, toluene/dioxane/methanol 12:7:1 ) and crystallization from ethyl acetate/n- heptane yielded the title compound as a colourless solid (1.69 g, 59 %). 1H-NMR (d6-DMSO): δ (ppm) 9.26 (br s, 1 H, NH), 7.13-7.23 (m, 4 H), 6.71 (s, 1 H), 5.47 (br s, 1 H, NH), 3.75 (t, J = 6.4 Hz, 2 H), 3.58 (s, 3 H), 2.90-3.07 (m, 6 H), 2.73 (t, J = 6.3 Hz, 2 H), 2.42 (s, 3 H), 1.85 (t, J = 6.2 Hz, 2 H).
D. 4-Chloro-N-(2,3-dimethyl-1',3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]-5- yl)butanamide
To a suspension of 2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'-inden]-5- amine (0.6 g, 1.9 mmol) and triethylamine (0.26 ml, 1.9 mmol) in chloroform (5 ml) was slowly added 4-chlorobutyryl chloride (0.21 ml, 1.9 mmol) via syringe. After 2 h at room temperature, the mixture was poured into water and the pH was adjusted to pH = 8 with saturated aqueous NaHCO3. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Purification of the residue by column chromatography (silica gel, toluene/dioxane/methanol 30:19:1 ) and crystallization from ethyl acetate/n-heptane yielded the title compound as a colourless solid (0.68 g, 85 %). 1H-NMR (d6-DMSO): δ (ppm) 9.16 (br s, 1 H, NH), 7.14-7.27 (m, 4 H), 6.73 (s, 1 H), 5.47 (br s, 1 H, NH), 3.72 (t, J = 6.6 Hz, 2 H), 3.59 (s, 3 H), 2.92-3.06 (m, 4 H), 2.70 (t, J = 6.5 Hz, 2 H), 2.49 (t, J = 7.6 Hz, 2 H), 2.43 (s, 3 H), 2.02-2.09 (m, 2 H), 1.85 (t, J = 6.5 Hz, 2 H). E. 5-Chloro-N-(2,3-dimethyl-1>,3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2'-inden]-5- yl)pentanamide
To a suspension of 2,3-dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-inden]-5- amine (2.0 g, 6.3 mmol) and triethylamine (0.9 ml, 6.3 mmol) in chloroform (25 ml) was slowly added 5-chlorovaleryl chloride (96%, 0.85 ml, 6.3 mmol) via syringe at 0 0C. After 3 h at room temperature, the mixture was poured into water. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Crystallization of the residue from ethyl acetate yielded the title compound as a colourless solid (2.27 g, 83 %). 1H-NMR (d6-DMSO): δ (ppm) 9.08 (br s, 1 H, NH), 7.13-7.22 (m, 4 H), 6.71 (s, 1 H), 5.44 (br s, 1 H, NH), 3.69 (t, J = 6.3 Hz, 2 H), 3.58 (s, 3 H), 2.91-3.06 (m, 4 H), 2.70 (t, J = 6.5 Hz, 2 H), 2.42 (s, 3 H), 2.35 (t, J = 7.0 Hz, 2 H), 1.73-1.87 (m, 6 H).
F. 2-Chloroethyl (2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2>-inden]- 5-yl)carbamate
To a suspension of 2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'-inden]-5- amine (1.5 g, 4.7 mmol) and triethylamine (0.66 ml, 4.7 mmol) in chloroform (25 ml) was slowly added 2-chloroethyl chloroformiate (97%, 0.5 ml, 4.7 mmol) via syringe at 0 0C. After 1 h at room temperature, the mixture was poured into water. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Crystallization of the residue from ethyl acetate yielded the title compound as a colourless solid (1.75 g, 87 %). 1H-NMR (d6-DMSO): δ (ppm) 8.83 (br s, 1 H, NH), 7.14-7.22 (m, 4 H), 6.71 (s, 1 H), 5.64 (br s, 1 H, NH), 4.31 (t, J = 5.3 Hz, 2 H), 3.85 (t, J = 5.3 Hz, 2 H), 3.62 (s, 3 H), 2.93-3.05 (m, 4 H), 2.74 (t, J = 6.2 Hz, 2 H), 2.46 (s, 3 H), 1.85 (t, J = 6.2 Hz, 2 H).
G. 2-(2-Chloroethoxy)-N-(2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline- 8,2'-inden]-5-yl)acetamide
To a suspension of 2,3-dimethyl-1',3,3',6,7,9-hexahydrospiro[imidazo[4,5-/?]quinoline-8,2'-inden]-5- amine (1.0 g, 3.1 mmol) and triethylamine (0.44 ml, 3.1 mmol) in chloroform (10 ml) was slowly added 2-(2-chloroethoxy)acetyl chloride (0.5 g, 3.1 mmol) via syringe at 0 0C. After 1 h at room temperature, the mixture was poured into water and saturated aqueous NaHCO3 was added. The mixture was extracted with dichloromethane and the organic layer was separated and evaporated. Crystallization of the residue from ethyl acetate yielded the title compound as a colourless solid (1.06 g, 77 %). 1H-NMR (d6-DMSO): δ (ppm) 8.94 (br s, 1 H, NH), 7.13-7.22 (m, 4 H), 6.92 (s, 1 H), 5.50 (br s, 1 H, NH), 4.15 (s, 2 H), 3.85 (s, 4 H), 3.59 (s, 3 H), 2.91-3.08 (m, 4 H), 2.71 (t, J = 6.5 Hz, 2 H), 2.42 (s, 3 H), 1.87 (t, J = 6.5 Hz, 2 H). H. Ethyl {2-[(triethylsilyl)oxy]-2,3-dihydro-1H-inden-2-yl}acetate
Ethyl (2-hydroxy-2,3-dihydro-1/-/-inden-2-yl)acetate (100 g, 0.454 mol) was dissolved in dichlorome- thane (250 ml). The solution was cooled to O0C. Imidazole (34 g, 0.499 mol) was added. Triethylsilyl trifluoromethansulfonate (1 14 ml, 0.499 mol) was added dropwise during 1.5 h. The mixture was allowed to warm to room temperature overnight. Water and dichloromethane were added, and the layers were separated. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo to yield a brown oil which was purified by column chromatography (silica gel, ethyl acetate/n-heptane 0:100 to 1.5:98.5). The title compound was obtained as a dark brown oil (48.3 g, 32 %). 1H NMR (CDCI3): δ (ppm) 7.22-7.08 (m, 4 H), 4.07 (q, 2 H), 3.18 (dd, 4 H), 2.69 (s, 2 H), 1.21 (t, 3 H), 0.83 (t, 9 H), 0.45 (q, 6 H).
