Substituted alpha, beta-anellated butyrolactones

Abstract

The present invention relates to novel substituted α,β-fused butyrolactones, to processes for their preparation and to their use for the prevention and/or treatment of disorders caused by hyper- or hypofunction of the glutamatergic system, in particular of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms.

Description

[0001] The present invention relates to α,β-fused butyrolactones, to processes for their preparation and to their use as pharmaceuticals.

[0002] The amino acid L-glutamate is the most important excitatory neurotransmitter in the brain. Glutamate receptors can be divided into two major classes: 1 ionotropic receptors which control ion channels directly and 2. metabotropic receptors (mGluRs)

[0003] Metabotropic glutamate receptors are a heterogeneous class of G-protein-coupled receptors. Pre- and postsynaptically, they modulate the release of glutamate and the sensitivity of the cell to glutamate, respectively. The effects are caused via different second-messenger cascades. This response, in turn, has an effect on the ionotropic glutamate receptors.

[0004] Presently, 8 different subtypes of metabotropic glutamate receptors are known, differing in the second-messenger cascade, pharmacology and the localization in the brain (review in: Ann. Rev. Pharmacol. Toxicol. 1997, 37, 205).

[0005] The present invention relates to α,β-fused butyrolactones of the general formula (I) 1

[0006] in which

[0007] A represents radicals of the formulae —CH2—, —CO—, —CR4(OH)— or —(CH2)a—CHR5—,

[0008] in which

[0009] a represents a number 0, 1, 2, 3 or 4,

[0010] R4 represents hydrogen or (C1-C6)-alkyl

[0011] and

[0012] R5 represents phenyl,

[0013] or

[0014] represents (C2-C8)-alkanediyl, (C2-C6)-alkenediyl or (C2-C6)-alkinediyl,

[0015] R1 represents hydrogen, (C3-C6)-cycloalkyl or represents a 5- to 6-membered heterocycle which may contain up to 3 heteroatoms from the group consisting of S, O, N and/or a radical of the formula —NR6,

[0016] in which

[0017] R6 represents hydrogen or methyl,

[0018] or

[0019] represents a 5- to 6-membered benzo-fused heterocycle which may contain up to 2 heteroatoms from the group consisting of S, O, N and/or a radical of the formula —NR7, and which may be attached both via the phenyl ring and via the heterocycle,

[0020] in which

[0021] R7 has the meaning of R6 given above and is identical to or different from this meaning,

[0022] or

[0023] represents radicals of the formulae 2

[0024] in which

[0025] b and c are identical or different and represent a number 1 or 2,

[0026] or

[0027] represents (C6-C10)-aryl,

[0028] where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, hydroxyl, (C1-C6)-alkoxy, (C1-C6)-alkyl-carbonyloxy and (C3-C6)-cycloalkyl, phenyl, phenoxy, benzyloxy and a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano and halogen,

[0029] and/or are substituted by (C1-C6)-alkyl and (C2-C6)-alkylene, which for their part may be substituted by halogen, (C6-C10)-aryl or by radicals of the formula —SR8, —OR9 or —NR10R11 or 3

[0030] in which

[0031] R8 represents (C1-C6)-alkyl or phenyl,

[0032] R9 represents hydrogen or (C1-C6)-alkyl,

[0033] and

[0034] R10 and R11 are identical or different and represent hydrogen, phenyl or (C1-C6)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C1-C6)-alkoxy,

[0035] or

[0036] R10 and R11 together with the nitrogen atom form a radical of the formula 4

[0037] in which

[0038] C represents an oxygen atom, a —CH2— group or a radical of the formula —NR12—,

[0039] in which

[0040] R12 represents hydrogen, phenyl, benzyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-carbonyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O,

[0041] and/or are substituted by groups of the formulae —CO2—R13, —NR14R15, —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21,

[0042] in which

[0043] R13 represents hydrogen, or represents (C1-C9)-alkyl or (C2-C6)-alkenyl, which for their part may be substituted by radicals of the formulae 5

[0044] (C6-C10)-aryl or by a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O,

[0045] in which

[0046] d represents a number 1 or 2,

[0047] or

[0048] represents (C6-C10)-aryl, which is optionally substituted by phenyl, which for its part may be substituted by cyano or halogen,

[0049] R14 and R15 are identical or different and represent hydrogen, (C3-C6)-cycloalkyl, phenyl or (C1-C6)-alkyl, which is optionally substituted by (C3-C6)-cycloalkyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl or (C1-C6)-alkoxy,

[0050] R16 represents hydrogen or (C1-C6)-alkyl,

[0051] R17 represents hydrogen, adamantyl, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl or (C1-C12)-alkyl which is optionally substituted by adamantyl, (C3-C6)-cycloalkyl, (C6-C10)-aryl, phenoxy or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and/or O, where aryl and the heterocycle for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxyl, nitro or halogen,

[0052] and/or alkyl is optionally substituted by a radical of the formula 6

[0053] in which

[0054] e represents a number 0 or 1 and

[0055] R22 represents (C1-C6)-alkyl or (C6-C10)-aryl, which is optionally mono- to polysubsituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C1-C6)-alkoxy,

[0056] or

[0057] represents (C6-C10)-aryl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C6)-alkoxy, (C1-C6)-alkyl, hydroxyl, nitro and halogen,

[0058] or

[0059] represents a radical of the formula 7

[0060] in which

[0061] L and M are identical or different and represent hydrogen or halogen,

[0062] R23 and R24 have the meaning of R10 and R11 given above and are identical to or different from this meaning,

[0063] R18 has the meaning of R16 given above and is identical to or different from this meaning,

[0064] R19 represents (C3-C8)-cycloalkyl, or represents (C1-C8)-alkyl or (C2-C8)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of halogen, phenyl, hydroxyl, morpholinyl, (C3-C8)-cycloalkyl and by a group of the formula —Si25R26R27,

[0065] in which

[0066] R25, R26 and R27 are identical or different and represent (C1-C6)-alkyl,

[0067] R20 and R21 are identical or different and represent hydrogen, adamantyl, (C3-C8)-cycloalkyl, phenyl, phenoxy-substituted phenyl or a 5- to 6-membered, aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, or

[0068] represent (C2-C8)-alkenyl, (C1-C12)-alkyl or (C2-C6)-alkinyl, which are optionally substituted by hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, halogen, hydroxyl, trifluoromethyl, phenyl or by a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, halogen, phenoxy, hydroxyl and (C1-C6)-alkyl,

[0069] and/or the alkyl listed under R20/R21 is optionally substituted by radicals of the formulae 8

[0070] in which

[0071] R28 and R29 are identical or different and represent hydrogen or (C1-C6)-alkyl,

[0072] or

[0073] represents a radical of the formula 9

[0074] in which

[0075] R30 has the meaning of R12 given above and is identical to or different from this meaning,

[0076] or

[0077] R20 and R21 together with the nitrogen atom form a radical of the formula 10

[0078] in which

[0079] G′ has the meaning of G given above and is identical to or different from this meaning,

[0080] R2 and R3 are identical or different and represent hydrogen or (C1-C6)-alkyl,

[0081] and

[0082] D and E together form radicals of the formulae 11

[0083] in which

[0084] R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen, phenyl or (C1-C6)-alkyl,

[0085] and their pharmaceutically acceptable salts.

[0086] The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform components in a known manner.

[0087] 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 sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

[0088] Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.

[0089] In the context of the invention, (C3-C8)-cycloalkyl and (C3-C6)-cycloalkyl represent cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferred examples which may be mentioned are: cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0090] In general, (C6-C10)-aryl represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

[0091] In the context of the invention, (C1-C12)-alkyl, (C1-C9)-alkyl, (C1-C8)-alkyl and (C1-C6)-alkyl represent a straight-chain or branched alkyl radical having 1 to 12, 1 to 9, 1 to 8 and 1 to 6 carbon atoms, respectively. Preference is given to a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.

[0092] In the content of the invention, (C2-C8)-alkanediyl represents a straight-chain or branched alkanediyl radical having 2 to 8 carbon atoms. Preference is given to a straight-chain or branched alkanediyl radical having 2 to 6 carbon atoms, particularly preferably 2 to 4 carbon atoms. Examples which may be mentioned are ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl, 2-methyl-pentane-2,4-diyl.

[0093] In the content of the invention, (C2-C6)-alkenediyl represents a straight-chain or branched alkenediyl radical having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, particularly preferably 3 carbon atoms. Examples which may be mentioned are ethene-1,2-diyl, ethene-1,1-diyl, propene-1,1-diyl, propene-1,2-diyl, propene-1,3-diyl, propene-3,3-diyl, propene-2,3-diyl, but-2-ene-1,4-diyl, pent-2-ene-1,4-diyl, hex-2-ene-1,4-diyl.

[0094] In the context of the invention, (C2-6)-alkinediyl represents a straight-chain or branched alkinediyl radical having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, particularly preferably 2 to 3 carbon atoms. Examples which may be mentioned are ethine-1,2-diyl, propine-1,3-diyl, but-2-ine-1,4-diyl, pent-2-ine-1,4-diyl, hex-2-ine-1,4-diyl.

[0095] In the context of the invention, (C1-C6)-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

[0096] In the context of the invention, (C1-C6)-alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

[0097] In the context of the invention, (C2-C8)-alkenyl and (C2-C6)-alkenyl represent a straight-chain or branched alkenyl radical having 2 to 8 carbon atoms and 2 to 6 carbon atoms, respectively. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

[0098] In the context of the invention, (C2-C6)-alkinyl represents a straight-chain or branched alkinyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkinyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: ethinyl, n-prop-2-in-1-yl and n-but-2-in-1-yl.

[0099] In the context of the invention, a 5- to 6-membered heterocycle generally represents a 5- to 6-membered, optionally also aromatic, heterocycle which may contain up to 3 heteroatoms from the group consisting of S, O and/or N or a radical of the formula —NH or —NCH3. Examples which may be mentioned are: pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, piperidinyl or morpholinyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl.

[0100] In the context of the invention, a 5- to 6-membered, benzo-fused heterocycle generally represents a 5- to 6-membered, preferably 5-membered heterocycle having up to 2 heteroatoms from the group consisting of S, O, N and/or a radical of the formula —NH, whose ring carbon atoms are the attachment points for the benzene ring. Examples which may be mentioned are: indolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, quinolyl, quinoxalinyl or quinazolyl. Preference is given to benzimidazolyl, quinolyl, quinoxalinyl, quinazolyl, benzothiophenyl and benzofuranyl.

[0101] Preference is given to compounds of the general formula (I) according to the invention,

[0102] in which

[0103] A represents radicals of the formulae —CH2—, —CO—, —CR4(OH)— or —(CH2)a—CHR5—,

[0104] in which

[0105] a represents a number 0, 1, 2 or 3,

[0106] R4 represents hydrogen or (C1-C4)-alkyl

[0107] and

[0108] R5 represents phenyl,

[0109] or

[0110] represents (C2-C6)-alkanediyl, (C2-C4)-alkenediyl or (C2-C4)-alkinediyl,

[0111] R1 represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, furyl, quinazolyl, quinoxalinyl or quinolyl,

[0112] or

[0113] represents radicals of the formulae 12

[0114] in which

[0115] b and c are identical or different and represent a number 1 or 2,

[0116] or

[0117] represents phenyl or naphthyl,

[0118] where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, hydroxyl or (C1-C5)-alkoxy, (C1-C5)-alkyl-carbonyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine,

[0119] and/or are substituted by (C1-C5)-alkyl and (C2-C4)-alkenyl, which for their part may be substituted by fluorine, chlorine, bromine, iodine, phenyl, naphthyl or by radicals of the formula —SR8, —OR9 or —NR10R11 or 13

[0120] in which

[0121] R8 represents (C1-C4)-alkyl or phenyl,

[0122] R9 represents hydrogen or (C1-C4)-alkyl,

[0123] and

[0124] R10 and R11 are identical or different and represent hydrogen, phenyl or (C1-C4)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C1-C4)-alkoxy,

[0125] or

[0126] R10 and R11 together with the nitrogen atom form a radical of the formula 14

[0127] in which

[0128] G represents an oxygen atom, a —CH2— group or a radical of the formula —NR12—.

