DK165294B - Quinoxaline compounds, process for preparing them, and pharmaceutical preparations which comprise the compounds - Google Patents

Description

in

DK 165294B

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

5 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 transmitters for the majority of mammalian excitatory neurons in the CNS.

Interaction with glutamic acid-mediated neurotransmission 15 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 20 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. after 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).

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

Such receptors are currently subdivided for convenience.

DK 165294B

There are two reasons for three groups, based on results of electrophysiological and neurochemical studies: 1 NMDA (N-methyl-D-aspartate) receptors, 2 quisqualate receptors, and 3 kainate receptors. L-glutamic acid and L-aspartic acid presumably activate all of the aforementioned types of excitatory amino acid receptors and possibly other types of receptors.

The result of excitatory amino acid interaction 10 with postsynaptic receptors is an increase in intracellular cGMP values (G.A. Foster et al., Life 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 finally 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.

20

The above division of excitatory amino acid receptors into NMDA, quisqualate, and kainate receptors is based primarily 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-phosphonephaleric acid (D-APV) and 2-amino-7-phosphonepheptonic acid (D-APH), while moderate antagonistic activity is exhibited by D-isomers of long chain 2-amino dicarboxylic acids (e.g., D-2-amino-adipic acid) and long chain diaminodi-carboxylic acids (e.g., diaminopimelic acid). The NMDA

DK 165294 B

3 induced synaptic responses have been extensively studied 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 strongly inhibited by Mg 5 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. Quisqualate receptors are relatively insensitive to Mg +.

It is well known that an excitatory amino acid projection exists from the prefrontal cortex to nucleus 15 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)) as well as the hyperactivity-associated presynaptic stimulation of the dopamine system by AMPA in the nucleus accumbens (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 carboxylic 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-glutamyl-glycine also shows some selectivity for kainate-2 +. 2+ 35 receptors. Ca, but not Mg, is a strong inhibitor of kainic acid binding.

DK 165294B

4

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.

10

Quisqualate receptor binding can be studied using 3 of 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 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 relates to N-hydroxy quinoxalindions. That is, these are cyclic hydroxy acids and thus compounds of a completely different type and with substantially different

DK 165294B

5 physical-ceramic properties than those known from the DK application. Thus, the compounds in question cannot be regarded as being homologous or closely related to the compounds known from the Danish application.

DK Application No. 1421/88 describes substituted tri-cyclic aromatic structures containing as a sub-element of the aromatic structure a dihydroxyquinoxaline. Thus, since the present application as mentioned above relates to cyclic hydroxy acids, there are again two completely different types of compounds, so the compounds of the present invention cannot be regarded as homologous or closely related to those known from DK application no. 1421/88. compounds.

15

From Danish Patent Application No. 6206/88, quinoxaline-2,3-dione compounds are also known to have affinity for the quis-qualate receptors, which are publicly available prior to the filing date of the compounds 20 disclosed in the present application in Examples 34, 36 and 39. In the data listed in Table 2, it is evident that the compounds mentioned in Examples 34, 36 and 39, in contrast to the known, closely related compounds, exhibit a markedly lower acute toxicity.

25

The quinoxaline compounds of the invention have the general formula I

__ 8 1

30 R R

R Ύ NH 0 0

P

where 35

DK 165294B

6 R * is hydroxy, alkoxy, allyloxy, aralkyloxy, carboxymethyloxy, cycloalkoxy, or OCOR, wherein R is phenoxy, allyl, ethoxy or phenyl; and 5 6 7 8 5 R, R, R and R are independently hydrogen, methyl, halogen, CN, acetyl, methoxycarbonylmethyl, SC1 NR'R ', CF3 or OR' wherein R 'is hydrogen or C1-6 alkyl or five salts thereof; provided R is not Cl when R is hydroxy or acetoxy and R5 is not CH3 or R6 is not CF3 when hydroxy.

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

a) reducing a compound of formula II

8

R

Wherein R, R, R7 and R ° have the above meanings to form a compound of formula III

R OH

XXX

30 * y R5

wherein R 1, R 2, R 7, R 2 have the above meanings, whereupon this compound, if desired, is reacted with a compound of formula IV

DK 165294B

7

R1 '- X IV

wherein R 1 is alkyl, allyl, aralkyl, carboxymethyl, cyclo-alkyl, or COR where R is phenoxy, allyl, ethoxy or phenyl and X is a leaving group to form a compound of formula I wherein R is alkoxy, allyloxy, aralkyloxy, carboxymethyloxy, cycloalkoxy, el-2 2 OCOR where R is phenoxy, allyl, ethoxy or phe-5 6 7 8 10 nyl, and wherein R, R °, R, R ° have 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, 15 Pt-C or Pd-C as catalyst.

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 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.

25

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

30

Antagonism is measured by determining the ECgg value which represents the concentration which reduces the rate of quisqualic acid-stimulated H-GABA efflux by 50%.

35

DK 165294B

8 µH-AMPA binding (Test 1) 500 μΐ thawed cerebral cortical membrane homogenate from rats in Tris-HCl (30 mM), CaCl2 (2.5 mM) and KSCN (100 5 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 10 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. The IC ^ was determined by Hill analysis of at least four concentrations of the test compound.

15 IC ^ Q = (wife of test substance used) x --- pg / ml 20 (¾ - x] where CQ is specific binding in control samples and Cx is specific binding in test samples.

25

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 mild trypsin treatment (0.1% (wt / vol) trypsin, 37 ° C, 15 min) and then seeded in poly-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% 35 (v / v) equine serum. The cells are cultured for 5-7 days with the addition of the antimitotic drug cytosine arabinoside (40 μΜ) from day 2 in vitro to prevent glial growth.

DK 165294B

9

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

Release experiments 5

Release experiments are performed using the model as described by Drejer et al. (Life Sci. 38, 2077 (1986)). Cerebral cortex interneurons grown in petri dishes (30 mm) are added to 100 μΜ of gamma-vinyl-GABA 10 one hour before the experiment to inhibit degradation of GABA in the neurons, 30 min. prior to 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 the Petri dishes are placed in a superfusion system. This system consists of a peristaltic pump that continuously supplies thermostatically heated 37 ° C superfusion medium (HE-20 PES (hydroxyethylpiperazinethanesulfonic acid) buffered salt (HBS): 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6 mM MgSO 1.0 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 lower portion 25 of the bowl and fed to a fraction collector. First, the cells are overheated 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. Release of H-GABA in the presence of quisqualate (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 relative to the stimulated release of quisqualate alone and the IC ICQ value of the antagonist can be calculated from a dose-response curve.

DK 165294B

10

The test result is given as K 2, which is the expected IC 2 -Q value if the tests were performed using a QUIS concentration (Kp 0, 0.015 pg / ml) which gives half the maximum ³H-GABA release.

5

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

Table 1

Test 1 Test 2 15 Compound IC, -,. K.

DU X

in example pg / ml pg / ml 6 d 0.15 0.08 20 10 0.39 0.21 12 0.49 0.20 30 d 0.37 0.12 33 d 0.14 0.02 34 e 0 .09 0.27 25 35 0.52 36 0.45 37 0.72 0.54 38 0.69 0.50 39 0.35 0.66 30

To determine the acute toxicity in mice of the known, most closely related compounds from DK Patent Application No. 6206/88 and the compounds mentioned in Examples 34, 36 and 39, the following tests are performed:

DK 165294 B

11

Acute toxicity in mice

The test compound is administered i.v. in increasing doses to 5 male or female NMRI mice (20-25 g) at each dose level.

The animals were observed for 48 hours and mortality was noted after this time.

Three or four doses are administered to 4 mice per dose, with 10 doses both above and below the ED ^Q value.

The EDgg 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.

15

Table 2; :ά: i 6 7

Compound R R R7 TOX MUS i.v.

25 mg / kg 34 OH CN, CH3 CO = 60 30 36 OCH2CH = CH2 CF3 CN> 50 39 0CH2C00H CF3 CN> 50 29 * OH Cl H = 30 35

DK 165294B

12 *

Danish patent application no. 6206/88.

As shown in Table 2, these data show that the compounds of Examples 34, 36 and 39 in the present application have a markedly lower toxicity compared to the closely related compounds known from DK ans. No. 6206/88.

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

An effective amount of the active compound or a pharmaceutically acceptable salt thereof can 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.

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.

25

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

The pharmaceutical preparations may, if desired, be sterilized and blended with adjuvants such as lubricants, preservatives, stabilizers, wetting agents,

DK 165294B

13 emulsifiers, a salt that influences osmotic pressure, buffers and / or dyes, and the like, which do not adversely react with the active compounds.

5

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

10

Ampoules are appropriate unit doses.

Tablets, dragons, or capsules containing talc and / or a carrier or binder or the like are particularly suitable for oral administration. The carrier is most often lactose and / or corn starch and / or potato 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 30 to patients, e.g. people, as a drug.

A typical tablet which can be prepared by conventional tablet manufacturing techniques contains: 35

DK 165294B

14 Core:

Active Compound (as a free 100 mg compound or salt thereof) Colloidal Silicone Dioxide (Aerosil) 1.5 mg

Cellulose, microcryst. (Avicel) 70 mg

Modified Cellulose Rubber (Ac-Di-Sol) 7.5 mg

Magnesium stearate 1 mg 10 Coatings: HPMC approx. 9 mg

Mywacett 9-40 T® approx. 0.9 mg of ice Acylated monoglyceride used as a plastic coating agent

The free guinoxaline compounds of the invention which form alkali metal or alkaline earth metal salts can be used in such a salt form. Such alkali metal or alkaline earth metal salts are usually formed by reacting the quinoxaline compound with an equivalent amount or more of the selected alkali metal or alkaline earth metal as hydroxide, most often and best by mixing in the presence of a neutral solvent from which the salt can be precipitated or otherwise collected way, e.g. 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 solid carrier or diluent.