I. {2-[(Triethylsilyl)oxy]-2,3-dihydro-1H-inden-2-yl}acetaldehyde
A solution of ethyl {2-[(triethylsilyl)oxy]-2,3-dihydro-1/-/-inden-2-yl}acetate (56 g, 167 mmol) in dichloromethane (240 ml) was cooled to -780C. A solution of diisobutylaluminium hydride in toluene (200 ml, 200 mmol, 1 M) was added dropwise during 75 min. The mixture was stirred at -780C for 4 h, was allowed to warm to -5O0C and quenched carefully with methanol (15 ml). After stirring for 15 min at this temperature, the reaction mixture was poured into a saturated aqueous solution of seignette salt (500 ml). Water (1000 ml) and dichloromethane (500 ml) were added, and the mixture was stirred for 18 h. The layers were separated. The organic layer was washed with a solution of seignette salt (2 x) and water (1 x), dried (MgSO4) and concentrated in vacuo to yield an orange oil which was purified by column chromatography (silica gel, toluene). The title compound was obtained as a clear oil (36.9 g, 76 %). 1H NMR (CDCI3): δ (ppm) 9.91 (t, 1 H), 7.18 (s, 4 H), 3.15 (dd, 4 H), 2.68 (d, 2 H), 0.86 (t, 9 H), 0.47 (q, 6 H).
J. Ethyl 5-[1-hydroxy-2-(2-hydroxy-2,3-dihydro-1H-inden-2-yl)ethyl]-1,2-dimethyl-4-oxo-4,5,6,7- tetrahydro-1H-benzimidazole-6-carboxylate
A solution of ethyl 1 ,2-dimethyl-4-oxo-4,5,6,7-tetrahydro-1/-/-benzimidazole-6-carboxylate (12.5 g, 52.7 mmol) in dichloromethane (160 ml) was cooled to 1O0C and fert-butyldimethylsilyl trifluoromethane- sulfonate (12.5 ml, 54.6 mmol) was added during 15 min. After cooling down to -4O0C, a solution of {2-[(triethylsilyl)oxy]-2,3-dihydro-1 H-inden-2-yl}acetaldehyde (14.3 g, 49.2 mmol) in dichloromethane (20 ml) was added, stirring was continued for 10 min, and a solution of boron trifluoride diethyl ether- ate (13.7 ml, 54.6 mmol, 50%) was added carefully. The reaction mixture was stirred for one hour at - 4O0C and was allowed to warm to room temperature overnight. After dilution with dichloromethane, the reaction mixture was poured into saturated aqueous NH4CI. The aqueous layer was extracted with dichloromethane, the combined organic phases were washed with saturated aqueous NH4CI, dried (MgSO4), and concentrated in vacuo. The resulting oil was purified by column chromatography (silica gel, toluene/dioxane/methanol 20:10:3) and crystallized from ethyl acetate/diisopropyl ether. The title compound was obtained as a slightly yellow solid (8.38 g, 41 %). 1H NMR (d6-DMSO): δ (ppm) 7.22- 7.03 (m, 4 H), 5.09 (d, 1 H), 4.71 (s, 1 H), 4.13-3.95 (m, 3 H), 3.72-3.58 (m, 1 H), 3.49 (s, 3 H), 3.28- 2.68 (m, 7 H), 2.29 (s, 3 H), 2.02-1.71 (m, 2 H), 1.10 (t, 3 H).
K. Ethyl 2,3-dimethyl-1',3'-dihydro-3H-spiro[chromeno[7,8-cy]imidazole-8,2'-indene]-5- carboxylate
A solution of fert-butyldimethylsilyl trifluoromethanesulfonate (2.60 ml, 11.0 mmol) in dichloromethane (10 ml) was added dropwise to a suspension of ethyl 5-[1-hydroxy-2-(2-hydroxy-2,3-dihydro-1/-/-inden- 2-yl)ethyl]-1 ,2-dimethyl-4-oxo-4,5,6,7-tetrahydro-1/-/-benzimidazole-6-carboxylate (2.27 g, 5.50 mmol) and MgSO4 (4.0 g) in dichloromethane (75 ml). After stirring for 10 min at room temperature, solid 2,3- dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ, 1.89 g, 8.25 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The solids were filtered off, saturated aqueous Na2CO3 was added to the filtrate, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with water, dried (MgSO4) and concentrated in vacuo. The resulting oil was crystallized from diisopropyl ether to afford the title compound as a pale brown solid (0.61 g, 30 %). 1H NMR (CDCI3): δ (ppm) 7.53 (s, 1 H), 7.43 (d, 1 H), 7.18 (s, 4 H), 5.76 (d, 1 H), 4.41 (q, 2 H), 3.71 (s, 3 H), 3.62 (d, 2 H), 3.20 (d, 2 H), 2.53 (s, 3 H), 1.40 (t, 3 H).
L. Ethyl 2,3-dimethyl-1',3l,6,7-tetrahydro-3H-spiro[chromeno[7,8-d]imidazole-8,2l-indene]-5- carboxylate
A solution of ethyl 2,3-dimethyl-1',3'-dihydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-indene]-5-carb- oxylate (75 mg, 0.200 mmol) in ethanol (40 ml) was treated with palladium on charcoal (10%) and hydrogenated under an atmosphere of hydrogen for 2.5 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting oil was crystallized from diisopropyl ether to afford the title compound (56 mg, 75 %). 1H NMR (CDCI3): δ (ppm) 7.58 (s, 1 H), 7.19-7.11 (m, 4 H), 4.40 (q, 2 H), 3.72 (s, 3 H), 3.44 (d, 2 H), 3.30 (t, 2 H), 3.17 (d, 2 H), 2.57 (s, 3 H), 2.13 (t, 2 H), 1.44 (t, 3 H).
