DK165293B - Quinoxaline compounds, process for preparing them, and pharmaceutical preparations which comprise the compounds - Google Patents

Description

DK 165293 B

The invention relates to novel therapeutically active quinoxaline compounds and their salts, a process for their preparation and pharmaceutical compositions comprising the compounds.

10 L-glutamic acid, L-aspartic acid and a number of closely related amino acids all have the ability to activate central nervous system (CNS) neurons. Biochemical / electrophysiological and pharmacological studies have documented this and demonstrated that acidic amino acids are transmitted for the majority of mammalian excitatory neurons in the CNS.

Interaction with glutamic acid-mediated neurotransmission 20 is considered a useful approach in the treatment of neurological and psychiatric disorders. Thus, known antagonists of excitatory amino acids such as 2-amino-7-phos-phonoheptanoic acid, β-D-aspartylaminomethylphosphonate and alpha-D-glutamylaminomethylphosphonate have shown 25 strong antiepileptic and muscle relaxant properties (A. Jones et al., Neurosci. Lett. 45 , 157-61 (1984) and L. Turski et al., Neurosci. Lett. 53, 321-6 (1985)).

It has been suggested that accumulation of extracellular excitatory and neurotoxic amino acids, followed by hyperstimulation of neurons, may explain the degeneration of neurons seen in neurological diseases such as Huntington's chorea, Parkinsonism, epilepsy, senile dementia, and lack of mental and motor performance. brain ischemia, oxygen deficiency and hypoglycemia (EG Mc-Geer et al., Nature, 263, 517-19 (1976) and R. Simon et al., Science, 226, 850-2 (1984).

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2

Excitatory amino acids act via specific receptors that are postsynaptic or presynaptically located.

Such receptors are currently subdivided for convenience into three groups, based on results of electrophysiological and neurochemical studies: NMDA

(N-methyl-D-aspartate) receptors, 2 quisqualate receptors, and 3 kainate receptors. L-glutamic acid and L-asparaginic acid presumably activate all of the aforementioned types of excitatory amino acid receptors and possibly 10 other types of receptors.

The result of excitatory amino acid interaction with postsynaptic receptors is an increase in intracellular cGMP values (G.A. Foster et al., Life 15 Sci. 27, 215-21 (1980)) and opening of Na + channels (A.

Luini et al., Proc. Natl. Acad. Sci. 78, 3250-54 (1981)). Na + influx in the neurons will depolarize the neuron membranes, initiate an action potential and ultimately lead to release of the transmitter substance from the nerve end. The effect of the test compounds on the aforementioned secondary response to receptor interaction can be tested via simple in vitro systems.

The above division of excitatory amino acid receptors into NMDA, quisqualate, and kainate receptors is primarily based on the following results of electrophysiological and neurochemical studies.

1) N-methyl-D-aspartate (NMDA) receptors exhibit high selectivity to the excitant NMDA. Ibotenic acid, L-homocysteic acid, D-glutamic acid and trans-2,3-piperidinediacarboxylic acid (trans-2,3-PDA) exert a strong to moderate agonistic activity on these receptors. The most potent and selective antagonists are the D-isomers of 2-amino-5-phosphonecarboxylic acids, for example, 2-amino-5-phosphon-valeric acid (D-APV) and 2-amino-7-phosphonepheptonic acid ( D-APH) while exhibiting moderate antagonistic activity

DK 165293B

3 of D-isomers of long-chain 2-amino dicarboxylic acids (e.g., D-2-amino-adipic acid) and long-chain diaminodicarboxylic acids (e.g., diaminopiraelic acid). The NMDA-induced synaptic response has been extensively investigated in mammalian CNS, especially in the spinal cord (J.Davies et al., J. Physiol. 297, 621-35 (1979) and these responses 2+ have been shown to be highly 2) Quisqualate receptors are selectively activated by quisqualate and other potent agonists are AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and L-glutamic acid. Glutamic acid diethyl ester (GDEE) is a selective but very weak antagonist at this binding site. Quis-2+ qualat receptors are relatively insensitive to Mg 15

It is well known that an excitatory amino acid projection exists from the prefrontal cortex to the nucleus accumbens (a special part of the forebrain containing dopamine neurons) (Christie et al., J. Neurochem.

45, 477-82 (1985)). Furthermore, it is well known that glutamate regulates the dopaminergic transmission in the striatum (Rudolph et al., Neurochem. Int. 5, 479-86 (1983)) and the hyperactivity-associated presynaptic stimulation of the dopamine system by AMPA in the nucleus accumbens 25 (Arnt Life Sci. 28, 1597-1603 (1981)).

Quisqualate antagonists are therefore useful as neuroleptics.

3) Kainate receptors. Excitatory responses to kainic acid are relatively unaffected by antagonism from NMDA antagonists and GDEE, and it is suggested that kainic acid activates a third subclass of acidic amino acid receptors. Certain lactonized derivatives of kainic acid are selective antagonists (0. Goldberg et al., Neosroci. Lett. 23, 187-91 (1981)) and the dipeptide of 3-glulamyl-glycine also shows some selectivity for kainate. - 4

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2+ 2+ receptors. Ca, but not Mg, is a strong inhibitor of kainic acid binding.

The affinity of a compound to one or more of the different types of excitatory amino acid receptors can be studied in simple binding experiments. Briefly, the method is to incubate a specially selected radioactive ligand and the specific substance to be investigated with brain homogenate containing the receptor. Receptor saturation is measured by determining the radioactivity bound to the homogenate and by subtracting the nonspecific binding.

Quisqualate receptor binding can be studied using H-AMPA as a radioligand.

The influence of glutamic acid analogues on secondary effects of glutamate receptor interactions can be studied in vitro using brain slices. Such experiments provide information on the efficacy of the test substances (agonist / antagonist). This is not the case in binding studies which only provide information on the affinity of the compounds for the receptor.

It has now been found that the quinoxaline compounds as well as salts thereof of the present invention have affinity for the quisqualate receptors and are antagonists of these types of receptors, making them useful in the treatment of any of the numerous symptoms caused by hyperactivity of the excitatory amino acids and especially as neuroleptics.

