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
2002-08-13
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S468000, C514S470000, C549S058000, C549S301000, C549S307000, C549S312000
Reexamination Certificate
active
06433004
ABSTRACT:
The present invention relates to &bgr;,&ggr;-fused 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 into two major classes: 1. ionotropic receptors which control the 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 suptypes 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 &bgr;,&ggr;-fused lactones of the general formula (I)
in which
R
1
and R
2
together represent radicals of the formulae
which are optionally substituted up to 3 times by hydroxyl,
R
3
represents hydrogen, (C
1
-C
6
)-alkyl or represents (C
2
-C
6
)-alkenyl
and
R
4
represents a radical of the formula —CH
2
—R
5
,
in which
R
5
represents aryl having 6 to 10 carbon atoms or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to polysubstituted by identical or different substituents from the group consisting of halogen and (C
1
-C
6
)-alkyl,
or
R
3
represents (C
2
-C
6
)-alkenyl
and
R
4
represents hydrogen
and their pharmaceutically acceptable salts.
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.
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.
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, ethyldiusopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
In general, aryl represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
In the context of the invention, (C
1
-C
6
)-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
In the context of the invention, (C
2
-C
6
)-alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl, but-3-en-1-yl, n-pent-3-en-1-yl and n-hex-3-en-1-yl.
Preference is given to compounds of the general formula (I) according to the invention in which
R
1
and R
2
together represent radicals of the formulae
which are optionally substituted up to 3 times by hydroxyl,
R
3
represents hydrogen or represents (C
2
-C
5
)-alkenyl
and
R
4
represents a radical of the formula −CH
2
—R
5
,
in which
R
5
represents phenyl, naphthyl or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and (C
1
-C
4
)-alkyl,
or
R
3
represents (C
2
-C
5
)-alkenyl
and
R
4
represents hydrogen
and their pharmaceutically acceptable salts.
Particular preference is given to compounds of the general formula (I) according to the invention,
in which
R
1
and R
2
together represent radicals of the formulae
which are optionally substituted up to 2 times by hydroxyl,
R
3
represents hydrogen or represents (C
3
-C
5
)-alkenyl
and
R
4
represents a radical of the formula −CH
2
—R
5
,
in which
R
5
represents phenyl, naphthyl or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and (C
1
-C
3
)-alkyl,
or
R
3
represents (C
3
-C
5
)-alkenyl
and
R
4
represents hydrogen
and their salts.
Very particular preference is given to compounds according to the invention of the following structure:
Structure:
The compounds of the general formula (I) according to the invention can be prepared by
[A] reacting compounds of the general formula (II),
in which
R
1
and R
2
are as defined above.
with compounds of the general formula (III)
R
4
—A (III)
in which
R
4
is as defined above
and
A represents halogen, preferably bromine,
in inert solvents and in the presence of a base to give the compounds of the general formula (Ia)
in which
R
1
, R
2
and R
4
are as defined above,
and, in the case that R
3
does not represent hydrogen, reacting the compounds of the general formula (Ia) with compounds of the general formula (IV)
R
3′
—D (IV)
in which
R
3′
has the meaning of R
3
given above. but does not represent hydrogen.
D represents halogen, preferably bromine,
in inert solvents and in the presence of a base,
or
[B] initially reacting compounds of the general formula (II) with compounds of the general formula (IV) as described under [A] to give the compounds of the general formula (Ib)
in which
R
1
. R
2
and R
3′
are as defined above,
and in a second step with compounds of the general formula (III).
The processes according to the invention can be illustrated in an exemplary manner by the formula scheme below:
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.
Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide, 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.
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 formulae (III) and (IV).
The reaction is generally carried out in a temperature range of from −78° C. to reflux temperature, preferably from −78° C. to +20° C.
The reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 b
Antonicek Horst-Peter
Baumgarten Jörg
de Vry Jean-Marie-Viktor
Horváth Ervin
Lensky Stephen
LandOfFree
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