The compounds of the invention may, together with a conventional excipient, carrier, or diluent.

DK 165294B

15, 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. use in the form of suppositories for rectal administration; 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 active compound. daily dose that is thought 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.

Because of their high degree of neuroleptic, especially quisqualate antagonistic, activity and their low toxicity, which together signify 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, together 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. Suitable doses are 50-200 milligrams daily, preferably 50-100 milligrams daily, and especially 70-100 milligrams daily, depending on the actual mode of administration, the form in which it is administered, which

DK 165294B

The symptom treatment is aimed at the body weight of the individual and the individual involved, as well as 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 especially the quisgualate receptors, in a subject in need thereof, comprising administering to said subject a neurologic or neuroleptic -10 effective amount of a quisqualate antagonistic quinoxaxine compound of the invention.

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

EXAMPLE 1 a. 1-Chloro-4-ethoxalylamino-3-nitrobenzene 20.

A solution of 1.0 g (5.8 mmol) of 4-chloro-2-nitroaniline and 0.85 ml (6.2 mmol) of dry triethylamine in 50 ml of dry tetrahydrofuran was added to a solution of 0.7 ml (6). (27 mmol) of ethyl oxalyl chloride in 10 ml of dry tetrahydrofuran.

The mixture was stirred at 25 ° C for 1 hour and filtered. The filtrate was evaporated and the residue was stirred with water to give 1.32 g (84%) of 1-chloro-4-ethoxalylamino-3-nitrobenzene. Mp. 156-7 ° C.

B. 7-Chloro-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

A solution of 0.5 g (1.83 mmol) of 1-chloro-4-ethoxyalylamino-3-nitrobenzene in 15 ml of dimethylformamide was hydrogenated at atm. pressure with 30 mg of 5% Pd-C as catalyst. The reaction mixture was filtered and evaporated in vacuo. The evaporation residue was recrystallized (

DK 165294B

(Thylformamide water) to give 0.25 g (65%) of 7-chloro-1- hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec. H-NMR (DMSO-d 6): 12.2 (1H, broad s), 7.2 (3H, m). MS (m / e): 212 (M +, 50%).

EXAMPLE 3 a. 4-Ethoxalylaminobenzonitrile 10 -

A solution of 5.0 g (42.4 ramol) of 4-aminobenzonitrile and 8 ml (58.4 mmol) of dry triethylamine in 100 ml of dry tetrahydrofuran was added to a solution of 7 ml (63.0 mmol) of ethyloxalyl chloride in 25 ml. ml of dry tetrahydrofuran. Stirring was continued at 25 ° C for one hour and then the mixture was evaporated in vacuo. The residue was stirred with water to give. 8.9 g (85%) of 4-ethoxalylaminobenzonitrile.

Mp. 187.8 ° C.

B. 4-Ethoxalylamino-3-nitrobenzonitrile

A mixture of 1.0 g (4.0 mmol) of 4-ethoxalylaminobenzoitrile in 4 ml of ice-cold acetic acid was added to 4 ml of acetic anhydride. At 0 ° C, a solution of 1 ml of 100% nitric acid in 2 ml of ice-cold acetic acid was added dropwise and after 15 min. an additional 1 ml of 100% nitric acid was added. Stirring was continued at 0 ° C for 1 hour. The reaction mixture was poured into 50 ml of ice water to give 0.95 g (81%) of 4-ethoxalylamino-3-nitrobenzonitrile. Mp. 151.8 ° C.

c. 7-Cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

A solution of 5.0 g (19.0 mmol) of 4-ethoxalylamino-3-nitrobenzonitrile in 200 ml of ethanol and 200 ml of ethyl acetate 35

DK 165294B

18 was hydrogenated at atm. pressure using 5 g of Ra-Ni as catalyst. The catalyst was filtered off and washed several times with dimethylformamide. The combined filtrates were evaporated in vacuo. The residue was stirred with ethanol to give 2.4 g (62%) of 7-cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec.

1 H NMR (DMSO-d 6): 12.3 (2H, m), 7.77 (1H, s), 7.4 (2H, dd).

EXAMPLE 4 a. 5-Chloro-2-ethoxalylaminobenzotrifluoride A solution of 2.0 g (10.0 mmol) of 2-amino-5-chlorobenzoitrifluoride and 1.4 ml (10.0 mmol) of dry triethylamine in 25 To dry ml of dry tetrahydrofuran was added a solution of 1.2 ml (11.0 mmol) of ethyloxalyl chloride in 5 ml of dry tetrahydrofuran. Stirring was continued at 25 ° C for 3 hours and then the mixture was filtered and evaporated in vacuo. The residue was stirred with ethanol-water to give 2.4 g (82%) of 5-chloro-2-ethoxalylaminobenzotrifluoride.

Mp. 55-58 ° C.

B. 5-Chloro-2-ethoxalylamino-3-nitrobenzotrifluoride

A solution of 2.4 g (8.1 mmol) of 5-chloro-2-ethoxalylaminobenzotrifluoride in 13 ml of 95-97% sulfuric acid was added dropwise with 12 ml of 100% nitric acid in 24 ml of 95-97% sulfuric acid. 0-5 ° C. Stirring was continued at 25 ° C for 20 min. The reaction mixture was poured into 100 ml of ice water to give an oil. Extraction with dichloromethane gave 2.1 g (76%) of 5-chloro-2-ethoxalylamino-3-nitrobenzotrifluoride as crystals. Mp. 100-101 ° C.

DK 165294B

19 c. 7-Chloro-1-hydroxy-5-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione 5 A solution of 1.0 g (2.94 mmol) of 5-chloro-2-ethoxalylamino-3 Nitrobenzotrifluoride in 75 ml of tetrahydrofuran was added 25 ml of dimethylformamide and 1.0 ml of 25% ammonia water. The mixture was hydrogenated at atm. pressure using 100 mg of 5% Pt-C as catalyst. When hydrogen uptake was complete, the catalyst was filtered off and the filtrate was evaporated in vacuo. The evaporation residue was stirred with 1N hydrochloric acid to give 0.66 g (80%) of 7-chloro-1-hydroxy-5-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. Mp. 275 ° C decomp. 1 H NMR (DMSO-d 6): 11.7 (2H, 15 m), 7.60 (1H, d), 7.43 (1H, d).

EXAMPLE 5 a. 4,5-Dichloro-2-ethoxalylamino-1-nitrobenzene

A solution of 1.0 g (4.8 mmol) of 4,5-dichloro-2-nitroaniline and 1.0 ml (7.3 mmol) of dry triethylamine in 100 ml of dry tetrahydrofuran was added to a solution of 0.9 ml ( 8.1 mmol) of ethyl oxalyl chloride in 25 ml of dry tetrahydro furan. Stirring was continued at 25 ° C for 3 hours, after which the mixture was filtered and evaporated in vacuo. The residue was stirred with a mixture of ethanol and light petroleum to give 1.17 g (79%) of 4,5-dichloro-2-ethoxalylamino-1-nitrobenzene. Mp. 96-97 ° C.

b. 6,7-Dichloro-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione 35 A solution of 0.4 g (1.3 mmol) of 4,5-dichloro-2-ethoxylylamino-1- nitrobenzene in 30 ml of tetrahydrofuran was added 10 ml of dimethylformamide and 0.4 ml of 25% ammonia water.

DK 165294 B

20

The mixture was hydrogenated at atm. pressure using 50 mg of 5% Pd-C as catalyst. The precipitate 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 0.14 g (45%) of 6,7-dichloro-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 12.2 (2H, m), 7.50 (1H, s), 7.27 (1H, s). MS (m / e): 246 (M +, 35%).

EXAMPLE 6 a. 2-Cyano-5-nitrobenzotrifluoride A solution of 10.0 g (48.5 mmol) of 2-amino-5-nitrobenzotrifluoride in 60 ml of ice-cold acetic acid was added to 200 ml of 2N hydrochloric acid, and then 0 ° C diazotized with a solution of 3.36 g (48.6 mmol) of sodium nitrite in 100 ml of water. Stirring was continued at 0 ° C for 1 hour, then a solution of 18 g (75 mmol) of potassium tetracyanone nickel (Ni NiCN ^) in 500 ml of saturated sodium hydrogen carbonate was added dropwise at 25 ° C. Extraction with ethyl acetate followed by distillation (95-100 ° C / 0.5 mmHg) of the crude oil gave 6.8 g (65%) of 2-cyano-5-nitrobenzotrifluoride.

b. 2-Cyano-5-ethoxalylaminobenzotrifluoride A solution of 6.8 g (31.5 mmol) of 2-cyano-5-nitrobenzo trifluoride in 200 ml of ethanol was hydrogenated at atm. pressure using 0.4 g of 5% Pd-C as catalyst. The reaction mixture was filtered and evaporated in vacuo. The crude product was dissolved in 150 ml of dry tetrahydrofuran and 6.0 ml (43.6 mmol) of dry triethylamine was added. A solution of 4.4 ml (39.4 mmol) of ethyloxalyl chloride in 30 ml of dry tetrahydrofuran was added dropwise, and then

DK 165294B

Stirring was continued at 25 ° C for 3 hours. The filtered and evaporated reaction product was stirred with ethanol water to give 7.3 g (82%) of 2-cyano-5-ethoxalylaminobenzotrifluoride. Mp. 112-114 ° C.

