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  • 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
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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  • 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
  • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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  • 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
  • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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  • 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
  • C07D405/10—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 carbon chain containing aromatic rings
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to ⁇ , ⁇ -fused butyrolactones, processes for their preparation and their use as medicaments
• the amino acid L-glutamate is the most important excitatory neurotransmitter in the brain.
• Glutamate receptors can be divided into two broad classes: 1. ionotropic receptors that control ion channels directly and 2. metabotropic receptors (mGluRs).
• Metabotropic glutamate receptors are a heterogeneous class of G protein-coupled receptors. They pre- or post-synaptically modulate the release of glutamate or the sensitivity of the cell to glutamate. The effects are caused by different second messenger cascades. This response in turn affects the ionotropic glutamate receptors.
• There are currently 8 different subtypes of the metabotropic glutamate receptors that differ in their second messenger cascade, pharmacology and localization in the brain for an overview: Ann. Rev. Pharmacol. Toxicol. 1997, 37, 205).
• the present invention relates to ⁇ , ⁇ -fused butyrolactones of the general formula (I)
• A represents radicals of the formulas -CH 2 -, -CO-, -CR 4 (OH) - or - (CH 2 ) a -CHR 5 -, wherein
• a represents a number 0, 1, 2, 3 or 4,
• R 4 represents hydrogen or (C, -C 6 ) alkyl
• R 5 denotes phenyl
• R 1 represents hydrogen, (C 3 -C 6 ) cycloalkyl or a 5- to 6-membered heterocycle which contains up to 3 heteroatoms from the series S, O, N and / or a radical of the formula -NR 6 can,
• R 6 represents hydrogen or methyl
• R 7 has the meaning of R 6 given above and is the same or different with it
• b and c are the same or different and represent a number 1 or 2
• R 8 denotes (C, -C 6 ) alkyl or phenyl
• R 9 denotes hydrogen or (C, -C 6 ) alkyl
• R 10 and R u are the same or different and are hydrogen, phenyl or
• R 10 and R u together with the nitrogen atom represent a radical of the formula
• G represents an oxygen atom, a -CH 2 group or a radical of the formula -NR 12 -, wo ⁇ n
• R 12 is hydrogen, phenyl, benzyl, (C, -C 6 ) -alkyl, (C, -C 6 ) -alkoxy-carbonyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means
• R 13 represents hydrogen, or
• (C 6 -C 10 ) aryl or can be substituted by a 5- to 7-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O,
• d represents a number 1 or 2, or
• R 14 and R 15 are identical or different and are hydrogen, (C 3 -C 6 ) cycloalkyl,
• R 16 denotes hydrogen or (C r C 6 ) alkyl
• R 17 is hydrogen, adamantyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 6 ) alkenyl or
• (C * -C 12 ) alkyl optionally by adamantyl, (C 3 -C 6 ) cycloalkyl, (C 6 -C 10 ) aryl, phenoxy or a 5- to 6-membered aromatic heterocycle with up to 4 heteroatoms from the series S, N and / or O is substituted, the aryl and the heterocycle in turn being substituted one or more times, identically or differently by (C, -C 6 ) alkyl, (C, -C 6 ) alkoxy, Hydroxy, nitro or halogen can be substituted,
• R 22 is (C, -C 6 ) alkyl or (C 6 -C ] 0 ) aryl, which may be one or more times, identical or different, by halogen, nitro, hydroxy or (C - C 6 ) alkoxy is substituted,
• Heterocycle with up to 3 heteroatoms from the series S, N and / or O which in turn may be one or more times, identically or differently, by (CC 6 ) alkoxy, (C, -
• L and M are identical or different and denote hydrogen or halogen
• R 23 and R 24 have the meaning of R '° and R u given above and are the same or different with this,
• R 18 has the meaning of R 16 given above and is the same or different with this, R 19 denotes (C 3 -C 8 ) cycloalkyl, or
• R 25 , R 26 and R 27 are the same or different and are (C, -C 6 ) -alkyl
• R 20 and R 21 are the same or different and are hydrogen, adamantyl, (C 3 -
• R 28 and R 29 are identical or different and are hydrogen or (C, -C 6 ) -alkyl
• R 30 has the meaning of R 12 given above and is the same or different with this,
• R 20 and R 21 together with the nitrogen atom represent a radical of the formula
• G ' has the meaning of G given above and is the same or different with it
• R 2 and R 3 are identical or different and represent hydrogen or (C, -C 6 ) alkyl
• R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 and R 38 are identical or different and are hydrogen, phenyl or (C r C 6 ) -alkyl,
• the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates to both the enantiomers or diastereomers or their respective mixtures.
