Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-14
2002-04-23
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S462000, C549S060000, C549S229000, C549S295000, C549S297000, C549S302000, C549S304000, C549S305000
Reexamination Certificate
active
06376539
ABSTRACT:
The present invention relates to substituted bicyclic lactones, to processes for their preparation and to their use as pharmaceuticals.
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).
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.
Presently, 8 different subtypes of metabotropic glutamate receptors are known, differing in the second-messenger cascade, pharmacology and localization in the brain (review in: Ann. Rev. Pharmacol. Toxicol. 1997, 37, 205).
The present invention relates to substituted bicyclic lactones of the general formula (I)
in which
A represents radicals of the formulae —CH
2
—, —CO—, —CR
4
(OH)— or —(CH
2
)
a
—CHR
5
—,
in which
a represents a number 0, 1, 2, 3 or 4,
R
4
represents hydrogen or (C
1
-C
6
)-alkyl and
R
5
represents phenyl, or
represents (C
2
-C
8
)-alkanediyl, (C
2
-C
6
)-alkenediyl or (C
2
-C
6
)-alkinediyl,
R
1
represents hydrogen, (C
3
-C
6
)-cycloalkyl or represents a 5- to 6-membered heterocycle which may contain up to 3 hetero-atoms from the group consisting of S, O and N and/or a radical of the formula —NR
6
,
in which
R
6
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 and N and/or a radical of the formula —NR
7
, and which may be attached both via the phenyl ring and via the heterocycle,
in which
R
7
has the meaning of R
6
given above and is identical to or different from this meaning, or
represents radicals of the formulae
in which
b and c are identical or different and represent a number 1 or 2, or
represents (C
6
-C
10
)-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, (C
1
-C
6
)-alkoxy and (C
3
-C
6
)-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 (C
1
-C
6
)-alkyl and (C
2
-C
6
)-alkylene, which for their part may be substituted by halogen, (C
6
-C
10
)-aryl or by radicals of the formula —SR
8
, —OR
9
or —NR
10
R
11
or
in which
R
8
represents (C
1
-C
6
)-alkyl or phenyl,
R
9
represents hydrogen or (C
1
-C
6
)-alkyl, and
R
10
and R
11
are identical or different and represent hydrogen, phenyl or (C
1
-C
6
)-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 (C
1
-C
6
)-alkoxy, or
R
10
and R
11
together with the nitrogen atom form a radical of the formula
in which
G represents an oxygen atom, a —CH
2
group or a radical of the formula —NR
12
—,
in which
R
12
represents hydrogen, phenyl, benzyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-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 —CO
2
—R
13
, —NR
14
R
15
, —NR
16
CO—R
17
, —NR
18
CO
2
—R
19
and —CO—NR
20
R
21
,
in which
R
13
represents hydrogen, or represents (C
1
-C
9
)-alkyl or (C
2
-C
6
)-alkenyl, which for their part may be substituted by radicals of the formulae
(C
6
-C
10
)-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 (C
6
-C
10
)-aryl, which is optionally substituted by phenyl, which for its part may be substituted by cyano or halogen,
R
14
and R
15
are identical or different and represent hydrogen, (C
3
-C
6
)-cycloalkyl, phenyl or (C
1
-C
6
)-alkyl, which is optionally substituted by (C
3
-C
6
)-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 (C
1
-C
6
)-alkoxy,
R
16
represents hydrogen or (C
1
-C
6
)-alkyl,
R
17
represents hydrogen, adamantyl, (C
3
-C
8
)-cycloalkyl, (C
2
-C
6
)-alkenyl or (C
1
-C
12
)-alkyl which is optionally substituted by adamantyl, (C
3
-C
6
)-cycloalkyl, (C
6
-C
10
)-aryl, phenoxy or a 5-to 6-membered aromatic heterocycle having up to 3 hetero-atoms 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 (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, hydroxyl, nitro or halogen,
and/or alkyl is optionally substituted by a radical of the formula
in which
e represents a number 0 or 1 and
R
22
represents (C
1
-C
6
)-alkyl or (C
6
-C
10
)-aryl, which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C
1
-C
6
)-alkoxy, or
represents (C
6
-C
10
)-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 (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkyl, hydroxyl, nitro and halogen, or
represents a radical of the formula
in which
L and M are identical or different and represent hydrogen or halogen,
R
23
and R
24
have the meaning of R
10
and R
11
given above and are identical to or different from this meaning,
R
18
has the meaning of R
16
given above and is identical to or different from this meaning,
R
19
represents (C
3
-C
8
)-cycloalkyl, or represents (C
1
-C
8
)-alkyl or (C
2
-C
8
)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of halogen, phenyl, hydroxyl, morpholinyl, (C
3
-C
8
)-cycloalkyl and by a group of the formula —SiR
25
R
26
R
27
,
in which
R
25
, R
26
and R
27
are identical or different and represent (C
1
-C
6
)-alkyl,
R
20
and R
21
are identical or different and represent hydrogen, adamantyl, (C
3
-C
8
)-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 (C
2
-C
8
)-alkenyl, (C
1
-C
12
)-alkyl or (C
2
-C
6
)-alkinyl, which are optionally substituted by hydroxyl, (C
3
-C
6
)-cycloalkyl, (C
1
-C
6
)-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 (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl, halogen, phenoxy, hydroxyl and (C
1
-C
6
)-alkyl,
and/or the alkyl listed under R
20
/R
21
is optionally substituted by radicals of the formulae
in which
R
28
and R
29
are identical or different and represent hydrogen or (C
1
-C
6
)-alkyl, or
represents a radical of the formula
in which
R
30
has the meaning of R
12
given above and is identical to or different from this meaning, or
R
20
and R
21
together with the nitrogen atom form a radical of the formula
in which
G′ has the meaning of G given above and is identical to or different from this meaning,
R
2
and R
3
are identical or different and represent hydrogen or (C
1
-C
6
)-alkyl, and
D and E
Antonicek Horst-Peter
Baumgarten Jörg
de Vry Jean-Marie-Viktor
Horváth Ervin
Lensky Stephen
Bayer Aktiengesellschaft
Chiu Jerrie L.
Owens Amelia
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