[0129] in which

[0130] R12 represents hydrogen, phenyl, benzyl, (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl,

[0131] and/or are substituted by groups of the formulae —CO2-R13, —NR14R15, —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21,

[0132] in which

[0133] R13 represents hydrogen, or represents (C1-C8)-alkyl or (C2-C5)-alkenyl, which for their part may be substituted by radicals of the formulae 15

[0134] phenyl, naphthyl, pyridyl, thienyl or furyl,

[0135] in which

[0136] d represents a number 1 or 2,

[0137] or

[0138] represents phenyl or naphthyl, which are optionally substituted by phenyl, which for its part may be substituted by cyano, fluorine, chorine or bromine,

[0139] R14 and R15 are identical or different and represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or (C1-C5)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl or (C1-C4)-alkoxy,

[0140] R16 represents hydrogen or (C1-C3)-alkyl,

[0141] R17 represents hydrogen, adamantyl, cyclopropyl, cyclopentyl or cyclohexyl, or represents (C2-C4)-alkenyl or (C1-C10)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-naphthyl, pyridyl, thienyl, tetrazolyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,

[0142] and/or alkyl is optionally substituted by a radical of the formula 16

[0143] in which

[0144] e represents a number 0 or 1 and

[0145] R22 represents (C1-C4)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C1-C4)-alkoxy,

[0146] or

[0147] represents phenyl, naphthyl, thienyl, furyl or pyridyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl, hydroxyl, nitro, fluorine, chlorine and bromine,

[0148] or

[0149] represents a radical of the formula 17

[0150] in which

[0151] L and M are identical or different and represent hydrogen, fluorine, chlorine or bromine,

[0152] R23 and R24 have the meaning of R10 and R11 given above and are identical to or different from this meaning,

[0153] R18 has the meaning of R16 given above and is identical to or different from this meaning,

[0154] R19 represents cyclopropyl, cyclopentyl or cyclohexyl, or

[0155] represents (C1-C7)-alkyl or (C2-C6)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of fluorine, chlorine, bromine, phenyl, hydroxyl, morpholinyl, cyclopropyl, cyclopentyl, cyclohexyl and by a group of the formula —SiR25R26R27,

[0156] in which

[0157] R25, R26 and R26 are identical or different and represent (C1-C4)-alkyl,

[0158] R20 and R21 are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, pyridyl, furyl, thienyl, thiazolyl or pyrryl, or

[0159] represent (C2-C6)-alkenyl, (C1-C10)-alkyl or (C3-C6)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C5)-alkoxy, (C1-C6)-alkoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C4)-alkoxy, fluorine, chlorine, bromine, phenoxy, hydroxyl or (C1-C4)-alkyl,

[0160] and/or the alkyl listed under R20/R21 is optionally substituted by radicals of the formulae 18

[0161] in which

[0162] R28 and R29 are identical or different and represent hydrogen or (C1-C4)-alkyl,

[0163] or

[0164] represents a radical of the formula 19

[0165] in which

[0166] R30 has the meaning of R12 given above and is identical to or different from this meaning,

[0167] or

[0168] R20 and R21 together with the nitrogen atom form a radical of the formula 20

[0169] in which

[0170] G′ has the meaning of C given above and is identical to or different from this meaning,

[0171] R2 and R3 are identical or different and represent hydrogen or (C1-C3)-alkyl,

[0172] and

[0173] D and E together form radicals of the formulae 21

[0174] in which

[0175] R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen, phenyl or (C1-C3)-alkyl,

[0176] and their pharmaceutically acceptable salts.

[0177] Particular preference is given to compounds of the general formula (1) according to the invention,

[0178] in which

[0179] A represents radicals of the formulae —CH2—, —CO—, —CR4(OH)— or —(CH2)a—CHR5—,

[0180] in which

[0181] a represents a number 0, 1, 2 or 3,

[0182] R4 represents hydrogen or (C1-C3)-alkyl

[0183] and

[0184] R5 represents phenyl,

[0185] or

[0186] represents (C2-C4)-alkanediyl, propenediyl or (C2-C3)-alkinediyl,

[0187] R1 represents hydrogen, cyclopropyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, quinazolyl or quinoxalinyl,

[0188] or

[0189] represents radicals of the formulae 22

[0190] in which

[0191] b and c are identical or different and represent a number 1 or 2,

[0192] or

[0193] represents phenyl or naphthyl,

[0194] where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C1-C4)-alkoxy, (C1-C4)-alkyl-carbonyloxy, cyclohexyl, phenyl, phenoxy, pyridyl, pyrimidyl, pyridazinyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine,

[0195] and/or are substituted by (C1-C4)-alkyl and (C2-C3)-alkenyl, which for their part may be substituted by chlorine, bromine, iodine or phenyl or by radicals of the formula —OR9 or —NR10R11 or 23

[0196] in which

[0197] R9 represents hydrogen or (C1-C3)-alkyl,

[0198] and

[0199] R10 and R11 are identical or different and represent hydrogen, phenyl or (C1-C3)-alkyl, which is optionally substituted by phenyl, which for its part may be substituted by chlorine, bromine, hydroxyl or (C1-C3)-alkoxy,

[0200] or

[0201] R10 and R11 together with the nitrogen atom form a radical of the formula 24

[0202] in which

[0203] G represents an oxygen atom or a radical of the formula —NR12,

[0204] in which

[0205] R12 represents hydrogen, phenyl, benzyl, (C1-C3)-alkyl, (C1-C3)-alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl,

[0206] and/or are substituted by groups of the formulae —CO2—R13, —NR14R15, —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21,

[0207] in which

[0208] R13 represents hydrogen, or

[0209] represents (C1-C6)-alkyl or allyl, which for their part may be substituted by radicals of the formulae 25

[0210] phenyl, naphthyl or pyridyl,

[0211] in which

[0212] d represents a number 1 or 2,

[0213] or

[0214] represents phenyl, which is optionally substituted by phenyl, which for its part may be substituted by cyano, chlorine or bromine,

[0215] R14 and R15 are identical or different and represent hydrogen, cyclohexyl, phenyl or (C1-C4)-alkyl, which is optionally substituted by cyclopropyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of chlorine and (C1-C3)-alkoxy,

[0216] R16 represents hydrogen, methyl or ethyl,

[0217] R17 represents hydrogen, adamantyl, cyclopentyl or cyclohexyl, or represents (C2-C3)-alkenyl or (C1-C8)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,

[0218] and/or alkyl is optionally substituted by a radical of the formula 26

[0219] in which

[0220] e is a number 0 or 1 and

[0221] R22 represents (C1-C3)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C1-C3)-alkoxy,

[0222] or

[0223] represents phenyl, naphthyl, thienyl or furyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C3)-alkoxy, (C1-C3)-alkyl, nitro, fluorine, chlorine and bromine,

[0224] or

[0225] represents a radical of the formula 27

[0226] in which

[0227] L and M are identical or different and represent hydrogen, fluorine or chlorine,

[0228] R23 and R24 have the meaning of R10 and R11 given above and are identical to or different from this meaning,

[0229] R18 has the meaning of R16 given above and is identical to or different from this meaning,

[0230] R19 represents (C1-C4)-alkyl or (C3-C5)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of chlorine, phenyl, hydroxyl, morpholinyl, cyclopropyl, cyclohexyl and by a group of the formula —SiR25R26R27,

[0231] in which

[0232] R25, R26 and R27 are identical and represent methyl,

[0233] R20 and R21 are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, thiazolyl or pyrryl, or

[0234] represent (C2-C3)-alkenyl, (C1-C7)-alkyl or (C3-C5)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C3)-alkoxy, hydroxyl, trifluoromethyl, phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C3)-alkoxy, (C1-C6)-alkoxycarbonyl, fluorine, chlorine, bromine, phenoxy, hydroxyl and (C1-C3)-alkyl, and/or the alkyl listed under R20/R21 is optionally substituted by radicals of the formulae 28

[0235] in which

[0236] R28 and R29 are identical or different and represent hydrogen or (C1-C3)-alkyl,

[0237] or

[0238] R20 or R21 represents a radical of the formula 29

[0239] in which

[0240] R30 has the meaning of R12 given above and is identical to or different from this meaning,

[0241] or

[0242] R20 and R21 together with the nitrogen atom form a radical of the formula 30

[0243] in which

[0244] G′ has the meaning of G given above and is identical to or different from this meaning,

[0245] R2 and R3 are identical or different and

[0246] represent hydrogen or methyl,

[0247] and

[0248] D and E together form radicals of the formulae 31

[0249] in which

[0250] R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen or methyl,

[0251] and their pharmaceutically acceptable salts.

[0252] Particular preference is likewise given to compounds of the general formula (I) according to the invention in which A represents the —CH2— group.

[0253] Very particular preference is given to compounds of the general formula (I) according to the invention, in which

[0254] A represents —CH2—,

[0255] R1 represents phenyl or naphthyl,

[0256] where all of the abovementioned ring systems are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C1-C4)-alkoxy,

[0257] and/or are substituted by (C1-C4)-alkyl,

[0258] and/or are substituted by groups of the formulae —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21,

[0259] in which

[0260] R16 is hydrogen,

[0261] R17 is (C1-C8)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,

[0262] R18 has the meaning of R16 given above and is identical to or different from this meaning,

[0263] R19 represents (C1-C4)-alkyl or (C3-C5)-alkenyl,

[0264] R20 and R21 are identical or different and represent hydrogen, (C2-C3)-alkenyl, (C1-C7)-alkyl or (C3-C5)-alkinyl, which are optionally substituted by phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C3)-alkoxy, fluorine, chlorine, bromine and (C1-C3)-alkyl,

[0265] R2 and R3 represent hydrogen or methyl,

[0266] and

[0267] D and E together form radicals of the formulae 32

[0268] in which

[0269] R31, R32, R33, R34, R34, R35 represent hydrogen,

[0270] and their pharmaceutically acceptable salts.

[0271] Very particular preference is given to the structures listed in the table below, which can be present in racemic form or enantiomerically pure: 3334

[0272] Moreover, we have found a process for preparing the compounds of the general formula (1) according to the invention, characterized in that

[0273] compounds of the general formula (II) 35

[0274] in which

[0275] D, E, R2 and R3 are as defined above

[0276] are reacted with compounds of the general formula (III),

T-A-R1  (III)

[0277] in which

[0278] T represents halogen, preferably bromine,

[0279] and

[0280] A and R1 are as defined above,

[0281] in inert solvents and in the presence of a base,

[0282] and the substituent R1 is, if appropriate, derivatized by customary methods.

[0283] The process according to the invention can be illustrated in an exemplary manner by the formula scheme below: 36

[0284] Suitable solvents are all inert solvents which 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. Particular preference is given to tetrahydrofuran.

[0285] Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis-(trimethylsilyl)amide, lithium diisopropylamide, or organometallic compounds, such as butyllithium or phenyllithium. Preference is given to lithium diisopropylamide and lithium bis-(trimethylsilyl)amide.

[0286] Here, the base is employed in an amount of from 1 to 5, preferably from 1 to 2 mol, based on 1 mol of the compounds of the general formula (II).

[0287] The reaction is generally carried out in a temperature range of from −78° C. to reflux temperature, preferably from −78° C. to +20° C.

[0288] The reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

[0289] Derivatizations in the context of the invention which may preferably be mentioned are reactions at the radical R1 with substituent groups (C1-C6)-alkoxy, —NR14R15, —NR16—COR17—, —NR18-CO2R19 and —CO—NR20R21. Starting with the carboxylic-acid-substituted aryls, these are reacted with the corresponding amines in inert solvents and in the presence of an auxiliary. Also possible is a Curtius rearrangement in the presence of (C6H5O)2—PON3. Likewise, it is possible, starting from amino-substituted aryls (R1), to introduce the amide function via the corresponding acid chlorides in the presence of bases or via the corresponding carboxylic acids in the presence of an auxiliary.

[0290] The derivatizations can be illustrated in an exemplary manner by the following formula scheme: 3738

[0291] The amidation is generally carried out in inert solvents in the presence of a base and a dehydrating agent.

[0292] Here, suitable solvents are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons, such as dichloro-methane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorothylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane, or mineral oil fractions, nitromethane, dimethyl-formamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Particular preference is given to dichloromethane.

[0293] Suitable bases for the derivatizations are the customary basic compounds. These preferably include alkali metal hydroxides 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 carbonates or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, or alkali metal alkoxides, such as, for example, sodium methoxide or sodium ethoxide, potassium methoxide or potassium ethoxide or potassium tert-butoxide, or organic amines, such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine.

[0294] The derivatizations are generally carried out in a temperature range of from −20° C. to 150° C., preferably at from 0° C. to 25° C.

[0295] The derivatizations are generally carried out under atmospheric pressure. However, it is also possible to carry out the processes under reduced pressure or under elevated pressure (for example in a range from 0.5 to 5 bar).

[0296] When carrying out the derivatizations, the bases are generally employed in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol, based on 1 mol of the carboxylic acid in question.

[0297] Suitable dehydrating agents are carbodiimides, such as, for example, diisopropyl-carbodiimide, dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride, or carbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate, or propanephosphoric anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexyfluorophosphate or diphenyl phosphonamidate or methanesulphonyl chloride, if appropriate in the presence of bases, such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbo-diimide or N-hydroxysuccinimide.