• the racem Like the diastereomers, shapes can be separated into the stereoisomerically uniform constituents in a known manner.
• Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
• Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
• Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine,
• alkali metal salts e.g. sodium or potassium salts
• alkaline earth metal salts e.g. calcium or magnesium salts
• ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine,
• (C 3 -C 8 ) cycloalkyl and (C 3 -C 6 ) cycloalkyl stand for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl.
• cyclopropyl cyclopentyl, cyclohexyl or cycloheptyl.
• aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• (C, -C ") alkyl, (C, -C 8 ) alkyl, (C, -C 8 ) alkyl and (C, -) alkyl stand for a straight-chain or branched alkyl radical with 1 to 12, 1 to 9, 1 to 8 or 1 to 6 carbon atoms.
• a straight-chain or branched alkyl radical having 1 to 6 carbon atoms is preferred. Examples include: methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.
• (C9-Cs) -alkanediyl represents a straight-chain or branched alkanediyl radical having 2 to 8 carbon atoms.
• a straight-chain or branched alkanediyl radical having 2 to 6 carbon atoms is preferred, particularly preferably having 2 to 4 carbon atoms.
• Examples include ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane
• (C 6 -C (;) - Alkenediyl in the context of the invention represents a straight-chain or branched alkenediyl radical having 2 to 6 carbon atoms, preferably having 2 to 4 carbon atoms, particularly preferably having 3 carbon atoms.
• Ethene-1,2-diyl may be mentioned as examples , Ethene-l, l-diyl, propene-1,1-diyl, propene-1,2-diyl, propene-1,3-diyl, propene-3,3-diyl, propene-2,3-diyl, but -2-en-l, 4-diyl, pent-2-en-l, 4-diyl, hex-2-en-l, 4-diyl.
• (C- * > -C ( ⁇ ) - alkynediyl in the context of the invention represents a straight-chain or branched alkynediyl radical having 2 to 6 carbon atoms, preferably having 2 to 4 carbon atoms, particularly preferably having 2 to 3 carbon atoms.
• Examples include ethyne-1 , 2-diyl, propin-1,3-diyl, but-2-in-l, 4-diyl, pent-2-in-l, 4-diyl, hex-2-in-l, 4-diyl.
• (C r C 6 ) -alkoxy stands for a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms.
• a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
• (C-) alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms.
• a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
• (C 6 -C 8 ) alkenyl and (C 2 -C 6 ) alkenyl stand for a straight-chain or branched alkenyl radical having 2 to 8 carbon atoms or 2 to 6 carbon atoms.
• a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.
• (C 6 -C 6 ) alkynyl represents a straight-chain or branched alkynyl radical having 2 to 6 carbon atoms.
• a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms is preferred. Examples include: ethynyl, n-prop-2-in-1-yl and n-but-2-in-1-yl.
• a 5- to 6-membered heterocycle generally represents a 5- to 6-membered, optionally also aromatic heterocycle of up to 3 heteroatoms from the series S, O and / or N or a radical of the formula -NH or
• -NCH 3 can contain. Examples include: pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, piperidinyl or morpholinyl. Pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl are preferred.