Some compounds of the present invention have also exhibited glycine receptor activity.

DK Application No. 4716/87 relates to simple substituted quinoxalindions, while the present invention 35

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relates to substituted tricyclic hydroxy acids. Thus, since these are two different heterocyclic skeletal types, the compounds of the present invention cannot be considered as homologous or closely related to the compounds known from this DK patent.

Danish Patent Application No. 1421/88 discloses tricyclic aromatic structures containing a quinoxalin ion, whereas the compounds of the invention are cyclic hydroxy acids and thus compounds of a completely different type and with substantially different physicochemical properties than the compounds known from the above application. . The compounds in question can therefore not be considered to be closely related to those from DK application no.

15 1421/88 known compounds.

From Danish Patent Application No. 6206/88, quinoxaline-2,3-dione compounds are also known with affinity for the quis-qualat receptors, which compounds are publicly available prior to the filing date of the compounds disclosed in this application in Examples 8, 9 and 10. In the data listed in Table 2, it is evident that the compounds mentioned in Examples 8 and 10, in contrast to the known, closely related compounds, exhibit a markedly lower acute toxicity.

The quinoxaline compounds of the invention have the general formula I

30 7 f8 «Η

Zcc R5 35

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Wherein R 6 and R 5 together form a further condensed 7 8 benzene, cyclohexyl or pyridine ring and R 5 and R 5 are independently hydrogen, halogen, acetyl, CN or SO 2 NHCCO 2 CO 2 H 5, or 7 8 R and R together form a further condensed 5 6 is a benzene, cyclohexyl or pyridine ring, and R and R 10 are independently hydrogen, halogen, acetyl, CN or SO 2 NHCCO 2 CO 2 H 5, or 5 6 7 6 * 7 8 R, R and R. or R, R and R together represent a benzopyranodione ring, or salts thereof.

15

The invention also relates to a process for preparing the above-mentioned compounds, which process is characterized by:

A) reduction of a compound of formula II

8

R

25 XX

Wherein R, R °, R7 and R ° have the above meanings, to form the compound of formula I wherein R, R, R

Q

R has the above meanings.

Reduction of compound II is typically carried out at room temperature in dimethylformamide, ethanol, ethyl acetate or tetrahydrofuran and using Ra-Ni,

Pt-C or Pd-C as catalyst.

7

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The pharmacological properties of the compounds of the invention can be illustrated by determining their ability to displace radiolabeled 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) from quisqualate 5 receptors. The antagonistic properties of the compounds of the invention can be demonstrated by their ability to antagonize quisqualic acid-stimulated H-GABA efflux from cultured rat cortex neurons.

The displacement activity of the compounds can be shown by determining the IC₂ value which represents the concentration (pg / ml) causing a displacement of 50% 3 of the specific H-AMPA binding.

The antagonism is measured by determining the ECg ^ value which represents the concentration which reduces the rate of quisqualic acid-stimulated H-GABA efflux by 50%.

20 3H-AMPA binding (Test 1) 500 μΐ thawed cerebral cortical membrane homogenate from rats in Tris-HCl (30 mM), CaCl3 (2.5 mM) and KSCN (100 25 mM) pH 7.1 was incubated at 0 ° C for 30 min. with 25 μΐ 3 H-AMPA (5 nM final concentration) and the test compound and buffer. Nonspecific binding was determined by incubation with L-glutamic acid (600 μΜ final concentration). The binding reaction was stopped by the addition of 5 ml of 30 ice-cold buffer followed by filtration through Whatman GF / C fiberglass filters and 2x5 ml wash with ice-cold buffer. Bound radioactivity was measured by scintillation counting. ICgg was determined by Hill analysis of at least four concentrations of the test compound.

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8 IC50 = (applied test substance wife) x --- pg / ml [% -] where C is specific binding in control samples and C is

O .X

specific binding in test samples.

10 Cell Cultures (Test 2)

Cerebral cortices from 16-day-old embryos are cut into 0.4 x 0.4 mm cubes. The tissue is separated by gentle trypsin treatment (0.1% · (wt / vol) trypsin, 37 ° C, 15 min) and then seeded into pbly-L-lysine coated 3 cm Petri dishes containing a slightly modified DMEM (DULBECO minimal essential medium ) (24.5 mM KCl, 30 mM glucose) added p-aminobenzoate (7μΜ), insulin (100 mU / 1) and 10% (v / v) horse serum. The cells are cultured for 5-7 days with 20 addition of the antimitotic drug cytosine arabinoside (40 μΜ) from day 2 in vitro to prevent glial growth.

For further details and references see Drejer et al. (Exp. Brain Res. 47, 259 (1982)).

25 Release experiments

Release experiments are performed using the model as described by Drejer et al. (Life Sci. 38, 2077 (1986)). Cerebral cortex interneurons grown in 30 petri dishes (30 mm) are added to 100 μΜ gamma-vinyl-GABA one hour before the experiment to inhibit degradation of GABA in the neurons. 30 min. before the experiment, 35 µCi of H-GABA is added to each culture, and after this preincubation period, the cell monolayer is covered with a piece of nylon sieve at the bottom of the dish to protect the cells from mechanical damage and to facilitate distribution of the medium over the cell layer. The pre-incubation medium is removed and Pe- 9

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the tricycles are placed in a superfusion system. This system consists of a peristaltic pump which continuously supplies thermostatically heated 37 ° C superfusion medium (HE-PES (hydroxyethylpiperazinethanesulfonic acid) buffered salt (HBS): 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6 mM MgSO , 0 mM CaCl 2 and 6 mM D-glucose; pH 7.4) from a reservoir to the top of the slightly inclined petri dish. The medium is continuously collected from the bottom of the bowl and fed to a fraction collector. First, cells are poured with HBS for 15 min. (flow rate 2 ml / min). The cells are stimulated for 30 seconds. every 4 min. by changing the superfusion medium from HBS to a corresponding medium containing quisqualate and test compound 3. Release of H-GABA in the presence of quis-15 qualat (stimulated release in cpm) is corrected for mean base release (Cpm) before and after the stimulation. The stimulated release in the presence of antagonists is expressed in relation to the stimulated release of quisqualate alone and the IC1Q value of the antagonist can be calculated from a dose-response curve.

