The present invention is a pyrazine derivative which has glutamate receptor antagonizing activity, represented by formula: ##STR1## wherein Z represents C or N, provided that two Zs are not N atoms at the same time; R.sup.1 represents: ##STR2## wherein ##STR3## represents ##STR4## R.sup.6 represents H or alkyl, and R.sup.7 and R.sup.8 represent each H, alkyl, nitro or phenyl, or alternatively R.sup.7 and R.sup.8 are combined together to represent butadienylene or 1,4-butylene; R.sup.2 and R.sup.3 represent each H, F, cyano, acyl, nitro, alkyl, morpholino or one of said species of R.sup.1 ; R.sup.4 and R.sup.5 represent each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents hydroxyl, acyloxy, F-substituted methyl, cycloalkyl, tetrahydrofuryl, carboxyl, alkoxycarbonyl or ##STR5## R.sup.9 and R.sup.10 represent each H or alkyl, or alternatively R.sup.9 and R.sup.10 are combined together to represent a 5- or 6-membered cyclic group which may contain oxygen atom(s).

TECHNICAL FIELD 
The present invention relates to a fused pyrazine derivative or a salt 
thereof, which has glutamate receptor antagonizing activity, particularly 
NMDA-glycine receptor antagonizing activity and AMPA receptor antagonizing 
activity. 
BACKGROUND ART 
Certain amino acids such as L-glutamic acid and L-aspartic acid are known 
to be central neurotransmitters. It is said that accumulation of these 
excitatory amino acids results in a persistent overstimulation of the 
nerves which, in turn, causes neuronal degeneration and mental and motor 
dysfunctions as are observed in Huntington's chorea, Parkinson's disease, 
epilepsy and senile dementia, or after cerebral ischemia, oxygen 
deficiency or hypoglycemia. 
Therefore, it is by now considered that drugs which may modulate abnormal 
actions of these excitatory amino acids are useful for the treatment of 
neuronal degeneration and mental disease. 
Excitatory amino acids exert their effects via the specific receptors 
present in the post- or presynaptic regions. These receptors have been 
classified into the following five groups based on electrophysiological 
and neurochemical evidence. 
1) NMDA (N-methyl-D-aspartate) receptor 
2) AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)-propionic acid] 
receptor 
3) Kainate receptor 
4) Metabotropic glutamate receptor 
5) AP-4 (2-amino-4-phosphobutanoic acid) receptor 
L-Glutamic acid and L-aspartic acid activate the above-mentioned receptors 
to transmit stimuli. Permitting an excessive amount of NMDA, AMPA or 
kainate to act on nerves causes neuropathy. It is reported that 
2-amino-5-phosphonovalerianic acid and 2-amino-7-phosphonoheptanoic acid, 
both of which are selective antagonists of NMDA receptor, were effective 
in NMDA-induced neuropathy and in animal models of epilepsy or brain 
ischemia (JPET, 250, 100 (1989); JPET, 240, 737 (1987); Science, 226, 850 
(1984)). 
While NMDA receptor is reported to be allosterically functioning by glycine 
receptor (EJP, 126, 303 (1986)), HA-966 which is a glycine receptor 
antagonist is reported to be effective in an animal model of brain 
ischemia (1989 Congress of American Society of Neuroscientists). 
NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline), a selective antagonist of 
AMPA receptor, is also reported to be effective in an animal model of 
brain ischemia (Science, 247, 571 (1990)). On the other hand, there is no 
report with respect to selective antagonists of kainate, metabotropic 
glutamate and AP-4 receptors. 
DISCLOSURE OF INVENTION 
The object of the present invention is to provide a diketoquinoxaline or 
diketopyridopyrazine compound having glutamate receptor antagonizing 
activity, particularly NMDA-glycine receptor and/or AMPA receptor 
antagonizing activity. Several diketoquinoxaline derivatives having 
NMDA-glycine antagonizing and/or AMPA antagonizing activity have been 
reported (JP-A-63-83074, JP-A-63-258466, JP-A-1-153680, JP-A-48578, 
JP-A-2-221263, and JP-A-2-221264; the term "JP-A" as used herein means an 
"unexamined published Japanese patent application"). However, the compound 
of the present invention is a novel compound which has structural 
characteristic that it has an imidazolyl or triazolyl group on the 
diketoquinoxaline or diketopyridopyrazine ring. 
Thus, the present invention relates to a pyrazine derivative represented by 
the general formula: 
##STR6## 
wherein ring A represents a benzene ring of the formula 
##STR7## 
or a pyridine ring of the formula 
##STR8## 
R.sup.1 represents 
##STR9## 
(X represents a nitrogen atom, or a carbon atom substituted by R.sup.8, 
R.sup.6 represents a hydrogen atom or a lower alkyl group, R.sup.7 and 
R.sup.8 are the same or different and each represents hydrogen, lower 
alkyl, nitro or phenyl, or R.sup.7 and R.sup.8 are combined together to 
represent butadienylene (--CH.dbd.CH--CH.dbd.CH--) or 1,4-butylene 
(--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --)); R.sup.2 and R.sup.3 are 
the same or different and each represents hydrogen, fluoro, cyano, lower 
acyl, nitro, unsubstituted or fluorine-substituted lower alkyl, 
morpholino, or one of said species of R.sup.1 which may be either the same 
as or different from R.sup.1 ; R.sup.4 and R.sup.5 are the same or 
different and each represents hydrogen, hydroxyl, C.sub.1-10 
straight-chain or branched alkyl, C.sub.5-8 cycloalkyl which may be 
substituted by amino, a nitrogen-containing 5- or 6-membered heterocyclic 
group which may be substituted by lower alkyl and which may be bridged by 
1 to 3 methylene group(s), phenyl, or Y-substituted C.sub.1-6 
straight-chain or branched alkyl; Y represents hydroxyl, lower acyloxy, 
fluorine-substituted methyl, C.sub.5-8 cycloalkyl, tetrahydrofuryl, 
carboxyl, lower alkoxycarbonyl, or 
##STR10## 
(R.sup.9 and R.sup.10 are the same or different and each represents 
hydrogen or lower alkyl, or alternatively R.sup.9 and R.sup.10 are 
combined together to represent a 5- or 6-membered cyclic group which may 
contain oxygen), or a salt thereof. 
The "nitrogen-containing 5- or 6-membered heterocyclic group" in the above 
definition means piperidinyl and pyrrolidinyl and s on. The 
"nitrogen-containing 5- or 6-membered heterocyclic group which is bridged 
by 1 to 3 methylene group(s)" means quinuclidinyl and so on. 
The "5- or 6-membered cyclic group which may contain oxygen" represented by 
R.sup.9 and R.sup.10 combined together means morpholino, among others. 
The "lower alkyl group" in the above definition means a straight-chain or 
branched C.sub.1-6 hydrocarbon group. Typical groups of the same are 
methyl, ethyl, butyl, isopropyl and so on. The "lower acyl group" means, 
formyl, acetyl, propionyl, butanoyl and so on. 