• a 5- to 6-membered, benzo-condensed heterocycle is part of the
• Invention in general for a 5- to 6-membered, preferably 5-membered heterocycle with up to 2 heteroatoms from the series S, O, N and / or a radical of the formula -NH, the ring carbon atoms of which are the points of attachment for the benzene ring.
• Examples include: indolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, quinolyl, quinoxalinyl or quinazolyl.
• Benzimidazolyl quinolyl, quinoxalinyl, quinazolyl, benzothiophenyl and benzofuranyl.
• A represents radicals of the formulas -CH 2 -, -CO-, -CR 4 (OH) - or - (CH 2 ) a -CHR 5 -,
• a represents a number 0, 1, 2 or 3
• R 4 is hydrogen or (C, -C 4 ) alkyl
• R 5 denotes phenyl
• R 1 represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, furyl, quinazolyl, quinoxalinyl or quinolyl,
• b and c are the same or different and represent a number 1 or 2
• R 8 denotes (C, -C 4 ) alkyl or phenyl
• R 9 denotes hydrogen or (C, -C 4 > alkyl
• R 10 and R 11 are the same or different and are hydrogen, phenyl or
• (C, -C 4 ) - Alkyl which is optionally substituted by phenyl, which in turn can be substituted one or more times, identically or differently, by fluorine, chlorine, bromine, nitro, hydroxy or (C - C 4 ) alkoxy can,
• R 10 and R 11 together with the nitrogen atom represent a radical of the formula
• G represents an oxygen atom, a -CH 2 group or a radical of the formula -NR 12 -,
• R 12 represents hydrogen, phenyl, benzyl, (C, -C 4 ) alkyl, (C, -C 4 ) alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl, and / or are substituted by groups of the formulas -CO 2 -R 13 , -NR 14 R 15 , -NR 16 CO-R -NR , 8 CO 2 -R 19 and -CO-NR 20 R 21 ,
• R 13 represents hydrogen, or
• Phenyl, naphthyl, pyridyl, thienyl or furyl can be substituted
• R 14 and R 15 are the same or different and are hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or (C, -C 5 ) alkyl, that optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which in turn can be substituted one or more times, identically or differently, by fluorine, chlorine, bromine, hydroxy or (C, -C 4 ) alkoxy,
• R 16 denotes hydrogen or (C r C 3 ) -alkyl
• R 17 is hydrogen, adamantyl, cyclopropyl, cyclopentyl or cyclohexyl, or (C 2 -C 4 ) alkenyl or (C, -C 10 ) alkyl, which may be replaced by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, naphthyl, pyridyl, thienyl, tetrazolyl or furyl is substituted, the ring systems in turn one or more times, identically or differently, by (C, -C 4 ) -alkyl, (C, -C 4 ) -alkoxy, hydroxy, nitro, fluorine , Chlorine or bromine can be substituted,
• R 22 denotes (C, -C 4 ) alkyl, phenyl or naphthyl, which are optionally substituted one or more times, identically or differently, by fluorine, chlorine, bromine, nitro, hydroxyl or (C, -C 4 ) alkoxy,
• L and M are identical or different and denote hydrogen, fluorine, chlorine or bromine,
• R 23 and R 24 have the meaning of R 10 and R "given above and are identical or different with this,
• R 18 has the meaning of R 16 given above and is the same or different with it
• R ! 9 denotes cyclopropyl, cyclopentyl or cyclohexyl, or
• R 25 , R 26 and R 27 are the same or different and are (C, -C 4 ) -alkyl
• d R 21 are the same or different and are hydrogen, adamantyl,
• R 28 and R 29 are the same or different and are hydrogen or (C r C 4 ) -alkyl
• R 30 has the meaning of R 12 given above and is the same or different with this,
• R 20 and R 21 together with the nitrogen atom represent a radical of the formula
• G ' has the meaning of G given above and is the same or different with it
• R 2 and R 3 are identical or different and represent hydrogen or (C, -C 3 ) alkyl
• R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 and R 38 are identical or different and are hydrogen, phenyl or (C, -C 3 ) alkyl,
• A represents radicals of the formulas -CH 2 -, -CO-, -CR 4 (OH) - or - (CH 2 ) a -CHR 5 -,
• a represents a number 0, 1, 2 or 3
• R 4 is hydrogen or (C, -C 3 ) alkyl
• R 5 denotes phenyl
• R 1 represents hydrogen, cyclopropyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, quinazolyl or quinoxalinyl,