The test result is given as K +, which is the expected ICgQ value if the experiments were performed using a QUIS concentration (K_ = 0.015 µg / ml) which gives 3 to 25 half of the maximum H-GABA release.

Test results obtained by testing some compounds of the present invention will be shown in Table 1 below.

30 35 5 10

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Table 1

Test 1 Test 2

Compound IC, - K, ou in Example pg / ml pg / ml 10 lb 0.61 0.12 2 c 0.39 0.13 4 b 0.23 0.16 5b. . 0.49 0.14 10 0.21 0.1 15

For the determination of acute toxicity in mice for the known, most closely related compounds from DK Patent Application No. 6206/88 and the compounds mentioned in Examples.

The following tests 8, 9 and 10 are performed:

Acute toxicity in mice

The test compound is administered i.v. in increasing doses to 25 male or female NMRI mice (20-25 g) at each dose level. The animals are observed for 48 hours and mortality was noted after this time period. *

Three or four doses are administered to 4 mice per dose, with 30 doses both above and below the ED ^Q value.

The ED ^ value was calculated as the dose at which 50% of the mice died, using a computer program based on Litchfield and Wilcoxon's (1949) method.

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11

Table 2 5 8

R OH

χάχ id V NH ^ 0 10

Compound R ^ R ^ Tox mice i.v.

mg / kg 15 -: - 8c benzopyranodione ring> 50 lOd CH 3 CO 0 H> 50 20 29 * Cl Η Η I = 30 *

Danish patent application no. 6206/88.

25

As can be seen from Table 2, these data show that the compounds of Examples 8 and 10 of the present application have a markedly lower toxicity compared to the closely related compounds known from DK ans.

30 No. 6206/88.

The pharmaceutical compositions or compositions containing the compounds of the invention can be administered to humans or animals by oral or parenteral route.

An effective amount of the active compound or a »

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12 pharmaceutically acceptable salt thereof may be determined according to the usual factors, such as the nature of the disease, its severity, and the weight of the mammal in need of treatment.

5

Conventional carriers are pharmaceutically acceptable organic or inorganic carriers suitable for parenteral, oral or rectal administration and which do not adversely react with the active compounds.

Examples of such carriers are water, saline, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pyrythrityl acid hydroxyl acid hydroxyl acid, pentaerythritol fatty acid fatty acid fatty acid

The pharmaceutical preparations may, if desired, be sterilized and blended with auxiliaries such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, a salt which influences osmotic pressure, buffers and / or dyes and the like, which are not harmful. reacts with the active compounds.

Injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil, are particularly well suited for parenteral administration.

Ampoules are appropriate unit doses.

Tablets, dragons, or capsules containing talc and 35 or a carrier or binder or the like are especially suitable for oral administration. The carrier is most often lactose and / or corn starch and / or potato.

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13 starch.

A syrup, elixir, or the like can be used in cases where a sweetened carrier can be used or desired.

Generally, the compounds of this invention are dispensed in unit dosage form containing 50-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dose.

The dosage of the compounds of this invention is 1-500 mg / day, e.g. ca. 100 mg per dose, administered to patients, e.g. people, as a drug.

15

A typical tablet which can be prepared by conventional tablet manufacturing techniques contains: Core: 20

Active Compound (as 100 mg free compound or salt thereof)

Colloidal silicone dioxide (Aerosil) 1.5 mg

Cellulose, microcryst. (Avicel) 70 mg 25 Modified Cellulose Rubber (Ac-Di-Sol) 7.5 rag

Magnesium stearate 1 mg *

Coating: 30 HPMC approx. 9 mg

Mywacett 9-40 τ approx. 0.9 mg *

Acylated monoglyceride used as plastic coating agent 35

The free quinoxaline compounds of the invention which form alkali metal or alkaline earth metal salts can be used.

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14 is reversed in such a salt form. Such alkali metal or alkaline earth metal salts are usually formed by reacting the guinoxaline compound with an equivalent amount or more of the selected alkali metal or alkaline earth metal 5 as hydroxide, most often and best when mixed in the presence of a neutral solvent from which the salt can be precipitated or otherwise collected. eg. by evaporation. Administration of a compound of the invention is often preferred in the form of a pharmaceutically acceptable water-soluble alkali metal or alkaline earth metal salt thereof, and orally, rectally, or parenterally in the form of a pharmaceutical composition in which it is present together with a pharmaceutically acceptable liquid or a liquid. solid carrier or diluent.

The compounds of the invention, together with a conventional excipient, carrier, or diluent, may be formulated into pharmaceutical compositions and unit doses thereof, and in this form may be used in solid form such as tablets or filled capsules, or liquids such as solutions, suspensions. , emulsions, elixirs or capsules filled with the same, all for oral use, in the form of rectal suppositories; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional conditions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitably effective neuroleptic, especially quisqualate-antagonistic, amount of the active compound corresponding to the daily dose intended to be used. Thus, tablets containing 10-200 mg, and more specifically 50-100 mg of active compound per tablet, are suitably representative unit dosage forms.

15

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Because of their high degree of neuroleptic, especially quisqualatan tagonic, activity and their low toxicity, which together signifies an extremely favorable therapeutic index, the compounds of the invention can be administered to an individual, e.g. a human or animal in need of such neuroleptic treatment, elimination, relief, or relief of a symptom sensitive to change in the quisqualate system, often best in the form of an alkali metal or alkaline earth metal salt thereof, concurrently with, simultaneously with, or together with a pharmaceutically acceptable carrier or diluent, in particular and preferably in the form of a pharmaceutical composition thereof, either orally, rectally, or parenterally (including subcutaneously), in an effective amount. Appropriate doses are 50-200 milligrams daily, preferably 50-100 milligrams daily, and especially 70-100 milligrams daily, depending on the actual mode of administration, form under which the treatment is targeted, the individual involved and the patient involved. the individual's body weight, and the preference and experience of the responsible physician or veterinarian. Such a method of treatment may be described as treating a symptom caused by, or related to, hyperactivity of the excitatory neurotransmitters, and in particular the quisqualate receptors, of a subject in need comprising administering to said subject a neurological or neuroleptic effective amount of a quisqualate antagonistic quinoxa-lin compound of the invention.