M. 2,3-Dimethyl-1',3',6,7-tetrahydro-3H-spiro[chromeno[7,8-cy]imidazole-8,2'-indene]-5- carboxylic acid
Ethyl 2,3-dimethyl-1',3',6,7-tetrahydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-indene]-5-carboxylate (60 mg, 0.16 mmol) was dissolved in a mixture of dioxane (2 ml) and water (0.5 ml). The solution was treated with an aqueous solution of LiOH (80 μl; 6N) and heated to 100 0C for 2 h. After cooling down to room temperature, the reaction mixture was neutralized by adding 2N HCI, concentrated in vacuo and the residue was dried at 4O0C in vacuo. The crude product (100 mg) was used as such without further purification and characterization in the following step. N. tert-Butyl (2,3-dimethyl-1',3l,6,7-tetrahydro-3H-spiro[chromeno[7,8-d]imidazole-8,2l-inden]- 5-yl)carbamate
A suspension of 2,3-dinnethyl-1',3',6,7-tetrahydro-3/-/-spiro[chronneno[7,8-c/]innidazole-8,2'-indene]-5- carboxylic acid (1.0 g, 2.90 mmol), triethylamine (1.60 ml, 11.6 mmol) and diphenylphosphoryl azide (1.90 ml, 8.7 mmol) in 20 ml fert-butanol was refluxed for 16 h. Then, the mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was separated, washed with water (100 ml), dried (MgSO4), and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, dichloromethane/methanol 20:1 ) and crystallization from diisopropyl ether yielded the title compound (0.3 g, 21 %) as a colourless solid. 1H-NMR (d6-DMSO): δ (ppm) 8.40 (s, 1 H), 7.29- 7.11 (m, 4 H), 6.95 (s, 1 H), 3.59 (s, 3 H), 3.10 (dd, 4 H), 2.78 (t, 2 H), 2.37 (s, 3 H), 2.09 (t, 2 H), 1.47 (s, 9 H).
O. 2,3-Dimethyl-1',3l,6,7-tetrahydro-3H-spiro[chromeno[7,8-c(]imidazole-8,2l-inden]-5-amine
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 mixture was washed with saturated aqueous NaHCO3, dried (MgSO4), and concentrated in vacuo. The resulting pale brown solid (0.18 g, 95 %) was used in the next step without further purification. 1H-NMR (d6-DMSO): δ (ppm) 7.28-7.10 (m, 4 H), 6.19 (s, 1 H), 4.68 (br s, 2 H), 3.47 (s, 3 H), 3.09 (dd, 4 H), 2.57 (t, 2 H), 2.30 (s, 3 H), 2.10 (t, 2 H).
P. 6-Bromo-N-(3,4-dihydro-2H-chromen-4-yl)-1,2-dimethyl-1H-benzimidazol-4-amine
A suspension of 6-bromo-1 ,2-dimethyl-1/-/-benzimidazol-4-amine (10.0 g, 41.7 mmol), 4-chlorochro- mane (14.0 g, 83.0 mmol), potassium carbonate (20.2 g, 146 mmol) and sodium iodide (3.12 g, 20.8 mmol) was stirred overnight at 70 0C. The reaction mixture was cooled down and partitioned between water and dichloromethane. The aqueous layer was separated and extracted with dichloromethane (4 x). The combined organic layers were dried over anhydrous MgSO4 and evaporated. Purification of the residue by column chromatography (silica gel, ethyl acetate/petroleum ether 4:6) and crystallization from ethyl acetate/n-heptane yielded the title compound (9.94 g, 64 %) as a solid. 1H-NMR (CDCI3): δ (ppm) = 7.14-7.32 (m, 2 H), 6.82-6.91 (m, 3 H), 6.63 (d, 1 H), 5.16 (br d, 1 H, NH), 4.75 (dt, 1 H), 4.24-4.30 (m, 2 H), 3.63 (s, 3 H, CH3), 2.51 (s, 3 H, CH3), 2.17-2.25 (m, 2 H).
Q. ferf-Butyl {4-[(2,6-dimethylbenzyl)amino]-1,2-dimethyl-1H-benzimidazol-6-yl}carbamate
A suspension of 4-[(2,6-dimethylbenzyl)amino]-1 ,2-dimethyl-1/-/-benzimidazol-6-carboxylic acid (6.5 g, 20 mmol), N-ethyldiisopropylamine (14 ml, 80 mmol) and diphenylphosphoryl azide (13 ml, 60 mmol) in ferf-butanol (100 ml) was refluxed for 1.5 h. Then, the mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and evaporated. Purification of the residue by column chromatography (silica gel, first: ethyl acetate/petroleum ether 1 :1 , second: ethyl acetate/petroleum ether/triethylamine 5:5:1 ) and crystallization from ethyl acetate/n- heptane yielded the title compound as a colourless solid (5.1 g, 59 %). 1H-NMR (CDCI3): δ (ppm) 7.01- 7.13 (m, 4 H), 6.57 (br s, 1 H, NH), 6.18 (s, 1 H), 4.48 (br t, 1 H, NH), 4.32 (d, J = 4.2 Hz, 2 H), 3.62 (s, 3 H), 2.48 (s, 3 H), 2.37 (s, 6 H), 1.55 (s, 9 H).