• b and c are the same or different and represent a number 1 or 2
• R 9 denotes hydrogen or (C, -C 3 ) alkyl
• R 10 and R 11 are the same or different and are hydrogen, phenyl or
• R 10 and R 11 together with the nitrogen atom represent a radical of the formula
• R 12 is hydrogen, phenyl, benzyl, (C, -C 3 ) -alkyl, (C, -C 3 ) -alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl,
• R 13 represents hydrogen, or
• Phenyl, naphthyl or pyridyl can be substituted
• d represents a number 1 or 2, or
• R 14 and R 15 are the same or different and are hydrogen, cyclohexyl, phenyl or (C, -C 4 ) -alkyl, which may be replaced by cyclopropyl,
• Cyclohexyl or phenyl is substituted, which in turn can be substituted one or more times, identically or differently, by chlorine or (C, -C 3 ) alkoxy,
• R 16 denotes hydrogen, methyl or ethyl
• R 17 represents hydrogen, adamantyl, cyclopentyl or cyclohexyl, or (C 2 -C 3 ) alkenyl or (C, -C 8 ) alkyl, which may be replaced by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, thienyl or Furyl is substituted, the ring systems in turn being substituted one to more times, identically or differently, by (C, -C 3 ) alkyl, (C, -C 3 ) alkoxy, hydroxy, nitro, fluorine, chlorine or bromine,
• e is a number 0 or 1
• R 22 denotes (C, -C 3 ) -alkyl, phenyl or naphthyl, which may be one or more times the same or different Fluorine, chlorine, bromine, nitro, hydroxy or (C, -C 3 ) alkoxy are substituted,
• Phenyl, naphthyl, thienyl or furyl which in turn may be substituted one or more times, identically or differently, by (C, -C 3 ) alkoxy, (C, -C 3 ) alkyl, nitro, fluorine, chlorine or bromine can,
• L and M are the same or different and denote hydrogen, fluorine or chlorine
• R 23 and R 24 have the abovementioned meaning of R 10 and R 11 and are the same or different with this,
• R 18 has the meaning of R 16 given above and is the same or different with it
• R 19 denotes (C, -C 4 ) -alkyl or (C 3 -C 5 ) -alkenyl, which in turn is optionally substituted by substituents selected from the group chlorine, Phenyl, hydroxy, morpholinyl, cyclopropyl, cyclohexyl and substituted by a group of the formula -SiR 25 R 26 R 27 ,
• R 25 , R 26 and R 27 are the same and are methyl
• d R 21 are the same or different and are hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, thiazolyl or pyrryl, or
• R 28 and R 29 are identical or different and are hydrogen or (C, -C 3 ) -alkyl
• R or R is a radical of the formula
• R 30 has the meaning of R 12 given above and is the same or different with this,
• R 20 and R 21 together with the nitrogen atom represent a radical of the formula
• G ' has the meaning of G given above and is the same or different with it
• R 2 and R 3 are the same or different and represent hydrogen or methyl
• R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 and R 38 are identical or different and are hydrogen or methyl
• A stands for -CH 2 -
• R 1 represents phenyl or naphthyl
• R 16 represents hydrogen
• R 17 denotes (C, -C 8 ) -alkyl, which may be replaced by cyclopropyl,
• Cyclopentyl, cyclohexyl, phenyl, thienyl or furyl is substituted, the ring systems in turn one or more times, the same or different, by (C, -C 3 ) alkyl, (C - C 3 ) alkoxy, hydroxy, nitro, fluorine , Chlorine or bromine can be substituted,
• R 18 has the meaning of R 16 given above and is the same or different with it
• R 19 denotes (C, -C 4 ) -alkyl or (C 3 -C 5 ) -alkenyl
• R 20 and R 21 are identical or different and denote hydrogen, (C 2 -C 3 ) alkenyl, (C, -C 7 ) alkyl or (C 3 -C 5 ) alkynyl, which are optionally substituted by phenyl, pyridyl, Furyl, thienyl or pyrryl are substituted, the ring systems optionally being substituted up to 2 times, identically or differently, by (C, -C 3 ) alkoxy, fluorine, chlorine, bromine or (C, -C 3 ) alkyl,
• R 2 and R 3 represent hydrogen or methyl
• R 31 , R 32 , R 33 , R 34 , R 35 are hydrogen
• T represents halogen, preferably bromine
• Suitable solvents are all inert solvents that do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether.