30

The invention will now be described in further detail with reference to the following examples.

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EXAMPLE 1 a. 4-Bromo-1-ethoxalylamine-2-nitronaphthalene 5

A solution of 4.0 g (15.0 mmol) of 4-bromo-2-nitro-1-naphthylamine and 4.0 ml (29.1 mmol) of dry triethylamine in 200 ml of dry tetrahydrofuran was added to a solution of 3, 8 ml (34.2 mmol) of ethyloxalyl chloride in 30 ml of dry tetrahydrofurfuran. The reaction mixture was stirred at 25 ° C for 24 hours, filtered and evaporated in vacuo. The residue was recrystallized (ethanol-water) to give 4.5 g (82%) of 4-bromo-1-ethoxalylamino-2-nitronaphthalene.

Mp. 190-1 ° C.

B. 4-Hydroxy-benzo [f] quinoxaline-2,3 (1H, 4H) -dione

A solution of 0.5 g (1.36 mmol) of 4-bromo-1-ethoxalyl-20-amino-2-nitronaphthalene in 30 ml of tetrahydrofuran was added to 10 ml of dimethyl formamide and 0.7 ml of 25% ammonia water. The mixture was hydrogenated at atm. pressure using 50 mg of 5% Pd-C as catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. The filtrate was acidified with 4N hydrochloric acid and recrystallization (dimethylformamide-water) of the precipitated product gave 0.2 g (65%) of 4-hydroxy-benzo [f] quinoxaline-2,3 (1H, 4H) -dione . Mp. 270 ° C decomp. 1 H-NMR (DMSO-dg 12.1 (1H, broad s), 8.6 (1H, m), 7.7 (5H, m). MS (m / e): 228 ( M +, 90%).

EXAMPLE 2

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17 a. 4-Cyano-1-ethoxalylaminonaphthalene 5

A solution of 6.73 g (40.0 mmol) of 4-cyano-1-naphthyl-amih and 11.2 ml (80 mmol) of dry triethylamine in 200 ml of dry tetrahydrofuran was added at 0 ° C to a solution of 8.9 ml (80 mmol) of ethyloxalyl chloride in 40 ml of dry tetrahydrofuran. Stirring was continued at 25 ° C for 1 hour, then the mixture was filtered and evaporated in vacuo. The residue was stirred with ethanol to give 10.0 g (94%) of 4-cyano-1-ethoxalylaminonaphthalene. Mp. 163.8 ° C.

B. 4-Cyano-1 ~ ethoxalylamino-2-nitronaphthalene

A solution of 4.2 g (15.7 mmol) of 4-cyano-1-ethoxalyl-aminonaphthalene in 125 ml of ice-cold acetic acid was added to 125 ml of acetic anhydride. At 15 ° C, a solution of 12 ml of 100% nitric acid in 60 ml of ice-cold acetic acid was added dropwise. Stirring was continued at 25 ° C for 24 hours and then at 50 ° C for 1.5 hours. The reaction mixture was poured into 500 ml of ice water to give 3.5 g (72%). Mp.

178.0 ° C.

c. 6-Cyano-4-hydroxy-benzo [f] quinoxaline-2,3 (1H, 4H) -dione A solution of 0.5 g (1.59 mmol) of 4-cyano-1-ethoxalylamino 2-nitronaphthalene in 30 ml of tetrahydrofuran was added 10 ml of dimethylformamide and 0.7 ml of 25% ammonia water. The mixture was hydrogenated at atm. pressure using 100 mg of 5% Pd-C as catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. The filtrate was made acidic

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18 with 4n hydrochloric acid to give 0.2 g (50%) of 6-cyano-4-hydroxybenzo [f] quinoxaline-2,3 -3 (1H, 4H) -dione. Mp. 275 ° C decomp. IR (KBr): 3420 (m, wide), 330-2800 (m), 2220 (m), 1760 (s), 1585 (m), 1530 (m), 1370 (m) cm .

EXAMPLE 3 a. 6-Bromo-2-ethoxalylamino-1-nitronaphthalene 10

A solution of 1.0 g (3.75 ml) of 6-bromo-1-nitro-2-naphthylamine and 0.8 ml (5.81 mmol) of dry triethylamine in 100 ml of dry tetrahydrofuran was added to a solution of 0 7 ml (6.27 mmol) of ethyloxalyl chloride in 25 ml of dry tetrahydrofuran. The reaction mixture was stirred at 25 ° C for 24 h, then filtered and evaporated in vacuo. The residue was recrystallized (ethanol) to give 1.2 g (87%) of 6-bromo-2-ethoxalylamino-1-nitronaphthalene. Mp. 174-5 ° C.

B. 1-Hydroxy-benzo [f] quinoxaline-2,3 (1H, 4H) -dione

A solution of 0.5 g (1; 36 mmol) of 6-bromo-2-ethoxalyl-25-amino-1-nitronaphthalene in 30 ml of tetrahydrofuran was added to 10 ml of dimethylformamide and 0.7 ml of 25% ammonia water. The mixture was hydrogenated * at atm. pressure using 100 mg of 5% Pd-C as catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. The filtrate was acidified with 4N hydrochloric acid to give 0.15 g (50%) of 1-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione. Mp. 220 ° C decomposition X H-NMR (DMSO-d 6): 12.3 (1H, broad s), 9.2 (1H, 35 m), 7.5 (5H, m).

