JP2889150B2 - Oxopyridinylquinoxaline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to oxopyridinylquinoxaline derivatives having an antagonistic effect on glutamate receptors of central nervous cells, particularly NMDA receptors and AMPA receptors.

[0002]

2. Description of the Related Art Amino acids such as L-glutamic acid and L-aspartic acid are important for neuronal activation as neurotransmitters in the central nervous system. However, excessive accumulation of these excitatory amino acids extracellularly induces excessive stimulation of nerve cells, causing various neurological diseases such as Parkinsonism, senile dementia, Huntington's chorea, epilepsy, and the like. It is thought to cause mental and motor deficits such as those found during hypoxia, ischemia, hypoglycemia, head or spinal cord injury (Mc
Geer et al., Nature, 263, 517-519 (1976), Simon et al., Scien
ce, 226, 850-852 (1984), Wieloch, Science, 230, 681
-683 (1985), Faden et al., Science, 244, 798-800 (1989),
Turski et al., Nature, 349, 414-418 (1991)).

It is known that the activity of the above-mentioned excitatory amino acids on central nervous cells acts via a glutamate receptor present on the nervous cells. Therefore, a substance that antagonizes the binding of the excitatory amino acid to such a receptor is useful as a therapeutic drug for the above-mentioned diseases and conditions, for example, an antiepileptic drug, a preventive drug for ischemic encephalopathy, and an antiparkinson drug. It is believed that. Regarding the important role played by such a glutamate receptor, see JP-A-6-2529.
4, JP-A-6-239747, JP-A-6-228112 (Yamanouchi Pharmaceutical), W
O93 / 8173 (SCHERING), EP5725852A1 (BASF) and the like have also been reported.

[0004] The glutamate receptors are classified into an ion channel type and a metabolic type, and the ion channel type is further classified into three types based on selectivity for an agonist. These are the N-methyl-D-aspartate (NMDA) receptor, the 2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl) propanoate (AMPA) receptor and the kainate receptor, respectively. Called the body.

[0005] The NMDA receptor is selectively activated by agonists such as NMDA and ibotenic acid. This strong stimulation of the NMDA receptor causes a large amount of calcium ions to flow into nerve cells, which is considered to be one of the causes of nerve cell death. As selective antagonists for this NMDA receptor, D-2-amino-5-phosphovaleric acid (D-AP5), 3- [2-
Carboxypiperazin-4-yl] propyl-1-phosphate (CPP) and the like are known.

The AMPA receptor is selectively activated by agonists such as AMPA, glutamate and quisqualate. As antagonists for the AMPA receptor, 6,7-dinitroquinoxaline-2,3-dione (DNQX) (Ferrosan), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 2,3-dione
Dihydroxy-6-nitro-7-sulfamoylbenzo
(f) Quinoxaline (NBQX) (Ferrosan) and 6-
Imidazolyl-7-nitroquinoxaline-2,3- (1
Derivatives based on quinoxaline such as (H, 4H) -dione (YM900) (Yamanouchi Pharmaceutical Co., Ltd.) have been developed (Honore et al., Science, 241, 701-703 (19).
88), Sheardown et al., Eur. J. Pharmacol., 174, 197-204 (1
989), International Publication Number WO92 / 07847, published May 14, 1992). Several types of the above derivatives have been reported so far: JP-A-63-83074, JP-A-63-258466, JP-A-1-153680, JP-A-2-48578, JP-A-2-221263, and Kaihei 2-221264.

The NMDA receptor has an allosteric site to which glycine binds, in addition to the site that recognizes the above-mentioned agonist. It is known that binding of glycine to this allosteric site significantly enhances NMDA receptor function. Recently, there has also been interest in developing antagonists or modulators for the glycine binding site that act allosterically on the NMDA receptor as described above. As an antagonist to such a glycine binding site, 5,7-dichlorokynurenic acid, HA966 (Eur. J. Pharmacol., 151, 161-163 (1
988)).

The above-mentioned DNQX and CNQX are AMPA
In addition to the receptor, it has been confirmed that the NMDA receptor also has an antagonistic effect on the glycine binding site of the NMDA receptor (Birch
Eur. J. Pharmacol., 156, 177-180 (1988), Drejer
Et al., Neurosci. Lett., 98, 333-338 (1989), Sheardown.
Et al., Science, 247, 571-574 (1990)). Dioxotetrahydroquinolines also have glycine binding sites and AM
It is known that any of the PA receptors exhibits antagonism. In general, however, these compounds effectively antagonize either the NMDA receptor or the AMPA receptor, but have less pronounced effects on the other (Larsen et al., Eds.). , EXCITATORY AMINO A
CID RECEPTORS, Chapter 11, published by ELLIS HORWOOD (1992)). In addition, these compounds have not been put to practical use as central nervous drugs because of their poor transfer to the brain.

The compound which protects nerve cells from nerve cell death or degeneration caused by excitatory amino acids and is used as an effective therapeutic agent for the above diseases and conditions is described in the above NMD.
It is necessary to effectively function as an antagonist for both the A receptor and the AMPA receptor (Mosing
er et al., Exp. Neurol., 113, 10-17 (1991)). Therefore, development of such compounds is desired.

[0010]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned conventional problems, and an object of the present invention is to provide an excellent antagonism against NMDA receptor and AMPA receptor existing in central nervous cells. And quinoxaline derivatives.

[0011]

Means for Solving the Problems The present inventors have proposed that oxopyridinyl quinoxaline derivatives can be used as glycine binding sites of NMDA receptors and AMPA present on central nervous cells.
The present inventors have found that they have an antagonistic effect on the receptor and are effective for the above-mentioned diseases and symptoms caused by excessive stimulation of nerve cells by excitatory amino acids, and have completed the present invention.

The oxopyridinylquinoxaline derivative of the present invention is represented by the following formula I.

[0013]

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Here, R ¹ is hydrogen, halogen, nitro or methyl trihalide, and R ² may be substituted by hydrogen, halogen, nitro, cyano, methyl trihalide or lower alkyl. Carbamoyl or sulfamoyl optionally substituted by lower alkyl, R ³ is hydrogen, nitro, or halogen; R ⁴ is hydrogen, optionally substituted lower alkyl, or optionally substituted A good lower cycloalkyl, wherein each R ⁵ is the same or different and is a substituent selected from the group consisting of halogen, nitro, cyano, lower alkyl, and carbamoyl optionally substituted by lower alkyl; Is an integer of 0 to 4 (that is, n = 0, 1, 2, 3, or 4).

In the compound (I) of the present invention, the introduction of an oxopyridinyl group which may be substituted at the 6-position or the 7-position of the quinoxaline skeleton is a particularly novel structure, and is important for pharmacological activity. is there.

Examples of the halogen include chlorine, fluorine, bromine and iodine. Examples of the methyl trihalide include trifluoromethyl and the like. In the present specification, lower alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms, typically, a methyl group, an ethyl group, a propyl group, a butyl group or an isopropyl group. It is. Lower cycloalkyl means a cycloalkyl group having 3 to 6 carbon atoms, and is typically a cyclopropyl group or a cyclobutyl group. R ⁴ above
Examples of the substituent of the substituted lower alkyl or lower cycloalkyl include a halogen, an amino group and a carboxyl group.