While the above compound (I) may occur as stereoisomers or tautomers 
according to substituents, such isomers in an isolated form as well as in 
mixtures also fall within the scope of the compound of the present 
invention. 
The salt of the above compound (I) includes salts with inorganic acids such 
as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., salts with 
organic acids such as fumaric acid, tartaric acid, alkanesulfonic acids, 
arylsulfonic acids, etc. and salts with inorganic bases such as sodium 
hydroxide, potassium hydroxide, etc. and salts with organic bases such as 
diethylamine and so on. 
Production Process 
The compound of the present invention can be produced in accordance with 
the following reaction schema. 
##STR11## 
(wherein Y means a halogen atom; ring A, X, R.sup.4, R.sup.2, R.sup.3, 
R.sup.7, R.sup.5 and R.sup.6 are as defined hereinbefore). 
For conducting the above reaction, halide (II) and either imidazole or 
triazole compound (III) are reacted in stoichiometric amounts. This 
reaction is generally conducted in a solvent, such as dimethylformamide, 
dimethyl sulfoxide, acetonitrile, acetone, tetrahydrofuran or the like, 
under warming. The reaction may be accelerated by adding a base such as 
sodium hydroxide, potassium hydroxide or the like. 
The compound of the present invention can also be produced in accordance 
with the following reaction schema. 
##STR12## 
This production process is carried out by reacting diamino compound (IV) 
with an equimolar or excess of oxalic acid or a reactive derivative 
thereof (V) at room temperature or under warming. The reactive derivative 
of oxalic acid may, for example, be the corresponding salt, ester, 
hydrate, anhydride or acid chloride. This reaction is generally conducted 
in an aqueous solvent or an alcoholic solvent. It is preferable to add an 
acid such as hydrochloric acid or the like to accelerate the reaction. 
For the production of compound (I,), the following alternative process can 
be used. 
##STR13## 
(wherein R.sup.8 represents a lower alkyl group; the other symbols are as 
defined hereinbefore). 
This reaction, involving reductive cyclization of lower alkoxalylamino 
compound (VI), can be carried out by the catalytic reduction method using 
Raney nickel or the like as the catalyst. 
A still another process for the production of the compound of the present 
invention comprises introducing a new substituent group into ring A of the 
compound obtained by any of the above processes or exchanging 
substituents. The compound of the invention in which R.sup.1 is a nitro 
group, for instance, can be obtained by nitrating the corresponding 
compound in which R.sup.1 is hydrogen. This nitration reaction can be 
conducted by a process comprising reacting the compound not having a nitro 
group with nitric acid or a salt thereof under acidic conditions in the 
presence of sulfuric acid or acetic anhydride-acetic acid or sulfuric 
acid-acetic anhydride-acetic acid or by a process comprising heating said 
compound together with nitronium tetrafluoroborate in an organic solvent 
such as sulfolane. 
The compound of the present invention has a strong affinity for 
NMDA-glycine receptor and/or AMPA receptor. The action on NMDA receptor 
([.sup.3 H]-MK-801 binding inhibitory activity) was observed at the 
concentration of 1 .mu.M. The AMPA receptor binding inhibitory activity, 
for example of the compound of Example 8, was 96% at 1 .mu.M and its Ki 
value was 21 nM. The compounds of Examples 9 and 15 inhibited audiogenic 
convulsions at 3 mg/kg when given 15 minutes before sound stimulation. 
Furthermore, when the compound of this invention, for example the compound 
of Example 15, was administered 60, 70 and 85 minutes after 5-minute 
ischemia, it exhibited 60% neuron protecting activity with a lesion score 
of 1.2. 
Experimental Methods 
The activity of the compound of the present invention on NMDA-glycine 
receptor ([.sup.3 H]-MK-801 binding inhibitory activity) and the [.sup.3 
H]-AMPA binding inhibitory activity, audiogenic convulsion inhibitory 
activity and neuron protecting activity of the compound were determined by 
the following methods. 
Effect on NMDA-Glycine Assay Receptor Assay of [.sup.3 H]-MK-801 Binding 
Inhibitory Activity] 
The binding activity and antagonistic activity with respect to NMDA-glycine 
receptors were determined by a binding assay using [.sup.3 H]-MK-801 as 
the ligand. 
Determination of [.sup.3 H]-AMPA Binding Activity 
A mixture (0.5 ml) of about 45 nM [.sup.3 H]-AMPA 
(2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)propionic acid), about 300 mg 
of rat cerebral membrane specimen and the test compound was allowed to 
react on ice-water for 45 minutes. The amount of [.sup.3 H]-AMPA bound to 
quisqualic acid receptors was determined by the filtration method. Of the 
total amount of binding, the portion substituted for by 10 .mu.M 
quisqualic acid was regarded as specific binding. The test compound was 
evaluated by determining the percentage inhibition of the specific 
binding. 
Determination of Audiogenic Convulsion Inhibitory Activity in DBA/2 Mice 
Ten male mice, 21-28 days old, were placed in a soundproof box and loaded 
with a sound stimulus of 12 KHz and 120 dB for 1 minute or until the mice 
developed tonic convulsions. 
The test compound was suspended in 0.5% methylcellulose solution or 
dissolved in physiological saline and administered intraperitoneally 45 or 
15 minutes before sound stimulation. 
The effect of the test compound was evaluated according to the onset of 
convulsion and the minimum effective dose (MED) was determined. 
Neuron-Protective Action in the Hippocampus 
The protective action on nerve cell necrosis due to cerebral ischemia was 
tested using a gerbil model of ischemia constructed by occlusion of the 
bilateral common carotid arteries. 
Procedure 
The bilateral common carotid arteries of the gerbil were occluded for 5 
minutes under halothane anesthesia with the animal kept warm to avoid 
hypothermia and, then, the animal was allowed to recover from anesthesia. 
After 4 days, the brain was isolated and sections were prepared for 
histological examination of the degree of neuronal damage in the 
hippocampus CA1. 
Method of Administration 
The test compound, either suspended in 0.5% methylcellulose solution or 
dissolved in physiological saline, was administered intraperitoneally. Two 
dosage regimens were employed. In regimen 1, 30 mg/kg/dose was 
administered 45 and 15 minutes before ischemia and 5 minutes and 1, 2, 3, 
6 and 24 hours after obtaining re-patency. In regimen 2, 30 mg/kg/dose was 
administered 60, 70 and 85 minutes after obtaining re-patency. 
Method of Evaluation 
Histopathological examination was performed using a light microscope. The 
degree of nerve cell impairment in the hippocampus CA1 area was rated on a 
4-point scale of no lesion (score 0), slight necrosis (score 1), moderate 
necrosis (score 2) and complete necrosis (score 3). 
The compound of this invention and salt thereof have glutamate receptor 
antagonizing activity, particularly antagonistic activity against one of 
or both of NMDA-glycine and/or AMPA receptors, inhibitory activity against 
the neurotoxic effect of excitatory amino acids, and anticonvulsant 
activity. Therefore, they are useful especially for preventing nerve 
degeneration and mental and motor dysfunctions in Huntington's chorea, 
Parkinson's disease, epilepsy and senile dementia or following cerebral 
ischemia, oxygen deficiency, hypoglycemia or convulsion. 