5 c. 2-Cyano-5-ethoxalylamino-4-nitrobenzotrifluoride 75 ml of ice-cooled 100% nitric acid was gradually added 7.25 g (25.3 mmol) of 2-cyano-5-ethoxalylaminobenzotrifluoride. Stirring was continued at 25 ° C for 3 hours. The reaction mixture was poured into 500 ml of ice water to give a crude product. Recrystallization (ethanol-water) gave 5.1 g (61%) of 2-cyano-5-ethoxalylamino-4-nitrobenzotrifluoride. Mp.

101-102 ° C.

d. 7-Cyano-1-hydroxy-6-trifluoromethylquinoxaline ~ 2,3- (1H, 4H) -dione

A solution of 10.5 g (31.7 mmol) of 2-cyano-5-ethoxalyl-amino-4-nitrobenzotrifluoride in 450 ml of ethanol was added to 45 ml of ice-cold acetic acid. The mixture was hydrogenated at atm. pressure using 0.2 g of 5% Pd-C as a catalyst. The filtered and evaporated reaction product was recrystallized (ethyl acetate-light petroleum) to give 6.91 g (81%) of 7-cyano-1-hydroxy-6-trifluoro-methyl-quinoxaline-2,3 (1H, 4H) -dione. Mp. Decomp. 180 ° C.

1 H-NMR (DMSO-d 6): 7.93 (1H, s), 7.53 (1H, s). MS (m / e): 27 271 (M +, 70%).

EXAMPLE 7 a. 5-Amino-2-chlorobenzonitrile 35 -

A solution of 10.0 g (54.8 mmol) of 2-chloro-5-nitrobenzene

DK 165294B

22 zonitrile in 500 ml of ethanol was hydrogenated at 30 psi using 0.5 g of 5% Pd-C as catalyst. After the hydrogen uptake was complete, the mixture was filtered and evaporated in vacuo. The residue was recrystallized (ethanol water) to give 3.6 g (44%) of 5-amino-2-chlorobenzonitrile. Mp. 129-130 ° C.

b. 2 = -Chloro-5-ethoxalylaminobenzonitrile 10

To a solution of 3.6 g (23.4 mmol) of 5-amino-2-chlorobenzonitrile and 3.6 ml (26.2 mmol) of dry triethylamine in 200 ml of dry tetrahydrofuran was added a solution of 3.0 ml (26 (9 mmol) of ethyloxalyl chloride in 20 ml of dry tetrahydrofuran. Stirring was continued at 25 ° C for 2 hours, then the reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water to give 5.8 g (99%) of 2-chloro-5-ethoxalylaminobenzonitrile.

Mp. 182-83 ° C.

20 c. 6-Chloro-3-ethoxalylamino-2-nitrobenzonitrile and 2-chloro-5-ethoxalylamino-4-nitrobenzonitrile 75 ml of ice-cooled 100% nitric acid were gradually added 8.1 g (32.1 mmol) of 2-chloro-5 -ethoxalylaminobenzonitril.

Stirring was continued at 0 ° C for 1.5 hours and then the reaction mixture was poured into 500 ml of ice water. The precipitated product was filtered off and recrystallized (ethanol-water) to give 8.25 g (86%) of 6-chloro-3-ethoxalyl-amino-2-nitrobenzonitrile. Mp. 143-45 ° C. 1 H NMR (CDCl 3 -DMSO-d 6): 11.3 (1H, broad s), 8.1 (2H, dd, J = 10 Hz), 4.3 (2H, q), 1.4 (3H, t). The filtrate was extracted with 150 ml of ethyl acetate to give 2-chloro-5-ethoxalylamino-4-nitrobenzonitrile as an oil (0.67 g, 7%). 1 H-NMR (CDCl 3 -DMSO-d6): 11.4 (1H, broad s), 8.57 (1H, s), 8.33 (1H, s), 4.3 (2H, q), 1 , 4 (3H, t).

DK 165294 B

23 d. 7-Chloro-8-cyano-1-hydroxyquinoxylin-2,3 (1H, 4H) -dlon

To a solution of 1.0 g (3.36 mmol) of 6-chloro-3-ethoxalyl-5-amino-2-nitrobenzonitrile in 75 ml of tetrahydrofuran was added 25 ml of dimethylformamide and 1.0 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 0.57 g (72%) of 7-chloro-8-cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. 280 ° C decomp.

1 H-NMR (DMSO-d 6): 12.3 (2H, broad s), 7.5 (2H, s). MS 15 (m / e): 237 (M +, 10%).

EXAMPLE 8 a. 4-Ethoxalylaminophthalamide

A solution of 13.9 g (77.5 mmol) of 4-aminophthalamide in 250 ml of dry dimethylformamide was added to 12.0 ml (86.4 mmol) of dry triethylamine, and then dropwise a solution of 10.1 ml (88 (7 mmol) of ethyloxalyl chloride in 50 ml of dry dimethylformamide. Stirring was continued at 25 ° C for 1 hour. The reaction mixture was poured onto 800 ml of ice-cooled methanol to give 15.8 g (73%) of 4-ethoxalylaminophthalamide. Mp. 229-230 ° C.

B. 4-Ethoxalylaminophthalonitrile

A suspension of 7.0 g (25.1 mmol) of 4-ethoxalylamino-phthalamide in 75 ml of dry pyridine was gradually added 4.1 ml (44.8 mmol) of phosphorus oxychloride. Stirring was continued at 25 ° C for 30 min. The reaction mixture was poured into 300

DK 165294B

24 ml of ice-cooled 4N hydrochloric acid yielded 4.7 g (77%) of 4-ethoxalylaminophthalonitrile. Mp. 193.7 ° C.

c. 4-Ethoxalylamino-5-nitrophthalonitrile and 5 4-Ethoxalylamino-3-nitrophthalonitrile 50 ml of ice-cooled 100% nitric acid were gradually added 2.0 g (8.2 mmol) of 4-ethoxalylaminophthalonitrile. Stirring was continued at 25 ° C for 48 hours. The reaction mixture was poured into 300 ml of ice water to give 1.6 g of crude product. Column chromatography (200 g of silica gel; eluents; toluene containing ethyl acetate) gave 0.7 g (30%) of 4-ethoxylamino-5-nitrophthalonitrile. Mp. 140-141 ° C. 1 H-NMR (DMSO-d 6): 11.7 (1H, s), 8.97 (1H, s), 8.70 (1H, s), 4.4 (2H, q), 1.4 (3H, t), and 0.75 g (32%) of 4-ethoxalylamino-3-nitrophthalonitrile. Mp. 140-141 ° C. 1 H-NMR (DMSO-d6): 11.7 (1H, s), 8.4 (2H, dd, J = 9Hz), 4.4 (2H, q), 1.4 (3H, t).

D. 6,7-Dicyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

A solution of 0.8 g (3.03 mmol) of 4-ethoxalylamino-5 to 25 nitrophthalonitrile in 50 ml of dimethylformamide was hydrogenated at atm. pressure using 25 mg of 5% Pd-C as catalyst. When the hydrogen uptake was complete, the reaction mixture was filtered and evaporated in vacuo. The residue was recrystallized (dimethylformamide-water) to give 0.4 g (66%) of 6,7-dicyano-1-hydroxy-quinoxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 7.97 (1H, s), 7.57 (1H, s). MS (m / e): 228 (M +, 80%).

35

DK 165294B

EXAMPLE 9 7-Cyano-1-phenoxycarbonyloxy-6-trifluoromethyl-quinoxaline-2,3 (1H, 4H) -dione

To a solution of 0.4 g (1.48 nmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 50 ml of dry tetrahydrofuran was added 0.225 ml (1.63 mmol) dry 10 triethylamine and 0.2 ml (1.58 mmol) of phenyl chloroformate.

The mixture was stirred at 25 ° C for 30 min, then filtered and evaporated in vacuo. The evaporation residue was stirred with ether to give 0.48 g (83%) of 7-cyano-1-phe-nonexycarbonyloxy-6-trifluoromethyl-quinoxaline. -2,3- (1H, 4H) -15 dione. Mp. 190 ° C decomp. 1 H-NMR (DMSO-d 6): 8.43 (1H, s), 7.63 (1H, s), 7.3 (5H, broad s).

Example 10 7-Cyano-1-propionyloxy-6-trifluoromethyl-quinoxaline-2,3 (1H, 4H) -dione

To a solution of 0.4 g (1.48 mmol) of 7-cyano-1-hydroxy-6-25 trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 50 ml of dry tetrahydrofuran was added 0.25 ml (1.82 dry triethylamine and 0.15 ml (1.72 mmol) of propionyl chloride. The mixture was refluxed for 30 minutes and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (95%) of 7-cyano-1-propionyloxy-6-trifluoromethyl-quinoxaline-2,3 (1H, 4H) -dione. Mp. 227 ° C. 1 H-NMR (DMSO-d 6): 8.37 (1H, s), 7.73 (1H, s), 4.5 (2H, q), 1.35 (3H, t).

35

DK 165294B

EXAMPLE 11 26 7 - Cyano -1 - ethoxycarbony loxy- 6 -1 rifluoromethyl 1- quinoxaline-2,3 (1H, 4H) -dione 5 ------------------ ......

