Quinoxaline-carboxylic acid derivatives

Details Quinoxaline-carboxylic acid derivatives Quinoxaline-carboxylic acid derivatives

1998-06-23

2001-09-11

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S228200, C514S234800, C514S241000, C514S242000, C544S182000, C544S215000, C544S062000, C544S116000, C544S119000, C544S238000, C544S295000, C544S354000

Reexamination Certificate

active

06288065

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to quinoxalinedione-carboxylic and -phosphonic acid derivatives, their production and use in medicinal agents.
It is known that quinoxaline derivatives exhibit affinity to the quisqualate receptors and are suitable, based on the affinity, as medicinal agents for the treatment of diseases of the central nervous system.
It has now been found that the compounds of this invention, as compared with the quinoxalines known from EP-A-315,959 and WO 91/138 78, are distinguished by their good binding capacity to the quisqualate receptors.
The compounds according to this invention have the Formula I
wherein
R
1
means R
2
-substituted C
1-12
alkyl, R
2
-substituted C
2-12
alkenyl, R
2
-substituted C
2-12
alkynyl, R
2
-substituted C
3-7
cycloalkyl, —(CH
2
)
n
-C
6-12
aryl substituted by R
2
in the aryl or in the alkyl residue, or —(CH
2
)
n
hetaryl substituted by R
2
in the hetaryl or alkyl residue,
R
4
means hydrogen, R
2
-substituted C
1-12
alkyl, R
2
-substituted C
2-12
alkenyl, R
2
-substituted C
2-12
alkynyl, (CH
2
)
n
-C
6-12
aryl R
2
-substituted in the aryl or alkyl residue, or —(CH
2
)
n
hetaryl R
2
-substitute in the hetaryl or alkyl residue,
R
5
, R
6
, R
7
and R
8
, being identical or different, mean hydrogen, halogen, nitro, NR
9
R
10
, NHCOR
11
, SO
2
R
12
, C
3-7
cycloalkyloxy, COR
13
, cyano, CF
3
, C
1-6
alkyl, C
1-4
alkoxy, or imidazole optionally substituted by cyano, C
1-4
alkyl or —COO—C
1-6
alkyl, or
R
5
and R
6
or R
7
and R
8
represent a fused benzene ring,
wherein
R
2
is —CO—R
3
or —PO—XY, R
2
being present once to twice in identical or different form, and
n is 0, 1, 2, 3, 4 or 5, and
R
3
is hydroxy, C
1-6
alkoxy or NR
9
R
10
,
X and Y, being identical or different, mean hydroxy, C
1-6
alkoxy, C
1-4
alkyl or NR
9
R
10
, and
R
9
and R
10
, being identical or different, mean hydrogen, C
1-4
alkyl or jointly with the nitrogen atom form a saturated 5- or 6-membered heterocycle which can contain an additional oxygen, sulfur or nitrogen atom,
R
11
means C
1-6
alkyl or phenyl,
R
12
means hydrogen, C
1-4
alkyl, NH
2
, N(C
1-4
alkyl)
2
and
R
13
means hydroxy, C
1-6
alkoxy, C
1-6
alkyl or NR
9
R
10
,
as well as their isomers or salts,
wherein,
if R
4
, R
5
, R
6
, R
7
and R
8
mean hydrogen, R
1
cannot be carbamoylmethyl, 1-carboxy-1-phenylmethyl, or straight-chain C
1-6
alkyl substituted in the 1-position by —COOH or —COO—C
1-6
alkyl, and
if R
1
means straight-chain C
1-6
alkyl substituted in the 1-position by —COOH or —COO—C
1-6
alkyl, R
6
and/or R
7
and, respectively, R
6
and R
8
cannot be fluorine, chlorine or bromine, and R
4
-R
8
in each case hydrogen, and
if R
1
is —CH
2
-COOH,
(a) R
6
and R
7
cannot be simultaneously methyl or
(b) R
6
or R
7
cannot be NO
2
and R
4
-R
8
respectively hydrogen.
The compounds of general Formula I also include the possible tautomeric forms and comprise the E or Z isomers or, in case a chiral center is present, the racemates or enantiomers.
The substituents are preferably present in the 6 and/or 7-position.
The R
2
substituent is present singly to doubly in identical or different form in any desired position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl or aryl residue.
Alkyl means in each case a straight-chain or branched alkyl residue, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, wherein C
1-6
alkyl residues are preferred.
Alkenyl includes, in particular, C
2-6
alkenyl residues which can be straight-chain or branched, such as, for example, 2-propenyl, 2-butenyl, 3-methyl-2-propenyl, 1-propenyl, 1-butenyl, vinyl.
Ethynyl, 1-propynyl, 2-propynyl, 1-butynyl of 2-4 carbon atoms are especially suitable as the alkynyl residues.