The compound represented by formula (I) or a salt thereof is usually 
administered systemically or topically, for example orally or 
parenterally. The dosage may vary with age, body weight, clinical 
condition, therapeutic response, route of administration, treatment period 
and so on. For oral administration, the usual daily dosage for adults is 1 
to 1000 mg, preferably 50 to 200 mg, to be administered in a single dose 
or in a few divided doses. For parenteral administration, 1 mg to 500 mg 
of the compound is administered intravenously in a single dose or in a few 
divided doses or by intravenous infusion over a period of 1 to 24 hours. 
Of course, as mentioned above, the dosage should vary depending on various 
conditions, sufficient efficacy may be obtained with a dosage lower than 
the above range.

EXAMPLES 
The present invention is described in further detail with reference to 
Examples, but it should not deemed to be limited thereto. Examples of 
processes for the production of major starting materials for use in the 
examples are described below as Reference Examples. 
Among the symbols used in the presentation of physicochemical data, NMR 
stands for nuclear magnetic resonance spectrum, MS for mass spectrum, m.p. 
for melting point and E.A. for elemental analysis. 
REFERENCE EXAMPLE 1 
##STR14## 
In 80 ml of N,N-dimethylformamide were dissolved 4.00 g of 
2-amino-6-chloro-3-nitropyridine and 15.69 g of imidazole, and the 
solution was stirred at 120.degree. C. overnight. After spontaneous 
cooling to room temperature, 100 ml of water was added and the resulting 
crystals were collected by filtration. The crystals were rinsed with a 
small amount of water and dried under reduced pressure to provide 3.76 g 
of 2-amino-6-imidazolyl-3-nitropyridine. Physicochemical properties: 
NMR (DMSO-d.sub.6 : .delta. from TMS): 7.16 (d, 1H), 7.16 (q, 1H), 7.95 (t, 
1H), 8.18 (br, 2H), 8.56 (d, 1H), 8.57 (d, 1H). MS (EI): 205 (M.sup.+). 
REFERENCE EXAMPLE 2 
##STR15## 
To a mixture of 5.6 g of 2-ethoxalylamino-5-fluoronitrobenzene and 170 ml 
of DMF was added 0.3 g of 10% Pd-C, and hydrogenation reaction was carried 
out at ordinary temperature and pressure. The reaction mixture was then 
filtered and concentrated under reduced pressure. The resulting residue 
was recrystallized from ethanol to provide 3.68 g (85%) of 
7-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione 
Physicochemical properties: 
NMR (DMSO-d.sub.6 : .delta. from TMS): 6.93-7.31 (m, 3H), 11.83 (s, 1H), 
12.1 (s, 1H). MS (FAB): 197 (M+1). 
m.p.: 138.degree.-140.degree. C. (dec.) (EtOH). 
______________________________________ 
E.A. (for C.sub.8 H.sub.5 N.sub.2 O.sub.3 F): 
C H N 
______________________________________ 
Calcd. (%) 48.99 2.57 14.28 
Found (%) 48.79 2.68 14.16 
______________________________________ 
REFERENCE EXAMPLE 3 
##STR16## 
In 20 ml of sulfuric acid was dissolved 1.34 g of 
7-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione followed by addition of 
0.76 g of potassium nitrate under ice-cooling. The mixture was cooled to 
at room temperature, and after 1 hour, the reaction mixture was poured in 
ice-water. The resulting crystals were recovered by filtration, rinsed 
with water and recrystallized from ethanol-water to provide 0.82 g (50%) 
of 7-fluoro-1-hydroxy-6-nitroquinoxaline-2,3-(1H,4H)-dione. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.50 (d, 1H), 7.91 (d, 1H), 12.20 
(1H), 12.32 (1H). MS (EI): 241 (M.sup.+). 
m.p.: 202.degree. C. (dec.) (EtOH-H.sub.2 O) 
______________________________________ 
E.A. (for C.sub.8 H.sub.4 N.sub.3 O.sub.5 F): 
C H N 
______________________________________ 
Calcd. (%) 39.85 1.67 17.43 
Found (%) 40.24 1.80 17.18 
______________________________________ 
REFERENCE EXAMPLE 4 
##STR17## 
In 10 ml of DMF were dissolved 1.00 g of 
4-fluoro-2-nitro-5-trifluoromethylacetanilide and 2.56 g of imidazole, and 
the solution was stirred at 150.degree. C. for 3 hours. The reaction 
mixture was then diluted with 30 ml of water and the resulting crystals 
were recovered by filtration and purified by column chromatography 
chloroform-methanol=20:1) to provide 0.53 g (52%) of 
4-(1-imidazolyl)-2-nitro-5-trifluoromethylaniline. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.05 (s, 1H), 7.31 (s, 1H), 7.61 (s, 
1H), 7.75 (s, 1H), 7.95 (s, 2H), 8.04 (s, 1H). MS (EI): 272 (M.sup.+). 
REFERENCE EXAMPLE 5 
##STR18## 
In 20 ml of DMF were dissolved 0.70 g of 
4-amino-2-fluoro-5-nitroacetophenone and 1.20 g of imidazole, and the 
mixture was stirred at 130.degree. C. for 1 hour. After spontaneous 
cooling, the reaction mixture was diluted with 60 ml of water. The 
resulting crystals were recovered by filtration and purified by column 
chromatography (chloroform-methanol=3:1) to provide 0.28 g (32%) of 
4-amino-2-(1-imidazolyl)-5-nitroacetophenone. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 2.18 (s, 3H), 6.98 (s, 1H), 7.08 (s, 
1H), 7.37 (t, 1H), 7.84 (s, 1H), 8.03 (br, 2H), 8.52 (s, 1H). MS (EI): 246 
(M.sup.+). 
REFERENCE EXAMPLE 6 
##STR19## 
In 5 ml of DMF were dissolved 1 g of 4-amino-2-fluoro-5-nitrobenzonitrile 
and 1.1 g of imidazole, and the mixture was stirred at 100.degree. C. for 
1 hour. The reaction mixture was then diluted with water and the resulting 
crystals were recovered by filtration to provide 1.2 g of 
4-amino-2-(1-imidazolyl)-5-nitrobenzonitrile. Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.11 (s, 1H), 7.18 (s, 1H), 7.61 (s, 
1H), 8.10 (s, 1H), 8.21 (s, 2H), 8.64 (s, 1H). MS (EI): 229 (M.sup.+). 
EXAMPLE 1 
##STR20## 
In a mixed solution of 40 ml of methanol and 2 ml of acetic acid was 
suspended 3.68 g of 2-amino-6-imidazolyl-3-nitropyridine. Then, 0.20 g of 
10% palladium-on-carbon was added and hydrogenation was carried out at 
atmospheric pressure. The reaction mixture was filtered and the filtrate 
was concentrated under reduced pressure. To the residue were added 24 ml 
of 4N-hydrochloric acid and 1.61 g of oxalic acid and the mixture was 
refluxed overnight. After spontaneous cooling to room temperature, the 
resulting crystals were recovered by filtration and recrystallized from 
N,N-dimethylformamide to provide 2.30 g of 
-imidazolylpyrido[2,3-b]pyrazine-2,3-dione hydrochloride monohydrate. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.80 (s, 2H), 7.88 (q, 1H), 8.24 (t, 
1H), 9.75 (t, 1H), 12.43 (s, 1H), 12.67 (s, 1H). MS (FAB): 230 (M.sup.+ 
+1). 
m.p.: &gt;300.degree. C. (DMF). 