To a solution of 0.4 g (1.48 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 50 ml of dry tetrahydrofuran was added 0.2 ml (1.50 mmol) dry triethylamine and 0.15 ml (1.58 mmol) of ethyl chloroformate.

The mixture was refluxed for 45 minutes and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (91%) of 7-cyano-1-ethoxycarbonyloxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. Mp. 190 ° C decomp. 1 H NMR (DMSO-d 6): 8.33 (1H, s), 7.73 (1H, s), 2.9 (2H, q), 1.2 (3H, t).

EXAMPLE 12 1-Benzoyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione

To a solution of 0.4 g (1.48 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 50 ml of dry tetrahydrofuran was added 0.2 ml (1.45 dry triethylamine and 0.175 ml (1.50 mmol) of benzoyl chloride. The mixture was refluxed for 30 minutes and then evaporated in vacuo. The residue was stirred with water to give 0.54 g (98%) of 1-benzoyloxy-7-cyano-6-trifluoromethyl-quinoxaline-2,3 (1H, 4H) -dione. Mp. 186 ° C. 1 H-NMR (DMSO-d 6): 8.47 (1H, s), 8.2 (2H, m), 7.8 (4H, m).

EXAMPLE 13

DK 165294 B

27 1-Acetoxy-7-cyano-6-trifluoromethylquinoxaline-2,3- (1H, 4H) -dione 5-

A solution of 0.4 g (1.48 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 50 ml of dry tetrahydrofuran was added 0.3 ml (2.18 mmol) dry triethylamine and 0.15 ml (2.10 mmol) of acetyl chloride. The mixture was refluxed for 3 hours and then evaporated in vacuo. The residue was stirred with vapd to give 0.42 g (92%) of 1-acetoxy-7-cyano-6-trifluoromethyl-quinoxaline-2,3 (1H, 4H) -dione. Mp. 230 ° C. 1 H-NMR (DMSO-15 dg): 8.16 (1H, s), 7.53 (1H, s), 2.37 (3H, s).

Example 14 a. N-Ethoxalyl-3,5-bistrifluoromethylaniline

A solution of 3.0 ml (19.2 mmol) of 3,5-bistrifluoromethylaniline in 100 ml of dry tetrahydrofuran was added 3.0 ml (21.4 mmol) of dry triethylamine. The reaction mixture was cooled to 0 ° C and 2.3 ml (20.6 mmol) of ethyloxalyl chloride in 25 ml of dry tetrahydrofuran was added dropwise. Stirring was continued at 25 ° C for 1 hour. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with n-pentane and the precipitate filtered off to yield 4.8 g (76%) of N-ethoxalyl-3,5-bistrifluoromethylaniline. Mp. 86.8 ° C.

b. N-Ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline

A solution of 4.3 g (13 mmol) of N-ethoxalyl-3,5-bistrifluoromethylaniline in 15 ml of concentrated sulfuric acid was added.

DK 165294B

28, 1.5 g (15 mmol) of potassium nitrate was added at 0 ° C. Stirring was continued at 0 ° C for 90 min, and then at 25 ° C for 120 min. The reaction mixture was poured into 100 ml of ice water and the precipitate was filtered off. The crude product was purified by column chromatography on silica gel with toluene / ethyl acetate 5: 1 as eluent to give 0.44 g (9%) of N-ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline. Mp.

115.0 ° C.

C. 6,8-Bistrifluoromethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione 0.20 g (0.5 mmol) N-ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline in 10 ml tetrahydrofuran: dimethylformamide: 25% ammonia water (30: 10: 0.7) was hydrogenated at atm. pressure using 5% Pd-C (0.02 g) as catalyst. The reaction mixture was filtered and evaporated in vacuo. The evaporation residue was stirred with water and the precipitate was filtered off to give 0.11 g (84%) of 6,8-bisfluoromethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 8.1 (s). MS (m / e): 314 (M +, 40%), 173 (45%), 69 (100%).

EXAMPLE 15-t a. N-Ethoxalyl-4-methoxy-2-nitroaniline A solution of 3.0 g (18 mmol) of 4-methoxy-2-nitroaniline in 100 ml of dry tetrahydrofuran was added 6 ml (43 mmol) of dry triethylamine. The reaction mixture was cooled to 0 ° C and 3.4 ml (30 mmol) of ethyloxalyl chloride in 50 ml of dry tetrahydrofuran was added dropwise. Stirring was continued at 25 ° C for 1 hour. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with ether and the precipitate filtered off to give. 1.4 g

DK 165294 B

29 (29%) N-ethoxalyl-4-methoxy-2-nitroaniline. Mp.

151.3 ° C.

b. 1-Hydroxy-7-methoxyquinoxaline-2,3 (1H, 4H) -dione 5-

0.1 g (0.4 mmol) of N-ethoxalyl-4-methoxy-2-nitroaniline in 10 ml of dimethylformamide was hydrogenated at atm. pressure using 5% Pt-C (0.01 g) as catalyst. The reaction mixture was filtered and 10 ml of IN was added

hydrochloric acid. The reaction mixture was cooled to 0 ° C and the precipitate filtered off, washed with water, ethanol and ether to give 0.03 g (39%) of 1-hydroxy-7-methoxyquine-oxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 12.0 (broad s), 7.0 (3H, m), 3.8 (3H, s). MS (m / e): 208 (M +, 70%), 163 (100%).

EXAMPLE 16 a. N-Ethoxalyl-4,5-dimethoxy-2-nitroaniline

A solution of 1.0 g (5.1 mmol) of 4,5-dimethoxy-2-nitroaniline and 2.0 ml (14.3 mmol) of dry triethylamine in 50 ml of dry tetrahydrofuran was added to a solution of 1.1 ml ( 9.8 mmol) of ethyloxalyl chloride in 25 ml of dry tetrahydrofuran. The reaction mixture was stirred at 25 ° C for 1 hour and filtered. The filtrate was evaporated in vacuo and the residue was washed with ether and water to give 1.05 g (70%) of N-ethoxalyl-4,5-dimethoxy-2-nitroaniline. Mp.

162.7 ° C.

b. 1-Hydroxy-6,7-dimethoxyquinoxaline-2,3 (1H, 4H) -dione 0.15 g (0.5 mmol) N-ethoxalyl-4,5-dimethoxy-2-nitroaniline in 10 ml of dimethylformamide hydrogenated at.atm.

DK 165294B

30 pressure and 15 ° C using 5% Pt-C (15 mg) as catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was washed with ether, ethanol and methanol to give 0.05 g (42%) of 1-hydroxy-5,7-dimethoxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec.

1 H-NMR (DMSO-d 6): 12.0 (1H, broad s), 7.3 (1H, s), 7.0 (1H, s), 3.9 (3H, s), 3.85 ( 3H, s). MS (m / e): 238 (M +, 60%), 193 (100%).

EXAMPLE 18 7,8-Dicyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione 15 0.2 g (0.9 mmol) of 4-ethoxalylamino-3-nitrophthalonitrile in 15 ml of tetrahydrofuran: dimethylformamide: 25% ammonia water: (30: 10: 0.7) was hydrogenated at atm. pressure using 25 mg of 5% Pt-C as catalyst. The precipitate 20 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. The precipitate was filtered off and washed with water, ethanol and ether to give 0.120 g (76%) of 7.8-25 dicyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 7.7 (2H, dd). IR (KBr): 2240 (m). MS (m / e): 228. (M +, 3%), 184 (100%).

Example 19 a. N-Ethoxalyl-5-methoxy-2-nitroaniline

A solution of 0.6 g (3.6 mmol) of 5-methoxy-2-nitroaniline and 1.0 ml (7.1 mmol) of dry triethylamine in 25 ml of dry tetrahydrofuran was added to a solution of 0.8 ml ( 7.2 mmol) of ethyloxalyl chloride in 10 ml of dry tetrahydrofuran.

DK 165294B

31

The reaction mixture was stirred at 25 ° C for 1 hour, then filtered. The filtrate was evaporated in vacuo and the residue was washed with cold ether and water to give 0.22 g (23%) of N-ethoxalyl-5-methoxy-2-nitro-aniline. Mp. 158.0 ° C.

b. 1-Hydroxy-6-methoxyquinoxaline-2,3 (1H, 4H) -dione 10 0.21 g (0.8 mmol) of N-ethoxalyl-5-methoxy-2-nitroaniline in 10 ml of dimethylformamide was hydrogenated by atm. pressure using 10 mg of 5% Pt-C as catalyst. The reaction mixture was filtered and 5 drops of 25% ammonia water were added to the filtrate. The precipitate was filtered off, and the filter cake was washed several times with 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid and the precipitate was filtered off, washed with water, ethanol and ether to give 0.07 g (44%) of 1-hydroxy-6-methoxyguanoxaline-2,3 (1H, 4H) -dione. Mp.

1 H-NMR (DMSO-d 6) 12.1 (1H, broad s), 7.6-6.6 (3H, m), 3.8 (3H, s). MS (m / e): 208 (M +, 50%), 163 (100%).

Example 20 a. N-Ethoxalyl-4,5-dimethyl-2-nitroaniline

A solution of 5.0 g (30 mmol) of 4,5-dimethyl-2-nitro-aniline and 9.0 ml (64 mmol) of dry triethylamine in 100 ml of dry tetrahydrofuran was added to a solution of 5.0 ml (45 mmol) ) Ethyloxalyl chloride in 25 ml of dry tetrahydrofuran. The reaction mixture was stirred at 80 ° C for 30 min.

After cooling to 25 ° C, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was washed with ether to give 2.3 g (29%) of N-ethoxalyl-4,5-dimethyl-2-nitroaniline. Mp. 108.8 ° C.