Preferably, R ¹ and R ³ are the same or different and are hydrogen or nitro, and more preferably R ¹ and R ³ are each hydrogen. Preferably, R ² is halogen, nitro, cyano, methyl trihalide, carbamoyl, carbamoyl substituted by lower alkyl, sulfamoyl, or sulfamoyl substituted by lower alkyl, more preferably,
Halogen, nitro, cyano, or methyl trihalide, most preferably nitro. Preferably,
R ⁴ is hydrogen or lower alkyl, more preferably hydrogen. Preferably R ^1, R ^3, and R ⁴ are each hydrogen.

Preferably, each R ⁵ is the same or different and is a substituent selected from the group consisting of halogen, nitro and lower alkyl, more preferably each R ⁵
Are the same or different substituents selected from the group consisting of halogen and nitro. The n may be an integer of 0 to 4. When n is 0, R ⁵ is absent and the oxopyridinyl group is unsubstituted. Alternatively, n can be 1, 2, 3, or 4. Therefore, (R ⁵ ) n on the oxopyridinyl group of the oxopyridinylquinoxaline derivative of the present invention
Can be a combination of various substituents, and 2,3,
Any of the positions 5 and 6 may be substituted. As a combination of substituents, n is 4, and each R ⁵ is all halogen; n is 2, each R ⁵ is both halogen, and substitutes the 3- and 5-positions; n
Is 1 and R ⁵ is halogen and substitutes position 3; n is 1 and R ⁵ is lower alkyl;
And substituting the 2-position; n is 1 and R ⁵ is nitro, and substituting the 3-position; and the like.
Preferably, n is 0.

In a preferred oxopyridinylquinoxaline derivative of the present invention, R ¹ and R ³ are the same or different and are hydrogen or nitro, and R ² is halogen, nitro, cyano, methyl trihalide, carbamoyl, lower alkyl. Substituted carbamoyl, sulfamoyl,
Or sulfamoyl substituted by lower alkyl, wherein R ⁴ is hydrogen or lower alkyl, and each R ⁵ is
The same or different, a substituent selected from the group consisting of halogen, nitro, and lower alkyl;
Is an integer from 0 to 4; in a more preferred oxopyridinylquinoxaline derivative of the present invention, R ¹ and R ³ are each hydrogen and R ² is halogen, nitro, cyano, or methyl trihalide. , R ⁴ is hydrogen or lower alkyl, and each R ⁵ is the same or different and is a substituent selected from the group consisting of halogen and nitro;
And n is an integer from 0 to 4; in a more preferred oxopyridinylquinoxaline derivative of the present invention, R ¹ ,
R ³ and R ⁴ are each hydrogen; R ² is nitro; and n is 0. Table 1 shows typical examples of the compounds of the present invention.

[0020]

[Table 1]

The present invention also includes a pharmaceutically acceptable salt of the compound I. These salts include the above compound and hydrochloric acid,
Salts with inorganic acids such as hydrobromic acid, sulfuric acid and phosphoric acid, salts with organic acids such as acetic acid, tartaric acid, fumaric acid and sulfonic acid, and salts with inorganic bases such as sodium hydroxide and potassium hydroxide ( That is, a salt with an organic base such as sodium salt, potassium salt or the like, or tris (hydroxymethyl) aminomethane or choline is included.

The above-mentioned compound I may exist in stereoisomers and tautomers depending on the possible substituents. Further, the compound I of the present invention or a salt thereof may be in the form of a hydrate such as a monohydrate or a dihydrate. These are also within the scope of the present invention.

The compound of the present invention can be produced, for example, by the synthesis method 1 or 2 shown by the following reaction formula.

(1) Synthesis method 1

[0025]

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(Wherein X represents a halogen, R ¹ ,
R ² , R ³ , R ⁴ and (R ⁵ ) n have the same meaning as defined above. In this method, a halogenated quinoxaline compound (II) is reacted with a 4-hydroxypyridine compound (III). The reaction is usually carried out in an organic solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and tetrahydrofuran, preferably about
Heating is performed at 80-180 ° C. Various bases can be added to promote the above reaction. Preferred bases are sodium hydroxide, potassium hydroxide, and potassium carbonate.

(2) Synthesis method 2

[0028]

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(Wherein R ¹ , R ² , R ³ and (R ⁵ ) n are
It has the same meaning as defined above. In the above method, the oxopyridinyl-o-phenylenediamine derivative (IV) is reacted with an equimolar or excessive molar amount of oxalic acid under room temperature or higher heating conditions.
As a substitute for oxalic acid, a reactive derivative of oxalic acid may be used in the above reaction, and preferred derivatives are salts, esters, hydrates, anhydrides, acid chlorides and the like. The above reaction is usually performed in an aqueous or alcoholic solvent. Various acids can be added to accelerate the reaction. A preferred acid is hydrochloric acid. Compound I ′ obtained by this reaction is a compound of the present invention in which R ^{4 in} Formula I is hydrogen.

The compound of the present invention can also be produced by introducing a new substituent or substituting the compound of the present invention obtained by the above-mentioned production method. For example, compound I-2 of the present invention in which R ² is a nitro group can also be obtained by nitrating compound I-1 of the present invention in which R ² is a hydrogen atom, as shown in the following reaction formula. Can be

[0031]

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(Wherein R ¹ , R ³ , R ⁴ and (R ⁵ ) n are
It has the same meaning as defined above. This nitration is carried out by subjecting the quinoxaline derivative (I-1) of the present invention in which R ² is hydrogen to nitric acid or a salt thereof under acidic conditions of sulfuric acid or acetic anhydride-acetic acid, or sulfuric acid-acetic anhydride-acetic acid. Or by heating compound I-1 with nitronium tetrafluoroborate in an organic solvent such as sulfolane.

Alternatively, by treating the compound of the formula (I-3) with chlorosulfonic acid or a salt thereof as shown in the following reaction formula under the same acidic conditions as described above,
It is also possible to introduce a sulfamoyl group as R ² by introducing a chlorosulfonyl group and further treating with an ammonia or ammonium salt.

[0034]

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The ability of the compound of the present invention to bind to each receptor is ³
It can be determined by a binding competition test using H-labeled glycine or AMPA. Further, the compound of the present invention was confirmed to exhibit an effective protective action against brain nerve cell injury in animal experiments using rats.

The binding ability of the present compound to the glycine site of the NMDA receptor can be measured, for example, by the following in vitro competition test.

The rat cerebral cortex is homogenized with a buffer, centrifuged and resuspended repeatedly to prepare a membrane preparation. This membrane sample is mixed with a solution containing [ ³ H] glycine and the compound of interest, incubated for a certain period of time, and the reaction is stopped by dilution and filtration (using filter paper). The radioactivity on the filter paper is measured by liquid scintillation chromatography. Measure with a counter. Non-specific binding is performed using a non-radioactive glycine 1 mM, the IC ₅₀ values are calculated.

The binding ability of the present compound to the AMPA receptor can be measured, for example, by the following competition test.

[0039] The rat cerebral cortex is homogenized with a buffer, centrifuged and resuspended repeatedly to prepare a membrane preparation. This membrane specimen is mixed with a solution containing [ ³ H] AMPA and the compound of interest, and after incubation for a certain period of time, the reaction is stopped by dilution and filtration (using a filter paper), and the radioactivity on the filter paper is measured by liquid scintillation chromatography. Measure with a counter. Non-specific binding is performed using a non-radioactive glutamate 1 mM, the IC ₅₀ values are calculated.

