Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1993-11-04
2001-02-20
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S250000, C514S282000, C514S288000, C514S567000, C514S588000
Reexamination Certificate
active
06191132
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the new use of antagonists of the quisqualate receptor complex or its physiologically compatible salts as pharmaceutical agents for the prevention and treatment of Parkinson's disease, as well as pharmaceutical agents which contain these compounds and their combination with anti-Parkinson's agents with synergistic action.
In the central nervous system of mammals, including humans, high concentrations of excitatory amino acids, such as glutamate and aspartate, are present (Fonnum, F., J. Neurochem. 42: 1-11, 1984). For the excitatory amino acids, various receptors exist, which are identified according to their specific agonists as N-methyl-D-aspartate (NMDA) receptor, kainate (KA) receptor and quisqualate (QUIS) receptor. The quisqualate receptors are also named AMPA receptors according to the specific agonists (RS)-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. The synaptic function of the excitatory amino acid L-glutamate is mainly imparted by AMPA receptors.
From clinical and animal-experimental findings, there are indications that in the case of Parkinson's disease (PD), increased glutamatergic neurotransmission in various nuclei of the basal ganglia results as a result of the striatal deficiency of dopamine. The neostriatum (NEO) represents the input structure of the basal ganglia: it obtains a massive glutamatergic projection from the cortex and the dopaminergic nigrostriatal pathway, which degenerates in the case of PD, from the substantia nigra pars compacta (SNC). From the NEO, there are direct pathways to the output nuclei of the basal ganglia, the internal pallidum link (GPi) and the substantia nigra pars reticulata (SNR), as well as indirect pathways, which run through the outer pallidum link (GPe) and the subthalamic nucleus (STH). The STH receives a direct glutamatergic innervation of its own from the cortex; its neurons projecting to the output nuclei also use L-glutamate as a transmitter.
The synaptic functions of dopamine in the NEO are complex. Its effect on the striatal neurons projecting to the GPe is mainly inhibitory, so that as a result of the striatal dopamine deficiency, as it is present in the case of PD, the excitatory glutamatergic influences on these neurons predominate. Since both the striatal pathway to the GPe, and the pathway projecting to the STH starting from there are inhibitory, in the case of PD in the STH the phenomenon of the disinhibition results with the increase of the tonic cellular activity. By its glutamatergic projections, the STH finally produces a pathologically increased neuronal activity in the output nuclei of the basal ganglia. Tests on animal models of the PD show that after administration of dopaminergic substances, a normalization of the increased excitatory neurotransmission results, which runs parallel to the “clinical” improvement.
SUMMARY OF THE INVENTION
Surprisingly, it has been discovered that quisqualate receptor antagonists inhibit the pathologically increased neuronal activity and block the glutamatergic transmission in the NEO, STH and the output nuclei of the basal ganglia and therefore are usable as pharmaceutical agents for the treatment of PD. Accordingly, the invention comprises a method for the treatment or prevention of Parkinson's Disease, comprising administering to a host an effective amount of a quisquilate receptor antagonist.
Because of their action mechanism, quisqualate receptor antagonists also have a neuroprotective effect, in particular also relative to the possible neurotoxic effects, which are triggered by dopaminergic pharmaceutical agents, which can be administered in combination with QA receptor antagonists. They can therefore also be used as pharmaceutical agents for preventive treatment of PD.