DK 165294B

32 b. 6,7-Dimethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione 1.0 g (3.8Nol) 4,5-dimethyl-2-nitroaniline in 30 ml of tetrahydrofuran: dimethylformamide: 25% ammonia water: 30: 10: 0.7) was hydrogenated at atm. pressure using 60 mg of 5% Pt-C as catalyst. The precipitate was filtered off and washed with tetrahydro uranium. The filter cake was washed several times with 1N aqueous potassium hydroxide, and the filtrate was acidified with concentrated hydrochloric acid. The precipitate was filtered off and washed with water, ethanol and ether to give 0.13 g (17%) of 6,7-dimethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 11.9 (1H, broad s), 7.3 (1H, s), 7.0 (1H, s), 2.3 (6H, s). MS (m / e): 206 (M +, 70%), 161 (100%).

Example 21 a. N-Ethoxalyl-5-methyl-2-nitroaniline 20 - N-ethoxalyl-5-methyl-2-nitroaniline was prepared in exactly the same way as N-ethoxalyl-4,5-dimethyl-2-nitroaniline. Yield: 3.0 g (36%). Mp. 114.4 ° C.

B. 1-Hydroxy-6-methylquinoxaline-2,3 (1H, 4H) -dione 1-hydroxy-6-methylquinoxaline-2,3 (1H, 4H) -dione is prepared in exactly the same way as 6, 7-Dimethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Yield: 0.22 g (29%).

Mp. dec. 1 H-NMR (DMSO-d 6): 11.9 (1H, broad s), 7.5- 6.7 (3H, m), 2.3 (3H, s). MS (m / e): 192 (M +, 65%), 147 (100%), 134 (45%).

35

DK 165294 B

EXAMPLE 22 a. N-Ethoxalyl-4-methyl-2-nitroaniline N-ethoxalyl-4-methyl-2-nitroaniline was prepared in exactly the same manner as N-ethoxalyl-4,5-dimethyl-2-nitroaniline. Yield: 1.5 g (18%). Mp. 126.4 ° C.

B. 1-Hydroxy-7-methylquinoxaline-2,3 (1H, 4H) -dione 1-hydroxy-7-methylquinoxaline-2,3 (1H, 4H) -dione was prepared in exactly the same way as 6,7-dimethyl -1-Hydro-xyquinoxaline-2,3 (1H, 4H) -dione. Yield: 0.15 g (20%).

Mp. dec. 1 H-NMR (DMSO-d 6): 12.0 (1H, broad s), 7.4- 6.8 (3H, m), 2.4 (3H, s). MS (m / e): 192 (M +, 80%), 147 (100%), 120 (75%).

EXAMPLE 24 a. 3-Ethoxalylamino-2-nitrobenzotrifluoride 25 A solution of ethyloxalyl chloride (0.68 ml, 6 mmol) in 10 ml dry tetrahydrofuran was added dropwise to a solution of 3-amino-2-nitrobenzotrifluoride (0.62 g, 3 mmol) in 30 ml of dry tetrahydrofuran with stirring at 0 ° C.

Then, a solution of dry triethylamine (0.84 ml, 6 mmol) in 5 ml of dry tetrahydrofuran was added dropwise. The mixture was stirred at 0 ° C for 40 min and filtered.

The filtrate was evaporated to dryness and the oily residue was triturated with a mixture of ether and light petroleum to give 0.69 g of the diethoxalylamino compound. By heating the title compound to reflux in 10 ml of ethanol for 30 min, followed by evaporation to dryness and trituration with ether / light petroleum

DK 165294B

34, a yield of 0.41 g (45%) was obtained. Mp. 93-94 ° C, 1 H-NMR (CDCl 3): 1.43 (t, J = 7 Hz, 3H, CH 2), 4.50 (g, J = 7 Hz, 2H, CH 2), 7.58-7 , 93 (m, 2H, ArH), 8.50-8.80 (m, 1H, ArH), 9.78 (broad s, 1H, NH).

B. 1-Hydroxy-8-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione

A solution of 3-ethoxalylamino-2-nitrobenzotrifluoride (0.28 g, 0.9 xunol) in 30 ml of 96% ethanol was hydrogenated at atmospheric pressure and room temperature in the presence of 28 mg of 5% platinum on coal for 5 min. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was triturated with 15 ether to give 77 mg (34%) of the title compound. Mp.

Decomp. 150 ° C. 1 H-NMR (DMSO-d 6): 7.20- 7.67 (m, 3H,

ArH), ca. 12 (very broad s, 1H, NH); IR (KBr): 1700 cm -1; MS (m / e): 246 (28%, M +).

EXAMPLE 25 a. 4-Ethoxalylamino-3-nitrobenzotrifluoride 25 A solution of ethyloxalyl chloride (3.2 ml, 28.2 mmol) in 20 ml of dry tetrahydrofuran was added dropwise to a solution of 4-amino-3-nitrobenzotrifluoride (2.9 g, 14.1 mmol) and dry triethylamine (4.0 ml, 28.2 mmol) in 100 ml dry tetrahydrofuran with stirring at 0 ° C. Then, the mixture was stirred at room temperature for 1 hour and filtered. The filtrate was evaporated to dryness and the residue was heated to reflux in a small amount of ethanol. After cooling on ice, the precipitate was isolated by filtration and washed with cold ethanol to give 3.9 g (90%) of the title compound. Mp. 124-125 ° C; 1 H-NMR (DMSO-d6): 1.33 (t, J = 7 Hz, 3H, CH 3), 4.38 (q, J = 7 Hz, CH 2), 8.06-8.53 (m, 3H , ArH), 11.5

DK 165294B

35 wide s, 1H, NH).

b. 1-Hydroxy-7-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione 5

A solution of 4-ethoxalylamino-3-nitrobenzotrifluoride (0.61 g, 2 mmol) in 40 ml of Ν, Ν-dimethylformamide was hydrogenated at atmospheric pressure and room temperature in the presence of 30 mg of 5% platinum on charcoal. The catalyst 10 was removed by filtration and the filtrate was evaporated to dryness. The residue was recrystallized from activated carbon ethanol / water to give 0; 22 g (45%) of the title compound. Mp. > 200 ° C decomp .; 1 H-NMR (DMSO-d 6): 7.13-7.73 (m, 3H, ArH), 12.4 (broad s, 1H, NH); IR (KBr): 1720, 1660 and 1620 cm -1; MS (m / e): 246 (100%, M +).

EXAMPLE 26 a. 4-Bromo-1-ethoxalylamino-2-nitrobenzene

A solution of ethyloxalyl chloride (2.1 ml, 18.7 mmol) in 10 ml of dry tetrahydrofuran was added dropwise to a solution of 1-amino-4-bromo-2-nitrobenzene (4.0 g, 18.4 mmol) and dry triethylamine (2.6 ml, 18.7 mmol) in 100 ml dry tetrahydrofuran with stirring at 0 ° C. Stirring was continued for 30 min. at room temperature. Then, an equivalent of dry triethylamine and 30 ethyl ethoxylyl chloride was added dropwise to the mixture. The mixture was now refluxed for 15 minutes, cooled to 0 ° C and filtered. The filtrate was evaporated to dryness and the residue was heated to reflux in a small amount of ethanol for 15 minutes. After cooling on ice, the title compound was obtained by filtration in a yield of 5.65 g (97%). Mp. 168-169 ° C; 1 H-NMR (DMSO-d 6): 1.33 (t, J -7 Hz, 3H, CH 3), 4.37 (q, J = 7 Hz, 2H, CH 2), 8.00-8.37

DK 165294 B

36 (m, 3H, ArH), 11.25 (broad s, 1H, NH).

b. 7-Bromo-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione 5

A solution of 4-bromo-1-ethoxalylamino-2-nitrobenzene (1.0 g, 3.2 mmol) in 50 ml of Ν, Ν-dimethylformamide was hydrogenated at atmospheric pressure and room temperature in the presence of a small amount of Raney-Ni. Catalyst 10 was removed by filtration and the filtrate was evaporated to dryness. The residue was triturated with ethanol to give 0.68 g (84%) of the title compound. Mp.

> 250 ° C decomp .; 1 H-NMR (DMSO-d 6): 6.98-7.63 (m, 3H,

ArH), ca. 11.9 (very broad s, 1H, NH); IR (KBr): 1700 cm -1; MS (m / e): 256 (M +, 62%), 258 ((M + 2) +, 58%).

EXAMPLE 27 5,6-Dimethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

A solution of 4.0 g (24.1 mmol) of 2,3-dimethyl-6-nitroaniline and 7.0 ml (50.0 mmol) of dry triethylamine in 100 ml of dry tetrahydrofuran was added to a solution of 5.5 ml (49, 2 mmol) of ethyl oxalyl chloride in 20 ml of dry tetrahydrofuran. The reaction mixture was stirred at 25 ° C for 10 h more and then filtered. The filtrate was evaporated in vacuo and the residue in ether was washed with water. The ether phase was dried and evaporated in vacuo to give an oil.

The oil in 40 ml of tetrahydrofuran: dimethylformamide: 25% ammonia water (30: 10: 1) was hydrogenated at atm. pressure with 200 mg of 5% Pt-C as catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in 20 ml of 1 N potassium hydroxide and the solution acidified with concentrated hydrochloric acid. The precipitate

DK 165294 B

37 it was filtered off and washed with water, ethanol and ether to give 0.45 g (9%) of 5,6-dimethyl-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. dec. 1 H-NMR (DMSO-d 6): 10.8 (1H, broad s), 7.8-7.1 (2H, m), 2.3 (6H, s).