[0298] Moreover, we have found a process for preparing the compounds of the general formula (I′) according to the invention 39

[0299] in which

[0300] A, R1, R2 and R3 are as defined above,

[0301] and

[0302] D and E together form radicals of the formulae 40

[0303] in which

[0304] R33, R35, R36 and R38 represent hydrogen, and

[0305] R34 and R37 are as defined above,

[0306] characterized in that

[0307] a compound of the general formula (I″) 41

[0308] in which

[0309] A, R1, R2 R3, R31 and R32 are as defined above,

[0310] is isomerized in the presence of a catalyst and, if appropriate, a solvent.

[0311] The process according to the invention can be illustrated in an exemplary manner by the formula scheme below: 42

[0312] Suitable solvents are, for example, alcohols.

[0313] Preference is given to n-butanol.

[0314] Suitable catalysts are transition metals, such as, for example, palladium, platinum or rhodium, preferably palladium, in an amount of from 0.01 to 1 equivalent, based on the amount of the compound of the general formula (I″) used, preferably from 0.05 to 0.2 equivalents.

[0315] Very particular preference is given to palladium adsorbed on activated carbon.

[0316] The reaction is generally carried out in a temperature range from 80 to 200° C., preferably from 100 to 150° C.

[0317] The reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out under atmospheric pressure.

[0318] Moreover, the present invention relates to compounds of the general formula (II) 43

[0319] in which

[0320] R2 and R3 are identical or different and represent hydrogen or (C1-C6)-alkyl,

[0321] and

[0322] D and E together form radicals of the formulae 44

[0323] in which

[0324] R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen, phenyl or (C1-C6)-alkyl.

[0325] Preference is given to compounds of the general formula (II), in which

[0326] R2 and R3 represent hydrogen or methyl,

[0327] and

[0328] D and E together form radicals of the formulae 45

[0329] in which

[0330] R31, R32, R33, R34 and R35 represent hydrogen.

[0331] Moreover, we have found processes for preparing the compounds of the general formula (II) according to the invention 46

[0332] in which

[0333] D, E, R2 and R3 are as defined above,

[0334] characterized in that in

[0335] [A] compounds of the general formula (IV) 47

[0336] in which

[0337] D and E are as defined above

[0338] and

[0339] R39 represents (C1-C4)-alkyl or (C2-C4)-alkenyl, which are optionally substituted by phenyl,

[0340] the ester group is selectively reduced and the reaction product is cyclized under acidic conditions, if appropriate after prior activation of the carboxyl group to give the lactone,

[0341] or

[0342] [B] compounds of the general formula (V) 48

[0343] in which

[0344] D and E are as defined above

[0345] and

[0346] R40 represents (C1-C4)-alkyl or (C3-C4)-alkenyl, which may optionally be substituted by phenyl,

[0347] the carboxyl group is selectively reduced and the reaction product is cyclized to give the lactone,

[0348] or

[0349] [C] compounds of the general formula (VI) 49

[0350] in which

[0351] D and E are as defined above,

[0352] are initially reduced under suitable reduction conditions to give a hydroxylactone and subsequently reacted in an inert solvent with a compound of the general formula (VII),

R2′-Q  (VII),

[0353] in which

[0354] R2′ represents (C1-C6)-alkyl, and

[0355] Q represents an alkali metal halide or alkaline earth metal halide, preferably Mg-X,

[0356] and cyclized under acidic conditions to give the corresponding lactone,

[0357] or

[0358] [D] compounds of the general formula (VI) are reacted in an inert solvent with at least two molar equivalents of a compound of the general formula (VII) and cyclized under acidic conditions to give the corresponding lactone,

[0359] or

[0360] [E] compounds of the general formula (VI) are, in an inert solvent, initially reacted with a molar equivalent of a compound of the general formula (VII), and then reacted with at least one further molar equivalent of a compound of the general formula (VIII)

R3′-Q′  (VIII),

[0361] in which

[0362] R3′ represents (C1-C6)-alkyl and

[0363] Q′ has the abovementioned meaning of Q and is identical to or different from this,

[0364] and cyclized under acidic conditions to give the corresponding lactone.

[0365] The processes according to the invention can be illustrated in an exemplary manner by the formula schemes below: 50

[0366] Suitable reducing agents for the process [A] are complex metal hydrides.

[0367] Preference is given to diisobutylaluminium hydride.

[0368] Suitable solvents are inert solvents, such as, for example, methylene chloride, THF, dioxane, diethyl ether, toluene, 1,2-dichloroethane.

[0369] Preference is given to methylene chloride.

[0370] The reaction is generally carried out in a temperature range of from −40° C. to the reflux temperature of the solvent, preferably from 0° C. to 30° C.

[0371] If appropriate, the cyclization of the hydroxycarboxylic acid intermediate can be supported by activating the carboxyl group, for example using alkyl chloroformates, preferably methyl chloroformate, in the presence of a base, such as, for example, triethylamine.

[0372] A suitable method of reduction for the process [B] is a stepwise reduction by pre-activating the carboxyl group using alkyl chloroformates, preferably methyl chloroformate, in the presence of a base, such as, for example, triethylamine, followed by reduction with a complex metal hydride, such as, for example, a borohydride, preferably sodium borohydride.

[0373] Suitable solvents for the activation are inert solvents, such as diethyl ether, THF, methylene chloride. Suitable solvents for the reduction with borohydrides are, for example, alcohols, in particular methanol.

[0374] The reaction is generally carried out in a temperature range from −40° C. to 40° C., preferably from −20° C. to 30° C.

[0375] Suitable reducing agents for the process [C] are complex metal hydrides having reduced reactivity, such as, for example, lithium tris-tert-butoxyaluminohydride.

[0376] Solvents which are suitable for this purpose are inert solvents, such as, for example, diethyl ether or THF.

[0377] The reaction is generally carried out in a temperature range of from −78° C. to 0° C., preferably from −50° C. to −20° C.

[0378] Suitable inert solvents for the reaction with the compounds of the general formulae (VII) and (VIII) in processes [C] to [E] are ethers, preferably diethyl ether or THF.

[0379] The reactions are generally carried out in a temperature range of from −78° C. to 35° C., preferably at from −60° C. to 25° C.

[0380] Suitable acids for the cyclization to the lactones are, in particular, mineral acids, such as, for example, dilute aqueous sulphuric acid or hydrochloric acid.

[0381] The compounds of the general formulae (IV) and (V) are known per se or can be prepared by customary methods.

[0382] The compounds of the general formula (1) according to the invention are suitable for use as medicaments in the treatment of humans and animals.

[0383] 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.

[0384] For the purpose of the invention, a modulator of the metabotropic glutamate receptor is an agonist or antagonist of this receptor.

[0385] 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.

[0386] Owing to their pharmacological properties, the compounds according to the invention can be used, on their own or in combination with other pharmaceuticals, for the treatment and/or prevention of neuronal damage or disorders associated with pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system.

[0387] For the treatment and/or prevention of neuronal damage caused, for example, by ischaemic, thromb- and/or thrombemolic and haemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and the skull. Furthermore for the treatment and/or prevention of cerebral ischaemias after surgical interventions in the brain or peripheral organs or body parts and conditions of pathological or allergic nature accompanying or preceding them, which can lead primarily and/or secondarily to neuronal damage.

[0388] Likewise, the compounds according to the invention are also suitable for the therapy of primary and/or secondary pathological conditions of the brain, for example during or after cerebral vasospasms, hypoxia and/or anoxia of previously unmentioned origin, perinatal asphyxia, autoimmune disorders, metabolic and organ disorders which can be accompanied by damage to the brain, and also damage to the brain as a result of primary brain disorders, for example convulsive conditions and artero- and/or arteriosclerotic changes. For the treatment of chronic or psychiatric conditions such as, for example, depression, neurodegenerative disorders, such as, for example, 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 multiinfarct dementia.

[0389] Moreover, they can be used as pharmaceuticals for the treatment of dementias of different origin, impaired brain performance owing to old age, memory disturbances, spinal injuries, states of pain, states of anxiety of different origin, medicament-related Parkinson's syndrome, psychoses (such as, for example, schizophrenia), brain oedema, neuronal damage after hypoglycaemia, emesis, nausea, obesity, addiction and withdrawal symptoms, CNS-mediated spasms, sedation and motor disturbances.

[0390] Furthermore, the compounds of the general formula (I) according to the invention can be used for promoting neuronal regeneration in the post-acute phase of cerebral injuries or chronic disorders of the nervous system.

[0391] They are preferably employed as pharmaceuticals for the treatment of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms (such as, for example, epilepsy).

[0392] The modulation of substances at the metabotropic glutamate receptor (direct or indirect effect on the coupling efficiency of the glutamate receptor to G-proteins) can be examined using primary cultures of granular cells from the cerebellum. Electrophysiological measurements on these cell cultures in the “cell attached” mode show that L-type Ca2+-channels in this preparation are activated by mGluRl-receptors (J. Neurosci. 1995, 15, 135), whereas they are blocked by group II receptors (J. Neurosci. 1994, 14, 7067-7076). By an appropriate experimental arrangement, it is possible to monitor the modulatory effect of pharmacological test substances on glutamate receptors. Detailed examination of subtype specificity under controlled conditions can be carried out by injecting the appropriate mGluR subtype DNA into Xenopus oocytes (WO 92/10583).

Permanent Focal Cerebral Ischaemia in the Rat (MCA-O)

[0393] Under isoflurane anaesthesia, the middle cerebral artery is exposed on one side and the latter and its side branches are irreversibly sealed by means of electrocoagulation. As a result of the intervention a cerebral infarct is formed. During the operation, the body temperature of the animal is kept at 37° C. After wound closure and wearing off of the anaesthesia, the animals are again released into their cage. Substance administration is carried out according to different time schemes and via different administration routes (i.v., i.p.) after occlusion. The infarct size is determined after 7 days. To do this, the brain is removed, worked up histologically and the infarct volume is determined with the aid of a computer-assisted analysis system.

Effectiveness in the model of permanent focal cerebral ischaemia
(MCA-O)
	% reduction of
Example	infarct volume	Dosea)
35	38	0.01 mg/kg/h
a)Substance administered as intravenous continuous infusion directly up to 4 hours after the occlusion

Subdural Haematoma in the Rat (SDH)

[0394] Under anaesthesia, the animal's own blood is injected subdurally on one side. An infarct is formed under the haematoma. Substance administration is earned out according to different time schemes and via different administration routes (i.v., i.p.).

[0395] The determination of the infarct size is carried out as described in the model of permanent focal ischaemia in the rat (MCA-O).

Effectiveness in the model “Subdural haematoma in the rat (SDH)”
	% reduction of
Example	infarct volume	Dosea)
35	51	0.01 mg/kg/h
a)Substance administered as intravenous continuous infusion directly up to 4 hours post-trauma

[0396] Using the method described in NeuroReport 1996, 7, 1469-1474, it is possible to test for antiepileptic activity.

[0397] The suitability of the compounds according to the invention for treating schizophrenia can be determined by the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136.

[0398] The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, comprise one or more compounds of the general formula (I), or which consist of one or more active compounds of the formula (I), and processes for producing these preparations.

[0399] In these preparations, the active compounds of the formula (I) should be present in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.

[0400] In addition to the active compounds of the formula (1), the pharmaceutical preparations may also comprise other pharmaceutical active compounds.

[0401] The abovementioned pharmaceutical preparations can be prepared in a customary manner by known methods, for example with the auxiliary(ies) or excipient(s).

[0402] In general, it has proved advantageous to administer the active compound(s) of the 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, of body weight per 24 hours, if appropriate in the form of a plurality of individual administrations, to achieve the desired result.

[0403] However, if appropriate, it may be advantageous to depart from the amounts mentioned, namely depending on the type and on the body weight of the object treated, on the individual response towards the medicament, the nature and severity of the disorder, the manner of formulation and administration, and the time or interval at which administration takes place.