According to the invention, compounds or their physiologically compatible salts, which have a high affinity to the central AMPA receptors and selectively offset the synaptic effects of quisqualate, are suitable. Such quisqualate receptor antagonists are described, for example, in EP-A-374 534, EP-A-348 872 (U.S. Pat. Nos. 4,977,155 and 5,057,516), EP-A-283 959 (U.S. Pat. Nos. 4,889,885 and 4,912,108), EP-A-377 112 (U.S. Pat. No. 5,061,706), and EP-A-315 959 (U.S. Pat. Nos. 4,948,794 and 5,026,704). Quinoxaline and quinoxalinedione derivatives with selective and nonselective effects on AMPA receptors, such as quinoxalinedione derivatives and their tautomeric forms of Formula I
in which
R
1
and R
2
each represent hydrogen or one of the substituents mentioned in the cited patents, and
R
5
, R
6
, R
7
, and R
8
are the same or different, and each means hydrogen, NO
2
, NH
2
, cyano, halogen (fluorine, chlorine, bromine, or iodine), CF
3
, SO
2
NR′R′ SO
2
R′ or OR′ and R′ is hydrogen or C
1-4
-alkyl, or
R
5
and R
6
or R
7
and R
8
together mean a fused-to benzene or hetaryl ring or (CH
2
)
4
, and the benzene or hetaryl radical can be substituted one to three the same or different with NO
2
, NH
2
, cyano, halogen, CF
3
, SO
2
NR′R′, SO
2
R′, or OR′ and R′ has the above meaning. Suitable hetaryl rings are pyridine, pyrazole, thiophene, pyrazine, triazole, imidazole, suitable substituents R
1
and R
2
are C
1-12
-alkyl, C
3-8
-cycloalkyl, C
4-8
-cycloalkylalkyl, C
6-10
-aryl, especially phenyl, C
7-11
-aralkyl, especially benzyl, C
2-7
-alkanoyloxy, hydroxy, C
1-6
-alkoxy, C
6-10
-aryloxy, especially phenoxy, C
7-11
-aralkyl, especially benzyloxy, C
3-8
-cycloalkyloxy, C
4-8
-cycloalkylalkyloxy and C
1-12
-alkyl substituted by hydroxy, NH
2
, carboxy, carboxylic acid esters, or carbocyclic acid amines.
Especially suitable are quinoxalinedione and benzo-quinoxalinedione derivatives and their tautomeric forms and salts with selective and non-selective effect on AMPA receptors which optionally are substituted once to twice with halogen, NO
2
, cyano, CF
3
, SO
2
NR′R′, SO
2
R′ or OR′ and R′ is hydrogen or C
1-4
-alkyl and R
1
and R
2
each represent hydrogen or a substituent. Compounds such as 6-nitro-7-sulfamoyl-benzo[f]-quinoxaline-2,3-(1H,4H)-dione (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are particularly suitable.
The physiologically compatible salts are derived from alkali or alkaline-earth metals or the usual inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, maleic acid or fumaric acid.
As a result of the blocking of the central AMPA receptors, i.e., the structures, which with Parkinson's disease exhibit an increased neuronal activity, compounds with selective and nonselective effect on AMPA receptors are suitable both for symptomatic treatment of Parkinson's disease and for combining with usual anti-Parkinson's agents, such as L-DOPA, L-DOPA in combination with benserazide and dopaminergic agonists, such as, for example, lisuride, bromocryptine, amantadine derivatives, memantine and its derivatives and compounds such as those described in EP-A-351 352 (U.S. Pat. No. 5,037,832).
By combining the pharmaceutical agents according to the invention with usual anti-Parkinson's agents, the dose to be administered of the usual pharmaceutical agent is reduced and its effect is increased.
Because of the test results, the quisqualate receptor antagonists used according to the invention also have a neuroprotective effect, which prevents the degeneration of dopaminergic neurons, in particular relative to the possible neurotoxic effects, which are caused by the usual anti-Parkinson's agents. The absence of psychotomimetic side effects is also advantageous.
The invention also comprises pharmaceutical agents, which contain said compounds, their production as well as the use of the compounds according to the invention for production of pharmaceutical agents, which are used for treatment and prophylaxis of the above-mentioned diseases. For example, agents of the invention may be prophylactic
Klockgether Thomas
Loschmann Peter-Andreas
Stephens David Norman
Turski Lechoslaw
Wachtel Helmut
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
Weddington Kevin E.
LandOfFree
Use of quisqualate receptor antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of quisqualate receptor antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of quisqualate receptor antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2564272