EXAMPLE 30 a. 4-Chloro-3-trifluoromethylaniline hydrochloride 10 -

A solution of 5.0 ml (34 mmol) of 2-chloro-5-nitrobenzo trifluoride in 100 ml of ethanol was hydrogenated at atm. pressure with Raney-Ni (1 g) as catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was dissolved in ethanol and the solution acidified with concentrated hydrochloric acid. The precipitate was filtered off to give 6.3 g (81%) of 4-chloro-3-trifluoro-methylaniline hydrochloride. Mp. > 200 ° C.

B. N-Ethoxalyl-4-chloro-3-trifluoromethylaniline

A solution of 6.0 g (30.7 mmol) of 4-chloro-3-trifluoromethylaniline hydrochloride in 100 ml of dry tetrahydrofuran was added to 10 ml (71 mmol) of dry triethylamine and the reaction mixture was cooled to 0 ° C. 3.6 ml (32 mmol) of ethyl oxalyl chloride in 25 ml of dry tetrahydrofuran was added dropwise and the reaction mixture was evaporated in vacuo and the residue was stirred with water. The precipitate was filtered off to give 7.35 g (96%) of N-ethoxalyl-4-chloro-3-trifluoromethylaniline. Mp. 128.5-129.5 ° C.

c. N-Ethoxalyl-4-chloro-6-nitro-3-trifluoromethylaniline - 6.0 g (20.6 mmol) of N-ethoxalyl-4-chloro-3-trifluoromethyl

DK 165294B

38 aniline was dissolved in 30 ml of 100% nitric acid and the reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into 500 ml of ice water. The crude product was filtered off, washed with water and recrystallized (ethanol) to give 4.95 g (72%) of N-ethoxalyl-4-chloro-6-nitro-3-trifluoromethylaniline. Mp. 96.5-97.5 ° C.

d. 7-Chloro-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione 10

A solution of 2.0 g (5.9 mmol) of N-ethoxalyl-4-chloro-6-nitro-3-trifluoromethylaniline in 50 ml of dimethylformamide was hydrogenated at atm. pressure with 200 mg of 5% Pt-C 15 as catalyst. The reaction mixture was stirred with 4N hydrochloric acid and the crude product was filtered off. The crude product was dissolved in 25 ml 1N potassium hydroxide and the solution acidified with concentrated hydrochloric acid. The precipitate was filtered off to give 310 mg (19%) of 7-chloro-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. Mp. de-Comp. MS (m / e): 280, 1 H-NMR (DMSO-d 6): 12.2 (1H, broad s), 7.6 (2H, m).

EXAMPLE 31 a. N-Ethoxalyl-3,4,5-trichloroaniline

A solution of 6.0 g (30.5 mmol) of 3,4,5-trichloroaniline 30 in 80 ml of dry tetrahydrofuran was added to 6 ml (42.7 mmol) of dry triethylamine. 4 ml (35.8 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 35 was stirred with water. The precipitate was filtered off to give 5.0 g (55%) of N-ethoxalyl-3,4,5-trichloroaniline. Mp. 148-151 ° C.

DK 165294 B

39 b. N-Ethoxalyl-2-nitro-3,4,5-trichloroaniline 20 ml of 100% nitric acid was cooled to 0 ° C and 2.0 g (6.8 5 mmol) of N-ethoxalyl-3,4,5- trichloroaniline was added. The reaction mixture was stirred at 0 ° C for 10 min. and 200 ml of ice water was added. The precipitate was filtered off, washed with water and ethanol to give 1.2 g (52%) of N-ethoxyl-2-nitro-3,4,5-trichloroaniline. Mp. 84 ° C.

C. 1-Hydroxy-6,7,8-trichloro-guinoxaline-2,3 (1H, 4H) -dione

A solution of 2.0 g (5.9 mmol) of N-ethoxalyl-2-nitro-3,4,5-trichloroaniline in 50 ml of ethanol was hydrogenated at atm. pressure with 70 mg Pt-C (5%) as catalyst.

The precipitate was filtered off and the filter cake washed with 10 ml of 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid and the precipitate was filtered off, washed with water, ethanol and ether to give 0.18 g (11%) of 1-hydroxy-6,7,8-trichloroquinoxaline-2.3 (1H). , 4H) -dione. Mp. dec. NMR (DMSO-d 6): 7.4 (1H, s) MS m / z: 280 (M +, trace, 3 Cl), 265 (35%), 237 (100%), 173 (55%).

EXAMPLE 32 a. 4-Amino-3-nitrobenzenesulfonamide 30

A 100 ml stainless steel autoclave was refilled approx. 50 ml of ammonia water. Then 4-chloro-3-nitrobenzenesulfonamide (5.0 g, 21 mmol) was added and the bomb heated in an oil bath at 100 ° C for 3 hours. Excess ammonia was allowed to evaporate and the solid residue was washed successively with water, cold ethanol and ether to give 3.9 g (85%) of the title compound. Mp. 211.5 to 213 ° C

DK 165294B

40 (ethanol); 1 NMR (DMSO-d 6); 6.97 (d, J = 9Hz, 1H, H-5), 7.12 (s, 2H, NH 2), 7.57 (dd, Jg_5 = 9 Hz, Jg 2 HHz, H-6), 7.70 (broad s, 2H, NH 2), 8.22 (d, J 2Hz, H-2).

B. 4-Ethoxalylamino-3-nitrobenzenesulfonamide

A solution of ethyloxalyl chloride (1.7 ml, 15 nunol) in 10 ml dry tetrahydrofuran was added dropwise to a solution of 4-amino-3-nitrobenzenesulfonamide (3.26 g, 15 mmol) in 100 ml dry tetrahydrofuran with stirring. in an ice bath. A solution of dry triethylamine (2.1 ml, 15 mmol) in 10 ml of dry tetrahydrofuran was added dropwise over 40 minutes. at 0 ° C. The mixture was stirred for 1 hour at 0 ° C and filtered. The filtrate was evaporated to dryness and the solid evaporation residue was washed with cold ethanol and ether to give 4.14 g (87%) of the title compound. Mp. 193-195 ° C, 1 H NMR (DMSO-d 6): 1.32 (t, J = 7Hz, 3H, CH 3), 4.32 (q, J - 7Hz, 2H, CH 2), 7.53 ( broad 20 s, 2H, SO 2 NH 2), 8.05 (dd, Jg_5 = 9Hz, 3Q_2 2Hz, 1H, H-6), 8.28 (d, J = 9Hz, 1H, H-5), 8.42 ( d, J 2Hz, 1H, H-2), 11.5 (broad s, 1H, NH).

c. 1-Hydroxy-7-sul famoylquinoxaline-2,3 (1H, 4H) -dione 25 ---

A suspension of 4-ethoxalylamino-3-nitrobenzenesulfonamide (1.59 g, 5 mmol) in 300 ml of 96% ethanol was hydrogenated at atmospheric pressure and room temperature for 30 min.

30 in the presence of 50 mg 5% platinum on charcoal. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was washed with ethanol and dissolved in 25 ml of saturated aqueous ammonium hydroxide. An undissolved orange precipitate was removed by filtration, and most of the ammonia was removed from the filtrate under reduced pressure. After treatment with activated charcoal, the filtrate was acidified with wife. hydrochloric acid to give 0.76 g (59%) of the title compound as an off-white precipitate. Mp. > 250 ° C decomp. (DSC); NMR (DMSO-d 6): 7.07-7.93 (m, 3H, ArH), 7.33 (broad s, 2H, NH 2), about 11.9 (very broad s, 1H, NH or OH) , 12.3 (wide s, 5H, OH or NH); IR (KBr): 3300-2100, 1690 cm -1; MS (m / e): 257 (10%, M +).

EXAMPLE 33 10 a. 4-Ethoxalylamino-1-ethoxalylaminosulfonyl-2-trifluoro-methylbenzene Dry triethylamine (54.4 ml, 0.39 mol) was added to a solution of 4-amino-2-trifluoromethylbenzenesulfonamide (31.2 g, 0.13 mol) in 400 ml of dry tetrahydrofuran. Then, a solution of ethyl oxalyl chloride (43.6 ml, 0.39 mol) in 50 ml of dry tetrahydrofuran was added dropwise at 0 ° C. The mixture was stirred overnight at room temperature. Triethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness to give an oil which was triturated with 150 ml of ethanol. The resulting white precipitate was filtered off and washed with ethanol and ether to give 46.9 g (82%) of the pure title compound. Mp. 161-162 ° C; NM-NMR (DMSO-d)): 1.25 (t, J = 7Hz, 3H, CH)), 1.33 (t, J = 7Hz, 3H, CHg), 4.18 (q, J = 7Hz, 2H) , CH2), 4.30 (q, J = 7Hz, 2H, CH2), 8.13-8.41 (m, 3H, ArH), 9.07 (broad s, 1H, NH), 11.43 ( wide s, 1H, NH).