General Section

[0404]

Mobile phases for chromatography
I      Dichloromethane/methanol
II     Dichloromethane/ethanol
III    Cyclohexane/ethyl acetate
IV     Cyclohexane/dichloromethane
V      Butyl acetate:butanol:acetic acid:phosphate buffer
       (pH = 6) 200:26:100:60
Abbreviations
DME    1,2-dimethoxyethane
HMPA   Hexamethylphosphone triamide
LiHMDS Lithium bistrimethylsilylamide
LDA    Lithium diisopropylamide
MTBE   Methyl tert-butyl ether
THF    Tetrahydrofuran
MPLC   Medium pressure liquid chromatography

Starting Materials

EXAMPLE 1A

(3aS*,6aR*)-5-Methylidene-hexahydro-cyclopenta[c]furan-1-one

[0405] 51

[0406] At −15° C., a solution of 2-methoxycarbonyl-4-methylidenecyclopentanecarboxylic acid (189.2 g; 1.027 mol) in THF (1 l ) was admixed with triethylamine (156.6 ml; 1.130 mol) and ethyl chloroformate (18.2 ml; 1.027 mol), and the reaction mixture was stirred at room temperature for 1 h. The precipitate was filtered off with suction and the filtrate was concentrated, taken up in methanol (1 l), NaBH4 (97.146 g; 2.568 mol) was added a little at a time at −15° C. and the mixture was stirred at room temperature for 1 h. For work-up, the mixture was admixed with 1 N HCl, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated, and the crude product was purified by chromatography.

[0407] Yield: 82.03 g (58%) Rf (II, 50:1)=0.42 MS (El): m/e=138 [M+]

EXAMPLE 2A

(−)-(3aS,6aR)-5-Methylidene-hexahydro-cyclopenta[c]furan-1-one

[0408] 52

[0409] Analogously to the procedure of Example 1A, the target compound was prepared from (1R,2S)-4-methylidene-2-(3-phenyl-2-propenyloxycarbonyl)-cyclopentane-carboxylic acid (31.5 g; 110.2 mmol; 97% ee; Example 1 in EP 805 145A1, p. 9).

[0410] Yield: 7.97 g (52%; 97% ee) Rf (I, 80:1)=0.56

EXAMPLE 3A

(+)-(3aR, 6aS)-5-Methylidene-hexahydro-cyclopentan[c]furan-1-one

[0411] 53

[0412] At 10° C., a solution of diisobutylaluminium hydride (1.5 M in CH2Cl2; 17.7 ml; 26.58 mmol) was added dropwise to a solution of (1S,2R)-4-methylidene-2-allyloxy-carbonyl-cyclopentane-carboxylic acid (2.0 g; 9.61 mmol; 75% ee; Example 5 in DOS (German Published Specification) 44 00 749, p. 11+12) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 1 h. The mixture was admixed with 1 N HCl and water and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), the solvent was removed under reduced pressure and the residue was taken up in THF (200 ml). At 0° C., triethylamine (6.59 ml; 47.57 mmol) and ethyl chloroformate (2.27 ml; 23.78 mmol) were added and the reaction mixture was allowed to stand at 8° C. for 14 h The mixture was then admixed with ethyl acetate and water. The organic phase was washed with 10% aqueous HCl, saturated NaCl solution, 10% aqueous NaHCO3 solution and saturated NaCl solution, dried (MgSO4) and concentrated, and the residue was purified by MPLC.

[0413] Yield: 260 mg (20%, 89% ee) Rf (I, 10:1)=0.88

EXAMPLE 4A

(3S*,3aR*,6aS*)-3-Methyl-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

[0414] 54

[0415] At −40° C., a solution of 4-exomethylene-1,2-cyclopentanedicarboxylic anhydride (10.0 g, 65.7 mmol; ref. DE 4400749) in THF (130 ml) was added to a solution of lithium tri-tert-butoxyaluminohydride (1M in THF, 82.16 ml), and the reaction mixture was stirred at −30° C. for 14 h. For work-up, the mixture was admixed with 1 N HCl, the THF was removed under reduced pressure and the aqueous phase was saturated with NaCl and extracted with dichloromethane. The combined organic phases were dried (MgSO4), the solvent was removed under reduced pressure and the residue was purified by MPLC. Yield: 2.24 g.

[0416] The resulting intermediate (1 g; 6.47 mmol) in diethyl ether (15 ml) was, at 0° C., added to a solution of methylmagnesium bromide (3M in diethyl ether, 4.3 ml, 12.0 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was admixed with 10% aqueous HCl, stirred at room temperature and extracted with ethyl acetate, the combined organic phases were dried (Na2SO4), the solvents were removed under reduced pressure and the crude product was purified by MPLC.

[0417] Yield: 412 mg (33%) Rf (CH2Cl2)=0.69 MS (DCI/NH3): m/e=170 [M+N4+]

EXAMPLE 5A

(3aS*,6aR*)-3,3-Dimethyl-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

[0418] 55

[0419] At 0° C., a solution of 4-exomethylene-1,2-cyclopentanedicarboxylic anhydride (1.0 g; 6.5 mmol) in diethyl ether (40 ml) was added to a solution of methylmagnesium bromide (3 M in diethyl ether, 6.6 ml; 19.7 mmol), and the reaction mixture was stirred at room temperature for 14 h. The mixture was admixed with 10% aqueous HCl, saturated with sodium chloride and extracted with ethyl acetate, and the combined organic phases were washed with 10% aqueous Na2CO3 and saturated NaCl solution and dried (Na2SO4). Removal of the solvents under reduced pressure gives the title compound.

[0420] Yield: 929 mg (85%) Rf (I, 10:1)=0.24 MS (EI): m/e=166 [M+]

Preparation Examples

Example 1

(3aS*,6aS*)-6a-Benzyl-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

[0421] 56

[0422] At −78° C., a solution of the compound from Example 1A (90 mg, 0.65 mmol) in toluene (3 ml) was added to a solution of LiHMDS (1M in THF, 0.65 ml, 0.65 mmol) diluted with toluene (7 ml). The mixture was allowed to warm to room temperature, stirred for a further 60 min and then admixed with the alkylating agent (benzyl bromide, 89.1 mg, 0.521 mmol). After 14 h at room temperature, water (1 ml) was added, the reaction mixture was filtered through a frit filled with bituminous earth/silica gel, the solvents were removed under reduced pressure and the crude product was, if appropriate, purified by MPLC;

[0423] Yield: 81 mg (68%) Rf (I, 80:1)=0.67 MS (EI): m/e=229 [M+H+]

[0424] The Examples 2 to 97 listed in the table below were prepared analogously to the procedure of Example 1. The alkylating agents used were the corresponding halides, aldehydes or esters.

		Starting
Ex.		Material	Yield
No.	Structure	Ex. No.	[%]	Rf	MS
2	57	1A	18	0.23 (III, 50:1)	153 [M + H+]
3	58	1A	8	0.582 (I, 80:1)	210 [M + NH4+]
4	59	1A	66	0.73 (I, 80:1)	223 [M + H+]
5	60	2A	65	0.45 (III, 5:1)	229 [M + H+]
6	61	1A	13	0.47 (III, 5:1)	235 [M + H+]
7	62	1A	6	0.63 (CH2Cl2)	260 [M + NH4+]
8	63	1A	2	0.16 (III, 5:1)	265 [M + Na+]
9	64	1A	90	0.44 (III, 5:1)	284 [M + CH3CN +H+]
10	65	1A	79	0.44 (III, 5:1)	284 [M + CH3CN +H+]
11	66	1A	18	0.42 (III, 5:1)	284 [M + CH3CN +H+]
12	67	1A	7	0.27 (CH2Cl2)	265 [M + Na+]
13	68	1A	33	0.15 (CH2Cl2)	262 [M + NH4+]
14	69	1A	96	0.32 (III, 5:1)	288 [M + CH3CN +H+]
15	70	1A	96	0.31 (III, 5:1)	288 [M + CH3CN +H+]
16	71	1A	98	0.31 (III, 5:1)	288 [M + CH3CN +H+]
17	72	1A	11	0.20 (III, 5:1)	361 [M + H+]
18	73	1A	47	0.20 (III, 5.1)	295 [M + CH3CN +H+]
19	74	1A	53	0.29 (III, 5:1)	296 [M + CH3CN +H+]
20	75	1A	70	0.62 (I, 80:1)	349 [M + H+]
21	76	1A	34	0.42 (III, 5:1)	274 [M + NH4+]
22	77	1A	71	0.44 (III, 5:1)	298 [M + CH3CN +H+]
23	78	1A	9	0.15 (III, 10:1)	281 [M + Na+]
24	79	1A	38	0.30 (III, 5:1)	300 [M + CH3CN +H+]
25	80	1A	100	0.42 (III, 5:1)	304 [M + CH3CN +H+]
26	81	1A	96	0.34 (III, 5:1)	304 [M + CH3CN +H+]
27	82	1A	20	0.32 (III, 5:1)	304 [M + CH3CN +H+]
28	83	1A	99	0.34 (III, 5:1)	306 [M + CH3CN +H+]
29	84	1A	2	0.42 (III, 5:1)	310 [M + CH3CN +H+]
30	85	1A	21	0.35 (III, 10:1)	284 [M + NH4+]
31	86	1A	58	0.242 (III, 50:1)	272 [M+]
32	87	1A	14	0.05 (IV, 1:1)	291 [M + Na+]
33	88	1A	2	0.42 (III, 5:1)	291 [M + NH4+]
34	89	1A	45	0.34 (III, 5:1)	296 [M + NH4+]
35	90	2A	42	0.60 (CH2Cl2)	296 [M + NH4+]
36	91	1A	5	0.24 (III, 5:1)	301 [M + Na+]
37	92	1A	1	0.58 (III, 1:1)	281 [M + H+]
38	93	1A	99	0.36 (III, 5:1)	322 [M + CH3CN +H+]
39	94	1A	15	0.35 (III, 10:1)	300 [M + NH4+]
40	95	1A	5	0.192 (III, 10:1)	326 [M + CH3CN +H+]
41	96	1A	28	0.46 (III, 5:1)	302 [M + NH4+]
42	97	1A	59	0.66 (I, 80:1)	309 [M + Na+]
43	98	1A	41	0.12 (III, 5:1)	328 [M + CH3CN +H+]
44	99	1A	3	0.42 (III, 4:1)	310 [M + NH4+]
45	100	1A	84	0.31 (III, 5:1)	338 [M + CH3CN +H+]
46	101	1A	80	0.31 (III, 5:1)	338 [M + CH3CN +H+]
47	102	1A	75	0.42 (III, 5:1)	338 [M + CH3CN +H+]
48	103	1A	44	0.44 (III, 5:1)	—
49	104	1A	12	0.24 (III, 10:1)	314 [M + NH4+]
50	105	1A	25	0.82 (I, 80:1)	327 [M + Na+]
51	106	1A	53	0.21 (III, 40:1)	305 [M + H+]
52	107	1A	53	0.44 (III, 5:1)	305 [M + H+]
53	108	1A	3	0.42 (III, 5:1)	348 [M + CH3CN +H+]
54	109	1A	24	0 42 (III, 5:1)	307 [M + H+]
55	110	1A	31	0.19 (III, 10.1)	307/309 [M + H+]
56	111	1A	96	0.42 (III, 5:1)	348 [M + CH3CN +H+]
57	112	2A	67	0.45 (III, 5:1)	307/309 [M + H+]
58	113	1A	9	0.42 (III, 5:1)	352 [M + CH3CN +H+]
59	114	1A	3	0.42 (III, 5:1)	352 [M + CH3CN +H+]
60	115	1A	49	0.32 (III, 2:1)	336 [M + H+]
61	116	1A	15	0.78 (I, 80:1)	—
62	117	1A	17	0.42 (III, 5:1)	336 [M + NH4+]
63	118	1A	50	0.41 (III, 5:1)	338 [M + NH4+]
64	119	2A	52	0.45 (III, 5:1)	321 [M + H+]
65	120	1A	46	0.61 (CH2Cl2)	323/321 [M + H+]
66	121	1A	37	0.16 (III, 10:1)	338 [M + NH4+]
67	122	1A	26	0.42 (III, 5:1)	340/342 [M + NH4+]
68	123	1A	39	0.27 (III, 5:1)	370 [M + CH3CN +H+]
69	124	1A	35	0.42 (III, 5:1)	—
70	125	1A	3	0.42 (III, 5:1)	372 [M + CH3CN +H+]
71	126	1A	51	0.22 (IV, 1:1)	355 [M + Na+]
72	127	1A	33	0.42 (III, 5:1)	380 [M + CH3CN +H+]
73	128	1A	40	0.42 (III, 5:1)	380 [M + CH3CN +H+]
74	129	1A	25	0.75 (III, 50:1)	362 [M + H+]
75	130	1A	62	0.20 (IV, 5:1)	347 [M + H+]
76	131	1A	38	0.42 (III, 5:1)	396 [M + CH3CN +H+]
77	132	1A	23	0.26 (III, 10:1)	372 [M + NH4+]
78	133	1A	17	0 42 (III, 5:1)	374/376 [M + NH4+]
79	134	1A	30	0.42 (III, 5:1)	398 [M + CH3CN +H+]
80	135	1A	4	0.42 (III, 5:1)	380 [M + NH4+]
81	136	1A	16	0.42 (III, 5:1)	409 [M + H+]
82	137	1A	5	0.39 (III, 5:1)	351 [M + H+]
83	138	1A	5	0.22 (III, 5:1)	337 [M + H+]
84	139	1A	29	0.24 (III, 10:1)	298 [M + NH4+]
85	140	1A	19	0.27 (III, 10:1)	287 [M + H+]
86	141	1A	9	0.30 (III, 10:1)	293 [M + H+]
87	142	1A	12	0.11 (III, 10:1)	458 [M + NH4+]
88	143	1A	42	0.25 (III, 10:1)	269 [M + H+]
89	144	2A	55	0.34 (III, 5:1)	—
90	145	2A	62	0.47 (III, 5:1)	310 [M + H +H3CN+]
91	146	2A	38	0.30 (III, 5:1)	—
92	147	2A	52	0.18 (III, 5:1)	304 [M + NH4+]
93	148	2A	74	0.34 (III, 5:1)	314 [M + H3CCN +H+]
94	149	2A	66	0.36 (III, 5:1)	326 [M + H3CCN +H+]
95	150	2A	56	0 39 (III, 5:1)	288 [M + H3CCN +H+]
96	151	1A	40	0.39 (III, 5:1)	346 [M + NH4+]
97	152	1A	10	0.35 (III, 10:1)	300 [M + NH4+]