______________________________________ 
E.A. (for C.sub.10 H.sub.7 N.sub.5 O.sub.2.HCl.H.sub.2 O.0.1Me.sub.2 
NCHO): 
C H N Cl 
______________________________________ 
Calcd. (%) 42.52 3.71 24.55 
12.18 
Found (%) 42.46 3.52 24.84 
12.02 
______________________________________ 
EXAMPLE 2 
##STR21## 
In 10 ml of sulfolane was dissolved 1.01 g of 
-imidazolylpyrido[2,3-b]pyrazine-2,3-dione hydrochloride monohydrate 
followed by addition of 1.35 g of nitronium tetrafluoroborate, and the 
mixture was stirred at 120.degree. C. for 4 hours. The reaction mixture 
was then allowed to cool to room temperature, diluted with 10 ml of water 
and neutralized with 1N aqueous sodium hydroxide solution. The resulting 
crystals were recovered by filtration and rinsed with a small amount of 
water. The resulting crystals were suspended in 2 ml of water followed by 
addition of a stoichiometric amount of 1N-hydrochloric acid and, further, 
5 ml of ethanol. The crystals were recovered by filtration and dried under 
reduced pressure to provide 0.63 g of 
6-imidazolyl-7-nitropyrido[2,3-b]pyrazine-2,3-dione hydrochloride. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.87 (m, 1H), 8.07 (m, 1H), 8.46 (s, 
1H), 9.53 (m, 1H), 12.74 (s, 1H), 13.16 (br, 1H). 
MS (FAB): 275 (M.sup.+ +1). 
m.p.: &gt;300.degree. C. (EtOH-H.sub.2 O). 
______________________________________ 
E.A. (for C.sub.10 H.sub.6 N.sub.6 O.sub.4.HCl.0.2H.sub.2 O): 
C H N Cl 
______________________________________ 
Calcd. (%) 38.22 2.37 26.74 
11.28 
Found (%) 38.33 2.34 26.63 
11.40 
______________________________________ 
EXAMPLE 3 
##STR22## 
In DMF, 1 g of 6-fluoro-7-nitroquinoxaline-2,3-(1H,4H)-dione and 1.8 g of 
2-methylimidazole were stirred with heating at 130.degree. C. for 8 hours. 
The reaction mixture was then concentrated and diluted with water, 
whereupon crystals separated out. The crystals were recrystallized from 
DMF-water to provide 540 mg of 
6-(2-methylimidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 2.09 (s, 3H), 6.93 (1H), 7.12 (s, 
1H), 7.19 (1H), 7.95 (s, 1H), 12.42 (2H). 
MS (FAB): 288 (M.sup.+ +1). 
m.p.: &gt;300.degree. C. (DMF-H.sub.2 O). 
______________________________________ 
E.A. (for C.sub.12 H.sub.9 N.sub.5 O.sub.4.H.sub.2 O): 
C H N 
______________________________________ 
Calcd. (%) 47.22 3.63 22.94 
Found (%) 46.64 3.57 22.59 
______________________________________ 
EXAMPLE 4 
##STR23## 
The same procedure as in Example 3 was repeated except 2-ethylimidazole was 
used in lieu of 2-methylimidazole. As a result, 450 mg of 
6-(2-ethylimidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione was obtained. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 1.10 (t, 3H), 2.38 (dd, 2H), 6.92 
(d, 1H), 7.09 (s, 1H), 7.15 (d, 1H), 7.92 (s, 1H). 
MS (FAB): 302 (M.sup.+ +1). m.p.: 249.degree.-250.degree. C. (DMF-H.sub.2 
O). E.A. (for C.sub.13 H.sub.11 N.sub.5 O.sub.4.H.sub.2 O): 
______________________________________ 
E.A. (for C.sub.13 H.sub.11 N.sub.5 O.sub.4.H.sub.2 O): 
C H N 
______________________________________ 
Calcd. (%) 48.91 4.10 21.94 
Found (%) 48.61 4.00 21.75 
______________________________________ 
EXAMPLE 5 
##STR24## 
The same procedure as in Example 3 was repeated except 4-methylimidazole 
was used in lieu of 2-methylimidazole. As a result, 
6-(4-methyl-1-imidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione or 
6-(5-methyl-1-imidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione was 
obtained as a single substance with respect to the nuclear magnetic 
resonance (NMR) spectrum. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 2.16 (s, 3H), 7.04 (t, 1H), 7.08 (s, 
1H), 7.72 (d, 1H), 7.85 (s, 1H), 12.39 (2H). 
MS (FAB): 288 (M.sup.+ +1) 
m.p.: &gt;300.degree. C. (DMF-H.sub.2 O) 
______________________________________ 
E.A. (for C.sub.12 H.sub.9 N.sub.5 O.sub.4): 
C H N 
______________________________________ 
Calcd. (%) 50.18 3.16 24.38 
Found (%) 49.55 3.30 23.87 
______________________________________ 
EXAMPLE 6 
##STR25## 
The same procedure as in Example 3 was repeated except 
4,5,6,7-tetrahydrobenzimidazole was used in lieu of 2-methylimidazole. As 
a result, 450 mg of 6-nitro-7-( 
4,5,6,7-tetrahydro-1-benzimidazolyl)quinoxaline-2,3-(1H,4H)-dione was 
obtained. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 1.70 (4H), 2.18 (2H), 2.50 (2H), 
12.35 (2H). 
MS (FAB): 328 (M.sup.+ +1). 
m.p.: &gt;300.degree. C.; 
______________________________________ 
E.A. (for C.sub.15 H.sub.13 N.sub.5 O.sub.4.1.5H.sub.2 O): 
C H N 
______________________________________ 
Calcd. (%) 50.85 4.55 19.77 
Found (%) 50.58 4.54 19.57 
______________________________________ 
EXAMPLE 7 
##STR26## 
A dry DMSO solution containing 1.2 g of 
6-fluoro-7-nitroquinoxaline-2,3-(1H,4H)-dione, 740 mg of potassium 
hydroxide powder and 1.3 g of benzimidazole was stirred with heating at 
130.degree. C. for 5.5 hours. The reaction mixture was then poured in 
ice-water, followed by addition of hydrochloric acid, and the mixture was 
filtered at pH about 9 to separate insolubles. The filtrate was then 
adjusted to pH about 7 with hydrochloric acid, whereupon crystals 
separated out again. These crystals were collected by filtration to 
provide 210 mg of 
6-(benzimidazol-1-yl)-7-nitroquinoxaline-2,3-(1H,4H)-dione. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.12-7.39 (4H), 7.73-7.84 (1H), 8.05 
(s, 1H), 8.45 (s, 1H), 12.37 (2H). 