EXAMPLE 4

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19 a. 5-Ethoxalylamino-6-nitroquinoline 5

A solution of 1.3 g (6.9 mmol) of 5-amino-6-nitroquinoline and 3.0 ml (21 mmol). dry triethylamine in 100 ml of dry tetrahydrofuran was added a solution of 2.5 ml (22.3 mmol) of ethyloxalyl chloride. The reaction mixture was stirred at 80 ° C for 1.5 hours. After cooling to 25 ° C, the mixture was evaporated in vacuo and the residue was stirred with water to give 1.9 g (96%) of 5-ethoxalylamino-6-ni-troguinoline. Mp. 180.7 ° C.

B. 4-Hydroxypyrido [3,2-f] quinoxaline-2,3 (1H, 4H) -dione 1.85 g (6.4 mmol) of 5-ethoxalylamino-6-nitroquinoline in 100 ml of tetrahydrofuranrdimethylformamide: 25% ammonia -20 water (30: 10: 0.7) was hydrogenated at atm. pressure using 200 mg of 5% Pt-C as catalyst. The precipitate was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid to give 0.78 g of crude product. The crude product was recrystallized (dimethylformamide-water) to give 0.58 g (34%) of 4-hydroxypyrido [3,2-f] quinoxaline-2,3- (1H, 4H) -dione hydrochloride. Mp. decomp. 1 H-NMR (DMSO-d 6): 12.5 (1H, broad s), 9.2-7.4 (5H, m). MS 30 (m / e): 229 (M +, 100%), 184 (60%).

EXAMPLE 5 a. 5-Ethoxalylamino-1,2,3,4-tetrahydro-6-nitronaphthalene

A solution of ethyloxalyl chloride (1.3 ml, 11.6 mmol)

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20 in 10 ml of dry tetrahydrofuran was added dropwise to a solution of 5-amino-1,2,3,4-tetrahydro-6-nitronaphthalene (2.2 g, 11.4 mmol) and dry triethylamine (1.6 ml (11.6 mmol) in 50 ml of dry tetrahydrofuran with stirring 5 at 0 ° C. Then the mixture was stirred at room temperature for 30 min. An additional equivalent of dry triethylamine and ethyloxalyl chloride was added dropwise to the mixture. After 1 hour at reflux temperature, the mixture was cooled on ice and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from ethanol to give 2.9 g (87%) of the pure title compound. Mp. 121-122 ° C; NMR (CDCl3): 1.47 (t, J = Hz, 3H, CH3), 1.66-2.02 (m, 4H, 2CH2), 2.57-3.05 (m, 4H, 2CH2) , 4.47 (q, J = 7 Hz, 2H, CH 2), 7.23 (d, J 15 = 9 Hz, 1H, ArH), 7.88 (d, J = 9 Hz, 1H, ArH), 9.77 (broad s, 1H, NH).

b. 7,8,9,10-Tetrahydro-4-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione

A solution of 25% ammonium hydroxide in water (0.7 ml) was added to a solution of 5-ethoxalylamino-1,2,3,4-tetrahydro-6-nitronaphthalene (0.30 g, 1 mmol) in a mixture. 25 of 10 ml of Ν, Ν-dimethylformamide and 30 ml of tetrahydrofuran. The mixture was hydrogenated at atmospheric pressure and room temperature in the presence of 5% platinum on coal until the starting material had disappeared. The mixture was filtered and the filtrate discarded. The filter was then washed with 5% aqueous potassium hydroxide and the filtrate acidified with 4N hydrochloric acid. The white precipitate was isolated by filtration and washed with water and ethanol to give 0.11 g (46%) of the title compound. Mp.

> 225 ° C decomposition; 1 H NMR (DMSO-d 6): 1.57-1.90 (m, 4H, 2CH 2), 2.50-2.93 (m, 4H, 2CH 2), 6.95 (d, J = 9 Hz , 1H, ArH), 7.30 (d, J = 9 Hz, 1H, ArH); ca. 11.1 (very broad s, 1H, NH); IR (KBr): 1670 cm -1; MS (m / e): 232

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21 (M +, 87%).

Example 6 a. 4-Bromo-1-ethoxalylamino-2-nitronaphthalene

A solution of ethyloxalyl chloride (1.1 ml, 9.8 mmol) in 15 ml of dry tetrahydrofuran was added dropwise to a solution of 1-amino-4-bromo-2-nitronaphthalene (0.9 g, 3.2 mmol) and dry triethylamine (1.37 ml, 9.8 mmol) in 20 ml of dry tetrahydrofuran with stirring at 0 ° C. The mixture was stirred for 1 hour at room temperature and filtered. The filtrate was evaporated to dryness and the oily residue was boiled in 25 ml of 96% ethanol for 15 minutes. After cooling on ice, the solid product was isolated by filtration and washed with a small amount of cold ethanol to give 0.9 g (74%) of the title compound.

Mp. 191-192 ° C; 1 H-NMR (CDCl 3): 1.4 (t, J = 7 Hz, 3H, CH 3), 4.40 (q, J = 7 Hz, 2H, CH 2), 7.43-8.33 (m, 5H,

ArH), 10.0 (broad s, 1H, NH).

b. 6-Bromo-4-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione

A solution of 4-bromo-1-ethoxalylamino-2-nitronaphthalene (0.20 g, 0.5 mmol) in 20 ml tf, N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of a small amount of Raney-Ni . After the hydrogen uptake was complete, the mixture was filtered. The filtrate was evaporated to dryness and the residue was triturated with water and hot ethanol to give 100 mg (62%) of the title compound. Mp. > 200 ° C decomposition; IR (KBr): 1690 cm ”1; MS (m / e): 306 (M +, 2%), 308 ((M + 2) +, 2%).

EXAMPLE 7

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22 a. 5-Bromo-8-ethoxalylaminoquinoline 5

A solution of 2.5 g (17.4 mmol) of 8-aminoquinoline in 60 ml of dry tetrahydrofuran was added 2.8 ml (20.0 mmol) of dry triethylamine and the reaction mixture was cooled to 0 ° C.

2.2 ml (19.7 mmol) of ethyloxalyl chloride in 20 ml of dry tetrahydrofuran was added dropwise and the reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was evaporated in vacuo and the residue was stirred with water. The precipitate was filtered off (4.0 g).