The oxopyridinylquinoxaline derivative of the present invention is a useful therapeutic agent for central nervous system diseases caused by binding of excitatory amino acids to NMDA receptors of the central nervous system, particularly glycine binding site and AMPA receptor. It can be administered orally or parenterally to the subject. Injectable solutions or suspensions, preferably aqueous solutions, are suitable for parenteral administration and tablets or capsules are suitable for oral administration in the form of the therapeutic agent. These therapeutic agents may contain the compounds of the present invention at various concentrations, and include pharmaceutically acceptable organic or inorganic excipients such as saline, alcohols, castor oil, gelatin, lactose, starch, and talc. It can be added. If desired, various adjuvants such as lubricants, stabilizers and emulsifiers may be added to the therapeutic agent.

The compounds of the present invention can be administered orally or parenterally (particularly intravenously) to humans. The dose of the compound of the present invention may vary depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc. of the subject.In the case of a normal adult, for oral administration, about 1 to 1000 mg per day, Preferably
In the range of 10-500 mg, for parenteral administration, about 1-500 mg
Range. Administration may be administered once or several times a day, or may be continuous administration.

The present invention will be described in more detail with reference to the following examples, which do not limit the present invention in any way.

[0043]

EXAMPLES In the examples, among the symbols indicating the properties of the compounds, NMR indicates a nuclear magnetic resonance spectrum and IR indicates an infrared spectrum.

Production examples of the main starting compounds used in the examples will be described as Reference Examples 1 to 6.

Reference Example 1

[0046]

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2-nitro-5- (4-oxo-4H-pi
8.628 g of lysin-1-yl) -aniline 5-chloro-2-nitroaniline, 7.161 g of 4-hydroxypyridine and 4.89 of ground potassium hydroxide
2 g was added to 60 ml of dry dimethyl sulfoxide, and the mixture was stirred at 130 ° C. for 3 hours under a nitrogen stream. 200 ml of ice water was added to the reaction solution,
After neutralizing with 4N-hydrochloric acid and stirring for 30 minutes, the precipitated precipitate was collected by filtration and washed with water. The precipitate was purified using silica gel column chromatography, and the fraction eluted with 20% methanol-methylene chloride was recrystallized from methanol to give 2-nitro-5- (4-oxo-4H-pyridine-1).
11.868 g of yellow-orange crystals of -yl) -aniline were obtained.

Melting point: 298-303 ° C. Elemental analysis (as C ₁₁ H ₉ N ₃ O ₃ .1 / 5 H ₂ O) Calculated: C, 56.27; H, 4.03; N, 17.90 (%) Experimental: C, 56.21; H, 4.01; N, 17.79 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.26 (2H, d, J = 7.8H)
z), 6.81 (1H, dd, J = 9.4,2.8Hz), 7.08 (1H, d, J = 2.8H
z), 7.61 (2H, br.s), 7.99 (2H, d, J = 7.8Hz), 8.12
(1H, d, J = 9.4Hz).

4- (4-oxo-4H-pyridine-1-i
2-nitro-5- (4-oxo-4H-pyridine-) was added to a suspension of 7.975 g of 1,2-phenylenediamine iron powder, 20 ml of water and 78 ml of ethanol.
1-yl) -aniline (5.515 g) was added, followed by 2N hydrochloric acid (2 ml)
Was added, and the mixture was heated under reflux for 6 hours. Then iron powder 1.
092 g and 2 ml of 2N hydrochloric acid were added, and the mixture was further refluxed for 1 hour. After the reaction, hot filtration was performed using celite, and insolubles were sufficiently washed with warm ethanol. The mother liquor and the washings were combined, concentrated to dryness, the residue was subjected to silica gel column chromatography, and the fraction eluted with 5% methanol-chloroform was collected in isopropanol-methanol (1: 1).
Recrystallization was carried out using 1) to give 4- (4-oxo-4H).
4.137 g of orange crystals of -pyridin-1-yl) -1,2-phenylenediamine were obtained.

Melting point: 257 to 259.5 ° C. Elemental analysis (as C ₁₁ H ₁₁ N ₃ O) Calculated: C, 65.66; H, 5.51; N, 20.88 (%) Experimental: C, 65.51; H, 5.58; N , 20.63 (%) H ¹ -NMR (d ₆ -DMSO) δ: 4.76 (2H, br.s), 4.85
(2H, br.s), 6.15 (2H, d, J = 7.6Hz), 6.46 (1H, dd, J =
8.2, 2.4Hz), 6.57 (2H, m), 7.75 (2H, d, J = 7.6Hz).

Reference Example 2

[0052]

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2-nitro-4-fluoro-5- (4-O
Oxo-4H-pyridin-1-yl) -aniline 2-nitro-4-fluoro-5-chloro-aniline 3.81
Using 1 g, 2.473 g of 4-hydroxypyridine, and 1.827 g of ground potassium hydroxide, the mixture was reacted at 130 ° C. for 3 hours under a nitrogen stream in the same manner as in Reference Example 1 to obtain 2-nitro-4-fluoro-5. 1.125 g of-(4-oxo-4H-pyridin-1-yl) -aniline was obtained.

Melting point:> 305 ° C. (decomposition) Elemental analysis (as C ₁₁ H ₈ N ₃ O ₃ F) Calculated value: C, 53.02; H, 3.24; N, 16.86; F, 7.62 (%) Experimental value: C H, 3.46; N, 16.64; F, 7.44 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.27 (2H, d, J = 7.8H)
z), 7.18 (1H, d, J _FH = 7.0Hz), 7.57 (2H, br.s), 7.87
(2H, d, J = 7.8Hz), 8.07 (1H, d, J _FH = 11.2Hz).

4-fluoro-5- (4-oxo-4H-
Pyridin-1-yl) -1,2-phenylenediamine 2-nitro-4-fluoro-5- (4-oxo-4H-
1.065 g of pyridin-1-yl) -aniline was dissolved in 45 ml of dimethylformamide with heating, and 10% palladium-carbon catalyst 1
Atmospheric pressure catalytic reduction was performed using 95 mg. The reaction solution after the reaction was filtered using celite to remove the catalyst, and the mother liquor was concentrated to dryness. The residue was purified by column chromatography using 30 g of silica gel. Methylene chloride-methanol (20:
1) The fraction eluted with the solution was recrystallized from ethanol to give 4-fluoro-5- (4-oxo-4H-pyridine-
802 mg of 1-yl) -1,2-phenylenediamine were obtained.

Melting point: 227-229.5 ° C. Elemental analysis (as C ₁₁ H ₁₀ N ₃ OF) Calculated: C, 60.27; H, 4.60; N, 19.17; F, 8.67 (%) Experimental: C, 60.38; H N, 19.01; F, 8.62 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.24 (2H, d, J = 7.8H)
z), 6.50 (1H, d, J _FH = 12.6Hz), 6.58 (1H, d, J _FH = 7.8H
z), 7.70 (2H, d, J = 7.8Hz).