MS (FAB): 324 (M.sup.+ +1). 
m.p.: &gt;300.degree. C. (KOHaq-HClaq). 
______________________________________ 
E.A. (for C.sub.15 H.sub.9 N.sub.5 O.sub.4.H.sub.2 O): 
C H N 
______________________________________ 
Calcd. (%) 52.79 3.25 20.52 
Found (%) 52.20 3.37 20.12 
______________________________________ 
EXAMPLE 8 
##STR27## 
In 5 ml of DMF were dissolved 0.5 g of 
7-fluoro-1-hydroxy-6-nitroquinoxaline-2,3-(1H,4H)-dione and 0.7 g of 
imidazole, and the mixture was stirred with heating at 120.degree. C. for 
1.5 hours. After cooling to room temperature, the reaction mixture was 
diluted with water and adjusted to pH 6 with 1N-hydrochloric acid. The 
resulting crystals were recovered by filtration, rinsed with water and 
washed with ethanol to provide 0.33 g of solid matter. This solid was 
recrystallized from DMF and the resulting crystals were washed with 
ethanol to provide 0.12 g (20%) of 
1-hydroxy-7-imidazolyl-6-nitroquinoxaline-2,3-(1H,4H)-dione. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 3.5 (1H), 7.10 (s, 1H), 7.42 (s, 
1H), 7.45 (s, 1H), 7.91 (s, 1H), 7.97 (s, 1H), 12.5 (1H). 
MS (FAB): 290 (M.sup.+ +1). 
m.p.: 235.degree. C. (dec.) (DMF). 
______________________________________ 
E.A (for C.sub.11 H.sub.7 N.sub.5 O.sub.5.0.5DMF.0.5H.sub.2 O): 
C H N 
______________________________________ 
Calcd. 44.85 3.46 23.01 
Found (%) 45.05 3.51 22.99 
______________________________________ 
EXAMPLE 9 
##STR28## 
To a solution of 0.50 g of 
4-(1-imidazolyl)-2-nitro-5-trifluoromethylaniline in 10 ml of ethanol was 
added 0.05 g of 10% palladium-on-carbon and hydrogenation was carried out 
at ordinary temperature and pressure for 30 minutes. The reaction mixture 
was then filtered and the filtrate was concentrated. To the residue were 
added 0.17 g of oxalic acid and 15 ml of 4N-hydrochloric acid and the 
mixture was refluxed for 5 hours. After spontaneous cooling, the resulting 
crystals were recovered by filtration and rinsed with a small amount of 
water. The crystals were then dried under reduced pressure to provide 0.14 
g of 6-(1-imidazolyl)-7-trifluoromethylquinoxaline-2,3-(1H,4H)-dione 
hydrochloride hydrate. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.49 (s, 1H), 7.69 (s, 1H), 7.86 (s, 
1H), 8.00 (s, 1H), 9.43 (s, 1H), 12.41 (s, 1H), 12.60 (s, 1H). 
MS (FAB): 297(M.sup.+ +1). 
m.p.: &gt;300.degree. C. 
______________________________________ 
E.A. (for C.sub.12 H.sub.7 N.sub.4 O.sub.3 F.sub.3.HCl.H.sub.2 O): 
C H N F Cl 
______________________________________ 
Calcd. (%) 
41.10 2.87 15.98 16.25 
10.11 
Found (%) 41.14 2.95 15.96 16.22 
10.28 
______________________________________ 
EXAMPLE 10 
##STR29## 
In 30 ml of ethanol was dissolved 0.27 g of 
4-amino-2-(1-imidazolyl)-5-nitroacetophenone followed by addition of 0.27 
g of Raney nickel, and hydrogenation was carried out at ordinary 
temperature and pressure for 30 minutes. The reaction mixture was then 
filtered and the filtrate was concentrated under reduced pressure. To the 
residue were added 0.10 g of oxalic acid and 12 ml of 4N-hydrochloric 
acid, and the mixture was refluxed for 5 hours. The reaction mixture was 
allowed to cool and the resulting crystals were recovered by filtration. 
The crystals were washed with a small amount of hydrochloric acid and 
dried under reduced pressure to provide 0.08 g (23%) of 
6-acetyl-7-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione hydrochloride 1.5 
hydrate. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 2.45 (s, 3H), 7.34 (s, 1H), 
7.84-7.92 (m, 3H), 9.39 (t, 1H), 12.34 (s, 1H), 12.56 (s, 1H). 
MS (FAB): 271 (M.sup.+ +1). 
m.p.: 285.degree. C. (dec.). 
______________________________________ 
E.A. (for C.sub.13 H.sub.10 N.sub.4 O.sub.3.HCl.1.70 H.sub.2 O): 
C H N Cl 
______________________________________ 
Calcd. (%) 46.29 4.30 16.61 
10.51 
Found (%) 46.22 4.20 16.52 
10.69 
______________________________________ 
EXAMPLE 11 
##STR30## 
To 20 ml of 1N-hydrochloric acid was mixed 1.6 g of 
4-amino-2-(1-imidazolyl)-5-nitrobenzonitrile followed by addition of 0.2 g 
of 10% palladium-on-carbon, and hydrogenation was carried out. The 
reaction mixture was filtered and concentrated under reduced pressure. To 
the residue were added 20 ml of 4N-hydrochloric acid and 0.9 g of oxalic 
acid, and the mixture was refluxed for 4 hours. The reaction mixture was 
then allowed to cool to room temperature and the resulting crystals were 
recovered by filtration and recrystallized from 4N-hydrochloric acid to 
provide 760 mg of 6-(1-imidazolyl)-7-cyanoquinoxaline-2,3-dione 
hydrochloride. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.52 (s, 1H), 7.73 (s, 1H), 7.90 (s, 
1H), 8.14 (s, 1H), 9.54 (s, 1H), 12.48 (s, 1H), 12.69 (s, 1H). 
MS (FAB): 254 (M.sup.+ +1). 
m.p.: 300.degree. C. (4N-HCl). 
______________________________________ 
E.A. (for C.sub.12 H.sub.7 N.sub.5 O.sub.2.1HCl): 
C H N Cl 
______________________________________ 
Calcd. (%) 49.76 2.78 24.18 
12.24 
Found (%) 49.40 2.85 23.95 
12.32 
______________________________________ 
EXAMPLE 12 
##STR31## 
In a mixture of 10 ml of ethanol and 1 ml of concentrated hydrochloric acid 
was dissolved 0.60 g of 
4-[1-(4-methylimidazolyl)]-2-nitro-5-trifluoromethylaniline as synthesized 
from 4-fluoro-2-nitro-5-trifluoromethylacetanilide and 4-methylimidazole 
by the procedure described in Reference Example 4. To this solution was 
added 0.06 g of 10% palladium-on-carbon, and hydrogenation was carried out 
at ordinary temperature and pressure for 3 hours. The reaction mixture was 
then filtered and the filtrate was concentrated under reduced pressure. To 
the residue were added 0.20 g of oxalic acid and 12 ml of 4N-hydrochloric 
acid, and the mixture was refluxed for 6 hours. After spontaneous cooling, 
the resulting crystals were recovered by filtration, washed with a small 
amount of hydrochloric acid and dried under reduced pressure to provide 
0.28 g (37%) of 
6-[1-(4-methylimidazolyl)]-7-trifluoromethylquinoxaline-2,3-(1H,4H)-dione 
hydrochloride dihydrate. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 
2.37 (s, 3H), 7.51 (s, 1H), 7.74 (s, 2H), 
9.42 (s, 1H), 12.49 (s, 1H), 12.69 (s, 1H). 