R. Λ/4-(2,6-Dimethylbenzyl)-1,2-dimethyl-1H-benzimidazole-4,6-diamine
A suspension of fert-butyl {4-[(2,6-dimethylbenzyl)amino]-1 ,2-dimethyl-1 /-/-benzimidazol-6- yl}carbamate (4.66 g, 11.8 mmol) in methanol (60 ml) and cone, hydrochloric acid (7 ml) was stirred overnight at 45 0C. The solution was cooled down and neutralized with saturated aqueous NaHCO3. The resulting precipitate was collected and washed successively with water and diethyl ether to yield the title compound as a beige solid (3.33 g, 88 %). 1H-NMR (d6-DMSO): δ (ppm) 7.05-7.15 (m, 3 H), 5.86 (s, 2 H), 4.66 (br s, 2 H, NH2), 4.25 (br s, 3 H, CH2NH), 3.48 (s, 3 H), 2.34 (s, 9 H).
S. Λ/4-(2,6-Dimethylbenzyl)-Λ/6,1,2-trimethyl-1H-benzimidazole-4,6-diamine
To a suspension of Λ/4-(2,6-dimethylbenzyl)-1 ,2-dimethyl-1/-/-benzimidazole-4,6-diamine (1.18 g, 4.0 mmol) and paraformaldehyde (0.48 g, 16 mmol) in methanol (100 ml) was added dropwise a solution of sodium methoxide in methanol (30 %, 6.4 ml). The mixture was refluxed for 1 h and sodium boro- hydride (0.42 g, 11 mmol) was added. After 1 h at reflux, the mixture was poured into saturated aqueous NH4CI. The precipitate was collected and washed successively with saturated aqueous NH4CI, water and petroleum ether. The precipitate was dissolved in dichloromethane and the solution was dried over anhydrous MgSO4. Charcoal was added to the solution and the mixture was filtered through Celite. The filtrate was evaporated and the residue was recrystallized from ethyl acetate/n- heptane to yield the title compound as a colourless solid (0.99 g, 80 %). 1H-NMR (CDCI3): δ (ppm) 7.01-7.12 (m, 4 H), 5.89 (s, 1 H), 5.84 (s, 1 H, NH2), 4.42 (br s, 1 H, NH), 4.32 (d, J = 3.6 Hz, 2 H), 3.59 (s, 3 H), 2.92 (s, 3 H), 2.45 (s, 3 H), 2.38 (s, 6 H).
T. (δSJ^.S-Dimethyl-δ^-methylphenyO-S.ej.δ-tetrahydrochromenoty.δ-cdimidazole-S- carboxylic acid
(δS^N.N^.S-Tetramethyl-δ^-methylphenyO-S.ej.δ-tetrahydrochromeno^.δ-c/limidazole-S-carbox- amide (WO 06/136552, 90.0 g, 0.25 mol) and anhydrous sodium hydroxide beads (100 g, 2.5 mol) were dissolved in ethylene glycol (900 ml). In a three-neck flask equipped with a distillation bridge, the reaction mixture was heated at 195 0C for 2 d. The reaction mixture was cooled to room temperature, transferred into a 20 I vessel, and treated with concentrated hydrochloric acid (adjustment of a pH value of 4-5, approx. 210 ml) and water (9 I). The colourless suspension was stirred for 3 h at room temperature. The title compound (67.0 g of a colourless solid, 80 % yield) was isolated by filtration, m.p. >285 0C, decomposition). - 1H NMR (DMSOd6, 300 MHz): δ = 1.93 (mc, 1 H), 2.25 (mc, 1 H), 2.39 (s, 3 H), 2.50 (s), 3.24 (mc, 2 H), 3.72 (s, 3 H), 5.30 (dd, 1 H), 7.26 (mc, 3 H), 7.47 (mc, 1 H), 7.64 (s, 1 H), 12.56 (bs, 1 H).
U. (8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5- carboxamide
A suspension of (δS^.S-dimethyl-δ^-methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazole-S- carboxylic acid (5.00 g, 14.9 mmol) in DMF (100 ml) was treated with TBTU (4.δO g, 14.9 mmol) and diisopropylethylamine (6.40 ml, 4.δ2 g, 37.3 mmol) and stirred for 45 min at 45 0C. A 7 M solution of ammonia in methanol (6.5 ml) was added and stirring was continued for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (400 ml) and extracted with dichloromethane (3 x 300 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was washed with a mixture of acetone (20 ml) and diethyl ether (30 ml). The title compound (4.5 g of a colourless solid) was obtained in 90 % yield (m.p. 275-277 0C). - 1H NMR (DMSOd6, 300 MHz): δ = 1.95 (mc, 1 H), 2.25 (mc, 1 H), 2.39 (s, 3 H), 2.52 (s), 2.96 (mc, 1 H), 3.17 (mc, 1 H), 3.73 (s, 3 H), 5.32 (dd, 1 H), 7.2δ (mc, 5 H), 7.47 (mc, 1 H), 7.66 (bs, 1 H).
V. tert-Butyl [(δS)-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ-tetrahydrochromeno[7,δ-o(]imidazol- 5-yl]carbamate
A solution of (δS^.S-dimethyl-δ^-methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazole-S- carboxylic acid (1.00 g, 3.0 mmol), diphenylphosphoryl azide (1.9 ml, 2.4 g, 9 mmol), and triethylamine (1.5 ml, 1.2 g, 12 mmol) in tert-butanol (20 ml) was refluxed for 3 h. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The crude title compound (4.5 g of a yellow oil) was purified by column chromatography [150 g of silica gel, eluant: dichloromethane / methanol = 20:1 (v/v)] and subsequently washed with diethyl ether. The title compound was isolated in 32 % yield (390 mg of a pale yellow solid, m.p. 142-145 0C). - 1H NMR (DMSOd6, 300 MHz): δ = 1.47 (s, 9 H), 1.93 (mc, 1 H), 2.23 (mc, 1 H), 2.3δ (s, 3 H), 2.45 (s, 3 H), 2.73 (mc, 1 H), 2.δ7 (mc, 1 H), 3.64 (s, 3 H), 5.21 (dd, 1 H), 6.9δ (s, 1 H), 7.26 (mc, 3 H), 7.46 (mc, 1 H), δ.44 (s, 1 H).