Reference Example 3

[0058]

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4-Chloro-3- (4-oxo-4H-pi
Lysin -1-yl) -6-nitroaniline 3,4-dichloro-6-nitroaniline 14.3 g, 4-hydroxypyridine 9.01 g, 86% potassium hydroxide 5.87 g,
A mixture of dimethyl sulfoxide and 70 ml of the mixture was heated on a 130 ° C. oil bath for 3.5 hours, then cooled, and ice water was added, and the precipitated crystals were filtered. The crude crystals (16.9 g) were purified by silica gel (100 g) and eluted with a 10% methanol-chloroform mixture.
After concentration and filtration of the crystals, 9.78 g of crystals of 4-chloro-3- (4-oxo-4H-pyridin-1-yl) -6-nitroaniline were obtained (melting point: 288-291 ° C (decomposition)). . 300 mg of these crystals were recrystallized from methanol to give 4-chloro-3.
268 mg of crystals of-(4-oxo-4H-pyridin-1-yl) -6-nitroaniline were obtained.

Melting point: 290-293 ° C. (decomposition) Elemental analysis (as C ₁₁ H ₈ N ₃ O ₃ Cl) Calculated: C, 49.73; H, 3.04; N, 15.82; Cl, 13.35
(%) Experimental: C, 49.52; H, 3.20; N, 15.66; Cl, 13.08.
(%) H ¹ -NMR (d ₆ -DMSO) δ: 6.22 (2H, dd, J = 6 Hz, J = 2
Hz), 7.19 (1H, s), 7.73 (2H, br.s), 7.78 (2H, dd, J
= 6Hz, J = 2Hz), 8.23 (1H, s).

4-Chloro-5- (4-oxo-4H-pi
Lysin-1-yl) -1,2-phenylenediamine 4-chloro-3- (4-oxo-4H-pyridine-1-
Il) -6-nitroaniline 3.0g, iron powder 3.78g, water 10m
A mixture of 1, 90 ml of ethanol and 1.15 ml of 2N hydrochloric acid was heated to reflux on an oil bath for 3 hours. Then, 135 ml of ethanol was added, and the insoluble matter was separated by filtration using Hyflo Super Cell (registered trademark) to remove the solvent. The obtained crude crystals were purified using 30 g of silica gel, eluted with a 20% methanol-chloroform mixture, recrystallized from methanol / isopropanol, and purified with 4-chloro-5- (4-oxo-4H-pyridin-1-yl). -1,2-phenylenediamine crystals 2.04
g was obtained.

Melting point: 260-261 ° C. (decomposition) Elemental analysis (as C ₁₁ H ₁₀ N ₃ OCl) Calculated: C, 56.06; H, 4.28; N, 17.83; Cl, 15.05
(%) Experimental: C, 56.05; H, 4.30; N, 17.75; Cl, 15.17.
(%) H ¹ -NMR (d ₆ -DMSO) δ: 4.97 (2H, s), 5.12 (2
H, s), 6.12 (2H, d, J = 8Hz), 6.58 (1H, s), 6.64 (1H,
s), 7.57 (2H, d, J = 8Hz).

Reference Example 4

[0064]

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4-cyano-3- (4-oxo-4H-py
Lysin-1-yl) -6-nitroaniline 3-chloro-4-cyano-6-nitroaniline 1.0 g, 4
-Hydroxypyridine 507 mg, 86% potassium hydroxide 330
A mixture of mg, and 5 ml of dimethyl sulfoxide was heated on a 110 ° C. oil bath for 3 hours. The subsequent treatment was carried out in the same manner as in Reference Example 3 to obtain 836 mg of crystals of 4-cyano-3- (4-oxo-4H-pyridin-1-yl) -6-nitroaniline.

Melting point: 354-357 ° C. (decomposition) Elemental analysis (as C ₁₂ H ₈ N ₄ O ₃ ) Calculated: C, 56.25; H, 3.15; N, 21.87 (%) Experimental: C, 56.25; H , 3.27; N, 21.83 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.28 (2H, d, J = 8 Hz),
7.13 (1H, s), 7.92 (2H, d, J = 8Hz), 8.24 (2H, br.
s), 8.68 (1H, s).

4-cyano-5- (4-oxo-4H-py
Lysin-1-yl) -1,2-phenylenediamine 4-cyano-3- (4-oxo-4H-pyridine-1-
Il) -6-nitroaniline 490mg, iron powder 642mg, water 4m
A mixture of 1, 16 ml of ethanol and 0.2 ml of 2N hydrochloric acid was heated to reflux on an oil bath for 1 hour. The subsequent treatment was performed in the same manner as in Reference Example 3, and 405 mg of the obtained crude crystals were recrystallized from methanol / isopropanol to give 4-cyano-5- (4-oxo-4H-pyridin-1-yl) -1,2. -274 mg of phenylenediamine crystals were obtained.

Melting point: 321 to 323 ° C. (decomposition) Elemental analysis (as C ₁₂ H ₁₀ N ₄ O) Calculated value: C, 63.70; H, 4.46; N, 24.77 (%) Experimental value: C, 63.57; 4.59; N, 24.41 (%) H ¹ -NMR (d ₆ -DMSO) δ: 5.21 (2H, s), 5.90 (2
H, s), 6.17 (2H, d, J = 8Hz), 6.59 (1H, s), 6.82 (1H,
s), 7.73 (2H, d, J = 8Hz).

Reference Example 5

[0070]

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4-dimethylsulfamoyl-3- (4-
Oxo-4H-pyridin-1-yl) -6-nitroani
Phosphorus 3-chloro-4-dimethylsulfamoyl-6-nitroaniline 3.0 g, 4-hydroxypyridine 1.39 g, 86%
0.91 g of potassium hydroxide, and 20 m of dimethyl sulfoxide
l of the mixture was heated on a 130 ° C. oil bath for 1.5 hours. The subsequent processing was performed in the same manner as in Reference Example 3, and 4-dimethylsulfamoyl-3- (4-oxo-4H-pyridin-1-yl)
1.675 g of -6-nitroaniline crystals were obtained.

Melting point: 344 ° -347 ° C. (decomposition) Elemental analysis (as C ₁₃ H ₁₄ N ₄ O ₅ S) Calculated value: C, 46.15; H, 4.17; N, 16.56; S, 9.48 (%) Experimental value: C, 46.11; H, 4.22; N, 16.36; S, 9.37 (%) H ¹ -NMR (d ₆ -DMSO) δ: 2.56 (6H, s), 6.16 (2
H, d, J = 8Hz), 7.09 (1H, s), 7.71 (2H, d, J = 8Hz), 8.2
5 (2H, br.s), 8.51 (1H, s).

4-dimethylsulfamoyl-5- (4-
Oxo-4H-pyridin-1-yl) -1,2-phenyl
Diamine 4-dimethylsulfamoyl-3- (4-oxo-4H
-Pyridin-1-yl) -6-nitroaniline 1.50 g,
1.49 g of iron powder, 9 ml of water, 36 ml of ethanol, and 0.45 of 2N hydrochloric acid
The ml mixture was heated at reflux on an oil bath for 45 minutes. The subsequent processing was performed in the same manner as in Reference Example 3, and the obtained crude crystals were treated with methanol.
Recrystallized from isopropanol to give 4-dimethylsulfamoyl-5- (4-oxo-4H-pyridine-1.
1.30 g of -yl) -1,2-phenylenediamine crystals were obtained.