30 b. 1-Ethoxalylamino-4-ethoxalylaminosulfonyl-2-nitro-5-trifluoromethylbenzene Fine powdered potassium nitrate (11.1 g, 0.11 mol) was added portionwise to a stirred solution of 4-ethoxalylamino-1-ethoxalylaminosulfonyl -2-trifluormethylben-

DK 165294 B

42 zen (46.2 g, 0.105 mol) in 140 ml of concentrated sulfuric acid and the temperature was kept below 5 ° C. After the addition, the reaction mixture was stirred at room temperature overnight, poured into ice-water and filtered. The crude product was washed with water (1.5 L) and air dried to give the title compound in a yield of 35.5 g '(70%). A sample was purified by flash column chromatography with ethyl acetate. Mp. 175-180 ° C; 1 H NMR (CDCl 3): 1.17-1.67 (m, 6H, 2CH3), 4.07-4.67 (m, 4H, 2CH2), 9.05 (s, 10H, ArH), 9 , 23 (s, 1H, ArH), 11.73 (broad s, 1H, NH, only one interchangeable proton could be seen).

c. 7-Ethoxalylaminosulfonyl-1-hydroxy-6-trifluoromethyl-quinoxaline-2,3 (1H, 4H) -dione

A solution of 1-ethoxalylamino-4-ethoxalylaminosulfonyl-2-nitro-5-trifluoromethylbenzene (24.6 g, 50 mmol) in 200 ml of Ν, Ν-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of 1 g 5% platinum on charcoal for 2 hours. The catalyst was filtered off and washed with Ν, Ν-dimethylformamide. The filtrate was evaporated to dryness and the rubbery evaporation residue was refluxed with 100 ml of ethanol for approx.

25 20 min. The mixture was cooled and the precipitated product was collected by filtration and washed with ethanol and ether to give 12.7 g (59%) of the title compound.

Mp. 222 ° C decomp. (DSC); IR (KBr): 1685 cm "1; 1 H NMR (DMSO-d d): 1.25 (t, J - 7Hz, 3H, CH CH), 4.23 (q, J - 7Hz, 2H, CH₂), 7.67 (s, 1H, ArH), 8.30 (s, 1H, ArH), 10.8 (wide s, 2H, interchangeable), 12.5 (wide s, 1H, interchangeable) · d. 1- Hydroxy-7-sulfamoyl-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione

DK 165294B

43

A suspension of 7-ethoxalylaminosulfonyl-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione (12.0 g, 28 nunol) in 150 ml of 1 M hydrochloric acid was heated at reflux for 2 hours with stirring. The cooled mixture was filtered and the isolated solid washed with water and light petroleum. The crude product was recrystallized from activated charcoal water and dried in vacuo over phosphorus pentoxide for 3 hours to give 7.1 g (77%) of the pure title compound. Mp. 296 ° C decomp. (DSC); IR (KBr): 1700, 10 1615 cm "1; 1H NMR (DMSO-dg): 7.67 (s, 1H, ArH), 7.77 (s, 2H, NH₂), 8.26 (s , 1H, ArH), 12.2 (broad s, 2H, NH and OH); MS m / e: 325 (M +, 100%).

Example 34 a. 2-Bromo-4-methoxy-5-nitroacetophenone

A solution of 2-bromo-4-methoxyacetophenone (4.58 g,

(20 mmol) in 50 ml of acetic anhydride was cooled to -15 ° C

and a few drops of wife. sulfuric acid was added. A solution of 100% nitric acid (0.83 ml, 20 mmol) in 5 ml of acetic anhydride was added dropwise while maintaining the temperature of -10 to -15 ° C. After 1 hour of further stirring at this temperature, the mixture was poured into 200 ml of ice water. The separated white solid was collected by filtration and washed with water, ethanol and ether to give 4.4 g (80%) of a mixture of 2-bromo-4-methoxy-5-nitroacetophenone and 2-bromo-4-methoxy-3 -ni-troacetophenone. Recrystallization from 96% ethanol gave 2.83 g (52%) of the 5-nitro isomer. Mp. 116-117 ° C; 1 H-NMR (CDCl 3): 2.65 (s, 3H, COCH 3), 4.00 (s, 3H, OCH 3), 7.30 (s, 1H, ArH), 8.10 (s, 1H, ArH) ).

The mother liquor was evaporated to dryness and treated with ether column chromatography. The 5-nitro isomer was first eluted (0.50 g (9%)) followed by the 3-nitro isomer

DK 165294 B

44 in a yield of 0.68 g (12%); mp. 119-120 ° C.

b. 2-Acetyl-5-methoxy-4-nitrobenzonitrile 5

A solution of 2-bromo-4-methoxy-5-nitroacetophenone (2.1 g, 7.5 nmol) in 8 ml of dry N, N-dimethylformamide was heated to 80 ° C with stirring and copper cyanide (1.34 g, 15 mmol). mmol) was added. The reaction mixture was stirred for 10 hours at 80 ° C and then allowed to cool to room temperature. A solution of ferric chloride hexahydrate (4.0 g of FeCl 3 * 6 H 2 O in 1 ml of 12 M hydrochloric acid and 6 ml of water) was added and the mixture was stirred at 60 ° C for 30 min.

Then the mixture was poured into 100 ml of water and the separated solid was isolated by filtration. Recrystallization from activated carbon ethanol afforded 1.31 g (79%) of the title compound. Mp. 224 - 226 ° C? IR (KBr): 2232 cm ** 1 (CN); 1 H-NMR (DMSO-d 6): 2.60 (s, 3H, COCH 3), 4.03 (s, 3H, OCH 3), 7.95 (s, 1H, ArH), 8.57 (s, 1H , ArH).

C. 4-Acetyl-5-cyano-2-nitroaniline

Ammonia was bubbled through a solution of 2-acetyl-5-25 methoxy-4-nitrobenzonitrile (0.80 g, 3.6 mmol) in 10 ml of dry dimethyl sulfoxide with stirring at 80 ° C for 45 min.

Then the solution was poured into 100 ml of ice water. The product was isolated by filtration and washed with water to give 0.71 g (95%) of the title compound. Mp. 255-30 260 ° C; 1 NMR (DMSO-d 6): 2.57 (s, 3H, COCH 3), 7.50 (s, 1H, ArH), 8.20 (broad s, 2H, NH 2), 8.65 (s, IH, ArH).

d. 1-Acetyl-2-cyano-4-ethoxalylamino-5-nitrobenzene Dry triethylamine (1.7 ml, 12 mmol) was added to a solution of 4-acetyl-5-cyano-2-nitroaniline (0.62 g , 3

DK 165294B

45 mmol) in 100 ml of dry tetrahydrofuran. Then, a solution of ethyl oxalyl chloride (1.34 mL, 12 mmol) was added dropwise with stirring at room temperature. After 1 hour, the mixture was refluxed for 2 hours and allowed to cool to room temperature. The suspension was filtered and the filtrate evaporated to dryness to give an oil which was solidified by treatment with a small amount of ethanol. Yield 0.50 g (55%). Mp. 142-144 ° C; 1 H-NMR (CDCl3); 1.47 (t, J = 7Hz, 3H, CHg), 2.75 (s, 3H, COCHg), 4.47 (q, J - 7Hz, 2H, CH 2), 8.80 (S, 1H, ArH), 9.27 (s, 1H, ArH), 11.94 (broad s, 1H, NH).

e. 7-Acetyl-6-cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

A solution of 1-acetyl-2-cyano-4-ethoxalylamino-5-nitrobenzene (0.31 g, 1 mmol) in 10 ml of Ν, Ν-dimethylformamide was hydrogenated at atmospheric pressure and room temperature for 1 hour in the presence of 30 mg. % platinum 20 on charcoal. The catalyst was filtered off and the filtrate was evaporated to dryness. The pure product was obtained after recrystallization from activated charcoal water. Yield 0.12 g (49%). Mp. 340.8 ° C decomp. (DSC); IR (KBr): 2238 (CN), 1692 cm -1; 1 H NMR (DMSO-d 6): 2.62 (s, 3H, CH 3), 7.43 (s, 1H, ArH), 7.96 (s, 1H, ArH), about 12 (very broad s, 2H, NH and OH); MS m / e: 245 (M +, 26%).

EXAMPLE 35 1-Benzyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione

To a solution of 0.4 g (1.5 mmol) of 7-cyano-1-hydroxy-6-35 trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 30 ml of ethanol was added 10 ml of 0.5 M phosphate buffer pH 7.4. To the mixture was added 0.4 ml (2.3 mmol) of benzyl bromide, and

DK 165294B

46 was then stirred at 25 ° C for 4 hours. The precipitated product was filtered off and washed with water and ethanol to give 0.48 g (91%) of 1-benzyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. Mp. 265 ° C (ethyl acetate - light petroleum). NMR (DMSO-d 6): 8.0-7.3 (7H, m), 5.25 (2H, s).

EXAMPLE 36 1-Allyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione

A solution of 7,4-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 0.4 ml (1.5 mmol) in 40 ml of ethanol was added to 20 ml of 0.5 M phosphate buffer. pH 7.4. The mixture was added 0.8 ml (9.3 mmol) of allyl bromide and then stirred at 25 ° C for 4 hours. Addition of 80 ml of water gave 0.33 g (72%) of 1-allyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione as a precipitate.

Mp. 239 ° C decomp. (methanol-water). NMR (DMSO-d 6): 7.9 (1H, s), 7.6 (1H, s), 6.1 (1H, m), 5.4 (2H, m), 4.7 (2H, d) ).

EXAMPLE 37 7-Cyano-1-methoxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione 30

A solution of 0.3 g (1.1 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 30 ml of ethanol was added to 15 ml of 0.5 M phosphate buffer pH 7.4 . The mixture was added with 1 ml (16 mmol) of methyl iodide and then stirred overnight. The reaction mixture was evaporated and the residue was stirred with water to give a precipitate. Recrystallization (dimethylformamide-water)

DK 165294 B

47 gave 0.2 g (63%) of 7-cyano-1-methoxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. Mp. 250 ° C decomp. 1 H-NMR (DMSO- d 6): 7.9 (1H, s), 7.6 (1H, s), 4.07 (3H, s).