• Tetrahydrofuran is particularly preferred.
• bases are suitable as bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium. Lithium diisopropylamide and lithium bis (trimethylsilyl) amide are preferred.
• alkali metal hydroxides such as sodium or potassium hydroxide
• alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide
• amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium
• the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compounds of the general formula (II).
• the reaction generally takes place in a temperature range from -78 ° C to
• Reflux temperature preferably from -78 ° C to + 20 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• Derivatizations within the scope of the invention are preferably reactions on the radical R 1 with substituent groups (C r C 6 ) alkoxy, -NR 14 R 15 , -NR 16 -COR 17 -, -NR I8 " CO 2 R 19 and -CO- NR 20 R 21.
• the amidation is generally carried out in inert solvents in the presence of a base and a dehydrating agent.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents.
• solvents include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylphosphoramide, acetonitrile, acetonitrile, acetonitrile, acetic acid. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
• the usual basic compounds are suitable as bases for the derivatizations.
• bases preferably include alkali or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides such as sodium hydride, alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, or alkali metal alcoholates such as sodium methoxide or ethanolate, potassium methanolate or ethanolate or potassium tert-butoxide, or organic amines such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide,
• the derivatizations are generally carried out in a temperature range from -20 ° C to 150 ° C, preferably at 0 ° C to 25 ° C.
• the derivatizations are generally carried out under normal pressure. However, it is also possible to carry out the processes under reduced pressure or overpressure (e.g. in a range from 0.5 to 5 bar).
• the bases are generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the particular carboxylic acid.
• Suitable dehydrating reagents are carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-2- 5-phenyl-1-phenyl oxazolium-3-sulfonate or propanephosphoric anhydride or isobutylchloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid di-phenyl ester amide or methanesulfonic acid chloride, optionally in the presence of bases such as triethylamine or N-ethylmorphidine or N-cyclimidoxin or N-methylpyridyl or N-methylpyridy
• R 33 , R 35 , R 36 and R 38 represent hydrogen
• R 34 and R 37 have the meaning given above
• R 1 , R 2 R 3 , R 31 and R 32 have the meaning given above,
• Suitable solvents are, for example, alcohols.
• N-Butanol is preferred.
• Suitable catalysts are transition metals such as, for example, palladium, platinum or rhodium, preferably palladium, in an amount of 0.01 to 1 equivalent based on the mass of the compound of the general formula (I ") used, preferably 0.05 to 0.2 Equivalents.
• Palladium is very particularly preferably adsorbed on activated carbon.
• the reaction generally takes place in a temperature range from 80 to 200 ° C., preferably from 100 to 150 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
• the present invention also relates to compounds of the general formula (II) in which
• R 2 and R 3 are identical or different and represent hydrogen or (C, -C 6 ) alkyl
• R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 and R 38 are the same or different and are hydrogen, phenyl or (C, -C 6 ) alkyl.