MS (FAB): 311 (M.sup.+ +1). 
m.p.: &gt;300.degree. C. 
______________________________________ 
E.A. (for C.sub.13 H.sub.9 N.sub.4 O.sub.2 F.sub.3.HCl.2.1 H.sub.2 O): 
C H N F Cl 
______________________________________ 
Calcd. (%) 
40.61 3.72 14.57 14.82 
9.22 
Found (%) 40.60 3.42 14.51 14.45 
9.60 
______________________________________ 
EXAMPLE 13 
##STR32## 
In 5 ml of sulfolane were dissolved 0.5 g of 
6-fluoro-7-nitroquinoxaline-2,3-(1H,4H)-dione and 0.65 g of sodium 
triazole, and the mixture was stirred at 180.degree. C. for 2 hours. The 
reaction mixture was then diluted with ice-water and neutralized with 
hydrochloric acid. The resulting crystals were recovered by filtration, 
washed with water and then with alcohol to provide 470 mg of 
6-nitro-7-(1,2,4-triazol-1-yl)quinoxaline-2,3-(1H,4H)-dione. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.30 (s, 1H), 7.88 (s, 1H), 8.24 (s, 
1H), 9.02 (s, 1H), 12.40 (2H). 
MS (FAB): 275 (M.sup.+ +1). 
m.p.: &gt;300.degree. C. 
______________________________________ 
E.A. (for C.sub.10 H.sub.6 N.sub.6 O.sub.4.0.5 H.sub.2 O): 
C H N 
______________________________________ 
Calcd. (%) 42.41 2.49 29.68 
Found (%) 42.85 2.50 29.74 
______________________________________ 
EXAMPLE 14 
##STR33## 
In 4N-hydrochloric acid were dissolved 1.4 g of 
4-imidazolyl-1,2-diaminobenzene and 0.9 g of oxalic acid, and the solution 
was refluxed overnight. After cooling to room temperature, the resulting 
crystals were recovered by filtration and dissolved in sulfuric acid. The 
solution was poured in ice-water, whereupon crystals formed again. These 
crystals were recovered by filtration and dried to provide 0.65 g of 
6-imidazolylquinoxaline-2,3-(1H,4H)-dione hemisulfate monohydrate. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.22-7.36 (2H), 7.42 (d, 1H), 7.52 
(s, 1H), 7.90 (s, 1H), 8.90 (s, 1H). 
MS (EI): 228 (M.sup.+). 
m.p.: &gt;300.degree. C. (H.sub.2 SO.sub.4 -H.sub.2 O). 
______________________________________ 
E.A. (for C.sub.11 H.sub.6 N.sub.4 O.sub.2.1/2 H.sub.2 SO.H.sub.2 O): 
C H N S 
______________________________________ 
Calcd. (%) 44.75 3.76 18.98 
5.43 
Found (%) 44.85 3.77 19.07 
5.38 
______________________________________ 
EXAMPLE 15 
##STR34## 
In 5 ml of sulfuric acid was dissolved 0.5 g of 
6-imidazolylquinoxaline-2,3-(1H,4H)-dione hydrochloride followed by 
addition of 0.21 g of potassium nitrate, and the resulting mixture was 
heated at 70.degree. C. for 5 minutes. After spontaneous cooling to room 
temperature, the reaction mixture was poured in ice-water and adjusted to 
pH 4-5 with aqueous sodium hydroxide solution, whereupon crystals 
separated out. These crystals were recovered by filtration and 
recrystallized from DMF-water to provide 0.27 g of 
6-imidazolyl-7-nitroquinoxaline-2,3-(1H,4H)-dione. 
Physicochemical properties: 
NMR (DMSO-d.sub.6 ; .delta. from TMS): 7.28 (s, 1H), 7.50 (s, 1H), 7.82 (s, 
1H), 8.02 (s, 1H), 8.68 (s, 1H). 
MS (EI): 272 (M.sup.+ +1). 
m.p.: &gt;300.degree. C. (DMF-H.sub.2 O). 
______________________________________ 
E.A. (for C.sub.11 H.sub.7 N.sub.5 O.sub.4): 
C H N 
______________________________________ 
Calcd. (%) 48.36 2.58 25.63 
Found (%) 48.36 2.68 25.66 
______________________________________ 
EXAMPLE 16-1 
##STR35## 
A mixture of 4.2 g of 4-(1-imidazolyl)-2-n-propylaminonitrobenzene, 0.8 g 
of 10% palladium-on-carbon and 60 ml of 1N-hydrochloric acid was subjected 
to hydrogenation reaction. The reaction mixture was filtered and the 
filtrate was concentrated under reduced pressure. To the residue were 
added 20 ml of 4N-hydrochloric acid and 3 g of oxalic acid, and the 
mixture was refluxed for 5 hours. After spontaneous cooling to room 
temperature, the resulting crystals were recovered by filtration and 
recrystallized from 4N-hydrochloric acid to provide 3 g of 
7-(1-imidazolyl)-1-n-propylquinoxaline-2,3-(1H,4H)-dione hydrochloride. 
The following compounds were synthesized in the same manner (Examples 16-2 
through 16-12). 
16-2: 1-Hydroxyethyl-7-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione 
hydrochloride hydrate 
16-3: 7-(1-Imidazolyl)-1-(N-morpholino)ethylquinoxaline-2,3-(1H,4H)-dione 
dihydrochloride 2.5 hydrate 
16-4: 
7-(1-imidazolyl)-1-(2-tetrahydrofuranyl)-methylquinoxaline-2,3-(1H,4H)-dio 
ne hydrochloride hydrate 
16-5: 1-Decyl-7-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione hydrochloride 
1.5 hydrate 
16-6: 1-(Dimethylamino)ethyl-7-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione 
dihydrochloride 1.5 hydrate 
16-7: 1-(2-Aminocyclohexyl)-7-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione 
dihydrochloride dihydrate 
16-8: 
7-(1-Imidazolyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)quinoxaline-2,3-(1H, 
4H)-dione dihydrochloride trihydrate 
16-9: 7-(1-Imidazolyl)-1-methylquinoxaline-2,3-(1H,4H)-dione hydrochloride 
16-10: 7-(1-Imidazolyl)-1-cyclohexylquinoxaline-2,3-(1H,4H)-dione 
hydrochloride hydrate 
16-11: 7-(1-Imidazolyl)-1-cyclohexylmethylquinoxaline-2,3-(1H,4H)-dione 
hydrochloride 1.5 hydrate 
16-12: 7-(1-Imidazolyl)-1-isopentylquinoxaline-2,3-(1H,4H)-dione 
hydrochloride 1.5 hydrate 
EXAMPLE 17 
##STR36## 
To a solution of 1 g of 
7-(1-imidazolyl)-1-n-propylquinoxaline-2,3-(1H,4H)-dione hydrochloride in 
8 ml of sulfuric acid was added 0.4 g of potassium nitrate, and the 
mixture was stirred overnight. The reaction mixture was poured in 
ice-water and adjusted to pH 7. The resulting crystals were recrystallized 
from 1N-hydrochloric acid to provide 0.9 g of 
7-(1-imidazolyl)-6-nitro-1-n-propylquinoxaline-2,3-(1H,4H)-dione 
hydrochloride. 