W. Methyl [(δS)-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ-tetrahydrochromeno[7,δ-o(]imidazol-5- yljcarbamate
At a temperature of 0 0C, a suspension of (δS)-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ- tetrahydrochromeno[7,δ-c/]imidazole-5-carboxamide (2.30 g, 6.9 mmol) in methanol (60 ml) was treated with potassium hydroxide (0.96 g, 17.1 mmol) and stirred for 10 min. Over a period of 15 min, a solution of (diacetoxyiodo)benzene (3.10 g, 9.6 mmol) in methanol (20 ml) was added. The reaction mixture was stirred for 2 h at 0 0C 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 crude product was purified by column chromatography [100 g of silica gel, eluant: dichloromethane / methanol = 9:1 (v/v)] and treatment with a mixture of acetone (2 ml) and diethyl ether (20 ml). This afforded the title compound in 71 % yield (1.8 g of a pale-pink solid, 90 % purity, m.p. 181-184 0C). - 1H NMR (DMSOd6, 300 MHz): δ = 1.93 (mc, 1 H), 2.24 (mc, 1 H), 2.38 (s, 3 H), 2.45 (s, 3 H), 2.73 (mc, 1 H), 2.86 (mc, 1 H), 3.64, 3.65 (2 s, 6 H), 5.22 (dd, 1 H), 7.01 (s, 1 H), 7.26 (mc, 3 H), 7.47 (mc, 1 H), 8.78 (s, 1 H).
X. (8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-o(]imidazol-5-amine
1. by cleavage of the corresponding tert-butyl carbamate: At a temperature of 0 0C, a solution of tert- butyl [(δS^.S-dimethyl-δ^-methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazol-S-yllcarbamate (350 mg, O.δ6 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml). The reaction mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and sodium bicarbonate solution (20 ml). 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 0C).
2. by cleavage of the corresponding methyl carbamate: A solution of methyl [(δS)-2,3-dimethyl-δ-(2- methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazol-S-yllcarbamate (1.80 g, 4.9 mmol, 90 % purity) in 1 ,4-dioxane (100 ml) and 2 N sodium hydroxide solution (100 ml) was heated for 20 h at 100 0C. The reaction mixture was poured on ice water (150 ml) and extracted with a mixture of dichloromethane and methanol [30:1 (v/v), 3 x 100 ml]. The combined organic phases were concentrated in vacuo. The residue was treated with a mixture of acetone (2 ml) and diethyl ether (20 ml) and the title compound was isolated in 59 % yield (δO % purity).
1H NMR (DMSOd6, 300 MHz): δ = 1.98 (mc, 1 H), 2.24 (mc, 1 H), 2.37 (2 s, 6 H), 2.62 (mc, 2 H), 3.52 (s, 3 H), 4.66 (bs, 2 H), 5.15 (dd, 1 H), 6.23 (s, 1 H), 7.25 (mc, 3 H), 7.47 (mc, 1 H).
Y. N,2,3-Trimethyl-1>,3,3>,6,7,9-hexahydrospiro[imidazo[4,5-/}]quinoline-δ,2'-inden]-5-amine
Over a period of 15 minutes, 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-δ,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 reaction mixture was poured on saturated ammonium chloride solution (800 ml) and extracted with two portions of dichloromethane (500 ml / 200 ml). The combined organic phases were concentrated to dryness and the crude product purified by column chromatography [silica gel, eluant: toluene / 1 ,4-dioxane / methanol = 60:39:1 (v/v/v)] and subsequent crystallization from ethyl acetate / n-heptane. The title compound was isolated by filtration and dried at 50 0C: 2.82 g of a colourless solid, 68 % yield.
Z. 1-[4-(Benzyloxy)-1,2-dimethyl-1H-benzimidazol-6-yl]azetidin-2-one
A solution of 4-(benzyloxy)-6-bromo-1 ,2-dimethyl-1/-/-benzimidazole (9.94 g, 30.0 mmol), azetidin-2- one (5.0 g, 70 mmol), potassium carbonate (24.9 g, 180 mmol), copper iodide (2.86 g, 15 mmol), and N,N'-dimethylethylendiamine (1.6 ml, 15 mmol) in 1 ,4-dioxane (400 ml) was refluxed for 3 d, cooled, and poured on a mixture of water (1 I) and dichloromethane (1 I). The biphasic mixture was stirred for several minutes and filtered over Celite. 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).
AA. 1-(4-Hydroxy-1,2-dimethyl-1H-benzimidazol-6-yl)azetidin-2-one
A solution of 1-[4-(benzyloxy)-1 ,2-dimethyl-1/-/-benzimidazol-6-yl]azetidin-2-one (3.21 g, 10.0 mmol) in ethanol / dichloromethane was treated with activated carbon, refluxed for 10 minutes, cooled, and filtered over Celite. The Celite pad was washed with ethanol and dichloromethane. The filtrate was concentrated (removal of dichloromethane) and treated with 1 ,4-cyclohexadiene (14.0 ml, 150 mmol) and palladium on charcoal (10 weight-%, 3.50 g). The reaction mixture was refluxed for 17 hours, cooled, and diluted with dichloromethane. 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).
AB. 1-[4-(Benzyloxy)-1,2-dimethyl-1H-benzimidazol-6-yl]pyrrolidin-2-one
A solution of 4-(benzyloxy)-6-bromo-1 ,2-dimethyl-1/-/-benzimidazole (6.62 g, 20.0 mmol), pyrrolidin-2- one (5.7 ml, 100 mmol), potassium carbonate (16.6 g, 120 mmol), copper iodide (1.90 g, 10 mmol), and N,N'-dimethylethylendiamine (1.1 ml, 10 mmol) in 1 ,4-dioxane (250 ml) was refluxed for 5 d, cooled, and poured on water (1.4 I). In the course of 15 minutes, a precipitate was formed, which was isolated by filtration, washed with water, and dissolved in dichloromethane (500 ml). Insoluble inorganic residues were removed by filtration. The filtrate was 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 n-heptane, and dried. This afforded 3.67 g of a colourless solid (55 % yield).