C
3-7
cycloalkyl means in each case cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo-heptyl, especially C
3-5
cycloalkyl.
Examples for the aryl residue are phenyl, naphthyl, biphenylyl and indenyl, particularly (CH
2
)
n
-phenyl wherein n=0, 1 or 2.
As the hetaryl residue, suitable are 5- or 6-membered heteroaromatics of 1-3 nitrogen atoms, such as, for example, pyrazole, imidazole, pyrazine, pyridine, pyrimidine, pyridazine, triazine.
Halogen is understood to mean fluorine, chlorine, bromine and iodine.
In case R
9
and R
10
form, jointly with the nitrogen atom, a saturated heterocycle, then this means, for example, piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine.
If R
1
means C
1-12
alkyl and R
2
means COR
3
, then R
5
-R
8
are, in particular, substituents such as NO
2
, NR
9
R
10
, NHCOR
11
, SO
2
R
12
, C
3-7
cycloalkyloxy, COR
13
, cyano, CF
3
, C
1-4
alkoxy, optionally substituted imidazole, or a fused benzene ring. The compounds of Formula I wherein R
2
=—PO—XY are distinguished by very good water solubility.
Physiologically compatible salts mean salts of organic and inorganic bases, such as, for example, the well-soluble alkali and alkaline earth salts, as well as N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, Sovak base (2-amino-1, 3, 4-butanetriol), 1-amino-2, 3, 4-butanetriol.
Examples of compounds of formula I include:
3-(6-Nitro-2, 3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) benzoic acid methyl ester,
1-(3 -ethoxycarbonylpropyl)-6-nitroquinoxaline-2,3-(1H, 4H)-dione,
2-{4-(2-ethoxycarbonylbenzyl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl}benzoic acid ethyl ester, and
4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)benzoic acid ethyl ester.
High concentrations of excitatory amino acids such as glutamate and aspartate are present in the central nervous system of mammals, including humans, (Fonnum, F.,
J. Neurochem,
42:1-11, 1984). For the excitatory amino acids, various receptors exist which are designated corresponding to their specific agonists as N-methyl-D-aspartate (NMDA), kainate (KA) and quisqualate (QUIS) receptors. The quisqualate receptors are also named AMPA receptors after the specific agonists (RS)&agr;-amino-3-hydroxy -5-methyl-4-isoxazole proportionate. The synaptic function of the excitatory amino acid L-glutamate is also imparted by NMDA receptors.
From clinical and animal-experimental findings, there are indications that in Parkinson's disease (PD), increased glutamatergic neurotransmission occurs in various nuclei of the basal ganglia as a result of the striatal deficiency of dopamine. The neostriatum (NEO) represents the entry structure of the basal ganglia; it obtains from the cortex a massive glutamatergic projection and from the substantia nigra pars compacta (SNC) the dopaminergic nigrostriatal pathway, which degenerates in the case of PD. From the NEO, there are direct pathways to the initial nuclei of the basal ganglia, the internal pallidum link (GPi) and the substantia nigra pars reticulata (SNR), as well as indirect pathways, which run by the external pallidum link (GPe) and nucleus subthalamicus (STH). The STH receives a direct glutamatergic innervation of its own from the cortex; its neurons projecting to the initial nuclei also use L-glutamate as a transmitter.
The synaptic functions of dopamine in NOE are complex. Its effect on the striatal neurons projecting into the GPe is mainly inhibitory, so that as a result of the striatal dopamine deficiency, as it is present in 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 the phenomenon of disinhibition with increase of tonic cellular activity in the STH results. By its glutamatergic projections, the STH finally produces a pathologically increased neuronal activity in the initial nuclei of the basal ganglia. Tests on animal models of PD show that after administration of dopaminergic substances, a normalization of the increased excitat

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