The following compounds were obtained in the same manner (Examples 17-2 
through 17-13). 
17-2: 1-Hydroxyethyl-7-(1-imidazolyl)-5-nitroquinoxaline-2,3-(1H,4H)-dione 
hydrate 
17-3: 
7-(1-Imidazolyl)-1-(N-morpholino)ethyl-6-nitroquinoxaline-2,3-(1H,4H)-dion 
e hydrate 
17-4: 
7-(1-Imidazolyl)-1-(N-morpholino)ethyl-5nitroquinoxaline-2,3-(1H,4H)-dione 
dihydrate 
17-5: 
7-(1-Imidazolyl)-6-nitro-1-(3-quinuclidinyl)-quinoxaline-2,3-(1H,4H)-dione 
dihydrate 
17-6: 1-Decyl-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione 
hydrochloride 
17-7: 
1-(2-Dimethylamino)ethyl-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-d 
ione dihydrochloride 
17-8: 
1-(2-Aminocyclohexyl)-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dion 
e dihydrochloride 1 isopropyl alcohol 
17-9: 
7-(1-Imidazolyl)-6-nitro-1-(2,2,6,6-tetramethylpiperidin-4-yl)quinoxaline- 
2,3-(1H,4H)-dione 
17-10: 7-(1-Imidazolyl)-6-nitro-1-cyclohexylquinoxaline-2,3-(1H,4H)-dione 
sulfate hydrate 
17-11: 7-(1-Imidazolyl)-6-nitro-1-methylquinoxaline-2,3(1H,4H)-dione sodium 
dihydrate 
17-12: 
7-(1-Imidazolyl)-6-nitro-1-cyclohexylmethylquinoxaline-2,3-(1H,4H)-dione 
0.5 hydrate 
17-13: 7-(1-Imidazolyl)-6-nitro-1-isopentylquinoxaline-2,3-(1H,4H)-dione 
sodium salt 
EXAMPLE 18 
##STR37## 
A mixture of 680 mg of 2-(1-imidazolyl)-5-nitro-4-phenylaminobenzonitrile, 
200 mg of 10% palladium-on-carbon and 10 ml of 1N-hydrochloric acid was 
subjected to hydrogenation reaction. The reaction mixture was filtered and 
the filtrate was concentrated under reduced pressure. To the residue were 
added 8 ml of 4N-hydrochloric acid and 420 mg of oxalic acid and the 
mixture was refluxed for 2 hours. After spontaneous cooling to room 
temperature, the resulting crystals were recovered by filtration and 
recrystallized from 4N-hydrochloric acid. The crystals were neutralized 
with sodium hydroxide and rinsed with water to provide 186 mg of 
6-cyano-7-(1-imidazolyl)-1-phenylquinoxaline-2,3-(1H,4H)-dione hydrate. 
The following compounds were synthesized in the same manner. 
6-Cyano-7-(1-imidazolyl)-1-(2-carboxyethyl)-quinoxaline-2,3-(1H,4H)-dione 
hydrate 
6-Cyano-7-(1-imidazolyl)-1-(2,2,2-trifluoroethyl)-quinoxaline-2,3-(1H,4H)- 
dione hydrochloride dihydrate 
EXAMPLE 19 
##STR38## 
A mixture of 2.5 g of 3,5-di-(1-imidazolyl)-2-nitroaniline dihydrochloride, 
300 mg of 10% palladium-on-carbon and 25 ml of 1N-hydrochloric acid was 
subjected to hydrogenation reaction. The reaction mixture was then 
filtered and the filtrate was concentrated under reduced pressure. To the 
residue were added 15 ml of 4N-hydrochloric acid and 900 mg of oxalic 
acid, and the mixture was refluxed with stirring for 10 hours. The 
reaction mixture was then concentrated under reduced pressure, dissolved 
in water and neutralized with sodium hydroxide. The resulting crystals 
were washed with ethanol-water to provide 870 mg of 
5,7-di(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione. 
EXAMPLE 20 
##STR39## 
In 3 ml of concentrated sulfuric acid was dissolved 290 mg of 
5,7-di-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione hydrate followed by 
addition of 220 mg of potassium nitrate with ice-cooling. After cooling to 
room temperature, the reaction mixture was further stirred at 80.degree. 
C. for 30 minutes. After cooling to room temperature, the reaction mixture 
was poured in ice-water and adjusted to pH 7 with sodium hydroxide. The 
resulting crystals were recovered by filtration and washed with water to 
provide 124 mg of 
5,7-di(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione. 
EXAMPLE 21 
##STR40## 
In a mixture of 2 ml of methanol and 1 ml of 1N-hydrochloric acid was 
dissolved 0.16 g of 4-(1-imidazolyl)-3-methyl-6-nitroaniline, and the 
solution was subjected to hydrogenation in the presence of 16 mg of 10% 
Pd-C at ordinary temperature and pressure for 3 hours. The reaction 
mixture was filtered and the filtrate was concentrated. To the residue 
were added 46 mg of oxalic acid and 9 ml of 4N-hydrochloric acid, and the 
mixture was refluxed overnight. After spontaneous cooling of the reaction 
mixture to room temperature, the resulting crystals were recovered by 
filtration and recrystallized from water-DMF to provide 25 mg of 
6-(1-imidazolyl)-7-methylquinoxaline-2,3-(1H,4H)-dione hydrochloride. 
EXAMPLE 22-1 
In 40 ml of 4N-hydrochloric acid, 2 g of 
5-(1-imidazolyl)-3-(N-morpholino)-2-nitrobenzacetamide was heated for 1 
hour, and the reaction mixture was concentrated under reduced pressure. 
The concentrate was dissolved in 20 ml of 1N-hydrochloric acid followed by 
addition of 1 g of 10% palladium-on-carbon, and hydrogenation was carried 
out. The reaction mixture was filtered and the filtrate was concentrated 
under reduced pressure. To the residue was added 1 g of oxalic acid and 
the mixture was dissolved in 12 ml of 4N-hydrochloric acid. The reaction 
mixture was refluxed for 5 hours, after which it was allowed to cool to 
room temperature and the resulting crystals were recovered by filtration 
to provide 1.7 g of 
7-(1-imidazolyl)-5-(N-morpholino)quinoxaline-2,3-(1H,4H)-dione 
dihydrochloride 1.5 hydrate. 