Example 98

(3aS*,6aS*)-6a-(4-Allyloxycarbonylaminobenzyl)-5-methylene-hexahydro-cyclopenta[c]-furan-1-one

[0425] 153

[0426] A mixture of the compound from Example 124 (2.02 g; 7.5 mmol), allyl alcohol (4.3 g, 74.29 mmol), diphenylphosphoryl azide (2.25 g, 8.17 mmol), diazabicyclo-octane (DABCO, 0.17 g; 1.5 mmol) and triethylamine (0.9 g, 8.92 mmol) in toluene (70 ml) was stirred under reflux for 48 h. The reaction mixture was admixed with 2 g of silica gel, the solvent was removed under reduced pressure and the residue was purified by MPLC.

[0427] Yield: 1.29 g (53%) Rf (III, 5:1)=0.23 MS (DCI): m/e=345 [M+NH4+]

[0428] The Examples 99 to 103 listed in the table below were prepared analogously to the procedure of Example 98:

Ex. No.	Structure	Yield	Rf	MS
99	154	97	0.75 (III, 1:1)	/
100	155	25	0.35 (III, 2:1)	/
101	156	12	0.44 (III, 2:1)	/
102	157	68	0.50 (III, 2:1)	/
103	158	27	0.53 (III; 2:1)	/

Example 104

(3aS*,6aS*)-6a-(4-Aminobenzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

[0429] 159

[0430] Example 98 (1.275 g; 3.96 mmol) was added to a solution of tris(dibenzylidene-acetone)dipalladium(0) (181 mg; 0.198 mmol), bis(diphenyl-phosphino)ethane (315 mg; 0.79 mmol) and dimedone (4.44 g; 31.65 mmol) in THF (320 ml) and the reaction mixture was heated under reflux for 1 hour. The reaction mixture is poured into 1 N HCl and the aqueous phase is washed with ethyl acetate (2×), then adjusted to pH=9-10 and extracted with ethyl acetate (3×). The combined extracts are washed with saturated NaCl solution and dried (MgSO4) and the solvent is removed under reduced pressure.

[0431] Yield: 0.770 g (80%) Rf (III, 1:1)=0.42

[0432] The following compounds were prepared analogously:

Ex. No.	Structure	Yield	Rf
105	160	83	0.42 (II, 1:1)

Example 106

(3aS*,6aS*)-6a-(4-Acetylaminobenzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

[0433] 161

[0434] Triethylamine (12 μl, 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. For work-up, a saturated NaHCO3 solution (1 ml) was added and the mixture was filtered through a frit filled with bituminous earth/silica gel and the product was eluted with dichloromethane/ethanol.

[0435] Yield: 12.2 mg (quant.) Rf (II, 50:1)=0.18 MS (ESI): m/e=286 [M+H+]

[0436] The following compounds were prepared analogously:

Ex. No.	Structure	Yield	Rf	MS
107	162	quant.	0.12 (II, 100:1)	376 [M + H+]
108	163	quant.	0.10 (II, 100:1)	328 [M + H+]

Example 109

(3aS′″*,6a′″S*)-N-[3-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-yl-methyl)-phenyl]-morpholine

[0437] 164

[0438] A mixture of triethylamine (208 μl; 1.5 mmol), morpholine (131 μl; 1.5 mmol) and the compound from Example 65 (321 mg; 1.0 mmol) in dichloromethane (1 ml) were stirred at room temperature for 14 h. The mixture was concentrated and the crude product was purified by MPLC.

[0439] Yield: 230 mg (70%) Rf (I, 40:1)=0.25 MS (DCI/NH3): m/e=328 [M+H+]

[0440] Examples 110 to 116 listed in the table below were prepared analogously to Example 109:

		Starting
Ex.		material	Yield
No.	Structure	Ex. No.	(%)	Rf	MS
110	165	66	33	0.29 (I, 40:1)	328 [M + H+]
111	166	65	26	0.31 (I, 40:1)	340 [M + H+]
112	167	66	15	0.22 (I, 40:1)	340 [M + H+]
113	168	65	79	0.21 (I, 40:1)	403 [M + H+]
114	169	66	76	0.27 (I, 40:1)	403 [M + H+]
115	170	65	55	0.17 (I, 40:1)	436 [M + H+]
116	171	66	55	0.13 (I, 40:1)	436 [M + H+]

Example 117 and Example 118

(3aS*,6aS*)-5-Methyl -6a-naphth-2-ylmethyl-3,3a,6,6a-tetrahydro-cyclopenta[c]-furan-1-one (Example 117) and (3aS*,6aS*)-5-methyl-6a-naphth-2-ylmethyl-3,3a,4,6a-tetrahydro-yclopenta[c]furan-1-one (Example 118)

[0441] 172

[0442] A mixture of the compound from Example 34 (370 mg, 1.33 mmol) and Pd-C (10%, 10 370 mg) in n-butanol (10 ml) was stirred under reflux for 48 h. Filtration, distillative removal of the solvent under reduced pressure and purification of the crude product by MPLC gave the title compound;

[0443] Yield: 155 mg (42%, Example 117) Rf (III, 5:1)=0.36 MS (EI): m/e=279 [M+H+]Yield: 75 mg (21%, Example 118) Rf (III, 5:1)=0.30 MS (EI): m/e=301 [M+Na+]

Example 119 and Example 120

(3aS*,3R*,6aS*)-3-Methyl-5-methylidene-6a-naphth-2-ylmethyl-hexahydro-cyclo-penta(c)furan-1-one and (3aS*,3S*,6aS*)-3-methyl-5-methylene-6a-naphth-2-yl-methyl-hexahydro-cyclopenta(c)furan-1-one

[0444] 173

[0445] Analogously to the procedure of Example 1, the title compounds were prepared from the compound from Example 4A (200 mg, 1.314 mmol). Yield: 309 mg (93%, mixture of the diastereomers) Rf (CH2Cl2)=0.53 MS (DCI)JNH3): m/e=310 [M+NH4+]

[0446] The diastereomers were separated by HPLC (Kromasil 100 C 18, acetonitrile/water 1:1)

Example 121

Diastereomer A, fraction 1

Example 122

Diastereomer B, fraction 2

Example 123

(3aS *,6aS*)-3,3-Dimethyl-5-methylidene-6a-naphth-2-ylmethyl-hexahydro-cyclopenta[c]furan-1-one

[0447] 174

[0448] Analogously to the procedure of Example 1, the title compound was prepared from the compound from Example 5A (100 mg, 0.6 mmol);

[0449] Yield: 116 mg (63%) Rf (I, 10:1)=0.47 MS (ESI): m/e=307

Example 124

(3a″S*,6″a)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoic acid

[0450] 175

[0451] A solution of the compound from Example 43 (2.26 g, 7.89 mmol) in THF (100 ml) and aqueous NaOH (1 M, 127 ml) was stirred at room temperature for 4 h. The mixture was adjusted to pH=2 using 1 N aqueous HCl, stirred for 1 h, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and the solvents were removed under reduced pressure;

[0452] Yield: 2.14 g (quant.) Rf (II, 10:1)=0.47

Example 125

(3a″S*,6a″S*)-3-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoic acid

[0453] 176

[0454] Analogously to Example 124, the title compound was prepared from Example 42 (2.30 g, 8.03 mmol);

[0455] Yield: 1.38 g, (63.1%) Rf (II; 10:1)=0.45 MS (DCI/NH3): m/e=290 [M+NH4+]

Example 126

(3a″S ,6a″S )-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoic acid

[0456] 177

[0457] A solution of the compound from Example 92 (2.2 g, 7.68 mmol) in THF (100 ml) and aqueous NaOH (1 M, 127 ml) was stirred at room temperature for 4 h. The mixture was adjusted to pH=2 using 1 N aqueous HCl, stirred for 1 h, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and the solvents were removed under reduced pressure;

[0458] Yield: 2.1 g (quant.)

Example 127

(3a″S*,6a″S*)-1-[(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoyl]-4-phenylpiperazine

[0459] 178

[0460] A mixture of the compound from Example 124 (50 mg, 0.184 mmol), N-phenyl-piperazine (32.77 mg, 0.202 mmol), 1-ethyl-3-(3′-dimethylamino)propyl)-carbodiimide hydrochloride (38.7 mg, 0.202 mmol) and triethylamine (18.6 mg, 0.184 mmol) in dichloromethane (10 ml) was stirred at room temperature for 20 h. For work-up, 10% aqueous KHSO4 (1 ml) was added, the reaction mixture was filtered through a frit filled with bituminous earth/silica gel, the solvents were removed under reduced pressure and the crude product was purified by flash chromatography;

[0461] Yield: 90 mg (quant.) Rf (II, 20:1)=0.19 MS (ESI): m/e=417 [M+H+]

[0462] Analogously to the procedure of Example 127, the Examples 128 to 177 listed in the table below were prepared starting from Examples 124 or 124, and the Examples 178 to 197 starting from Example 126:

			Starting
			Material	Yield
	Ex. No.	Structure	Ex. No.	[%]	Rf	MS
	128	179	124	79	0.16 (II, 20:1)	312 [M + H+]
	129	180	125	81	0.21 (II, 20:1)	312 [M + H+]
	130	181	125	71	0.313 (II, 20:1)	314 [M + H+]
	131	182	124	60	0.06 (II, 20:1)	316 [M + H+]
	132	183	125	51	0.06 (II, 20:1)	316 [M + H+]
	133	184	124	77	0.19 (II, 20:1)	326 [M + H+]
	134	185	124	75	0.24 (II, 20:1)	326 [M + H+]
	135	186	125	85	0.20 (II, 20:1)	326 [M + H+]
	136	187	125	78	0.21 (II, 20:1)	326 [M + H+]
	137	188	124	27	0.24 (III, 4:1)	342 [M + H+]
	138	189	125	35	0.25 (II, 20:1)	368 [M + H+]
	139	190	124	70	0.22 (II, 20:1)	376 [M + H+]
	140	191	125	91	0.23 (II, 20:1)	376 [M + H+]
	141	192	124	59	0.25 (II, 20:1)	392 [M + H+]
	142	193	125	66	0.25 (II, 20:1)	392 [M + H+]
	143	194	124	82	0.21 (II, 20:1)	417 [M + H+]
	144	195	124	77	0.29 (II, 20:1)	431 [M + H+]
	145	196	125	58	0.213 (II, 20:1)	431 [M + H+]
	146	197	124	67	0.33 (II, 20:1)	440 [M + H+]
	147	198	125	81	0.43 (II, 20:1)	440 [M + H+]
	148	199	124	53	0.05 (II, 20:1)	445 [M + H+]
	149	200	125	52	0.04 (II, 20:1)	445 [M + H+]
	150	201	124	93	0.25 (II, 20:1)	452 [M + H+]
	151	202	125	71	0.28 (II, 20:1)	452 [M + H+]
Ex.		Starting Material		HPLC area %
No.	Structure	Ex. No.	MW [g/mol]	at 210 nm	MS [M + H+]
152	203	124	341.4542	97	342
153	204	124	449.5518	97	450
154	205	124	376.4593	92	377
155	206	124	375.4718	96	376
156	207	124	361.4447	96	362
157	208	124	341.4542	96	342
158	209	124	367.4925	95	368
159	210	124	430.3347	96	430
160	211	124	409.9168	95	410
161	212	124	440.3407	96	440
162	213	124	339.4383	96	340
163	214	124	444.3618	95	444
164	215	124	362.4322	97	363
165	216	124	377.4441	98	378
166	217	124	369.5084	94	370
167	218	124	347.4176	94	348
168	219	124	475.5958	94	476
169	220	124	399.4354	96	400
170	221	124	367.3714	93	368
171	222	124	313.4001	96	314
172	223	124	329.3995	99	330
173	224	124	311.3841	95	312
174	225	124	327.4272	94	328
175	226	124	379.5036	95	380
176	227	124	447.9662	64	448
177	228	124	354.4309	51	355
			HPLC
		Molecular	area
Ex.		weight	% at	MS
No.	Structure	[g/mol]	210 nm	[M + H+]
178	229	327.43	85	369
179	230	327.43	92	369
180	231	367.49	89	409
181	232	409.92	94	451
182	233	405.50	88	447
183	234	435.52	96	477
184	235	357.45	91	358
185	236	351.41	89	393
186	237	444.36	79	485
187	238	405.50	93	447
188	239	447.54	91	448
189	240	389.50	90	431
190	241	454.37	90	495
191	242	405.50	93	447
192	243	435.52	97	436
193	244	313.40	83	355
194	245	403.53	93	445
195	246	405.54	57	447
196	247	362.43	94	363
197	248	362.43	98	363