• R 2 and R 3 represent hydrogen or methyl
• R 31 , R 32 , R 33 , R 34 and R 35 are hydrogen.
• R 9 or represents (C1-C4) alkyl or (C2-C4) alkenyl, which are optionally substituted by phenyl,
• R 40 represents (C r C 4 ) alkyl or (C 3 -C 4 ) alkenyl, which may optionally be substituted by phenyl,
• R 2 ' represents (C j -C 6 ) alkyl
• Q represents an alkali or alkaline earth metal halide, preferably Mg-X,
• R 3 ' represents (C r C 6 ) alkyl
• Diisobutyl aluminum hydride is preferred.
• Inert solvents such as methylene chloride, THF, dioxane, diethyl ether, toluene, 1,2-dichloroethane, are suitable as solvents.
• Methylene chloride is preferred.
• the reaction generally takes place in a temperature range from -40 ° C. to the reflux temperature of the solvent, preferably from 0 ° C. to 30 ° C.
• the cyclization of the intermediate hydroxycarboxylic acid can be supported by activating the carboxyl group, for example with alkyl chloroformate, preferably methyl chloroformate, in the presence of a base, such as triethylamine.
• a suitable step-down method for process [B] is a stepwise reduction by preactivating the carboxyl group with alkyl chloroformate, preferably methyl chloroformate, in the presence of a base such as triethylamine, followed by a reduction with a complex metal hydride such as a borohydride, preferably sodium borohydride.
• solvents such as diethyl ether, THF, methylene chloride are suitable as solvents for the activation.
• Suitable solvents for the reduction with borohydrides are e.g. Alcohols, especially methanol.
• the reaction generally takes place in a temperature range from -40 ° C. to 40 ° C., preferably from -20 ° C. to 30 ° C.
• Suitable reducing agents for process [C] are complex metal hydrides with reduced reactivity, e.g. Lithium tris tert-butoxy aluminum hydride.
• Inert solvents such as diethyl ether or THF, are suitable as solvents for this.
• the reaction generally takes place in a temperature range from -78 ° C to 0 ° C, preferably from -50 ° C to -20 ° C.
• Suitable inert solvents for the reaction with the compounds of the general formulas (VII) and (VIII) in processes [C] to [E] are ethers, preferably diethyl ether or THF.
• the reactions generally take place in a temperature range from -78 ° C to 35 ° C, preferably at -60 ° C to 25 ° C.
• Particularly suitable acids for the cyclization to the lactones are mineral acids, such as, for example, dilute aqueous sulfuric acid or hydrochloric acid.
• mineral acids such as, for example, dilute aqueous sulfuric acid or hydrochloric acid.
• the compounds of the general formulas (IV) and (V) are known per se or can be prepared by customary methods.
• the compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.
• a modulator of the metabotropic glutamate receptor in the sense of the invention is an agonist or antagonist of this receptor.
• the compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.
• the compounds according to the invention can be used alone or in combination with other medicaments for the treatment and / or prevention of neuronal damage or diseases which are associated with pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system.
• neuronal damage for example caused by ischemic, thrombic and / or thrombemolic, and hemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and skull.
• cerebral ischemia after surgical interventions on the brain or peripheral organs or parts of the body and associated or previous conditions pathological or allergic in nature, which can primarily and / or secondarily lead to neuronal damage.
• the compounds according to the invention are also suitable for the therapy of primary and / or secondary pathological conditions in the brain, for example during or after cerebral vasospasm, hypoxia and / or anoxia of a genesis not mentioned above, perinatal asphyxia, autoimmune diseases, metabolic and organ diseases associated with Damage to the brain can go hand in hand as well as damage to the brain as a result of primary brain diseases, for example convulsions and arterosclerotic and / or arteriosclerotic changes.
• neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and / or chronic viral or bacterial infections and multi-infarct dementia.
• the compounds of the general formula (I) according to the invention can be used to promote neuronal regeneration in the post-acute phase of cerebral injuries or chronic diseases of the nervous system.
• the modulatory effect of pharmacological test substances on glutamate receptors can be controlled by appropriate experimental arrangement.
• a detailed examination of the subtype specificity under controlled conditions can be done on Xenopus oocytes by injection the corresponding mGluR subtype DNA (WO 92/10583).
• the cerebral artery is unilaterally dissected, and it and its secondary branches are irreversibly closed by means of electrocoagulation. As a result of the procedure, a cerebral infarction develops. During the operation, the animal's body temperature is kept at 37 ° C. After wound closure and
• the animals are injected with subdural autologous blood under anesthesia.
• An infarction forms under the hematoma.
• the substance is administered according to different time schedules and via different application routes (i.V., i.p.).
• the infarct size is determined as described in the model of permanent focal ischemia in the rat (MCA-O).
• the anti-epileptic effect can be tested according to the method described in NeuroReport 1996, 7, 1469-1474.
• the suitability of the compounds according to the invention for the treatment of schizophrenia can be determined according to the methods described in Science 1998, 218, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136 methods can be determined.
• the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and carriers or contain more compounds of the general formula (I) or which consist of one or more active compounds of the formula (I), and processes for the preparation of these preparations.
• the active compounds of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
• the pharmaceutical preparations can also contain other pharmaceutical active ingredients.
• the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
• the active ingredient (s) of formula (I) in total amounts of about 0.01 to about 100 mg / kg, preferably in total amounts of about 1 mg / kg to 50 mg / kg body weight Hours, if necessary in the form of several individual doses, to achieve the desired result.
• Triethylamine (6.59 ml; 47.57 mmol) and ethyl chloroformate (2.27 ml; 23.78 mmol) were added and the reaction mixture was left to stand at 8 ° C. for 14 h. Then ethyl acetate and water were added. The organic phase was washed with 10% aqueous HCl, saturated NaCl solution, 10% aqueous NaHCO 3 solution and saturated NaCl solution, dried (MgSO 4 ), concentrated and the
• Examples 2 to 97 listed in the following table were shown in analogy to the instructions in Example 1.
• the corresponding halides, aldehydes or esters were used as alkylating reagents.
• Triethylamine (12 ⁇ l, 0.080 mmol) and acetyl chloride (3.1 mg; 0.039 mmol) were added to a solution of the compound from Example 104 (10 mg; 0.036 mmol) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 20 h .
• a saturated NaHCO 3 solution (1 ml) was added and the
• Example 122 Diastereomer B, Fraction 2.
• Example 123 Diastereomer B, Fraction 2.
• examples 128 to 177 listed in the following table were shown based on examples 124 and 125, examples 178 to 197 based on example 126:
• Triethylamine (51 ⁇ l, 0.367 mmol) and methanesulfonic acid chloride (14.2 ⁇ l, 0.184 mmol) were added to a solution of the compound from Example 125 (50.0 mg, 0.184 mmol) in dichloromethane (2 ml) at room temperature. After 1 h 2-propanol (10.6 ⁇ l, 0.138 mmol) and dimethylaminopyridine (4.5 mg, 0.037 mmol) were added and the mixture was stirred at room temperature for a further 20 h.
• Diastereomer A Fraction 1 (HPLC, Kromasil 100C 18, methanol / H 2 O 65:35)
• Diastereomer B Fraction 2 (HPLC, Kromasil 100C 18, methanol / H 2 O 65:35)
• Example 104 The compound from Example 104 and 3-methoxyphenylacetic acid chloride were reacted analogously to the instructions in Example 106.
• the crude product was separated into the enantiomers by HPLC (Chiralpak AS, ethanol / iso-hexane 20:80).

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