EXAMPLE 22-2 
In a mixture of 15 ml of acetic anhydride, 3 ml of acetic acid and 2 ml of 
sulfuric acid was dissolved 1.5 g of 
7-(1-imidazolyl)-5-(N-morpholino)quinoxaline-2,3-(1H,4H)-dione followed by 
addition of 0.33 ml of fuming nitric acid at a temperature not exceeding 
10.degree. C. The mixture was allowed to stand at room temperature for 1 
hour, after which it was concentrated. The concentrate was diluted with 
ice-water and adjusted to pH 7 with alkaline solution. The mixture was 
then purified with HP-20 resin to provide 600 mg of 
6-(1-imidazolyl)-8-(N-morpholino)-5-nitroquinoxaline-2,3-(1H,4H)-dione 
hydrate. 
REFERENCE EXAMPLE 7 
To a mixture of 6.2 g of 2-ethoxalylamino-4-fluoronitrobenzene and 124 ml 
of DMF was added a solution of 5.64 g of ammonium chloride in 40 ml of 
water. Then, 5.7 g of zinc dust was added in small portions to the above 
mixture. The reaction mixture was stirred under TLC (5% 
methanol-chloroform) monitoring and, when the starting material had 
disappeared, the mixture was filtered using Celite and washed with hot 
DMF. The mixture was heated at 100.degree. C. for 3 hours, after which it 
was ice-cooled and the resulting inorganic salt crystals were filtered 
off. To the organic layer was added methanol and the resulting crystals 
were recovered by filtration to provide 2.73 g of 
6-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione. 
REFERENCE EXAMPLE 8 
In 22 ml of sulfuric acid was dissolved 1.6 g of 
6-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione followed by addition of 
0.9 g of KNO.sub.3. The mixture was reacted at room temperature for 3 
hours, after which it was poured in ice-water. The resulting crystals were 
recovered by filtration to provide 310 mg of 
6-fluoro-1-hydroxy-7-nitroquinoxaline-2,3-(1H,4H)-dione. 
EXAMPLE 23 
A mixture of 1 g of 4,5-di-(1-imidazolyl)-2-nitroaniline dihydrochloride, 5 
ml of acetic acid, 5 ml of methanol and 0.1 g of 10% palladium-on-carbon 
was subjected to hydrogenation reaction. The reaction mixture was filtered 
and the filtrate was washed with hydrochloric acid and concentrated under 
reduced pressure. The concentrate was dissolved in 350 mg oxalic acid-6 ml 
of 4N-hydrochloric acid and the solution was subjected to dry distillation 
overnight. The resulting crystals were recovered by filtration and 
recrystallized from 4N-hydrochloric acid to provide 170 mg of 
6,7-di-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione dihydrochloride 
dihydrate. 
EXAMPLE 24 
A mixture of 1.3 g of 4-fluoro-5-(1-imidazolyl)-2-nitroaniline 
hydrochloride, 20 ml of ethanol, 75 mg of platinum oxide and 0.5 ml of 
concentrated hydrochloric acid was subjected to hydrogenation reaction. 
The reaction mixture was filtered and washed with hydrochloric 
acid-ethanol. The filtrate was concentrated under reduced pressure, the 
concentrate was dissolved in 1 g oxalic acid-20 ml 4N-hydrochloric acid, 
and the mixture was refluxed for 3 hours. The resulting crystals were 
recovered by filtration and recrystallized from 1N-hydrochloric acid to 
provide 900 mg of 6-fluoro-7-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione 
hydrochloride hydrate. 
EXAMPLE 25 
A mixture of 370 mg of 
6-fluoro-1-hydroxy-7-nitroquinoxaline-2,3-(1H,4H)-dione, 320 mg of 
imidazole and 37 ml of DMF was stirred at 100.degree. C. for 4 hours. The 
reaction mixture was concentrated and, then, diluted with water. The 
aqueous layer was neutralized with hydrochloric acid and the resulting 
crystals were recovered by filtration and washed with water to provide 214 
mg of 1-hydroxy-6-(1-imidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione 1/2 
hydrate. 
EXAMPLE 26 
In 10 ml of 1N-hydrochloric acid was dissolved 0.5 g of 
4-(1-imidazolyl)-2-nitro-5-trifluoromethyl-N-propylaniline followed by 
addition of 50 mg of 10% palladium-on-carbon, and hydrogenation reaction 
was carried out. The reaction mixture was filtered and the filtrate was 
washed with water and concentrated under reduced pressure. The residue was 
dissolved in 250 mg oxalic acid-6 ml 4N-hydrochloric acid and the solution 
was refluxed. The resulting crystals were filtered off and the mother 
liquor was neutralized with 1N aqueous solution of sodium hydroxide. The 
resulting crystals were recovered by filtration to provide 110 mg of 
6-(1-imidazolyl)-1-propyl-7-trifluoromethylquinoxaline-2,3-(1H,4H)-dione 
hydrate. 
EXAMPLE 27 
The same procedure as in Example 3 was repeated except 4-phenylimidazole 
was used in lieu of 2-methylimidazole. As a result, 270 mg of 
6-nitro-7-(4-phenylimidazol-1-yl)quinoxaline-2,3-(1H,4H)-dione hydrate was 
obtained. 
EXAMPLES 17-14 
1-(2-Acetoxyethyl)-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione 
hydrate 
EXAMPLES 17-15 
In 5 ml of 4N-hydrochloric acid was dissolved 250 mg of 
1-(2-acetoxyethyl)-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione 
of Example 17-14 and the solution was stirred at 100.degree. C. for 3 
hours. The reaction mixture was concentrated, followed by addition of 
methanol, whereupon crystals separated out. The crystals were recovered by 
filtration to provide 200 mg of 
1-(2-hydroxyethyl)-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione 
hydrochloride. 
EXAMPLES 17-16 
7-(1-Imidazolyl)-6-nitro-1-(3-pyrrolidinyl)-quinoxaline-2,3-(1H,4H)-dione 
EXAMPLE 28 
The same procedure as in Example 3 was repeated except 4-nitroimidazole was 
used in lieu of 2-methylimidazole. As a result, 100 mg of 
6-nitro-7-(4-nitroimidazol-1-yl)quinoxaline-2,3-(1H,4H)-dione was 
obtained. 
EXAMPLE 29 
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Freeze-dried preparation 
In each vial: 
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Compound of Example 15 or 9 
50 mg (0.5%) 
Citric acid 210 mg (2.1%) 
D-Mannitol 100 mg (1.0%) 
10 ml 
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In 800 ml of water are serially dissolved 5 g of the compound of Example 15 
or 9, 21 g of citric acid and 10 g of D-mannitol, followed by addition of 
sufficient water to make the solution 1000 ml. This solution is 
aseptically filtered and the filtrate is filled, in 10 ml portions, into 
amber-colored vials and freeze-dried to provide an injectable preparation 
which is reconstituted for use.