Melting point: 334-336 ° C. (decomposition) Elemental analysis (as C ₁₃ H ₁₆ N ₄ O ₃ S) Calculated value: C, 50.63; H, 5.23; N, 18.17; S, 10.40 (%) Experimental value: H, 5.28; N, 18.16; S, 10.58 (%) H ¹ -NMR (d ₆ -DMSO) δ: 2.51 (6H, s), 5.21 (2
H, s), 5.90 (2H, s), 6.17 (2H, d, J = 8Hz), 6.59 (1H,
s), 6.82 (1H, s), 7.73 (2H, d, J = 8Hz).

Reference Example 6

[0076]

Embedded image

4-amino-5-nitro-2- (4-oxo
So-4H-pyridin-1-yl) -benzotrifluor
De 4-amino-2-chloro-5-nitro-benzotrifluoride 2.40 g, 4-hydro-oxy-pyridin 2.0 g, 86% potassium hydroxide 684 mg, and dimethyl sulfoxide for 2 hours on an oil bath at 70 ° C. A mixture of 15 ml, Heated. After cooling, ice water was added and the precipitated crystals were filtered. The obtained crude crystals were recrystallized from methanol / ethyl acetate to give 2.69 g of crystals of 4-amino-5-nitro-2- (4-oxo-4H-pyridin-1-yl) -benzotrifluoride. .

Melting point: 274 to 275 ° C. Elemental analysis (as C ₁₂ H ₈ N ₃ O ₃ F ₃ ) Calculated: C, 48.17; H, 2.70; N, 14.04; F, 19.05 (%) Experimental: C, H, 2.78; N, 13.98; F, 19.11 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.19 (2H, d, J = 8 Hz),
7.17 (1H, s), 7.74 (2H, d, J = 8Hz), 8.17 (2H, br.
s), 8.38 (1H, s).

4- (4-oxo-4H-pyridine-1-
Yl) -5-trifluoromethyl-1,2-phenylene
Diamine 4-amino-5-nitro-2- (4-oxo-4H-pyridin-1-yl) -benzotrifluoride 2.56 g, iron powder 2.87 g, water 14.4 ml, ethanol 57.6 ml, and 2N hydrochloric acid
0.86 ml of the mixture was heated to reflux on an oil bath for 45 minutes. Subsequent processing was performed in the same manner as in Reference Example 3 to obtain 4- (4-oxo-4).
H-pyridin-1-yl) -5-trifluoromethyl-
1.73 g of 1,2-phenylenediamine crystals were obtained.

Melting point: 264-266 ° C. (decomposition) Elemental analysis (as C ₁₂ H ₁₀ N ₃ OF ₃ ) Calculated value: C, 53.53; H, 3.74; N, 15.61; F, 21.17 (%) Experimental value: C H, 3.87; N, 15.52; F, 21.30 (%) H ¹ -NMR (d ₆ -DMSO) δ: 5.23 (2H, br.s), 5.53
(2H, br.s), 7.57 (2H, d, J = 8Hz), 6.09 (2H, d, J = 8H
z), 6.54 (1H, s), 6.86 (1H, s).

Embodiment 1

[0082]

Embedded image

6-nitro-7- (4-oxo-4H-py
Lysin-1-yl) -1,4-dihydroquinoxaline-
2,3-dione 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione 9.007 g, 4-hydroxypyridine
7.611 g, and 5.219 g of ground potassium hydroxide were added to 120 ml of dry dimethyl sulfoxide, and 130 ° C. under a nitrogen stream,
Stir for 2 hours. 50 ml of ice water and 30 ml of 4N hydrochloric acid are added to the reaction solution.
Was added to adjust the pH to weakly acidic (pH 3 to 4), and the precipitated yellow precipitate was collected by filtration and washed with water. The precipitate is then washed with 560 m of water.
l and concentrated ammonia water in a mixed solution of 56 ml with heating.
Activated carbon (1 g) was added to this solution, stirred, and filtered. The filtrate was neutralized with concentrated hydrochloric acid, cooled on ice, and the precipitated crystals were collected by filtration. After washing with water, methanol and ethanol in that order, drying and drying of 6-nitro-7- (4-oxo-
There was obtained 7.56 g of (4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione (hereinafter abbreviated as Ia).

Melting point:> 300 ° C. Elemental analysis (as C ₁₃ H ₈ N ₄ O ₅ ) Calculated: C, 52.01; H, 2.69; N, 18.66 (%) Experimental: C, 51.83; H, 2.89; N , 18.69 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.22 (2H, d, J = 7.4H
z), 7.21 (1H, s), 7.78 (2H, d, J = 7.4Hz), 8.00 (1H,
s) IR (Nujol): 3080, 2920, 2580, 17
30,1695,1635,1595Cm ^-1 sulfates of the above compound: mp:> 300 ° C. Elemental analysis _{(C 13 H 8 N 4 O} 5 · 1 / 2H 2 SO 4 · H 2 as O) Calculated: C, 42.51 H, 3.02; N, 15.25; S, 4.36 (%) Experimental value: C, 42.27; H, 3.10; N, 15.65; S, 4.36 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.81 ( 2H, d, J = 7.6H
z), 7.33 (1H, s), 8.05 (1H, s), 8.30 (2H, d, J = 7.4H
z).

The choline salt of compound Ia is obtained as follows. 6-nitro-7- (4-oxo-4H-pyridin-1-yl) -1,4-dihydroquinoxaline-
30 ml of acetone was added to 2.70 g (9.0 mmol) of 2,3-dione and stirred. 2.25 ml of a 50% aqueous solution of choline hydroxide (10.0 mm
ol, 1.1 equivalents), and the mixture was stirred. After 1.5 hours, the deposited precipitate was collected by filtration and washed with acetone. The obtained red-orange precipitate is dissolved by heating in 200 ml of ethanol and treated with activated carbon. The filtrate was concentrated to 3/4 volume, allowed to cool, and the precipitated crystals were collected by filtration.
3.58 g of crystals of choline salt are obtained with a yield of 88.9%.

Melting point: 230-233 ° C. Elemental analysis (as C ₁₃ H ₇ N ₄ O ₅ .C ₅ H ₁₄ NO.2.5 H ₂ O) Calculated: C, 48.21; H, 5.84; N, 15.62; H ₂ O, 10.04
(%) Found: C, 48.40; H, 5.80 ; N, 15.86; H 2 O, 10.20
(%) H ¹ -NMR (d ₆ -DMSO) δ: 3.11 (9H, s), 3.41 (2H, t, J = 4.6
Hz), 3.85 (2H, m), 6.14 (2H, d, J = 7.4Hz), 6.87 (1
H, s), 7.71 (2H, d, J = 7.8 Hz), 7.82 (1H, s).