EXAMPLE 38 7-Cyano-1-cyclohexyloxy-6-trifluoromethyl-1-quinoxal in-2,3 (1H, 4H) -dione 10

A solution of 0.3 g (1.1 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 30 ml of ethanol was added 0.7 ml of triethylamine and 1 , 5 ml (12 mmol) of cyclohexyl bromide. The reaction mixture was refluxed for 7 days and then evaporated in vacuo. The residue was stirred with water to give a precipitate (0.25 g). Recrystallization (dimethylformamide-water) gave 0.17 g (44%) of 7-cyano-1-cyclohexyloxy-6-trifluoromethylquinox-aline-2,3 (1H, 4H) -dione. Mp. 259 ° C decomp. 1 H-NMR (DMSO-20 dg); 8.0 (1H, s), 7.6 (1H, s), 4.3 (1H, m), 1.4 (8H, m).

Example 39 1-Carboxymethyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione

A solution of 0.3 g (1.1 mmol) of 7-cyano-1-hydroxy-6-30 trifluoromethylquinoxaline-2,3 (1H, 4H) -dione in 30 ml of ethanol was added to 30 ml of 0.5 M phosphate buffer. pH 7.4. The mixture was added with 0.9 g (6.5 mmol) of bromoacetic acid and then stirred at 25 ° C for 10 days. 4N hydrochloric acid was added to pH 1, then the reaction mixture was evaporated in vacuo. The residue was stirred with water to give 0.27 g (74%) of 1-carboxymethyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. Mp. 257 ° C.

in

DK 165294 B

1 H-NMR (DMSO-d 6): 8.2 (1H, s), 7.6 (1H, s), 4.8 (2H, S).

EXAMPLE 40 5 a. 5-Amino-2-chlorobenzonitrile

A solution of 10.0 g (54.8 nmol) of 2-chloro-5-nitrobenzonitrile in 500 ml of ethanol was hydrogenated at 40 psi with 0.5 g of 5% Pd-C as catalyst. The catalyst was filtered off and the filtrate was evaporated in vacuo. Recrystallization (ethanol water) gave 3.6 g (43%) of 5-amino-2-chlorobenzonitrile. Mp. 129-130 ° C.

B. 2-Chloro-5-ethoxalylaminobenzonitrile

A solution of 3.5 g (23.4 mmol) of 5-amino-2-chloro-nitrile and 3.6 ml (26.2 mmol) of dry triethylamine in 200 ml of dry tetrahydrofuran was added to a solution of 3.0 ml ( 26.9 mmol) of ethyloxalyl chloride in 20 ml of dry tetrahydrofuran. Stirring was continued at 25 ° C for 2 hours after which the reaction mixture was filtered. The filtrate was evaporated in vacuo. The residue was stirred with water to give 5.8 g (99%) of 2-chloro-5-ethoxalylaminobenzonitrile.

Mp. 182-183 ° C.

c. 2-Chloro-5-ethoxalylamino-4-nitrobenzonitrile 30 - 50 ml of ice-cold 100% nitric acid was gradually added 5.0 g (19.8 mmol) of 2-chloro-5-ethoxalylaminobenzonitrile. Stirring was continued at 0 ° C for 90 min. The reaction mixture was poured onto 300 ml of ice water to give 5.2 g of the 6-nitro isomer. The aqueous phase was extracted with ethyl acetate to give 0.7 g as an oil. The crude product was purified

DK 165294 B

49 column chromatography to give 0.6 g (10%) of 2-chloro-5-ethoxalylamino-4-nitrobenzonitrile. Mp. 80-82 ° C. 1 H-NMR (CDCl 3): 8.6 (1H, s), 8.3 (1H, s), 4.4 (2H, q), 1.4 (3H, t).

5 d. 7-Chloro-6-cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

To a solution of 0.6 g (2.0 mmol) of 2-chloro-5-ethoxalyl-10-amino-4-nitrobenzonitrile in 50 ml of tetrahydrofuran was added 15 ml of dimethyl formamide and 0.7 ml of 25% ammonia water. The mixture was hydrogenated at atm. pressure with 0.1 g Pd-C as catalyst. The catalyst was filtered off and the filter cake washed with tetrahydrofuran. The precipitated product was dissolved in 1N potassium hydroxide solution. Addition of concentrated hydrochloric acid to pH 1 gave 0.25 g (50%) of 7-chloro-6-cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp. Decomp. 320 ° C. 1 H-NMR (DMSO-d 6): 7.6 (1H, s), 7.5 (1H, s).

EXAMPLE 41 a. 3-Ethoxalylaminobenzonitrile 25

A solution of 2.5 g (21.1 mmol) of 3-aminobenzonitrile and 3.0 ml (21.8 mmol) of dry triethylamine in 150 ml of dry tetrahydrofuran was added to a solution of 2.45 ml (21.8 mmol) of ethyloxalyl chloride. in 50 ml of dry tetrahydrofuran. . The reaction mixture was stirred at 25 ° C for 2 hours, then filtered. The filtrate was evaporated in vacuo and the residue was stirred with water to give 4.35 g (95%) of 3-ethoxalylaminobenzonitrile. Mp.

149-150 ° C.

35

DK 165294B

50 b. 3-Ethoxalylamino-4-nitrobenzonitrile 50 ml 100% nitric acid cooled to ca. -5 ° C and then 5 g (22.9 mmol) of 3-ethoxalylaminobenzonitrile were gradually added. Stirring was continued at 0 ° C for 1 hour.

* The reaction mixture was poured onto 200 ml of ice water to give a precipitate (4.1 g) containing a mixture of 2-and 6-nitro isomers. The aqueous phase was extracted with ethylτ 10 acetate to give an oil (1.0 g). The crude product was column chromatographed to give 0.65 g (11%) of 3-ethoxalylamino? 4-nitrobenzonitrile as an oil. 1 H-NMR (CDCl3): 9.2 (1H, d, J = 2Hz), 8.4 (1H, d, J = 8Hz), 7.6 (1H, dd, J = 2Hz and 8Hz), δ , Δ (2H, q), 1.5 (3H, t).

C. 6-Cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione

A solution of 0.5 g (1.9 mmol) of 3-ethoxalylamino-4-nitrobenzonitrile in 50 ml of ethanol was hydrogenated at atm.

pressure with 25 mg of 5% Pt-C as catalyst. The catalyst was filtered off and the filtrate was evaporated in vacuo. Ring formation was obtained by evaporation with acetic acid. Recrystallization (dimethylformamide-water) gave 0.25 g (65%) of 6-cyano-1-hydroxyquinoxaline-2,3 (1H, 4H) -dione. Mp.

250 ° C decomp. 1 H-NMR (DMSO-d 6): 7.53 (s) and 7.40 (s) -ial 3H.

30 35

Claims (6)

1. Quinoxaline compounds of the general formula I 5 8 1 Ec ir nh ^ o io U ir where are hydroxy, alkoxy, allyloxy, aralkyloxy, carboxymethyl-thyloxy, cycloalkoxy, or OCOR, wherein R is phenoxy, allyl, ethoxy or phenyl; and R5, R8, R7 and R8 are independently hydrogen, methyl, halogen, CN, acetyl, methoxycarbonylmethyl, SC1 NR'R ', CF120 or OR', where R 'is hydrogen or C1-6 alkyl or c. salts thereof; provided R ° is not Cl when Rx is hydroxy 5 6 or acetoxy and R is not CH 2 or R is not CF 3 when is hydroxy. Compound according to claim 1 selected from the group 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione, 7-chloro-1-hydroxy-6-trifluoromethylquinoxaline-2.3 (1H , 4H) -dione, 1-hydroxy-7-sulfamoyl-6-1ri fluoromethylquinoxaline-2,3 (1H, 4H) -dione, and 7-acetyl-6-cyano-1-hydroxyquinox-30-aline-2.3 ( H, 4H) -dione. 3. Pharmaceutical composition characterized in that it contains as an active component a quinoxaline compound according to claims 1-2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. DK 165294B 52 Pharmaceutical composition according to claim 3 in the form of a dosage unit containing approx. 50-200 mg of the active compound, a pharmaceutical composition for the treatment of a symptom 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 claim 1. 2 or a pharmaceutically acceptable carrier. The quinoxaline compound of claims 1-2 for use as a neuroleptic. A process for the preparation of a compound of formula I according to claims 1-2, characterized in, a) reduction of a compound of formula II 8 20. R 5 YN ° 2 11 R 'l "" NHCOCOOC-Hr R5 5 6 7 8 25 wherein R, R, Ry and R ° have the above meanings to form a compound of formula III 8 R OH Wherein R, R, R, R have the above meanings, where after this compound, if desired, is reacted with a compound of formula IV R1, - X is wherein R 1 is alkyl, allyl, aralkyl, carboxymethyl, cyclo-2-alkyl, or COR where R is phenoxy, allyl, ethoxy or phenyl and X is a leaving group to form a compound of formula I wherein R "is alkoxy, allyloxy, aralkyloxy, carboxymethyloxy, cycloalkoxy, el-2C or OCOR wherein R is phenoxy, allyl, ethoxy or phenocynyl, and wherein R, R, R, R have the above meanings 15 20 25 30 35