AC. 1-(4-Hydroxy-1,2-dimethyl-1H-benzimidazol-6-yl)pyrrolidin-2-one
The cleavage of the benzyl protecting group proceeded slowly, when a mixture of 1-[4-(benzyloxy)- 1 ,2-dimethyl-1/-/-benzimidazol-6-yl]pyrrolidin-2-one (3.34 g, 10 mmol), 1 ,4-cyclohexadiene (14.2 ml, 150 mmol) and palladium on charcoal (10 weight-%, 0.5 g) in ethanol (140 ml) was refluxed for 1 d. The conversion did not increase significantly, when the reaction was continued for 1 d at reflux in the presence of more catalyst (2 g), 1 ,4-cylohexadiene (10 ml), and ethanol (150 ml). 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).
AD. 1-[4-(Benzyloxy)-1,2-dimethyl-1H-benzimidazol-6-yl]piperidin-2-one
A solution of 4-(benzyloxy)-6-bromo-1 ,2-dimethyl-1/-/-benzimidazole (6.62 g, 20.0 mmol), piperidin-2- one (7.93 g, 80 mmol), potassium carbonate (16.6 g, 120 mmol), copper iodide (1.90 g, 10 mmol), and N,N'-dimethylethylendiamine (1.1 ml, 10 mmol) in 1 ,4-dioxane (250 ml) was refluxed for 4 d, cooled, and poured on water and dichloromethane. The biphasic mixture was filtered over Celite. 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). The combined organic phases were dried over magnesium sulfate, treated with activated carbon, stirred for 15 min, and filtered over Celite. The solvent was removed under reduced pressure and 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 5.90 g of an off-white solid (84 % yield).
AE. 1-(4-Hydroxy-1,2-dimethyl-1H-benzimidazol-6-yl)piperidin-2-one
A solution of 1-[4-(benzyloxy)-1 ,2-dimethyl-1/-/-benzimidazol-6-yl]piperidin-2-one (3.49 g, 10.0 mmol) in ethanol (250 ml) was treated with 1 ,4-cyclohexadiene (14.0 ml, 150 mmol) and palladium on charcoal (10 weight-%, 3.50 g). The reaction mixture was heated to reflux for 1 day, cooled, and filtered over Celite. The Celite pad was washed with dichloromethane. The combined filtrates were evaporated and the residue was crystallized from a mixture of ethyl acetate and n-heptane. The title compound was isolated by filtration and dried. This afforded 2.28 g of an off-white solid (88 % yield).
AF. 3-(3,5-Difluorophenoxy)propanenitrile
A solution of 3,5-difluorophenol (79.2 g, 609 mmol) and Triton B (benzyltrimethylammonium hydroxide, 30 ml) in acrylonitrile (206 ml) was heated for 5 d to 80 0C. The reaction mixture was diluted with diethyl ether (300 ml) and washed with 1 N sodium hydroxide solution (3 x 1 1) and saturated sodium chloride solution (2 x 500 ml). The organic phase was dried over magnesium sulfate and concentrated to dryness. The title compound was obtained in 40 % yield (44.9 g of colourless crystals).
AG. 3-(3,5-Difluorophenoxy)propanoic acid
A suspension of 3-(3,5-difluorophenoxy)propanenitrile (44.9 g, 245 mmol) in concentrated hydrochloric acid (334 ml) was heated for 17 h to 90 0C and cooled to 0 0C. The resulting suspension was filtered. The solid was washed with water and suspended in 1 N sodium hydroxide solution (1000 ml). After a period of 15 minutes, the resulting solution was acidified by addition of concentrated hydrochloric acid. After a period of 20 minutes, the formed precipitate was isolated by filtration, washed with water, and dried. The title compound was obtained in 88 % yield (43.37 g of a colourless solid).
AH. 5,7-Difluoro-2,3-dihydro-4H-chromen-4-one
At a temperature of 50 0C, 3-(3,5-difluorophenoxy)propanoic acid (20.0 g, 99 mol) was dissolved portion-wise into 60 ml of concentrated sulfuric acid. The resulting yellow-green solution was stirred for 1.5 hours at 50 0C, cooled to room temperature, and poured on ice water (800 ml). After a period of 1 hour, the colourless precipitate was isolated by filtration and washed with water. The title compound was dried over phosphorous pentaoxide: 15.69 g of a colourless solid, 86 % yield.
Al. 5,7-Difluorochroman-4-ol
At a temperature of 0 0C, sodium borohydride (6.4 g, 168 mmol) was added portion-wise to a solution of 5,7-difluoro-2,3-dihydro-4/-/-chromen-4-one (15.5 g, 84.2 mmol) in methanol (150 ml). After a period of 2 hours at 0 0C, the reaction mixture was quenched with saturated ammonium chloride solution (200 ml) and water (200 ml), and extracted with dichloromethane (2 x). The combined organic phases were washed with saturated sodium chloride solution and water and the solvent was evaporated. The colourless residue crystallized in the course of 17 h and was washed with n-heptane. The title compound was isolated in 82 % yield (12.92 g of a colourless solid).
AJ. 4-Chloro-5,7-difluorochromane At room temperature, 5,7-difluorochroman-4-ol (10.0 g, 54 mmol) was dissolved portion-wise in thionyl chloride (20 ml) and stirring was continued for 2 hours. The reaction mixture was concentrated several times in the presence of toluene. The title compound was obtained as colourless liquid: 10.95 g, 99 % yield.
AK. 3-(3-Fluorophenoxy)propanenitrile
A solution of 3-fluorophenol (30.0 g, 267 mmol) and Triton B (benzyltrimethylammonium hydroxide, 4.2 ml) in acrylonitrile (90 ml) was heated for 36 h to reflux. The reaction mixture was diluted with diethyl ether (300 ml) and washed with 1 N sodium hydroxide solution (3 x 200 ml). The organic phase was washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over calcium chloride, and concentrated to dryness. The title compound was obtained in 53 % yield (23.2 g of a yellow oil).