Embodiment 2

[0088]

Embedded image

6-nitro-7- (3-chloro-4-oxo
So-4H-pyridin-1-yl) -1,4-dihydroxy
Noxalin-2,3-dione 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione 267 mg, 3-chloro-4-hydroxypyridine 171 mg, and powdered potassium hydroxide 92 mg
Was added to 3 ml of dry dimethyl sulfoxide, and 1
The reaction was performed at 30 ° C. for 80 minutes. Ice water and 4N hydrochloric acid were added to the reaction solution to adjust the pH to about 2, and a yellow precipitate was collected by filtration and washed with water. The precipitate was recrystallized from dimethylformamide and water to give a pale yellow 6-nitro-7- (3
-Chloro-4-oxo-4H-pyridin-1-yl)-
376 mg of 1,4-dihydroquinoxaline-2,3-dione
I got

Melting point:> 300 ° C. Elemental analysis (C ₁₃ H ₇ N ₄ O ₅ Cl.C ₃ H ₇ NO.H ₂ O) Calculated: C, 45.13; H, 3.79; N, 16.45; Cl, 8.33
(%) Experimental: C, 45.14; H, 3.46; N, 16.33; Cl, 8.57.
(%) H ¹ -NMR (d ₆ -DMSO) δ: 6.38 (1H, d, J = 7.8 Hz),
7.27 (1H, s), 7.86 (1H, dd, J = 7.8,2.4Hz), 8.02 (1H,
s), 8.42 (1H, d, J = 2.4Hz), 12.43 (2H, br.s).

Embodiment 3

[0092]

Embedded image

6-nitro-7- (3-nitro-4-oxo
So-4H-pyridin-1-yl) -1,4-dihydroxy
Noxalin-2,3-dione 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione 677 mg, 4-hydroxy-3-nitropyridine 840 mg, and powdered potassium hydroxide 403 mg
Was added to 6 ml of dry dimethyl sulfoxide, and
The reaction was performed at 30 ° C. for 2 hours. The subsequent treatment was carried out in the same manner as in Example 2, recrystallized from dimethylformamide and water, and treated with 6-nitro-7- (3-nitro-4-oxo-4H
-Pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione was obtained as red crystals (672 mg).

Melting point:> 300 ° C. Elemental analysis (as C ₁₃ H ₇ N ₅ O ₇ ) Calculated: C, 45.23; H, 2.04; N, 20.29 (%) Experimental: C, 45.25; H, 2.82; N , 20.20 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.62 (1H, d, J = 7.8H)
z), 7.40 (1H, s), 7.96 (1H, dd, J = 7.8,2.0Hz), 8.06
(1H, s), 9.11 (1H, d, J = 2.0Hz).

Embodiment 4

[0096]

Embedded image

6-nitro-7- (3,5-dichloro-4
-Oxo-4H-pyridin-1-yl) -1,4-dihi
Droquinoxaline- 2,3-dione 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione 1.129 g, 3,5-dichloro-4-
1.648 g of hydroxypyridine and 672 mg of ground potassium hydroxide were added to 10 ml of dry dimethyl sulfoxide, and reacted at 130 ° C. for 3 hours under a nitrogen stream. Subsequent treatment was performed in the same manner as in Example 2, and the obtained precipitate was heated and dissolved using dimethylformamide, and decolorized using activated carbon. Then, the same amount of water was added, and the mixture was left overnight to precipitate 6
-Nitro-7- (3,5-dichloro-4-oxo-4H
-Pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione (1.473 g) was obtained.

Melting point:> 300 ° C. Elemental analysis (as C ₁₃ H ₆ N ₄ O ₅ Cl ₂ .1 / 2H ₂ O) Calculated: C, 41.29; H, 1.87; N, 14.82; Cl, 18.75
(%) Experimental: C, 41.47; H, 1.84; N, 15.08; Cl, 19.01.
(%) H ¹ -NMR (d ₆ -DMSO) δ: 7.39 (1H, s), 8.06 (1
H, S), 8.55 (2H, s).

Embodiment 5

[0100]

Embedded image

6-Fluoro-7- (4-oxo-4H-
Pyridin-1-yl) -1,4-dihydroquinoxaline
-2,3-dione 4-fluoro-5- (4-oxo-4H-pyridine-1
-Yl) -1,2-phenylenediamine (4.266 g) and oxalic acid (1.927 g) were added to 48 ml of 4N hydrochloric acid, and the mixture was heated under reflux for 2.5 hours. After the reaction, the precipitated crystals are collected by filtration, washed with water and dried to give 6-
Fluoro-7- (4-oxo-4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione
3.920 g was obtained.

Melting point:> 300 ° C. Elemental analysis (as C ₁₃ H ₈ N ₃ O ₃ F · 0.2 H ₂ O) Calculated value: C, 56.40; H, 3.06; N, 15.18; F, 6.86 (%) Experimental value H, 3.19; N, 15.24; F, 6.93 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.23 (2H, d, J = 7.8H)
z), 7.13 (1H, d , J FH = 16Hz), 7.17 (1H, d, J FH = 12.6H
z), 7.80 (1H, d, J = 6.4Hz), 12.09 (1H, br.s), 12.15
(1H, br.s).

Embodiment 6

[0104]

Embedded image

6-chloro-7- (4-oxo-4H-py
Lysin-1-yl) -1,4-dihydroquinoxaline-
2,3-dione 4-chloro-5- (4-oxo-4H-pyridine-1-
Il) -1,2-phenylenediamine 1.93 g, oxalic acid
A mixture of 2.21 g and 40 ml of 2N hydrochloric acid was heated to reflux on an oil bath for 2 hours. After cooling, the precipitated crystals were filtered and 6-chloro-7- (4-oxo-4H-pyridin-1-yl)-
2.1 g of crude crystals of 1,4-dihydroquinoxaline-2,3-dione (melting point:> 400 ° C.) were obtained. 500 mg of the crude crystals were recrystallized from dimethylformamide / water to give 6-chloro-
7- (4-oxo-4H-pyridin-1-yl) -1,4
299 mg of dihydroquinoxaline-2,3-dione were obtained.

Melting point: 420-445 ° C. (decomposition) Elemental analysis (as C ₁₃ H ₈ N ₃ O ₃ Cl · 1 / 4H ₂ O) Calculated: C, 53.07; H, 2.91; N, 14.28; Cl, 12.05
(%) Experimental: C, 53.09; H, 2.83; N, 14.24; Cl, 12.36.
(%) H ¹ -NMR (D ₂ O-HNO ₃ ) δ: 7.46 (2H, d, J = 8 Hz), 7.57
(1H, s), 7.59 (1H, s), 8.57 (2H, d, J = 8Hz).

Embodiment 7

[0108]

Embedded image

6-cyano-7- (4-oxo-4H-py
Lysin-1-yl) -1,4-dihydroquinoxaline-
2,3-dione 4-cyano-5- (4-oxo-4H-pyridine-1-
Yl) -1,2-phenylenediamine 246 mg, oxalic acid 2
A mixture of 94 mg and 5 ml of 2N hydrochloric acid was heated to reflux on an oil bath for 2 hours. After cooling, the precipitated crystals were filtered. 284 mg of the obtained crude crystals were further recrystallized from 2N hydrochloric acid to give 6-cyano-7- (4-oxo-4H-pyridin-1-yl)-
1,4-dihydroquinoxaline-2,3-dione 201 mg
I got

[0110] mp: 410 to 415 ° C. (decomposition) Elemental analysis _{(C 14 H 8 N 4 O} 3 · 3 / 4H 2 O ) Calculated values: C, 57.23; H, 3.26 ; N, 19.07 (%) Found : C, 57.54; H, 3.33 ; N, 19.10 (%) H 1 -NMR (D 2 O-HNO 3) δ: 7.50 (2H, d, J = 8Hz), 7.68
(1H, s), 7.88 (1H, s), 8.72 (2H, d, J = 8Hz).