Example 198

Isopropyl (3a″S*,6a″S*)-4-(-methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoate

[0463] 249

[0464] At room temperature, triethylamine (51 μl, 0.367 mmol) and methanesulphonyl chloride (14.2 μl, 0.184 mmol) were added to a solution of the compound from Example 125 (50.0 mg, 0.184 mmol) in dichloromethane (2 ml). After 1 h, 2-propanol (10.6 μl, 0.138 mmol) and dimethylaminopyridine (4.5 mg, 0.037 mmol) were added, and the mixture was stirred at room temperature for another 20 h. For work-up, the mixture was admixed with 10% aqueous NaHCO3 solution (1 ml) and filtered through a frit filled with bituminous earth/silica gel, the solvents were removed and the crude product was purified by chromatography;

[0465] Yield: 19 mg (32%) Rf (II, 100:1)=0.47 MS (ESI): m/e=337 [M+Na+]

[0466] The Examples 199 to 209 listed in the table below were prepared analogously to the procedure given above.

		Starting
Ex.		Material	Yield
No.	Structure	Ex. No.	[%]	Rf	MS
199	250	124	49	0.43(II, 100:1)	342[M +CH3CN + H+]
200	251	125	53	0.61(II, 100:1)	349[M + H+]
201	252	124	49	0.90(II, 100:1)	364[M + H+]
202	253	124	64	0.62(II, 100:1)	384[M + H+]
203	254	125	61	0.27(II, 20.1)	—
204	255	124	71	0.63(II, 100:1)	386[M + H+]
205	256	124	79	0.54(II, 100:1)	411[M + Na+]
206	257	124	19	0.60(II, 100:1)	403[M + H+]
207	258	124	50	0.43(II, 100:1)	429[M + Na+]
208	259	125	62	0.46(II, 100:1)	424[M + NH4+]
209	260	124	56	0.41(II, 100:1)	450[M + H+]

[0467] Examples 210 to 214 listed in the table below were prepared analogously to the procedure of Example 98:

		Starting
Ex.		Material	Yield		MS
No.	Structure	Ex. No.	(%)	Rf	[M + NH4+]
210	261	124	56	0.80(III, 1:1)	361
211	262	124	45	0.52(III, 2:1)	347
212	263	124	44	0.48(III, 2:1)	333
213	264	124	15	0.51(III, 2:1)	342
214	265	126	64	0.23(III, 5:1)	345

[0468] Examples 215 to 231 listed in the table below were prepared analogously to the procedure of Example 1:

		Starting
Ex.		Material	Yield
No.	Structure	Ex. No.	(%)	Rf	MS
215	266	1A	30	0.52(III; 5:1)	404[M + H+]
216	267	1A	29	0.61(CH2Cl2)	342[M + H+]
217	268	1A	15	0.52(I, 80:1)	348[M + H+]
218	269	1A	5	0.17(I, 80:1)	269[M + H+]
219	270	1A	11	0.47(III, 5:1)	339[M + H+]
220	271	1A	30	0.20(IV, 5:1)	404[M + NH4+]
221	272	1A	20	0.50(IV, 1:1)	322[M + Na+]
222	273	1A	35	0.82(I, 80:1)	227[M + NH4+]
223	274	1A	18	0.42(III, 50:1)	339[M + NH4+]
224	275	2A	40	0.16(CH2Cl2)	—
225	276	1A	9	0.62(CH2Cl2)	310[MN + NH4+]
226	277	1A	31	0.35(CH2Cl2)	285[M + H+]
227	278	1A	7	0.24(III, 100:1)	329[M + H+]
228	279	1A	15	0.52(III, 5:1)a)	404[M + H+]
229	280	1A	15	0.52(III; 5:1)b)	404[M + H+]
230	281	1A	25	0.31(I, 40:1)	347[M + H+]
231	282	2A	52	0.42(I, 40:1)	339[M + H+]
a)Diastereomer A: fraction 1 (HPLC, Kromasil 100 C. 18, methanol/H2O 65:35)
b)Diastereomer B: fraction 2 (HPLC, Kromasil 100 C. 18, methanol/H2O 65:35)

[0469] Examples 232 to 255 listed in the table below were prepared analogously to the compound from Example 106:

Ex.			HPLC area
No.	Structure	MW (g/mol)	% at 210 nm	Mz + H
232	283	353.44	92	354
233	284	299.37	75	300
234	285	311.38	96	312
235	286	327.42	98	328
236	287	337.37	97	338
237	288	339.43	89	340
238	289	343.38	96	344
239	290	367.49	88	368
240	291	391.47	97	392
241	292	391.47	97	392
242	293	391.47	95	392
243	294	403.52	91	404
244	295	405.54	92	244
245	296	421.49	82	422
246	297	421.49	95	422
247	298	422.44	6	423
248	299	455.55	61	456
249	300	438.53	16	439
250	301	486.35	49	486
251	302	381.86	95	382
252	303	381.86	94	382
253	304	381.86	94	382
254	305	397.47	92	398
255	306	397.47	98	398

[0470] The compounds listed in the table below were prepared analogously to Example 106:

Ex.		Yield
No.	Structure	(%)	MS
256	307	87	362[M + H+]
257	308	80	409[M + H3CCN + H+]
258	309	97	392[M + H+]

Example 259

N[(3a″S*,6a″S)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl-phenyl]-4-methylpentanecarboxamide

[0471] 310

[0472] At 0° C., N,N-dimethylaminopyridine (10.1 mg, 0.09 mmol), 1-ethyl-3-(3′-dimethyl-amino)propyl)-carbodiimide hydrochloride (17.3 mg, 0.09 mmol) and 4-methyl-pentanecarboxylic acid (10.5 mg, 0.09 mmol) were added to a solution of the compound from Example 104 (20.0 mg, 0.082 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 6 hours. For work-up, 1 M aqueous HCl was added (0.7 ml), the mixture was filtered, with dichloromethane, through a frit filled with bituminous earth/silica gel, the filtrate was admixed with 10% aqueous NaHCO3 (0.7 ml) and filtered once more through a frit filled with bituminous earth, and the solvent was removed under reduced pressure.

[0473] Yield: 27.6 mg (98%) Rf (III, 2:1)=0.38 MS(ESI): m/e=342 [M+H+]

Example 260

(3aS*,6aS*)-6a-(4-(2-Methylpropylaminobenzyl)-5-methylidene-hexahydro-cyclo-penta[c]furan-1-one

[0474] 311

[0475] A solution of the compound from Example 104 (15 mg, 0.062 mmol), 2-methyl-propanal (4.5 mg, 0.062 mmol) in methanol/acetic acid (3:1, 1.2 ml) was stirred at room temperature for 20 minutes and then admixed with sodium cyanoborohydride (5.0 mg, 0.08 mmol) in methanol (0.6 ml). After 20 hours, the mixture was admixed with ether and the organic phase was washed with sat. NaHCO3 and dried (MgSO4). The residue was purified by chromatography.

[0476] Yield: 3.7 mg (20%) Rf (II, 50:1)=0.35 MS (ESI): m/e=300 [M+H+]

Example 261

(3aS*,6aS*)-6a-(4-Hydroxybenzyl)-5-methylidene-hexahydro-cycopenta[c]furan-1-one

[0477] 312

[0478] A mixture of the compound from Example 279 (192 mg, 0.59 mmol), K2CO3 (486 mg, 3.52 mmol) in water (4.7 ml) and methanol (7.1 ml) was stirred at room temperature for 30 minutes. The mixture was adjusted to pH=2 using 1 N aqueous HCl, saturated with NaCl and extracted with ethyl acetate. The combined organic phases was dried (Na2SO4) and the solvents were removed under reduced pressure.

[0479] Yield: 157 mg (quant.) Rf (II, 2:1)=0.31 MS (ESI): m/e=286 [M+H+]

Example 262

(3aS*,6aS*)-6a-(4-(3-Methylbutyloxy)benzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

[0480] 313

[0481] A mixture of the compound from Example 261 (13.3 mg, 0.054 mol), 1-bromo-3-methylbutane (6.8 mg, 0.045 mmol), Cs2CO3 (44.4 mg, 0.136 mmol) in dimethoxyethane (5 ml) was stirred at 75° C. for 48 hours. For work-up, the mixture was admixed with dichloromethane and 1 M aqueous NaOH and filtered through a frit filled with bituminous earth, the solvent was removed under reduced pressure and the residue was purified by chromatography.

[0482] Yield: 2.8 mg (16%) Rf (III, 5:1)=0.49 LCMS: m/e=356 [M+H3CCN+H+]

Example 263 and 264

N-[(3a″R*,6a″R*)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-yl-methyl)-phenyl]-(3-methoxyphenyl)acetamide (264) and N-[(3a″S*,6a″S*)-4-(5-Methyl-3,3a,6,6a-tetrahydro-cyclopenta[c]furan-1-on-6a-yl-methyl)-phenyl]-(3-methoxyphenyl)acetamide (265)

[0483] 314

[0484] The compound from Example 104 and 3-methoxyphenylacetyl chloride were reacted analogously to the procedure of Example 106. The crude product was separated into the enantiomers by HPLC (Chiralpak AS, ethanol/iso-hexane 20:80).

[0485] Fraction I (Example 265): Enantiomer A, [α]20D=−46° (c=0.473, CHCl3)

[0486] Fraction II: not identified

[0487] Fraction III (Example 264): Enantiomer A, [α]20D=−22.2° (c=0.200, CHCl3)

[0488] Fraction IV (Example . . . ): Enantiomer B

[0489] The compounds listed in the table were prepared analogously to the procedure of Example 1:

		Starting
		Material	Yield	Rf(cyclohexane/	MS(CI)
Ex.	Structure	Ex. No.	[%]	ethyl acetate 3:1)	[M+ + 1]
265	315	1A	9.9	0.50	303
266	316	1A	3.5	0.51	319
267	317	1A	6.8	0.42	337
268	318	1A	10.2	0.63	335
269	319	1A	29.2	0.46	309
270	320	1A	15.4	0.54	293
271	321	1A	9.1	0.52	364
272	322	1A	8.2	0.39	343
273	323	1A	21.0	0.35	310
274	324	1A	10.5	0.36	343
275	325	1A	13.0	0.46	309
				Procedure
Ex.		Yield	Starting	analogous to
No.	Structure	%	Material	Ex.	Rf	MS
276	326	39	1A	1	0.5(CH2Cl2)	324[M + NH4+]
277	327	22	1A	1	0.50(II, 1:1)	382/384[M + NH4+]
278	328	17	1A	1	0.53(III, 2:1)	382/384[M + NH4+]
279	329	30	1A	1	0.20(III, 5:1)
280	330	43	1A	1		407[M + H*]

[0490] Examples listed in the table below were prepared analogously to the procedures mentioned.