The precipitate was dissolved in 100 ml of dry dimethyl formamide and 3.5 g (19.7 mmol) of N-bromosuccinimide was added. The reaction mixture was stirred at 25 ° C for 18 hours and at 100 ° C for 1 hour. The reaction mixture was evaporated in vacuo and the residue was stirred with water. The precipitate was filtered off to give 5.0 g (89%) of 5-Bromo-8-ethoxalylaminoquinoline. Mp. 152 ° C.

b. 5-Bromo-8-ethoxalylamino-7-nitroquinoline 25 '10 ml of 100% nitric acid was cooled to 0 ° C and 1.0 g (3.1 mmol) of 5-Bromo-8-ethoxalylaminoquinoline was added gradually. The reaction mixture was stirred at 25 ° C for 1/2 hour and then poured into 150 ml of ice water. The precipitate was filtered off, washed with water and ethanol to give 1.0 g (88%) of 5-Bromo-8-ethoxalylamino-7-nitroquinoline. Mp. 213-215 ° C.

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23 c. 6-Bromo-4-hydroxypyrido [2,3-f] quinoxaline-2,3- (1H, 4H) -dione 5 0.59 (1.4 nmol) 5-Bromo-8-ethoxalylamino-7- nitroquinoline in 30 ml of ethanol was hydrogenated at atm. pressure with 100 mg (5%) of Pt / c as catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The evaporation residue was stirred with water and the precipitate was filtered off. The crude product was washed with ethanol to give 0.3 g (72%) of 6-Bromo-4-hydroxypyrido [2,3-f] quinoxaline-2,3- (1H, 4H) -dione. Snip, decomposition MS m / z: 307 (M +, 20%), 291 (70%), 156 (100%), 128 (70%).

D. 4-Hydroxypyrido [2,3-f] quinoxaline-2,3 (1H, 4H) -dione 0.3 g (1.0 mmol) 6-Bromo-4-hydroxypyrido [2,3-f] quinoxa -lin-2,3 (1H, 4H) -dione in 20 ml of dimethylformamide was hydrogenated at atm. pressure with 300 mg Pd / c (5%) as catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred with ethanol and the precipitate filtered off to give 0.2 g (90%) of 4-hydroxypyrido [2,3-f] quinoxaline-2,3 (1H, 4H) -25 dione. Mp. decomposing MS m / z: 229 (M +, 25%), 212 (100%), 185 (45%).

EXAMPLE 8 a. 3-Ethoxalylamino-1,8-naphthalene dicarboxylic anhydride

A solution of 3-amino-1,8-naphthalene dicarboxylic acid anhydride (2.13 g, 10 mmol) and dry triethylamine (1.53 ml, 11 mmol) in 90 ml of dry Ν, Ν-dimethylformamide, a solution of ethyl oxalyl chloride ( 1.23 ml, 11 mmol) in 10 ml

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Twenty-four dry N, N-dimethylformamide was added dropwise at 50 ° C with stirring. Stirring was continued for 30 min. at room temperature and then for 1.5 hours at 0 ° C. The mixture was filtered and the precipitate was washed successively with water, ethanol and ether to give 2.40 g (77%) of the pure title compound. Mp. 275-276 ° C; 1 H-NMR (DMSO-d 6): I, 35 (t, J = 7Hz, 3H, CH 3), 4.33 (q, J = 7Hz, 2H, CH 2), 7.73 (t, J = 8Hz, 1H, H-6), 8.20-8.83 (m, 4H, ArH), II, 33 (s, 1H, NH).

10 b. 3-Ethoxalylamino-4-nitro-1,8-naphthalene dicarboxylic acid anhydride Powdered potassium nitrate (0.51 g, 5 mmol) was added to a stirred solution of 3-ethoxalylamino-1,8-naphthalene dicarboxylic anhydride (1 , 57 g, 5 mmol) in 15 ml of wife. sulfuric acid at 0 ° C. Stirring was continued for 2 hours at the same temperature, after which the reaction mixture was poured into 150 ml of ice water. The precipitated yellow solid was isolated by filtration and washed with water, ethanol and ether. Trituration with a small amount of ethyl acetate afforded 1.38 g (77%) of the title compound. Mp. 221-222 ° C; hi-NMR (CDCl3 + DMSO- d6): 1.43 (t, J + 7Hz, 3H, CH3), 4.37 (q, J = 7Hz, 2H, CH2), 7.70-8.60 ( m, 3H, ArH), 8.82 (s, 1H, H-2), 11.3 (broad s, 1H, NH).

[?] 11-Hydroxy-4H, 6H- [2] benzopyrano [4,5-gf] quinoxaline-4,6,9,10 (8H, 11H) -tetron 30 -

A solution of 3-ethoxalylamino-4-nitro-1,8-naphthalene-dicarboxylic anhydride (0.63 g, 1.75 mmol) in 50 ml of ethanol and 25 ml of N, N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure over 5% platinum on charcoal until the theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration and filtered.

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The funnel was evaporated to dryness. The evaporation residue was triturated with ethanol to give the crude product, which was dissolved in 10 ml of 1N potassium hydroxide, treated with activated charcoal, filtered and redissolved with 4M hydrochloric acid 5 to give 100 mg (19%) of the title compound. Mp.

276 ° C decomposition (DSC); IR (KBr): 1770, 1705, 1668 cm -1; 1 H NMR (DMSO-d 6): 7.5-9.6 (m, 4H, ArH), 12.6 (broad s, 1H, NH or OH , only one interchangeable proton could be seen); MS m / e; 298 (M +, 7%).