Embodiment 8

[0112]

Embedded image

6-dimethylsulfamoyl-7- (4-
Oxo-4H-pyridin-1-yl) -quinoxaline-
2,3-dione 4-dimethylsulfamoyl-5- (4-oxo-4H
-Pyridin-1-yl) -1,2-phenylenediamine
A mixture of 500 mg, 438 mg of oxalic acid, and 10 ml of 2N hydrochloric acid was heated to reflux on an oil bath for 3 hours. After cooling, the mixture was made alkaline with aqueous ammonia, and the precipitated crystals were filtered. The crude crystals obtained
534 mg were further recrystallized from dimethylformamide / water to give 6-dimethylsulfamoyl-7- (4-oxo-
4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione (201 mg) was obtained.

Melting point: 400 to 405 ° C. (decomposition) Elemental analysis (as C ₁₅ H ₁₄ N ₄ O ₅ S · 1 / 4H ₂ O) Calculated: C, 49.11; H, 3.98; N, 15.27; S, 8.74 (%) Experimental value: C, 49.22; H, 4.10; N, 15.37; S, 8.72 (%) H ¹ -NMR (D ₂ O-HNO ₃ ) δ: 2.17 (6H, s), 6.91 (2H,
d, J = 7Hz), 7.13 (1H, s), 7.37 (1H, s), 8.10 (2H, d,
J = 7Hz).

Embodiment 9

[0116]

Embedded image

6-nitro-7- (4-oxo-4H-py
Lysin-1-yl) -1- (n-propyl) -1,4-
Dihydroquinoxaline-2,3-dione 7-fluoro-6-nitro-1- (n-propyl)-
1,244-dihydroquinoxaline-2,3-dione 1.244
g, 4-hydroxypyridine 952 mg, and powdered potassium hydroxide 711 mg were stirred at 130 ° C. for 3.5 hours in 10 ml of dry dimethyl sulfoxide under a nitrogen stream. Add 50 ml of water to this reaction solution.
Was adjusted to acidic (PH2 to 3) using 4N hydrochloric acid, and the yellow precipitate was collected by filtration. This was recrystallized from dimethylformamide to give 6-nitro-7- (4-oxo-4H-pyridin-1-yl) -1- (n-propyl) -1,4-dihydroquinoxaline-2,3-dione 1.08. g was obtained.

Melting point:> 300 ° C. Elemental analysis (as C ₁₆ H ₁₄ N ₄ O ₅ .0.2 H ₂ O) Calculated: C, 55.56; H, 4.20; N, 16.20 (%) Experimental: C, 55.63; H, 4.29; N, 16.37 (%) H ¹ -NMR (d ₆ -DMSO) δ: 0.94 (3H, t, J = 7.2H)
z), 1.65 (2H, m), 4.10 (2H, m), 6.21 (2H, d, J = 7.6H
z), 7.77 (2H, d, J = 7.6Hz), 7.86 (1H, s), 8.02 (1H,
s).

Embodiment 10

[0120]

Embedded image

[0121]6-nitro-7- (3-nitro-4-oxo
So-4H-pyridin-1-yl) -1- (n-propyl
Ru) -1,4-dihydroquinoxaline-2,3-dione 7-fluoro-6-nitro-1- (n-propyl)-
1,4-dihydroquinoxaline-2,3-dione 803m
g, 3-nitro-4-hydroxypyridine 700 mg, and
365 mg of potassium hydroxide was dried in the same manner as in Example 9
The reaction was carried out at 130 ° C. for 4.5 hours in sulfoxide,
-7- (3-nitro-4-oxo-4H-pyridine-1
-Yl) -1- (n-propyl) -1,4-dihydroxy
1.059 g of noxaline-2,3-dione was obtained.

Melting point:> 300 ° C. Elemental analysis (as C ₁₆ H ₁₃ N ₅ O ₇ · 0.3H ₂ O) Calculated: C, 48.94; H, 3.49; N, 17.83 (%) Experimental: C, 49.02; H, 3.68; N, 17.92 (%) H ¹ -NMR (d ₆ -DMSO) δ: 0.94 (3H, t, J = 7.4H)
z), 1.66 (2H, m), 4.06 (2H, m), 6.64 (1H, d, J = 7.8H
z), 7.98 (1H, m), 8.00 (1H, s), 8.10 (1H, s), 9.12
(1H, d, J = 1.8Hz), 12.46 (1H, br.s).

Embodiment 11

[0124]

Embedded image

6- (4-oxo-4H-pyridine-1-
Yl) -1,4-dihydroquinoxaline-2,3-dio
Emissions 4- (4-oxo -4H- pyridin-1-yl) -1,
4.449 g of 2-phenylenediamine and 2.402 g of oxalic acid
The solution was added to 60 ml of 4N hydrochloric acid, and heated under reflux for 2.5 hours under a nitrogen stream. After cooling, the precipitated crystals were collected by filtration and recrystallized from dimethylformamide to give 6- (4-oxo-4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,
4.786 g of 3-dione were obtained.

Melting point:> 300 ° C. Elemental analysis (as C ₁₃ H ₉ N ₃ O ₃ ) Calculated: C, 61.18; H, 3.55; N, 16.46 (%) Experimental: C, 60.94; H, 3.62; N , 16.37 (%).

6-nitro-7- (4-oxo-4H-py
Lysin-1-yl) -1,4-dihydroquinoxaline-
2,3-dione 6- (4-oxo-4H-pyridin-1-yl) -1,
510 mg of 4-dihydroquinoxaline-2,3-dione was added to 5 ml of concentrated sulfuric acid under ice cooling and dissolved. 253 mg of potassium nitrate was added to this solution, and the mixture was heated and stirred at 60 ° C. for 3 hours.
Next, 20 ml of ice water was added, the pH was adjusted to 5 using a 4N aqueous sodium hydroxide solution, and the precipitated yellow crystals were collected by filtration. The crystal was washed with water and dried to obtain 426 mg of 6-nitro-7- (4-oxo-4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione.

Melting point:> 300 ° C. H ¹ -NMR (d ₆ -DMSO) δ: 6.20 (2H, d, J = 7.8H)
z), 7.20 (1H, s), 7.76 (2H, d, J = 7.8Hz), 7.99 (1H,
s) By H ¹ -NMR and HPLC, the compound 6-nitro-7- (4-oxo-4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,3 obtained in Example 11 was obtained.
It was confirmed that -dione was the same substance as the compound (Ia) obtained in Example 1.

Embodiment 12

[0130]

Embedded image

6- (4-oxo-4H-pyridine-1-
Yl) -7-trifluoromethyl-1,4-dihydroxy
Noxalin-2,3-dione 4- (4-oxo-4H-pyridin-1-yl) -5
Trifluoromethyl-1,2-phenylenediamine 300 m
g, oxalic acid 301 mg and 2N hydrochloric acid 6 ml was heated to reflux on an oil bath for 7 hours. After cooling, the precipitated crystals were filtered. 333 mg of the obtained crude crystals was dissolved in dimethylformamide /
Recrystallization from water gave 216 mg of 6- (4-oxo-4H-pyridin-1-yl) -7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione.

