Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-01-27
2002-06-18
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S250000, C544S344000, C544S354000
Reexamination Certificate
active
06407109
ABSTRACT:
The present invention relates to novel pyrrolyltetrahydroquinoxalinediones, processes for the preparation thereof and the use thereof for controlling diseases.
Excitatory amino acids, in particular glutamic acid, are wide-spread in the central nervous system. The excitatory amino acid glutamate acts as transmitter substance for receptors of which various subtypes are known. One subtype is called, for example, the NMDA receptor after the specific agonist N-methyl-D-aspartate. This NMDA receptor has various binding sites for agonists and antagonists. The amino acid glycine likewise binds to the NMDA receptor and modulates the effect of the natural agonist glutamic acid. Antagonists on this glycine binding site may accordingly show antagonistic effects on the NMDA receptor and inhibit an overexcitation of this receptor.
Two other subtypes of glutamate receptors are the AMPA receptor and the kainate receptor which are each called after the specific agonists 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. In a similar way to the NMDA receptor already mentioned, antagonists of these receptors can likewise inhibit overexcitation.
Elevated glutamate activity occurs in a number of neurological disorders or psychological disturbances and leads to states of overexcitation or toxic effects in the CNS.
Derivatives of quinoxaline-2,3(1H,4H)-dione II
have been described as glutamate antagonists in several publications, such as EP-A 374 534 and EP-A 260 467. Many of the known derivatives are unsubstituted in the heterocyclic quinoxaline fragment (II, R
1
, R
2
=hydrogen). Furthermore, derivatives where R
1
in II is a radical which is not hydrogen are also known. Thus, EP-A 377 112 and EP-A 374 534 have claimed N-hydroxyquinoxalines (II; R
1
=OR
4
). EP-A 315 959, DE-A 4 135 871, WO 91/13 878 and WO 92/07 847 describe alkyl radicals as R
1
in II, and the alkyl chain can also be substituted by acids, esters or amides. Alkyl acids (=R
1
) are likewise mentioned in J. R. Epperson et al. Bioorg. & Med. Chemistry Lett. 3 (1993), 2801-4.
Quinoxalinedione derivatives II which carry a heterocycle as substituent R
3
are likewise known. Thus, EP-A 556 393 describes imidazoles, triazoles and pyrazoles. Quinoxaline dione derivatives which carry a pyrrolyl radical as R
3
have been described as glutamate antagonists in EP-A 572 852.
The substances according to the invention are suitable for treating all disorders in which a beneficial effect can be expected from glutamate antagonists.
Suitable indications are neurotoxic disturbances, especially acute and chronic oxygen/(nutrient) deficiency/states of the central nervous system. By these are meant acute hypoxic or ischemic states which occur, for example, as a consequence of cerebral infarct, subarachnoid hemorrhage or vasospasms of other etiology, also following heart/circulatory failure, eg. in cardiac arrest, cardiac arrhythmias or circulatory collapse; CNS damage following hypoglycemia, as a consequence of perinatal asphyxia or after craniocerebral trauma, spinal cord trauma, transient ischemic attacks (TIAs), prolonged reversible ischemic neurological deficits (PRINDs) and multi-infarct dementia and atherosclerotic dementia, and migraine.
Other possible indications are neurodegenerative disorders, eg. Parkinson's disease, Huntington's chorea, Alzheimer's disease, amyotropic lateral sclerosis (ALS).
Furthermore, glutamate antagonists may be suitable for use as antiepileptics, as anxiolytics and as antidepressants, and for the treatment of pain, likewise for the treatment is schizophrenia, of withdrawal symptoms in addicts, and as muscle relaxants in cases of spasticity of the skeletal muscles, eg. in multiple sclerosis (MS).
The invention relates to novel pyrrolylquinoxalinediones of the formula I
and their tautomeric and isomeric forms, and their physiologically tolerated salts, where the variables have the following meanings:
R
1
hydrogen, cyclohexyl
an aliphatic radical which has 1 to 4 carbon atoms and can carry the radical —COOR
5
, where R
5
is hydrogen or C
1
-C
4
-alkyl, preferably —(CH
2
)
m—
COOR
5
with m=1-4, particularly preferably —CH
2
COOH,
R
2
COOH, COO—C
1
-C
4
, alkyl, —COO—(CH
2
)
m
—Ph, —CONR
6
R
7
and
where m can be an integer from 1 to 6, R
6
can be hydrogen, C
1
-C
4
-alkyl or OH and R
7
can be hydrogen, C
1
-C
4
-alkyl,
where all the phenyl or pyridyl rings present in R
2
can also be substituted by up to 3 of the following radicals:
C
1
-C
4
-alkyl, halogen, —O—C
1
-C
4
-alkyl, —OCF
3
, NO
2
, CN, —COOR
5
or —CONHR
5
,
R
3
CF
3
, NO
2
, CN, and
R
4
hydrogen and
R
3
and R
4
can together be a fused-on benzene ring.