EXAMPLE 9 a. 1,2,3,4-Tetrahydro-8-nitro-5-naphthalenesulfonamide 15

A solution of 1,2,3,4-tetrahydro-8-nitro-5-naphthylamine (4.4 g, 25 mmol) in a mixture of 90 ml of acetic acid and 100 ml of 4M hydrochloric acid was diazotized with a solution of sodium nitrite ( 1.74 g, 25 mmol) in 50 ml of water while stirring at 0 ° C. Stirring was continued for 1 hour at this temperature. Meanwhile, a saturated solution of sulfur dioxide in 90 ml of acetic acid was prepared. Then, a solution of cuprichloride (0.55 g, 4 mmol) in 20 ml of water was added, followed by addition of diazonium brine 25 with stirring at 0 ° C. After 1 hour at this temperature, 50 ml of ice water was added and the solid product was isolated by filtration and washed with water to give 4.1 g of crude 1,2,3,4-tetrahydro-8-nitro-5-naphthalene sulfonyl chloride. Without further purification, this was dissolved in 50 ml of dry tetrahydrofuran, and ammonia gas was bubbled through the solution for 30 minutes. with stirring at room temperature. The mixture was evaporated to dryness and the solid precipitate triturated with water, filtered off and washed with water and ethanol to give 3.3 g (52%) of the title compound. Mp. 203-206 ° C; 1 H-NMR

(DMSO- d6): 1.57-1.95 (m, 4H, 2CH2), 2.62-3.33 (m, 4H, 2CH2), 7.53 (s, 2H, NH2), 7.65 (d, J -9Hz, 1H, ArH),

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Δ 7.85 (d, J = 9Hz, 1H, ArH).

b. 8-Amino-1,2,3,4-tetrahydro-5-naphthalenesulfonamide 5

A suspension of 1,2,3,4-tetrahydro-8-nitro-5-naphtha-lensulfonamide (3.1 g, 12 nunol) in 150 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over Raney-Ni. After the theoretical absorption, the reaction mixture was filtered and concentrated to dryness to give 2.6 g (95%) of the title compound. Mp. 216-219 ° C (ethanol); 1 H NMR (DMSO-d 6): 1.50-1.93 (m, 4H, 2CH 2), 2.17-2.57 (m, 2H, CH 2), 2.83-3.17 (m, 2H , CH2), 5.29 (wide s, 2H, NH2), 6.38 (d, J = 9Hz, 1H, ArH), 6.75 (wide s, 1H, SO2 NH2), 7.35 (d, J 9Hz, 1H, ArH).

c. 5-Ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydronaphthalene. Dry triethylamine (4.2 ml, 30 mole) was added to a solution of 8-amino-1,2,3,4-tetrahydro-hydroxide. 5-naphthalenesulfonamide (2.3 g, 10 mmol) in 100 ml dry tetrahydrofuran.

Then, a solution of ethyloxalyl chloride 25 (3.4 ml, 30 mmol) in 30 ml of dry tetrahydrofuran was added dropwise at 0 ° C with stirring. The mixture was stirred overnight at room temperature and filtered. The filtrate was evaporated to dryness and the residue was stirred with ethanol to give 2.5 g (59%) of the title compound. Mp.

160-161 ° C; 1 H-NMR (DMSO): 1.23 (t, J = 7Hz, 3H, CHg), 1.30 (t, J «7Hz, 3H, CHg), 1.55-1.92 (m, 4H, 2CH₂), 2.50-2.80 (m, 2H, CH2), 2.92 (m, 2H, CH2), 4.13 (q, J = 7Hz, 2H, CH2), 4.25 (q, J = 7Hz , 2H, CH 2), 7.38 (d, J = 9Hz, 1H, ArH), 7.77 (d, J - 9Hz, 1H, ArH), 9.56 (very broad s, 1H, SO 2 NH), 10.3 (s, 1H, NH).

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27 d. 5-Ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydro-6-nitronaphthalene 5 Potassium nitrate (0.24 g, 2.3 mmol) was added to a solution of 5-ethoxalylamino-8-ethoxalylaminosulfonyl -1,2,3,4-tetrahydronaphthalene (1.0 g, 2.3 mmol) in 12 ml of wife. sulfuric acid with stirring at 0 ° C. Stirring was continued for 2 hours at this temperature and then the mixture was poured into 75 ml of ice water. The separated product was isolated by suction and washed repeatedly with water to give 0.64 g (58%) of sufficiently pure title compound. Mp. 140-142 ° C (ethanol); α H NMR (DMSO-d 6): 1.20 (t, J = 7Hz, 3H, CH 3), 1.30 (t, J = 7Hz, 3H, CH 3), 1.58-1.90 (m, 4H, 2CH2), 2.60-2.90 (m, 2H, CH2), 3.05-3.33 (m, 2H, CH2), 3.95-4.60 (m, 4H, 2CH2), 8.27 (s, 1H, ArH), 10.9 (broad s, 1H, NH, only one interchangeable proton could be seen).

E. 6-Ethoxalylaminosulfonyl-7,8,9,10-tetrahydro-4-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione

A suspension of 5-ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydro-6-nitronaphthalene (0.61 g, I, 3 mmol) in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure at room temperature. presence of 60 mg 5% platinum on charcoal. After the theoretical absorption, the mixture was filtered and the filtrate was evaporated to dryness. The crude product (0.51 g) was triturated with 50 ml of water, filtered off and then washed with water and a small amount of cold ethanol to give 0.28 g (53%) of the title compound. Mp. 267 ° C decomposition (DSC); IR (KBr): 1725 cm "1; 1 H NMR (DMSO-d d); 1.23 (t, J = 7Hz, 3H, CH CH), 1.57-1.93 (m, 4H, 2CH₂), 2.63-3.20 (m, 4H, 2CH2), 4.20 (q, J = 7Hz, 2H, CH2), 7.98 (s, 1H, ArH), II (5 s, 1H, NH, only an interchangeable proton could

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28 ses).

EXAMPLE 10 a. 8-Acetyl-1,2,3,4-tetrahydro-5-methoxy-6-nitronaphthalene

A solution of 100% nitric acid (0.42 ml, 10 mmol) in 10 ml of acetic anhydride was added dropwise with stirring at -10 ° to -15 ° C to a solution of 8-acetyl-1,2,3,4-. tetrahydro-5-methoxynaphthalene (2.1 g, 10 mmol) in 25 ml of acetic anhydride containing one drop of a wife. sulfuric acid. Stirring was continued for 20 min. at the same temperature, after which the reaction mixture was poured into 100 ml of ice water. The precipitated crystals were collected by filtration and washed with water and a small amount of cold ethanol to give 1.48 g (59%) of the title compound.