AL. 3-(3-Fluorophenoxy)propanoic acid
A suspension of 3-(3-fluorophenoxy)propanenitrile (23.0 g, 139 mmol) in concentrated hydrochloric acid (100 ml) was heated to reflux for 4 h. The resulting suspension was filtered. The solid was washed with water and suspended in 1 N sodium hydroxide solution (200 ml). After a period of 15 minutes, the resulting solution was acidified to pH 1 by addition of concentrated hydrochloric acid. After a period of 1 hour, the formed precipitate was isolated by filtration, washed with water, and dried. The title compound was obtained in 81 % yield (20.69 g of a colourless solid).
AM. 7-Fluoro-2,3-dihydro-4H-chromen-4-one
A solution of 3-(3-fluorophenoxy)propanoic acid (20.0 g, 108 mmol) in toluene (230 ml) and thionyl chloride (64.3 g, 0.54 mol) was refluxed for 17 hours. The reaction mixture was concentrated several times in the presence of toluene. A solution of the yellow oily residue in chloroform (200 ml) was cooled to -65 0C and treated with trifluoromethanesulfonic acid (48.0 ml, 0.54 mol, addition over 45 min). The brown solution was gradually warmed to room temperature. After a period of 17 h, the reaction mixture was poured on ice water (1 I) and the phases were separated. 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).
AN. 7-Fluorochroman-4-ol At a temperature of 0 0C, sodium borohydride (7.4 g, 195 mmol) was added portion-wise to a mixture of 7-fluoro-2,3-dihydro-4/-/-chromen-4-one and 8-fluoro-2,3-dihydro-4/-/-chromen-4-one (16.2 g, 97.5 mmol) in methanol (200 ml). After a period of 1 hour at 0 0C and 17 hours at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (400 ml) and water (200 ml), and extracted with dichloromethane (2 x). The combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated. The yellow residue crystallized slowly. The title compound was isolated as mixture with 8- fluorochroman-4-ol (16.28 g, 99 % yield).
AO. 4-Chloro-7-fluorochromane
At room temperature, a mixture of 7-fluorochroman-4-ol and 8-fluorochroman-4-ol (5.0 g, 30 mmol) was dissolved portion-wise in thionyl chloride (15 ml) and stirring was continued for 2 hours. The reaction mixture was concentrated several times in the presence of toluene. The title compound was obtained as mixture with 4-chloro-8-fluorochromane: 5.47 g, 99 % yield.
Industrial applicability
The compounds of the formula (0), (1 ), (2), (3) and (4) and their pharmaceutically acceptable salts (= active compounds according to the invention) 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. In this connection, 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.
The term "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.
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).
D) Helicobacter pylori infection whose eradication is playing a key role in the treatment of gastrointestinal diseases.
E) Furthermore, "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).
In their excellent properties, 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. On account of these properties, 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.
As medicaments, 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%. By means of the appropriate selection of the excipients, it is possible to obtain a pharmaceutical 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.
The 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. In addition to solvents, antioxidants, stabilizers, surfactants, complexing agents (e.g. cyclodextrins), the following excipients may be mentioned as examples: For oral administration, gelling agents, antifoams, plasticizer, adsorbent agents, wetting agents, colorants, flavorings, sweeteners and/or tabletting excipients (e.g. carriers, fillers, binders, disintegrating agents, lubricants, coating agents); for intravenous administration, dispersants, emulsifiers, preservatives, solubilizers, buffer substances and/or isotonic adjusting substances. For percutaneous 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.
In general, it has been proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in 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. In the case of 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. Furthermore, 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. By choosing the appropriate pharmaceutical formulation of the drugs contained in the combination, 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. One example of 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.
A "kit-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. One example of 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.
To be emphasized in this connection is in particular the combination of the active compounds according to the invention with pharmaceuticals which buffer or neutralize gastric acid (such as, for example, magaldrat, aluminium hydroxide, magnesium carbonate, magnesium hydroxide or other antacids), or especially with pharmaceuticals which inhibit or reduce acid secretion, such as, for example:
(I) histamine-H2 blockers [e.g. cimetidine, ranitidine], or
(II) proton pump inhibitors [e.g. omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, tenatoprazole, ilaprazole, leminoprazole, all including their salts and enantiomers] or
(III) other potassium-competitive acid blockers [e.g. soraprazan and its stereoisomers, linaprazan, revaprazan, all including their salts]), or
(IV) so-called peripheral anticholinergics (e.g. pirenzepine), with gastrin antagonists such as CCK2 antagonists (cholestocystokinin 2 receptor antagonists). An important combination to be mentioned is the combination with 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. As suitable antibacterially active combination partner(s) may be mentioned, for example:
(A) cephalosporins, such as, for example, cifuroximaxetil
(B) penicillines, such as, for example, amoxicillin, ampicillin
(C) tetracyclines, such as, for example, tetracyline itself, doxycycline
(D) β-lactamase inhibitors, such as, for example, clavulanic acid
(E) macrolide antibiotics, such as, for example, erythromycin, clarithromycin, azithromycin
(F) rifamycines, such as, for example, rifamycine itself
(G) glycoside antibiotics, such as, for example, gentamicin, streptomycin
(H) gyrase inhibitors, such as, for example, ciprofloxaxin, gatifloxacin, moxifloxacin (I) oxazolidines, such as, for example, linezolid
(J) 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.
In view of their excellent activity regarding gastric and intestinal protection or cure, 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).
In addition, 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. 3,5-bis(1 ,1- dimethylethyl)-4-hydroxy-β,β-dimethylbenzenepropanol), 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). Pharmaceuticals 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; κ-opiate agonists like fedotozine.
Suitable combination partner(s) also comprise airway therapeutica, for example for the treatment of acid-related asthma and bronchitis. In some cases, the use of a hypnotic aid (such as, for example, Zolpidem [Bikalm®]) as combination partner(s) may be rational, for example for the treatment of GERD-induced sleep disorders.

