Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-05
2001-03-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S229000
Reexamination Certificate
active
06200970
ABSTRACT:
This application is a national stage entry under 35 U.S.C. § 371 PCT/DE97/00225, filed Jan. 29, 1997.
The invention relates to new 8-alkoxy-substituted 2,3-benzodiazepine derivatives, their production and use as pharmaceutical agents.
It is already known that selected 2,3-benzodiazepine derivatives have modulatory activity at quisqualate receptors and owing to this property are suitable as pharmaceutical agents for treating diseases of the central nervous system.
It has now been found that 8-alkoxy-substituted 2,3-benzodiazepine derivatives are distinguished by better properties compared to the known compounds.
The invention relates to the compounds of formula I
in which
X means hydrogen or halogen,
Y means —NR
3
— or —N═,
R
1
and R
2
are the same or different and mean hydrogen, C
1
-C
6
alkyl, nitro, halogen, the group —NR
8
R
9
, —O—C
1-4
alkyl, —CF
3
, —OH, C
1-6
alkanoyloxy,
R
3
means hydrogen, the group —CO—R
10
, C
1-6
alkyl or C
3-7
cycloalkyl,
R
4
means optionally substituted C
1
-C
6
alkyl,
R
5
means hydrogen or
R
4
and R
5
together mean oxygen,
R
6
means C
1-4
alkyl,
R
8
and R
9
are the same or different and mean hydrogen, C
1
-C
6
alkyl or —CO-C
1-6
alkyl,
R
10
means hydrogen, optionally substituted C
1
-C
6
alkyl, optionally substituted C
6-10
aryl, the group —NR
11
R
12
, —O—C
1-6
alkyl, C
3-7
cycloalkyl, C
2-6
alkenyl or —O—C
3-7
cycloalkyl,
R
11
and R
12
are the same or different and mean hydrogen, optionally substituted C
1
-C
6
alkyl or optionally substituted C
6-10
aryl and
—C
...
C
...
means a double bond or single bonds
as well as their isomers and physiologically compatible salts.
Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. As substituents of the alkyl radical, C
1
-C
6
alkoxy or halogen can be mentioned.
If a halogenated alkyl radical is present, the latter can be halogenated or perhalogenated in one or more places.
Halogen is defined as fluorine, chlorine, bromine and iodine.
As an aryl radical, for example, naphthyl and preferably phenyl can be mentioned. The substituent is, for example, C
1-6
alkoxy or halogen.
Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, especially C
3-5
cycloalkyl.
The alkenyl radicals can be straight-chain or branched. For example, 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl, methallyl and vinyl can be mentioned.
As alkanoyl radicals, straight-chain or branched aliphatic carboxylic acid radicals, such as formyl, acetyl, propionyl, butanoyl, isopropylcarbonyl, caproyl, valeroyl, trimethylacetyl, i.a., are suitable.
The physiologically compatible salts are derived from inorganic and organic acids. Suitable are inorganic acids, such as, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or organic acids, such as, for example, aliphatic or aromatic mono- or dicarboxylic acids such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example, C
1-4
alkanesulfonic acids such as methanesulfonic acid or benzenesulfonic acids that are optionally substituted by halogen or C
1-4
alkyl, such as p-toluenesulfonic acid.
The compounds of formula I also comprise the possible tautomeric forms, the E- or Z-isomers, or, if chiral centers are present, the diastereomers and their mixtures and the racemates and enantiomers.
Preferred compounds of general formula I are those in which R
1
means amino or nitro and R
2
means hydrogen.
The compounds of general formula I as well as their physiologically compatible salts can be used as pharmaceutical agents owing to their non-competitive inhibition of the AMPA receptors. Owing to their profile of action, the compounds according to the invention are suitable for treating diseases that are caused by hyperactivity of excitatory amino acids, such as, for example, glutamate or aspartate. Since the new compounds act as non-competitive antagonists of excitatory amino acids, they are suitable especially for treating those diseases that are influenced by the receptors of excitatory amino acids, especially the AMPA receptor.
The pharmacological action of the compounds of formula I was determined by means of the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 hours light/dark cycle, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5-16 animals. The observation of the animals was performed between 0800 and 1300 hours.
AMPA was sprayed into the left ventricles of mice that were allowed to move freely. The applicator consisted of a cannula with a device made of stainless steel, which limits the depth of injection to 3.2 mm. The applicator was connected to an injection pump. The injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow. The animals were observed up to 180 seconds until clonic or tonic seizures set in. The clonic movements, which last longer than 5 seconds, were counted as seizures. The beginning of the clonic seizures was used as an endpoint for determining the seizure threshold. The dose that was necessary to raise or reduce the seizure threshold by 50% (THRD
50
) was determined in 4-5 experiments. The THRD
50
and the confidence limit were determined in a regression analysis.
The results of these tests show that the compound of formula I and its acid addition salts influence functional disorders of the AMPA receptor. They are therefore suitable for the production of pharmaceutical agents for symptomatic and preventive treatment of diseases that are triggered by changing the function of the AMPA receptor complex.
The treatment with the compounds according to the invention prevents or delays the cell damage that occurs as a result of disease and functional disorders and reduces the concomitant symptoms.
According to the invention, the compounds can be used for treating neurological and psychiatric disorders that are triggered by overstimulation of the AMPA receptor. The neurological diseases, which can be treated functionally and preventatively, include, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotropic lateral sclerosis, and olivopontocerebellar degeneration. According to the invention, the compounds can be used for the prevention of postischemic cellular degeneration, cellular degeneration after brain trauma, in the case of stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, AIDS dementia, neurological symptoms that are related to HIV infections, multiinfarct dementia as well as epilepsy and muscle spasms. The psychiatric diseases include anxiety conditions, schizophrenia, migraines, pain conditions as well as the treatment of sleep disorders and withdrawal symptoms after drug abuse such as in alcohol, cocaine, benzodiazepine or opiate withdrawal. In addition, the compounds can be used in the prevention of tolerance development during long-term treatment with sedative pharmaceutical agents, such as, for example, benzodiazepines, barbiturates and morphine. Moreover, the compounds can be used as anesthetics (anesthesia), analgesics or anti-emetics.
For use of the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable pharmaceutical, organic or inorganic inert media, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene-glycols, etc. The pharmaceutical preparations can be present in solid form, for example, as tablets, coated table
Abraham Gizella
Andrasi Ferenc
Berzsenyi Pal
Csuzdi Emese
Hamori Tamas
Millen White Zelano & Branigan P.C.
Raymond Richard L.
Schering Aktiengesellschaft
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