Mp. 76-77 ° C; 1 H-NMR (CDCl 3): 1.60-1.93 (m, 4H, 2CH 2), 2.57 (s, 3H, COCH 3), 2.67-3.13 (m, 4H, 2CH 2), , 88 (s, 3H., OCH 3), 7.97 (s, 1H, H-7).

b. 8-Acetyl-1,2,3,4-tetrahydro-6-nitro-5-naphthylamine

A solution of 8-acetyl-1,2,3,4-tetrahydro-5-methoxy-6-nitronaphthalene (1.0 g, 4 mmol) in 15 ml of dry dimethyl sulfoxide was heated to 100 ° C and ammonia was bubbled through the solution. in 3 hours. After the solution was added to 100 ml of ice water, the crude product was filtered off and washed with water. Recrystallization from ethanol gave 0.71 g (75%) of the pure title compound. mp; 170-172 ° C; 1 H-NMR (DMSO-d 6): 1.47-1.93 (m, 4H, 2CH 2), 2.27-2.63 (m, 2H, CH 2), 2.48 (s, 3H, COCH 3) , 2.70-3.03 (m, 2H, CH 2), 7.50 (broad s, 2H, NH 2), 8.33 (s, 1H, H-7).

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29 c. 8-Acetyl-5-ethoxalylamino-1,2,3,4-tetrahydro-6-nitro-naphthaler 5 Dry triethylamine (0.78 ml, 5.6 mmol) was added to a solution of 8-acetyl-1 , 2,3,4-Tetrahydro-6-nitro-5-naphthylamine (0.66 g, 2.8 mmol) in 50 ml of dry tetrahydrofuran. Then, a solution of ethyloxalyl chloride (0.64 ml, 5.6 mmol) in 5 ml of dry tetrahydrofuran 10 was added dropwise with stirring at room temperature. Stirring was continued for 20 min. at the same temperature, after which the mixture was heated to reflux for 3 hours and cooled. The mixture was filtered and the filtrate evaporated to dryness.

The oily residue was treated with 25 ml of water overnight, and the precipitated solid was isolated by filtration and washed successively with water, cold ethanol and light petroleum to give 0.78 g (83%) of the pure title compound. Mp. 120-121 ° C; 1 H-NMR (CDCl 3): 1.42 (t, J = 7Hz, 3H, CH 2 CH 3), 1.60-1.93 (m, 4H, 2CH 2), 2.50-3.17 (m, 4H , 2CH2), 2.58 (s, 3H, COCHg), 4.37 (q, J »7Hz, 2H, CH2CH3), 8.00 (s, 1H, H-7), 9.57 (broad s, IH, NH).

d. 6-Acetyl-7,8,9,10-tetrahydro-4-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione

A

A solution of 8-acetyl-5-ethoxalylamino-1,2,3,4-tetrahydro-6-nitronaphthalene (0.67 g, 2 mmol) in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure above 50 mg 5% platinum on charcoal for 1 hour. Then, 50 ml of N, N-dime thyl formamide was added to dissolve the precipitated solid and the catalyst removed by filtration. The filtrate was concentrated and the precipitate was washed with 50 ml of ethanol to give 0.40 g (73%) of the title compound. Mp. > 200 ° C decomposition (DSC); IR (KBr): 1709, 1677 cm -1, 1 H NMR (DMSO-d 6): 1.43-1.93 (m,

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4H, 2CH2), 2.57 (s, 3H, COCHg), 2.53-3.07 (m, 4H, 2CH2), 7.57 (s, 1H, H-7), 11.4 (very broad s, 2H, OH and NH); MS (m / e: 274 (M +, 100%)).

5

In conclusion, it is clear from the foregoing that this invention provides new neurologically effective quisqualate antagonistic quinoxaline compounds and salts having favorable and unpredictable properties, as well as novel pharmaceutical compositions thereof, all possessing the above-mentioned more specifically characteristics and advantages.

15 20 25 t 30 35

Claims (8)

1. Quinoxaline compounds of the general formula I 5 8 R OH 'hbcx r γ m 10 i5 wherein 5 6 15. and R together form a further condensed 7 8 benzene, cyclohexyl or pyridine ring and R and R are independently hydrogen, halogen , acetyl, CN or SO2 NHC0CO2 CO2H5, or 7 8 20. and R together form an additional condensed 5 6 benzene, cyclohexyl or pyridine ring and R and R are independently hydrogen, halogen, acetyl, CN or SO2 NHC0CO2C2 Hg, or R, R ° and R 'or R, R' and R ° together represent a benzopyranodione ring, or salts thereof. A compound according to claim 1, characterized in that it is 4-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione. Compound according to claim 1, characterized in that it is 6-cyano-4-hydroxy-benzo [f] quinoxaline-2,3 (1H, 4H) -dione. A compound according to claim 1, characterized in that it is 4-hydroxypyrido [3,2-f] -quinoxaline-2,3 (1H, 4H) -dione. DK 165293B 32 5. A compound according to claim 1, characterized in that it is 7,8,9,10-tetrahydro-4-hydroxybenzo [f] quinoxaline-2,3 (1H, 4H) -dione. Pharmaceutical composition, characterized in that it contains as an active component a quinoxaline compound according to claims 1-5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 6 in the form of a dosage unit containing approx. 50-200 mg of the active compound. A pharmaceutical composition for treating a symptom 15 related to hyperactivity of the excitatory neurotransmitters and, in particular, to the quisqualate receptors, characterized in that it contains as an active ingredient a quinoxaline compound of formula I according to claims 1-5 or a pharmaceutically acceptable salt thereof 20 and a pharmaceutically acceptable carrier. The quinoxaline compound of claims 1-5 for use as a neuroleptic. Process for the preparation of a compound of formula I according to claims 1-5, characterized in. Λ a) reduction of a compound of formula II wherein R 2 MQR, R, Rx and R the formula I wherein R, 6 7 8 5 R, R and R have the above meanings. 10 15 20 25 30 35