Melting point: 410-420 ° C. Elemental analysis (C ₁₄ H ₈ N ₃ O ₃ F ₃ .1 / 4H ₂ O) Calculated: C, 51.31; H, 2.61; N, 12.82; F, 17.39 (%) Experimental value: C, 51.36; H, 2.87; N, 13.04; F, 17.11 (%) H ¹ -NMR (d ₆ -DMSO) δ: 6.18 (2H, d, J = 8 Hz),
7.22 (1H, s), 7.55 (1H, s), 7.70 (2H, d, J = 8Hz), 1
2.33 (2H, br).

Example 13 6-Nitro-7- (3-fluoro-4-oxo-4H-
Pyridin-1-yl) -1,4-dihydroquinoxaline
-2,3-dione

[0134]

Embedded image

127 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 96 mg of 3-fluoro-4-hydroxypyridine and 55 mg of powdered potassium hydroxide were added to 12 ml of dry dimethyl sulfoxide, and a nitrogen stream was added. Stir at 130 ° C for 3 hours. 50 ml of ice water in the reaction solution
, And the mixture is neutralized with 2N hydrochloric acid, and the resulting precipitate is collected by filtration and washed with water. This precipitate is dissolved in 3 ml of 1N sodium hydroxide, treated with activated carbon, and the filtrate is neutralized with concentrated hydrochloric acid. The precipitated crystals are collected by filtration and dried to give 147 mg of 6-nitro-7- (3-fluoro-4-oxo-4H-pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione.

Melting point:> 300 ° C. Elemental analysis (as C ₁₃ H ₇ N ₄ O ₅ F · 0.3H ₂ O) Calculated: C, 48.25; H, 2,37; N, 17.31; F, 5.87
(%) Experimental: C, 48.09; H, 2.61; N, 17.49; F, 6.27.
(%) H ¹ -NMR (d ₆ -DMSO) δ: 6.46 (1H, dd, J = 9.0, 7.4H
z), 7.28 (1H, s), 7.85 (1H, dd, J = 7.6, 2.0Hz), 8.
08 (1H, s), 8.37 (1H, dd, J = 7.8, 2.0Hz).

Test Example 1 6-nitro-7- (4-oxo-4H-pyridine-1-
Il) 1,4-Dihydroquinoxaline-2,3-dione (Ia) Binding Competition Test for NMDA Receptor Glycine Binding Site The cerebral cortex of Slc-Wistar rats (body weight 250-300 g) was
0 volume of 5 mM Tris acetate buffer (1 mM EGTA, 0.1 mM PMSF
And pH 7.4) containing 0.01% bacitracin, and centrifugation at 50,000 × g for 30 minutes and resuspension were repeated four times. The final suspension was stored at -80 ° C until the time of the experiment. Thaw the frozen product of this suspension at room temperature
After incubation with Triton X-100 solution at 2 ° C. for 10 minutes, the plate was washed twice, and then washed with 50 mM Tris acetate buffer (pH 7.0).
Suspended in 4) to make a membrane specimen. The membrane specimen was mixed with 100 nM [ ³ H] glycine and various concentrations of the compound (Ia) obtained in Example 1 and incubated at 0 ° C. for 10 minutes. The reaction was stopped by diluting and filtering (using Whatman GF / C filter paper), and the radioactivity of ³ H on the filter paper was measured by a liquid scintillation counter. Non-specific binding was tested with 1 mM non-radioactive glycine and IC ₅₀ values were calculated. As a control, an IC ₅₀ value was calculated in the same manner as above using YM900. Table 2 shows the results.

[0138]

[Table 2]

Compound (Ia) was prepared using YM90 used as a control.
It showed almost 10 times stronger antagonism than 0.

Test Example 2 6-nitro-7- (4-oxo-4H-pyridine-1-
Il) -1,4-Dihydroquinoxaline-2,3-dione (Ia) binding competition test for AMPA receptor Slc-Wistar rats (body weight 250-300 g)
0 volume of 30 mM Tris acetate buffer (containing 2.5 mM CaCl ₂
The mixture was homogenized in 7.1), and centrifugation at 30,000 × g for 15 minutes and resuspension were repeated three times. The final suspension was stored at -80 ° C until the time of the experiment. The frozen product of this suspension was thawed at room temperature, and 30 mM Tris acetate buffer (2.5 mM CaCl ₂ and 1 mM) was added.
The suspension was suspended in pH 7.1 containing 00 mM KSCN to prepare a membrane specimen. This membrane specimen was treated with 30 nM [ ³ H] AMPA and the compound (Ia)
And incubated at 0 ° C. for 30 minutes. The reaction was stopped by diluting and filtering (using Whatman GF / C filter paper), and the radioactivity of ³ H on the filter paper was measured by a liquid scintillation counter. Non-specific binding was tested with 1 mM non-radioactive glutamate and IC ₅₀ values were calculated. As a control, Y
With M900 IC ₅₀ values were calculated in the same manner as described above. Table 3 shows the results.

[0141]

[Table 3]

According to the present invention, NMDA of central nervous cells
An oxopyridinylquinoxaline derivative is provided, which is a novel compound that exhibits excellent antagonistic activity against the receptor and the AMPA receptor. This compound inhibits the binding of excitatory amino acids to the NMDA receptor or AMPA receptor, and is therefore useful as a therapeutic agent for central nervous system diseases caused by the excitatory amino acids.

──────────────────────────────────────────────────続 き Continuation of front page (51) Int.Cl. ⁶ identification symbol FI // (C07D 401/04 213: 68 241: 44) (58) Investigated field (Int.Cl. ⁶ , DB name) C07D 401 / 04 241 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] An oxopyridinylquinoxaline derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof: Wherein R ¹ is hydrogen, halogen, nitro, or methyl trihalide; R ² is hydrogen, halogen, nitro, cyano, methyl trihalide, carbamoyl optionally substituted by lower alkyl, or It is a sulfamoyl optionally substituted by lower alkyl; R ³ is hydrogen, nitro or halogen,; R ⁴
Is hydrogen, optionally substituted lower alkyl, or optionally substituted lower cycloalkyl;
⁵ is the same or different and is halogen, nitro, cyano,
A substituent selected from the group consisting of lower alkyl, and carbamoyl optionally substituted by lower alkyl; and n is an integer from 0 to 4. 2. R ¹ and R ³ are each independently hydrogen or nitro; R ² is carbamoyl optionally substituted by halogen, nitro, cyano, methyl trihalide, lower alkyl, or lower. optionally substituted by alkyl be a good sulfamoyl; R ⁴
Is hydrogen or lower alkyl; each R ⁵ is the same or different and is a substituent selected from the group consisting of halogen, nitro, and lower alkyl; and n is 0-4
The oxopyridinylquinoxaline derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is an integer of the following. 3. The method according to claim 1, wherein R ¹ and R ³ are each hydrogen.
² is halogen, nitro, cyano, or methyl trihalide; R ⁴ is hydrogen or lower alkyl;
Each R ⁵ is the same or different and is a substituent selected from the group consisting of halogen and nitro;
The oxopyridinylquinoxaline derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is an integer of 4. 4. The oxopyridinylquinoxaline derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein n is 0. 5. A method for preparing 6-nitro-7- (4-oxo-4H-
The oxopyridinylquinoxaline derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is (pyridin-1-yl) -1,4-dihydroquinoxaline-2,3-dione. 6. A glutamate receptor antagonist comprising the compound according to claim 1, 2, 3, 4, or 5.