US 2003/0158424 A1 · 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.

Compounds of the general formula (I)

530
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, 3 or 4,
R4 represents hydrogen or (C1-C6)-alkyl
and
R5 represents phenyl,
or
represents (C2-C8)-alkanediyl, (C2-C6)-alkenediyl or (C2-C6)-alkinediyl,
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,
in which
R6 represents hydrogen or methyl,
or
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,
in which
R7 has the meaning of R6 given above and is identical to or different from this meaning,
or
represents radicals of the formulae
531
in which
b and c are identical or different and represent a number 1 or 2,
or
represents (C6-C10)-aryl,
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-carbonyl 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,
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
532
in which
R8 represents (C1-C6)-alkyl or phenyl,
R9 represents hydrogen or (C1-C6)-alkyl,
and
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,
or
R10 and R11 together with the nitrogen atom form a radical of the formula
533
in which
G represents an oxygen atom, a —CH2— group or a radical of the formula —NR12—,
in which
R 12 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,
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-C9)-alkyl or (C2-C6)-alkenyl, which for their part may be substituted by radicals of the formulae
534
(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,
in which
d represents a number 1 or 2,
or
represents (C6-C10)-aryl, which is optionally substituted by phenyl, which for its part may be substituted by cyano or halogen,
R14and 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,
R16 represents hydrogen or (C1-C6)-alkyl,
R17 represents hydrogen, adamantyl, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl or (C1-C12)-alkyl which is optionally substituted by adamantyl, (C3-C6)-cycloalkyl, (C6-C0)-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,
and/or alkyl is optionally substituted by a radical of the formula
535
in which
e represents a number 0 or 1 and
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,
or
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,
or
represents a radical of the formula
536
in which
L and M are identical or different and represent hydrogen or halogen,
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 (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 —SiR25R26R27,
in which
R25, R26 and R27 are identical or different and represent (C1-C6)-alkyl,
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
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 substiutted 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,
and/or the alkyl listed under R20/R21 is optionally substituted by radicals of the formulae
537
in which
R28 and R29 are identical or different and represent hydrogen or (C1-C6)-alkyl,
or
represents a radical of the formula
538
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
539
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-C6)-alkyl,
and
D and E together form radicals of the formulae
540
in which
R31, R32, R33, R34, R35, R36, R37 and R38 are identical or different and represent hydrogen, phenyl or (C1-C6)-alkyl,
and their pharmaceutically acceptable salts.

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Substituted alpha, beta-anellated butyrolactones

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Substituted alpha, beta-anellated butyrolactones

Life of this patent

Abstract

Claims15