				Procedure
Ex.		Yield	Starting	analogous to
No.	Structure	%	Material	Ex.	Rf	MS
281	331	30	124	98	0.23(II, 20:1)	401[M + H + 9]
282	332	27	124	98	0.47(III, 2:1)	330[M + H+]
283	333	26	318	98	0.36(I, 40:1)	336[M + H+]
284	334	20	318	98	0.34(I, 40:1)	351[M + NH4+]
285	335	88	124	98	0.23(III, 5:1)	370[M + H+]
286	336	73	125	98	0.15 (CH2Cl2)
287	337	56	327	98	0.54(III, 1:1)	423/425[M +NH4+]
288	338	73	318	127	0.43(I, 40:1)	332[M + H+]
289	339	91	318	127	0.46(I, 40:1)	368[M + H+]
290	340	92	318	127	0.45(I, 40:1)	334[M + H+]
291	341	93	318	127	0.37(I, 40:1)	320[M + H+]
292	342	98	124	127	0.20(III, 2:1)	383[M +H3CCN + H+]
293	343	quant.	124	127	0.37(I, 40:1)
294	344	72	327	127	0.79(I, 10:1)	509/511[M +H3CCN + H+]
295	345	66	327	127	0.79(I, 10:1)	481/483[M +H3CCN + H+]
296	346	47	327	127	0.66(I, 10:1)	421/423[M +H3CCN + H+]
297	347	59	327	127	0.77(I, 10.1)	459/461[M +H3CCN + H+]
298	348	91	104	259	0.38(II, 2:1)	430[M + H+]
299	349	7	325	106	0.43(III, 1:1)	374[M + H+]
300	350	7	325	106	0.31(III, 1:1)	398[M + H+]
301	351	7	325	106	0.29(III, 1:1)	318[M + H+]
302	352	17	325	106	0.22(III, 1:1)	306[M + H+]
303	353	73	124	127	0.21(II, 20:1)	392[M + H+]
304	354	17	326	106	0.38(III, 1:1)	392[M + H+]
305	355	86	326	259	0.35(III, 1:1)	392[M + H+]
306	356	41	105	259	0.40(III, 1:1)
307	357	80	105	259	0.33(III, 1:1)
308	358	53	105	259	0.48(III, 1:1)
309	359	64	105	259	0.38(III, 1:1)
310	360	18	105	259	0.17(III, 1:1)	437[M + H+]
311	361	33	105	259	0.04(III, 1:1)
312	362	95	310	261	0.58(I, 10:1)	395[M + NH4+]
313	363	27	104	259		498[M + H+]
314	364	26	104	259		453[M + H+]
315	365	7	104	259		478[M + H+]
316	366	28	104	259		438[M + H+]
317	367	quant.	104	259	0.26(II, 50:1)	422[M + H+]
318	368	98	1A	1(alkylation) 124(hydroly- sis of the ester)		296[M + NH4+]
319	369	98	104	260	0.61(II, 20:1)	405[M +H3CCN + H+]
320	370	35	104	260	0.25(III, 2:1)	389[M +H3CCN + H+]
321	371	53	104	260	0.62(III, 2:1)	376[M + H+]
322	372	79	313	261	0.52(I, 10:1)	456[M + H+]
323	373	69	314	261	0.4(I, 10:1)	454[M + H+]
324	374	83	316	261	0.51(I, 10:1)	437[M +H3CCN + H+]
325	375	quant.	284	104	0.33(III, 1:1)	—
326	376	5	286	104	0.32(III, 1:1)	—
327	377	quant.	277	124	—	351[M + H+]
328	378	40	1A	1	0.49(III, 2:1)	346[M + NH4+]
329	379	83	328	261	0.31(II, 20:1)	262[M + NH4+]
330	380	28	1A	1	0.39 (CH2Cl2)	321[M + NH4+]
331	381	quant.	330	124	—	307[M + H+]
332	382		1	1A
333	383		332	261
334	384		329	262
335	385	quant.	280	261	0.35(II, 20:1)	—
336	386	90	331	127		465[M +H+ H3CCN]+
337	387	87	331	127		437[M +H3CCN + H]+
338	388	98	331	127		387[M +H3CCN + H]+
339	389	78	331	127		417[M +H3CCN + H]+
340	390	63	287	104	—	363/365[M +H3CCN + H+]
341	391	41	340	259	0.42(III, 1:1)	487/489[M +H+]
342	392	41	1A	1	0.35 (CH2Cl2)	—
343	393	96	105	259	0.37(III, 1:1)	422[M + H+]
344	394	79	342	261	0.21 (CH2Cl2)	—

[0491] The Examples listed in the table below were prepared analogously to the procedure of Example 127.

			Molecular
Ex.			weight
No.	Structure	Formula	[g/mol]	Mz + H
345	395	C20 H25 N O3	327.4272	328
346	396	C21 H27 N O3	341.4543	342
347	397	C25 H26 Cl N O3	423.9439	424
348	398	C25 H27 N O4	405.4982	406
349	399	C24 H24 Cl N O4	425.9162	426
350	400	C25 H26 Cl N O4	439.9433	440
351	401	C23 H24 N2 O3	376.4594	377
352	402	C23 H24 N2 O3	376.4594	377
353	403	C24 H25 N O4	391.4712	392

[0492] The compounds listed in the table were prepared analogously to the procedure of Example 259.

			Molecular
Ex.			weight
No.	Structure	Formula	[g/mol]	M + H
354	404	C24H31NO3	381.51957	382
355	405	C25H27NO3	389.49884	390
356	406	C25H27NO3	389.49884	390
357	407	C28H33NO3	431.58011	432
358	408	C25H26N2O5	434.49637	435
359	409	C24H25NO3	375.47175	376
360	410	C24H25NO3	375.47175	376
361	411	C23H22FNO3	379.43509	380
362	412	C23H22BrNO3	440.34069	440
363	413	C24H25NO3	375.47175	376
364	414	C27H25NO3	411.5052	412
365	415	C23H21BrClNO3	474.78572	474
366	416	C27H31NO3	417.55302	418
367	417	C23H18F5NO3	451.39681	452
368	418	C27H25NO3	411.5052	412
369	419	C23H21Cl2NO3	430.33472	430
370	420	C25H26ClNO3	423.94387	424
371	421	C23H22INO3	487.34109	488
372	422	C20H23NO4	341.41061	342
373	423	C20H18BrNO4	416.27476	416
374	424	C21H22N2O4	366.42049	367
375	425	C21H21NO3S	367.47042	368
376	426	C23H29NO3	367.49248	368
377	427	C23H22BrNO3	440.34069	441
378	428	C22H20BrNO3	426.3136	426
379	429	C21H20ClNO3S	401.91545	402
380	430	C21H21NO3S	367.47042	368
381	431	C23H20Cl3NO3	464.77975	464
382	432	C25H26ClNO3	423.94387	424
383	433	C24H25NO4	391.47115	392
384	434	C23H21Cl2NO3	430.33472	430
385	435	C24H23Cl2NO3	444.36181	444
386	436	C23H22N2O5	406.44219	407
387	437	C24H25NO5	407.47055	408
388	438	C24H25NO4	391.47115	392
389	439	C23H22BrNO3	440.34069	441
390	440	C23H22ClNO3	395.88969	396
391	441	C24H25NO3	375.47175	376
392	442	C25H27NO3	389.49884	390
393	443	C24H25NO5	407.47055	408
394	444	C23H23NO4	377.44406	378
395	445	C23H29NO3	367.49248	368
396	446	C22H27NO3	353.46539	354
397	447	C25H27NO4	405.49824	406
398	448	C21H23N3O3	365.43576	366
399	449	C24H25NO4	391.47115	392
400	450	C29H27NO4	453.54284	454
401	451	C24H25NO4	391.47115	392
402	452	C25H25NO5	419.4817	420
403	453	C25H25NO5	419.4817	420
404	454	C25H24N4O3	428.49503	429
405	455	C26H25N3O3	427.50745	428
406	456	C25H27NO4	405.49824	406
407	457	C27H31NO4	433.55242	434
408	458	C27H31NO4	433.55242	434
409	459	C27H29NO4	431.53648	432
410	460	C28H33NO4	447.57951	448
411	461	C27H31NO4	433.55242	434
412	462	C25H27NO4	405.49824	406
413	463	C25H27NO5	421.49764	422
413a	464	C30H29NO3	451.57053	452
414	465	C21H27NO3	341.45424	342
415	466	C23H22ClNO3	395.8897	396
416	467	C23H22N2O5	406.4422	407
417	468	C23H22BrNO3	440.3407	441
418	469	C23H22FNO3	379.4352	380
419	470	C26 H29 N O4	419.5254	419
420	471	C23H22ClNO3	395.8897	396
421	472	C25 H27 N O5	421.4977	422
422	473	C25 H27 N O3	389.4988	390
423	474	C24H23F2NO3	411.4526	412
424	475	C23H21ClFNO3	413.8802	414
425	476	C23H21ClFNO3	413.8802	414
426	477	C23H21Cl2NO3	430.3347	430
427	478	C21H21NO3S	367.47042	368
428	479	C21 H21 N O3 S	367.4704	368
429	480	C29 H27 N O3	437.5435	438
430	481	C23 H23 N O4	377.4441	378
431	482	C25 H27 N O5	421.4977	422
432	483	C27H31NO4	433.55242	434
433	484	C25 H27 N O3	389.4988	390
434	485	C25 H27 N O4	405.4982	406
435	486	C24H24ClNO3	409.9168	410
436	487	C25H27NO3	389.4988	390
437	488	C25 H27 N O4	405.4982	406
438	489	C24H24ClNO3	409.9168	410
439	490	C26 H29 N O5	435.5248	436
440	491	C22 H22 N2 O3	362.4323	363

Example 441

N [(3a″S*,6a″S)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on6a-yl methyl )]-phenyl-N′-(isopropyl)-urea

[0493] 492

[0494] A solution of the compound from Example 104 (20 mg, 0.084 mmol) and isopropyl isocyanate (7.8 mg, 0.092 mmol) in toluene (3 ml) was stirred at room temperature for 24 hours. For work-up, ethyl acetate (3 ml), dichloromethane (2 ml) and 1 M aqueous HCl (0.6 ml) were added, the mixture was filtered through a frit filled with bituminous earth and the solvents were removed under reduced pressure.

[0495] Yield: 7.2 mg (26%) Rf (II, 2:1)=0.18 MS (ECI)=329 [M+H+]

[0496] The compounds listed in the table were prepared analogously to the procedure of Example 441.

			Molecular
Ex.			weight
No	Structure	Formula	[g/mol]	M + H
442	493	C20 H26 N2 O3	342.4418	343
443	494	C19 H24 N2 O3	328.4147	329
444	495	C18 H22 N2 O3	314.3877	315

[0497] The compounds listed in the table below were prepared analogously to the procedure of Example 262.

			Molecular
Ex.			weight
No.	Structure	Formula	[g/mol]	M + H
445	496	C17 H20 O3	272.3472	273
446	497	C18 H22 O3	286.3743	287
447	498	C19 H24 O3	300.4013	301

[0498] The compounds listed in the table were prepared analogously to the procedure of Example 262, starting from Example 335.

			Molecular
Ex.			weight
No.	Structure	Formula	[g/mol]	Mz
448	499	C19 H23 Br O3	379.2974	378
449	500	C17H19BrO3	351.24318	350
450	501	C18H21BrO3	365.27027	364
451	502	C19H23BrO3	379.29736	378

[0499] The compounds listed in the table were prepared analogously to the procedure of Example 262, starting from Example 344.

			Molecular
Ex.			weight
No.	Structure	Formula	[g/mol]	M + H
452	503		348.8735	349.1
453	504		306.7922	307.1
454	505		320.8193	321.1
455	506		334.8464	335.1

[0500] The compounds listed in the table were prepared analogously to the procedure of Example 262, starting from Example 329.

			Molecular
Ex.			weight
No.	Structure	Formula	[g/mol]	M + H
456	507	C19H24O3	300.401	301
457	508	C17H20O3	272.347	273
458	509	C18H22O3	286.374	287
459	510	C19H24O3	300.401	301

[0501] The compounds listed in the table were prepared analogously to the procedures of Example 260.

		Starting		Rf
Ex.		material	Yield	(Cyclohexane/	MS (CI)
No.	Structure	Ex. No.	[%]	ethyl acetate 3:1)	[M+ + 1]
460	511	104		0.16	394
461	512	104		0.29	394
462	513	104		0.13	424
463	514	104		0.24	424

Example 464

[0502] 515

[0503] At 0° C., a solution of 60 μl of 3 M sulphuric acid and 40 mg (0.23 mmol) of 2,3-dichlorobenzaldehyde in 400 μl of THF is slowly added to an open flask with 49 mg (0.2 mmol) of the compound from Example 104, dissolved in 1 ml of THF and 350 μl of methanol. After 5 minutes, 14 mg of sodium borohydride are added, at 0° C., to the solution, which is stirred well. The mixture is stirred at room temperature for another 10 minutes.

[0504] For work-up, the batch is diluted with 400 μl of water, made alkaline, with ice-cooling, using solid NaOH, and immediately extracted with MTB ether. The combined ether phases are washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. Purification is carried out by column chromatography (mobile phase: cyclohexane:ethyl acetate 3:1).