Preferred compounds according to the invention are quinoxaline-dione derivatives of the formula
where
R
2
is —COOH or —CONHR
7
where R
7
is hydrogen, —CH
2
-C
6
H
5
,
R
3
is NO
2
or CF
3
and R
4
is hydrogen, or
R
3
and R
4
are a fused-on benzene ring.
Very particularly preferred compounds are:
1-Carboxymethyl-7-(3-carboxy-1-pyrrolyl)-6-nitroquinoxaline-2,3(1H, 4H)-dione,
1-Carboxymethyl-7-(3-carboxy-1-pyrrolyl)-6-trifluoromethyl-quinoxaline-2,3-(1H, 4H)-dione,
1-Carboxymethyl-7-(3-carboxy-1-pyrrolyl)-benzo[f]quinoxaline-2,3-(1H, 4H)-dione,
7-(3-Benzylcarbamoyl-1-pytrolyl)-1-carboxymethyl-6-trifluoro-methylquinoxaline-2,3-(1H, 4H)-dione,
7-(3-Benzylcarbamoyl-1-pyrrolyl)-1-carboxymethyl-6-nitro-quinoxaline-2,3-(1H, 4H)-dione,
1-Carboxymethyl-6-nitro-7-(3-(3-phenylpropylcarbamoyl)-1-pyrrolyl)-quinoxalin-2,3(1H,4H)-dione,
1-Carboxymethyl-6-nitro-7-(3-(4-pyridinylmethylcarbamoyl)-1-pyrrolyl)quinoxaline-2,3(1H, 4H)-dione,
7-(3-Carbamoyl-1-pyrrolyl)-1-carboxymethyl-6-nitroquinoxaline-2,3(1H,4H)-dione,
1-Carboxymethyl-6-nitro-7-(3-(4-nitrobenzylcarbamoyl)-1-pyrrolyl)quinoxaline-2,3(1H,4H)-dione.
It has been found, surprisingly, that the present pyrrole-carboxylic acid derivatives have advantages by comparison with the compounds mentioned in EP-A 572 852.
The compounds I according to the invention can be prepared in the way outlined in reaction scheme 1 below.
Synthesis of the aldehydes III has been described in EP-A 572 852. These aldehydes can be oxidized to the carboxylic acids I a according to the invention by customary literature methods which are listed, for example, in R. C. Larock, Comprehensive Organic Transformations, 1989, VCH Publisher, page 838 et seq. Particularly used for example is potassium permanganate in solvents such as acetone at 25-60° C. If there is an ester residue in R
1
, this can subsequently be hydrolyzed with acids and bases to result in the dicarboxylic acid I d. The hydrolysis is preferably carried out with lithium hydroxide in tetrahydrofuran/water mixtures at room temperature.
The pyrrolecarboxylic acid I a can be converted by reaction with amines or alcohols into the derivatives I b. In this case, the acid group COOH is activated in a suitable manner to COL where L is a leaving group such as azide, imidazole and others which are listed in R. C. Larock, Comprehensive Organic Transformations, New York 1989, pages 972 et seq. Subsequent addition of the reactants HNR
6
R
7
or alcohols results in the products I b according to the invention. If the radical R
1
has an ester group, this can be subjected to hydrolysis similar to the above with acids and bases to give the carboxylic acid, resulting in the derivatives I c according to the invention.
The compounds according to the invention are antagonists of the excitatory amino acid glutamate, in particular antagonists of the glycine binding site of the NMDA receptor, of the AMPA receptor and of the kainate receptor.
The pharmacological activity of the compounds I was investigated on isolated membrane material from rat cerebra. For this purpose, the membrane material was treated in the presence of the compounds according to the invention with the radiolabeled substance
3
H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (
3
H-AMPA), [
3
H]-glycine or [
3
H]-kainate which bind to specific receptors (AMPA, NMDA
Behl Berthold
Hofmann Hans-Peter
Lubisch Wilfried
Teschendorf Hans-Jürgen
Abbott Laboratories
Bernhardt Emily
Keil & Weinkauf
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