Claims

We claim:
1. A compound of the formula 0
Figure imgf000070_0001
where either
- A and B together form a CH2-CH2 group and C and D together form a group G1 ,
Figure imgf000070_0002
or where
- A, B and C are each hydrogen and D is a group G2,
Figure imgf000070_0003
or where
- A and B are each hydrogen and C and D together form a group G3,
Figure imgf000070_0004
or where
- A and B together form a CH2-CH2 group, C is hydrogen and D is a group G4,
Figure imgf000070_0005
and whereby 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- 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 its salts.
2. A compound of the formula 0 as claimed in claim 1 , characterized by the formula 1
)
Figure imgf000071_0001
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-
4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C- alkyl, R2 is hydrogen, 1-4C-alkyl, 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, I^C-alkoxy-I^C-alkoxycarbonylamino or sulfonyl,
X is NH or O, and its salts.
3. A compound of the formula 0 as claimed in claim 1 , characterized by the formula 2
Figure imgf000072_0001
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C- alkyl,
R2 is hydrogen, 1-4C-alkyl, 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 its salts.
4. A compound of the formula 0 as claimed in claim 1 , characterized by the formula 3
Figure imgf000073_0001
in which
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,
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 its salts.
5. A compound of the formula 0 as claimed in claim 1 , characterized by the formula 4
R3a
Figure imgf000074_0001
in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1- 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C- alkyl,
R2 is hydrogen, 1-4C-alkyl, 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.
6. A compound of the formula 0 as claimed in claim 1 , where either
- A and B together form a CH2-CH2 group and C and D together form a group G1 ,
Figure imgf000074_0002
or where - A, B and C are each hydrogen and D is a group G2,
Figure imgf000075_0001
or where
- A and B are each hydrogen and C and D together form a group G3,
Figure imgf000075_0002
or where
- A and B together form a CH2-CH2 group, C is hydrogen and D is a group G4,
Figure imgf000075_0003
and whereby
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 its salts.
7. A compound of the formula 0 as claimed in claim 1 , which is selected from the group consisting of 1-{4-[(2,6-Dimethylbenzyl)amino]-1 ,2-dimethyl-1/-/-benzimidazol-6-yl}azetidin-2-one 1-{4-[(2,6-Dimethyl benzyl )amino]-1 ,2-dimethyl-1/-/-benzimidazol-6-yl}pyrrolidin-2-one 1-[4-(3,4-Dihydro-2/-/-chromen-4-ylamino)-1 ,2-dimethyl-1/-/-benzimidazol-6-yl]azetidin-2-one 1-[4-(3,4-Dihydro-2/-/-chromen-4-ylamino)-1 ,2-dimethyl-1/-/-benzimidazol-6-yl]pyrrolidin-2-one 1-(2,3-Dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-inden]-5-yl)azetidin-2-one
1-(2,3-Dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-inden]-5-yl)pyrrolidin-2-one
1-(2,3-Dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-inden]-5-yl)piperidin-2-one
3-(2,3-Dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-inden]-5-yl)-1 ,3-oxazolidin-2- one
4-(2,3-Dinnethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-8,2'-inden]-5-yl)nnorpholin-3-one
1-(2,3-Dimethyl-1',3',6,7-tetrahydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-inden]-5-yl)pyrrolidin-2- one
1-(2,3-Dimethyl-1',3',6,7-tetrahydro-3/-/-spiro[chronneno[7,
8-c/]innidazole-8,2'-inden]-5-yl)piperidin-2-one
N-{4-[(2,6-Dimethylbenzyl)annino]-1 ,2-dinnethyl-1/-/-benzinnidazol-6-yl}-N-nnethylacetannide i-^δS^.S-Dimethyl-δ^-methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazol-S-yllpyrrolidin^- one i-^δS^.S-Dimethyl-δ^-methylphenyO-S.ΘJ.δ-tetrahydrochromeno^.δ-c/limidazol-S-yllpiperidin^- one
N^.S-Dimethyl-i'.S.S'.ΘJ.Θ-hexahydrospiroIinnidazo^.S-Λlquinoline-δ^'-indenl-S-yO-N-nnethylacet- amide
N-(2,3-Dimethyl-1',3,3',6,7,9-hexahydrospiro[innidazo[4,5-/?]quinoline-δ,2'-inden]-5-yl)-N-nnethylpro- panamide
N-(2,3-Dimethyl-1',3',6,7-tetrahydro-3/-/-spiro[chronneno[7,δ-c/]innidazole-δ,2'-inden]-5-yl)cyclopropane- carboxamide
1-(4-{[5,7-Difluoro-3,4-dihydro-2/-/-chromen-4-yl]oxy}-1 ,2-dinnethyl-1/-/-benzinnidazol-6-yl)azetidin-2- one
1-(4-{[5,7-Difluoro-3,4-dihydro-2/-/-chromen-4-yl]oxy}-1 ,2-dinnethyl-1/-/-benzinnidazol-6-yl)piperidin-2- one
1-(4-{[5,7-Difluoro-3,4-dihydro-2/-/-chromen-4-yl]oxy}-1 ,2-dinnethyl-1/-/-benzinnidazol-6-yl)pyrrolidin-2- one
1-(4-{[7-Fluoro-3,4-dihydro-2/-/-chromen-4-yl]oxy}-1 ,2-dinnethyl-1/-/-benzinnidazol-6-yl)piperidin-2-one
1-(4-{[7-Fluoro-3,4-dihydro-2/-/-chromen-4-yl]oxy}-1 ,2-dinnethyl-1/-/-benzinnidazol-6-yl)pyrrolidin-2-one and its salts.
δ. A compound according to any of claims 1 to 7 for the treatment and/or prophylaxis of gastrointestinal disorders.
9. Use of a compound according to any of claims 1 to 7 for the production of medicaments, which are employed for the treatment and/or prophylaxis of gastrointestinal disorders.
10. A medicament comprising one or more compounds according to any of claims 1 to 7 and/or a pharmaceutically acceptable salt thereof together with customary pharmaceutical excipients.
11. The use of a compound according to any of claims 1 to 7 and its pharmaceutically acceptable salts for the prevention and/or treatment of gastrointestinal disorders.
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