[0505] Yield: 2.4 mg (3.0%) Rf: 0.40 (cyclohexane:ethyl acetate 3:1) MS (EI): m/e=401 [M+]

				Procedure	Rf (Cyclo-	MS
Ex.		Yield	Starting	analogous to	hexane:ethyl	(EI: M+;
No.	Structure	(%)	Material	Example	acetate 3:1)	CI: M + H+)
465	516	40.7	104	464	0.52	313 (EI)
466	517	3.5	1A	1	0.19	299 (EI)
467	518	16	104	464	0.5	313 (EI)
468	519	8.1	1A	1	0.52	318 (EI)
469	520	3.1	1A	1	0.14 (1:1)	229 (EI)
470	521	35.6	1A	1	0.3	—
471	522	21.5	1A	1	0.31	353 (CI) [M + NH4+]
472	523	3.1	1A	1	0.21	352 (CI)
473	524	24.1	2A	1	0.38	309 (CI)
474	525	18.4	1A	1	0.31	351 (EI)
475	526	14.7	1A	1	0.4	402 (CI)
476	527	0.8	1A	1	0.43	—

[0506] The examples listed in the table below were prepared analogously to the procedure of Example 127:

			Molecular
Ex.			weight
No.	Structure	Formula	(g/mol)	Mz + H
477	528	C22 H20 Cl N O3	381.8626	382
478	529	C22 H20 Cl N O3	381.8626	382

Claims

1. Compounds of the general formula (I)

2. Compounds of the formula (I) according to claim 1, in which A represents radicals of the formulae —CH2—, —CO—, —CR4(OH)— or —(CH2)a—CHR5—, in which a represents a number 0, 1, 2 or 3, R4 represents hydrogen or (C1-C4)-alkyl and R5 represents phenyl, or represents (C2-C6)-alkanediyl, (C2-C4)-alkenediyl or (C2-C4)-alkinediyl, R1 represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, furyl, quinazolyl, quinoxalinyl or quinolyl, or represents radicals of the formulae 541 in which b and c are identical or different and represent a number 1 or 2, or represents phenyl or naphthyl, where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, hydroxyl or (C1-C5)-alkoxy, (C1-C5)-alkyl-carbonyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine, and/or are substituted by (C1-C5)-alkyl and (C2-C4)-alkenyl, which for their part may be substituted by fluorine, chlorine, bromine, iodine, phenyl, naphthyl or by radicals of the formula —SR8, —OR9 or —NR10R11 or 542 in which R8 represents (C1-C4)-alkyl or phenyl, R9 represents hydrogen or (C1-C4)-alkyl, and R10 and R11 are identical or different and represent hydrogen, phenyl or (C1-C4)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C1-C4)-alkoxy, or R10 and R11 together with the nitrogen atom form a radical of the formula 543 in which G represents an oxygen atom, a —CH2— group or a radical of the formula —NR12—, in which R12 represents hydrogen, phenyl, benzyl, (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl, and/or are substituted by groups of the formulae —CO2—R13, —NR14R15, —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21, in which R13 represents hydrogen, or represents (C1-C8)-alkyl or (C2-C5)-alkenyl, which for their part may be substituted by radicals of the formulae 544phenyl, naphthyl, pyridyl, thienyl or furyl, in which d represents a number 1 or 2, or represents phenyl or naphthyl, which are optionally substituted by phenyl, which for its part may be substituted by cyano, fluorine, chorine or bromine, R14 and R15 are identical or different and represent hydrogen, cyclo-propyl, cyclopentyl, cyclohexyl, phenyl or (C1-C5)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl or (C1-C4)-alkoxy, R16 represents hydrogen or (C1-C3)-alkyl, R17 represents hydrogen, adamantyl, cyclopropyl, cyclopentyl or cyclohexyl, or represents (C2-C4)-alkenyl or (C1-C10)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-naphthyl, pyridyl, thienyl, tetrazolyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine, and/or alkyl is optionally substituted by a radical of the formula 545 in which e represents a number 0 or 1 and R22 represents (C1-C4)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C1-C4)-alkoxy, or represents phenyl, naphthyl, thienyl, furyl or pyridyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C4)-alkoxy, (C1-C4)-alkyl, hydroxyl, nitro, fluorine, chlorine and bromine, or represents a radical of the formula 546 in which L and M are identical or different and represent hydrogen, fluorine, chlorine or bromine, R23 and R24 have the meaning of R12 and R11 given above and are identical to or different from this meaning, R18 has the meaning of R16 given above and is identical to or different from this meaning, R19 represents cyclopropyl, cyclopentyl or cyclohexyl, or represents (C1-C7)-alkyl or (C2-C6)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of fluorine, chlorine, bromine, phenyl, hydroxyl, morpholinyl, cyclopropyl, cyclopentyl, cyclohexyl and by a group of the formula —SiR25R26R27, in which R25, R26 and R27 are identical or different and represent (C1-C4)-alkyl, R20 and R21 are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, pyridyl, furyl, thienyl, thiazolyl or pyrryl, or represent (C2-C6)-alkenyl, (C1-C10)-alkyl or (C3-C6)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C5)-alkoxy, (C1-C6)-alkoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C4)-alkoxy, fluorine, chlorine, bromine, phenoxy, hydroxyl or (C1-C4)-alkyl, and/or the alkyl listed under R20/R21 is optionally substituted by radicals of the formulae 547 in which R28 and R29 are identical or different and represent hydrogen or (C1-C4)-alkyl, or or represents a radical of the formula 548 in which R30 has the meaning of R12 given above and is identical to or different from this meaning, or R20 and R21 together with the nitrogen atom form a radical of the formula 549 in which G′ has the meaning of G given above and is identical to or different from this meaning, R2 and R3 are identical or different and represent hydrogen or (C1-C3)-alkyl, and D and E together form radicals of the formulae 550 in which R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen, phenyl or (C1-C3)-alkyl, and their pharmaceutically acceptable salts.

3. Compounds of the formula (I) according to claim 1 or 2, in which A represents radicals of the formulae —CH2—, —CO—, —CR4(OH)— or —(CH2)a—CHR5—, in which a represents a number 0, 1, 2 or 3, R4 represents hydrogen or (C1-C3)-alkyl and R5 represents phenyl, or represents (C2-C4)-alkanediyl, propenediyl or (C2-C3)-alkinediyl, R1 represents hydrogen, cyclopropyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, quinazolyl or quinoxalinyl, or represents radicals of the formulae 551 in which b and c are identical or different and represent a number 1 or 2, or represents phenyl or naphthyl, where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C1-C4)-alkoxy, (C1-C4)-alkyl-carbonyloxy, cyclohexyl, phenyl, phenoxy, pyridyl, pyrimidyl, pyridazinyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine, and/or are substituted by (C1-C4)-alkyl and (C2-C3)-alkenyl, which for their part may be substituted by chlorine, bromine, iodine or phenyl or by radicals of the formula —OR9 or —NR10R11 or 552 in which R9 represents hydrogen or (C1-C3)-alkyl, and R10 and R11 are identical or different and represent hydrogen, phenyl or (C1-C3)-alkyl, which is optionally substituted by phenyl, which for its part may be substituted by chlorine, bromine, hydroxyl or (C1-C3)-alkoxy, or R10 and R11 together with the nitrogen atom form a radical of the formula 553 in which G represents an oxygen atom or a radical of the formula —NR12, in which R12 represents hydrogen, phenyl, benzyl, (C1-C3)-alkyl, (C1-C3)-alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl, and/or are substituted by groups of the formulae —CO2—R13, —NR14R15, —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21, in which R13 represents hydrogen, or represents (C1-C6)-alkyl or allyl, which for their part may be substituted by radicals of the formulae 554phenyl, naphthyl or pyridyl, in which d represents a number 1 or 2, or represents phenyl, which is optionally substituted by phenyl, which for its part may be substituted by cyano, chlorine or bromine, R14 and R15 are identical or different and represent hydrogen, cyclohexyl, phenyl or (C1-C4)-alkyl, which is optionally substituted by cyclopropyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of chlorine and (C1-C3)-alkoxy, R16 represents hydrogen, methyl or ethyl, R17 represents hydrogen, adamantyl, cyclopentyl or cyclohexyl, or represents (C2-C3)-alkenyl or (C1-C8)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine, and/or alkyl is optionally substituted by a radical of the formula 555 in which e is a number 0 or 1 and R22 represents (C1-C3)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C1-C3)-alkoxy, or represents phenyl, naphthyl, thienyl or furyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C3)-alkoxy, (C1-C3)-alkyl, nitro, fluorine, chlorine and bromine, or represents a radical of the formula 556 in which L and M are identical or different and represent hydrogen, fluorine or chlorine, R23 and R24 have the meaning of R10 and R11 given above and are identical to or different from this meaning, R18 has the meaning of R16 given above and is identical to or different from this meaning, R19 represents (C1-C4)-alkyl or (C3-C5)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of chlorine, phenyl, hydroxyl, morpholinyl, cyclopropyl, cyclohexyl and by a group of the formula —SiR25R26R27, in which R25, R26 and R27 are identical and represent methyl, R20 and R21 are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, thiazolyl or pyrryl, or represent (C2-C3)-alkenyl, (C1-C7)-alkyl or (C3-C5)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C3)-alkoxy, hydroxyl, trifluoromethyl, phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C3)-alkoxy, (C1-C6)-alkoxycarbonyl, fluorine, chlorine, bromine, phenoxy, hydroxyl and (C1-C3)-alkyl, and/or the alkyl listed under R20/R21 is optionally substituted by radicals of the formulae 557 in which R28 and R29 are identical or different and represent hydrogen or (C1-C3)-alkyl, or or R20 or R21 represents a radical of the formula 558 in which R30 has the meaning of R12 given above and is identical to or different from this meaning, or R20 and R21 together with the nitrogen atom form a radical of the formula 559 in which G′ has the meaning of G given above and is identical to or different from this meaning, R2 and R3 are identical or different and represent hydrogen or methyl, and D and E together form radicals of the formulae 560 in which R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen or methyl, and their pharmaceutically acceptable salts.

4. Compounds of the general formula (I) according to any of claims 1 to 3, in which A represents the —CH2— group.

5. Compounds of the formula (I) according to claims 1 to 4, in which A represents —CH2—, R1 represents phenyl or naphthyl, where all of the abovementioned ring systems are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C1-C4)-alkoxy, and/or are substituted by (C1-C4)-alkyl, and/or are substituted by groups of the formulae —NR16CO—R17, —NR18CO2—R19 and —CO—NR20R21, in which R16 is hydrogen, R17 is (C1-C8)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine, R18 has the meaning of R16 given above and is identical to or different from this meaning, R19 represents (C1-C4)-alkyl or (C3-C5)-alkenyl, R20 and R21 are identical or different and represent hydrogen, (C2-C3)-alkenyl, (C1-C7)-alkyl or (C3-C5)-alkinyl, which are optionally substituted by phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C1-C3)-alkoxy, fluorine, chlorine, bromine and (C1-C3)-alkyl, R2 and R3 represent hydrogen or methyl, and D and E together form radicals of the formulae 561 in which R31, R32, R33, R34, R35 represent hydrogen, and their pharmaceutically acceptable salts.

6. Compounds according to any of claims 1 to 3, selected from the group consisting of

7. Process for preparing the compounds of the formula (I) according to any one of claims 1 to 6, by reacting compounds of the general formula (II) 564 in which D, E, R2 and R3 are as defined above, with compounds of the general formula (III),T-A-R1  (III) in which T represents halogen, preferably bromine, and A and R1 are as defined above, in inert solvents and in the presence of a base, and, if appropriate, derivatizing the substituent R1 by customary methods.

8. Process for preparing the compounds of the general formula (I′) according to the invention according to any of claims 1 to 6

9. Compounds of the general formula (II),

10. Compounds of the general formula (II) according to claim 9, in which R2 and R3 represent hydrogen or methyl, and D and E together form radicals of the formulae 570 in which R31, R32, R34 and R35 represent hydrogen.

11. Process for preparing the compounds of the general formula (II) according to the invention according to claim 9 or 10,

12. Compounds according to claims 1 to 6 for use as medicaments in the treatment of humans and animals.

13. Pharmaceutical composition, comprising as active component at least one compound according to claims 1 to 6 mixed together with at least one pharmaceutically acceptable, essentially non-toxic vehicle or excipient.

14. Use of the compounds according to claims 1 to 6 for preparing a medicament for the prevention and/or treatment of disorders caused by hyper- or hypofunction of the glutamatergic system.

15. Use of the compounds according to claims 1 to 6 for preparing a medicament for the prevention and/or treatment of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms.