JPH04178385A - Diketopyridopyrazine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [group shown by formula II is pyrimidine ring shown by formula III or formula IV; R<1> is nitro, mono or di-lower alkylamino, morpholino, OH, lower alkoxy, lower alkyl(thio) or lower alkylsulfonyl; R<2> is H or R<1>]. EXAMPLE:6-Nitropyrido(2,3-b) pyrazine-2,3-dione. USE:A glutamate acceptor antagonist having antagonism on NMDA-glycine acceptor and AMPA acceptor antagonism. PREPARATION:A 1,2-diaminopyridine derivative shown by formula V is reacted with an equimolar amount to an excessive amount of oxalic acid (reactive derivative) at room temperature to under heating.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to glutamate receptor antagonism, particularly NMDA
- A novel diketopyridopyrazine derivative or a salt thereof having glycine receptor antagonism and AMPA receptor antagonism.

(Prior Art) Amino acids such as L-glutamic acid and L-aspartic acid are known to be transmitters in the central nervous system. When these excitatory amino acids accumulate and continue to stimulate the nerves excessively, Huntington's chorea, Parkin's disease, leprosy, senile dementia, and conditions of cerebral ischemia, oxygen deprivation, and hypoglycemia are observed. It is said to lead to neurodegeneration and mental and motor dysfunction.

Therefore, drugs that can regulate the abnormal functions of these excitatory amino acids are considered to be useful in the treatment of neurodegenerative and psychiatric diseases.

The effects of excitatory amino acids are exerted through specific receptors located postsynaptically or presynaptically. These receptors are currently subdivided into five nine groups based on electrophysiological and neurochemical evidence.

1) NMDA (N-methyl-D-aspartate) receptor 2) NMPA [2-amino-3-(3-hydroxy-5-methyl-4-inxazole) propionic acid] receptor 3) Kainate receptor 4) Metabotropinocglutamate receptor 5) AP-4
(2-Amino-4-phosphonobutanoic acid) receptors L-glutamic acid and L-aspartic acid activate the above receptors and transmit excitement.

Neuropathy occurs when excessive amounts of NMDA, AMPA, and kainate act on nerves. 2-Amino-5-phosphonovaleric acid or 2-amino-7-phosphonohebutanoic acid, which is a selective antagonist of the NMDA receptor, is a selective antagonist of the NMDA receptor.
Neuropathy due to A action.

It has also been reported to be effective in experimental animal models of leprosy and cerebral ischemia (JPET 250.100 (1989
).

JPET 240,737 (1987), 5c
ience 226, 850 (1984). NMD
It has been reported that the A receptor acts in an allosteric manner through the glycine receptor (EPJ, 126.3).
03 (1986)), and HA-966, a glycine receptor antagonist, has also been reported to be effective in experimental animal models of cerebral ischemia (American Academy of Neurology 1989).

Additionally, NBQX, a selective antagonist of AMPA receptors,
(6-nitrofusulfamoylpenzo[f]quinoxaline) has also been reported to be effective in experimental animal models of cerebral ischemia (5cIence 247.
571 (1990)). On the other hand, force inate receptors, metapotropic glutamate receptors.

A selective antagonist of AP-4 receptor has not been reported so far.

(Problems to be Solved by the Invention) An object of the present invention is to provide a compound having diketopyridopyrazine-based glutamate receptor antagonism, particularly antagonism of one or both of NMPA-glycine and AMPA receptors. It is something to do. As diketopyridopyrazine derivatives, several compounds having an amino group or a chlorine atom as a substituent on the pyridine ring have been reported (I, Kate, J. Med, Chem.
7.240 (1964); K, Wint@rfel
d, Arch, Pharm, 303.44 (1
970) )v Nothing is described about the pharmacological activity of these compounds.

The present invention provides a novel compound which has a substituent on the pyridine ring of the diketopyridopyrazine ring that is different from known compounds, and which has excellent glutamate receptor antagonism.

(Means for Solving the Problems) That is, 1 the present invention represents a pyridine ring represented by -shipra, RI is a nitro group, a mono- or di-lower alkylamino group, 9 a morpholino group,
Hydroxyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfonyl group, lower alkyl group, R2
represents a hydrogen atom or the same meaning as R1. ) A novel diketopyridopyrazine derivative or a salt thereof.

Here, the "lower alkyl" in the definition of the above compound is a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Typical examples include methyl,
Ethyl, butyl.

Inpropyl, etc. In addition, "mono- or di-lower alkylamino group" means that the above lower alkyl group is
It is an amino group substituted with one or two atoms, and examples thereof include a methylamine group, an ethylamino group, a dimethylamino group, and a methylethylamino group.

The above compound (I) has stereoisomers and tautomers depending on the type of substituent, and the object compound of the present invention includes separated or mixtures of these isomers.

Next, as the salt of the above compound (I), for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid.

Salts with organic acids such as fumaric acid, tartaric acid, alkanesulfonic acids, arylsulfonic acids, or sodium hydroxide,
Examples include salts with inorganic bases such as potassium hydroxide, and salts with organic bases such as diethylamine.

The compound of the present invention can be produced by the method shown by the following reaction formula.

(n) (m) (I) To carry out this production method, the 1,2-diaminopyridine derivative (II) and 9 equivalent moles to an excess of scheller's acid or its reactive derivative @) are heated at room temperature or heated. React below.

Reactive derivatives of oxalic acid include salts, esters,
Examples include hydrates, anhydrides, acid chlorides, and the like. This reaction is usually carried out in an aqueous or alcoholic solvent. It is preferred to add an acid such as hydrochloric acid to accelerate the reaction.

As another method for producing compound (I), a method shown by the following reaction formula may be used.

(In the formula, R3 represents a lower alkyl group. The meanings of the other symbols are the same as above.) This reaction reductively cyclizes the 2-lower alkoxalylamine nitropyridine compound (IV). , for example, by a catalytic reduction method using Raney nickel or the like as a catalyst.

Other methods for producing the compound of the present invention include a method of introducing a new substituent into the pyridine ring of the diketopyridopyrazine compound obtained by the above production method or converting the substituent.

Among the compounds of the present invention, for example, compounds in which R1 or R2 is a nitro group can be obtained by nitration of the corresponding compound in which R2 is a hydrogen atom. This nitration is a method in which the diketopyridopyrazine compound is treated with nitric acid or a salt thereof under acidic conditions of sulfuric acid or acetic anhydride-acetic acid.

Alternatively, it can be carried out by heating together with nitronium tetrafluoroborate in an organic solvent such as sulfolane. Also.

Compounds in which R1 or R2 is a hydroxyl group can be obtained by hydrolyzing a compound in which the corresponding lower alkyloxy group is hydrolyzed with hydrobromic acid, and compounds in which R1 or R2 is a lower alkylsulfonyl group can be obtained by hydrolyzing a compound in which the corresponding lower alkylthio group is It can also be obtained by oxidation with hydrogen peroxide.

(Effects of the Invention) The compounds of the present invention are effective for NMDA-glycine receptors and/or
or have strong affinity for AMPA receptors. Effect on NMDA receptor ([”H]-MK-80
1 binding activity), the activity is expressed at 1 μM.

In addition, the binding activity for AMPA receptor was 50 at 1 μM.
%.

Effect of the compound of the present invention on NMDA-glycine receptor (
[”H]-MK-so1 binding activity), [”HIAM
PA binding activity and audiogenic spasm suppressive effect were measured as follows.

Action on NMDA-glycine receptor ([3H]-MK-
Measurement of 801 binding activity): The binding activity and antagonistic activity to NMDA-glycine receptor were determined by a binding experiment using [''H]-MK-801 as a ligand.

Measurement of ['H]AMPA binding activity Approximately 45 nM of [3H-AMPA (2-amino-3-(
A total volume of 0.5 mt of a reaction solution containing 3-hydroxy-5-methyl-4-inxazole (propionic acid), about 300 mg of a rat cerebral membrane specimen, and a test compound was reacted in ice water for 45 minutes. The amount of [3H]AMPA bound to the quisqualic acid receptor was measured by filtration. The specific binding amount was defined as the portion of the total binding amount displaced by 10 μM quisqualic acid.

The test compound was evaluated by determining the binding inhibition rate on specific binding.

Measurement of the inhibitory effect on audiogenic convulsions in DBAI2 mice: io male mice aged 21-28 days after birth were placed in a soundproof box, and a sound stimulus of 12 kHz and 120 dB was applied for 1 minute or until the mice developed rigid convulsions. .

The compound was suspended in 0.5% methylcellulose solution.

It was administered intraperitoneally 45 minutes before sound stimulation. The drug efficacy was evaluated based on the presence or absence of seizures, and the minimum effective dose (MDO) was determined.

The compound of the present invention or a salt thereof exhibits glutamate receptor antagonism, particularly NMDA-glycine receptor and AMPA receptor antagonism.
Antagonizes the neurotoxic effects of amino acids that have antagonistic effects (especially excitatory effects) on one or both receptors,
It also has cervicogenic activity.

Hence Huntington's disease, Parkinson's disease.

leprosy, senile dementia, cerebral ischemia, oxygen deficiency, hypoglycemia,
It is a particularly useful agent in preventing postconvulsive neurodegeneration and/or mental and motor dysfunction.

The compound represented by formula (I) or a salt thereof is usually administered systemically or locally, orally or parenterally. Dosage for age 9, body weight, symptoms, and therapeutic effects.

Although it varies depending on the administration method, treatment time, etc., it is usually 1 to 1000 mg per adult per day, preferably 50 to 1000 mg per day.
Orally in doses ranging from 2 oomg once to several times a day or 1 rng to 5 oomg per day per adult.
00 mg, administered intravenously once to several times a day, or continuously administered intravenously over a period of 1 to 24 hours a day. Of course, as mentioned above, the dosage varies depending on various conditions.

Amounts less than the above dosage ranges may be sufficient in some cases.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

In addition, the manufacturing example of the raw material compound used in an Example is demonstrated as a reference example.

Reference example 1 (raw material of Example 1) 2.5 g of 2.3-diaminopyridine was dissolved in 25 g of 4N-hydrochloric acid.
rnl, 2.06 g of oxalic acid was added thereto, and the mixture was heated under reflux for 2 hours. Filter the formed crystals and wash thoroughly with water.

Pyrido(2,3-b)pyrazine-2,3-dione 2.
I got 2g.

NMR (DMSO-d,; δfrom TMS);
6.86 (dd, LH).

7.24 (dd, IH), 7.80 (dd, IH)
) MS (El); 163 (M”) m, p, ; >300'C (DMF-H, O) E, A
, ;C,HsNsOt Cacld: C,51,54; H,3,09;
N, 25.76 (%) Found: C, 51,
50; L 3.06; N, 25.8a (%)
Reference Example 2 (raw material of Example 7) e 21 g of 2-amino-4,6-dimethylpyridine was mixed with 1 ml of sulfuric acid.
Dissolve in OInt and add nitric acid (d21.42
) 1.2 ml was added dropwise. Stirring was continued until a slow exotherm occurred and the temperature returned to room temperature. The reaction solution is poured into ice water, and the pH is adjusted to 4 to 5 with diluted caustic soda water. Filter the formed crystals,
After washing with water, 1.5 g of 2-amino-4,6-dimethyl-3-nitropyridine was obtained.

MMR (CDCI,; δfromTMS); 2.
36 (8,3HL2.50(s, 3H), 6.40
(s, LH) MS (EI); 167 (M”) Reference Example 3 (Raw material for Example 8) 23 g of 2-amino-6-methylpyridine was reacted in the same manner as in Reference Example 2 to obtain 2-amino-6- 15.4 g of methyl-3-nitropyridine was obtained.

NMR (DMSO-d6; δfromTMS) +
2.73 (s, 3H).

6.64 (d, IH), 8.25 (d, IH),
8.64 (m, 2H) MS (GC-EI);
153 (M”) Reference Example 4 (Raw material for Example 9) 0.20g of sodium was dissolved in 20ml of methanol, stirred for 10 minutes, and then 2-amino-6-chloro-3
-1.30 g of ditropyridine was added, and the mixture was heated under reflux for 2 hours. The reaction suspension was filtered, and the resulting crystals were washed with a small amount of methanol and dried under reduced pressure to obtain 0.89 g of 2-amino-6-medoxy-3-nitropyridine.

NMR (CMSO-d6; δfromTMS); 3
．． 91 (st 3H) + 6.15 (d, IH),
8.16 (br, 2H), 8.26 (d, IH)
MS (El); 169 (M+) Reference Example 5 (Example 1017) Raw material) 40% methanolic methylamine 15 ml ik,
The mixture was cooled to below 10° C. using an ice water bath, and 1.50 g of 2-amino-5-rioo-3-nitropyridine was added little by little, followed by stirring at room temperature for 2 hours. The reaction suspension was filtered, washed with a small amount of methanol, and then dried under reduced pressure to obtain 1.13 g of 2-amino-6-(N-methylamine)-3-nitropyridine.

NMR (DMSO-d6; δfromTMS): 2.
86(d, 3H).

5.94 (d, LH), 7.93 (br, 3H)
MS (EI); 168 (M”) Reference example 6 (raw material of Example 14) 2-amino-6-chloro-3-nitropyridine 2.00
Suspend 9 g in 20 ml of methanol and add 3.0 morpholine.
After adding 2v:, the mixture was stirred at room temperature for 2 days. The suspension of the reaction solution was collected, washed with a small amount of methanol, and then dried under reduced pressure to obtain 1.76 g of 2-amino-6-morpholine-3-nitropyridine.

NMR (DMSO-d6; δfromTMS) *
3.68 (s, 8H).

6.32 (d, IH), 7.84 (br, 2H)
, 8.08 (d, IH) MS (EI); 24
4(M”) Reference Example 7 (Raw material of Example 15) 2-Amino-6-chloro-3-nitropyridine 2, OO
2-amino-6-methylthio-3-nitroviridine was treated for 3 days in the same manner as in Reference Example 6 using 5.92 ml of a 15% sodium methyl mercaptan aqueous solution instead of morpholine. .72g was obtained.

NMR (DMSO-d,; δf rom TMS
) ; 2.56 (s, 3H).

6.64 (d, IH), 8.10 (br, 2H)
, 8.17(d, IH) MS (EI); 18
5(M”) Example 1゜pyrido[2,3-b]pyrazine-2,3-dione 1.2
2 g of acetic anhydride, and 2.4 ml of acetic acid were added 0.93 ml of fuming nitric acid. The mixture was stirred until it spontaneously generated heat and returned to room temperature. When the reaction solution was poured into ice water and the resulting solid was filtered and washed with water, 0.44% of 6-nitropyrido(2,3-b) pyrazine-2,3-dione was obtained.
g was obtained.

NMR (DMSO-d, ; δfrom TSM);
7.64 (d, IH).

8.06 (d, IH), 12.44.12.82
(s, each IH) M S (EI): 208 (M
”)m,p,;)300℃(DMF-)[,0)E,
A; CtH4N404 Calcd, : C, 40,40; H, 1,94;
N, 26.92 (%) Found, : C, 39
,75; H,2,00; N, 26.86 (V=1
Example 2 3,4-diami/-5-nitropyridi: 500 mg.

5 ml of 4N hydrochloric acid and 0.32 g of ciuric acid were reacted in the same manner as in Reference Example 1 to obtain 8-nitropyride (314,b).
Bilasia 2.3-dione at 290 rI! @Obtained.

NMR (DMSO-d; δfrom TMS)
; 8.52 (+1. iH).

8.90 (s, IH), '11.50.12.4
7 (Each IH) MS (EI): 208 (M”
) m, p, ;) 300°C (4N-Hcl) E, A,
; CtH4N*O* Caled, : C,40,40; H,1,94;
N, 26.92 (74 Found, ; C, 4
0,21: H, 1,95; N, 26.86 (V4
Example 3゜2-amino-4-methyl-3-nitropyridine 4.95
g was dissolved in 50 rnl of :r-tal/-tar, 1 g of 10% palladium on carbon was added, and hydrogenated at normal pressure. The reaction solution was filtered, thoroughly washed with ethanol to remove insoluble matter, and concentrated under reduced pressure to obtain 3.8 g of 2,3-diamino-4-methylpyridine. Next, 4N-hydrochloric acid water 38 [Ilt, oxalic acid 3.3
g and the same reaction treatment as in Reference Example 1.

3.7g of 8-methylpyrido(2,3-b)pyrazine-2,3-dione was obtained.

NMR (DMSO-d; δfrom TMS)
; 3.31 (s, 3H)+7.00.7.95
(d, each IH), 11.48.12.28 (s, each IH
I()MS (EI); 177 (M+)m, p,
;〉300℃(DMF) E, A, : CaH? N5Ot Calcd: C,54,24; H,3,98;
N, 23.72 (Found, : C, 54,
09; H, 3,96; N, 23.93 ("j)
Example 4 5.9 g of 2-amino-5-methyl-3-nitropyridine
was hydrogenated in the same manner as in Example 3, and then reacted with 50 mt of 4N hydrochloric acid and 3.4 g of oxalic acid in the same manner as in Reference Example 1 to obtain 7-methylpyrido(2,3-b) pyracia 2.
．． 4.9g of 3-dione was obtained.

NMR(DMS O-do; J from'
TMS ); 3.30 (st 3 H)y7.2
4.7.88 (-Each IH), 11.94.12.22
(s, each IH) MS (EI); 177 (M
”) □, p, ;>300℃ (DMF-LO) E, A,
; CsHaN5Ot・1/2H,0Calcd,
: C, 51,61; H, 4,33; N, 22.
57 ('1dFound, : C, 51, 50; H
, 4,27; N, 22.65 (%) Example 5 3.73 g of 7-methylpyrido(2,3-b) pyrazine-2,3-dione was reacted in the same manner as in Example 1, and 7- Methyl-6-nitropyrido(2,3-b)pyrazine-2,
3.27 g of 3-dione was obtained.

NMR(DMS O-d,;δfrom TMS
) ; 2.44 (s, 3H) p7.44 (s,
IH), 12.34.12.66 (s, each IH) MS
(EI); 222 (M”)m, p, ;)3
00℃(DMF-H,O)E,A,; CaH6N,
O.

Calcd: C, 43,25; H, 2,72;
N, 25.22 (%) Found, : C, 43
, 65; H, 2,78; N, 25.16 (%) Example 6 2.6 g of 8-methylpyrido(2,3-b) pyrazine-2,3-dione was reacted in the same manner as in Example 1. and 8-methyl-6-nitropyrido(2,3-b)pyrazine-2,3
-1.45 g of dione was obtained.

NMR (DMSO-d,; δfrom TMS);
2.48 (s, 3H).

7.98 (s, IH), 11.92.12.79
(8, each IH) MS (EI): 222 (M) m-p,; 300°C (DMF-H, O) E, A,;
CaHeN*04 Calcd: C, 43, 25: H, 2, 7
2; N, 25.22 (%) Found, :
C, 42,74; H, 2,75; N, 25.
19 (Example 74 7゜2-Amino-4,6-dimethyl-3-nitroviridine 1
．． 5g was hydrogenated in the same manner as in Example 3, followed by 4N-
A reaction treatment was performed in the same manner as in Reference Example 1 using 12 ml of hydrochloric acid water and 1.2 g of oxalic acid to obtain 6,8-dimethylpyrido (2,3-b).
0.64 g of quinoxaline-2,3-dione was obtained.

NMR(DMS O-da; δfrom TMS
) ; 2.32.2.35 (II.

3H), 6.86(a, IH), 11.42.
12.21 (1, each IH) MS (EI); 191
(M”) m, p, ;) 300°C (DMF-HtO) E, A,;
C, H, N, 0t Calcd, : C, 56-54; H, 4,7
4; N, 21.98 (91 Found, :
C, 56,04; H, 4,77: N, 21.
80 (%11 conducted 8゜2-amino-6-methyl-3-nitropyridine 7.6g
was hydrogenated in the same manner as in Example 3, and then 54 ml of 4N hydrochloric acid water was added in the same manner as in Reference Example 1. 6-methylpyrid(2,3-b)pyrazine-2,
2.9g of 3-dione was obtained.

NMR(DMSO-ds; δfrom T
MS ) ; 2.40 (s, 3H) + 6.99
(d, IH), 7.36 (d, IH), 11.9
8 (m, 2H)tMS (EI); 177 (
M”)m, p, :)300℃(DMF-H,O)E,
A,; C5HtNsOt Calcd, : C,54,24; H,3,98;
N, 23.72 (%) Found, : C, 54
,45; H, 4,08; N, 23.83 (1%)
Example 9゜2-amino-6-medoxy 3-nitropyridine 0.8
8g was hydrogenated in the same manner as in Example 3, and then
A reaction treatment was performed with 12 mA of hydrochloric acid water and 0.47 g of oxalic acid in the same manner as in Reference Example 1 to obtain 6-medoxybi IJ)'' (2゜3-
b) 0.57 g of pyrazine-2,3-dione was obtained.

NMR (DMSO-de:δfrom TMS)”,
3.83 (8,3H) + 6.58 (d, IH),
7.44 (d, IH), 11.83 (s, LH
).

12.26 (s, IH) MS (FAB); 194 (M”+1)m, p
, ;) 300°C (DMF-H,0)E-A-; (Cm
H? NS Os ) Caled, : C,49,
74: )L 3.65: N, 21.75(%)F
ound, : C, 40, 21: H, 3, 57;
N, 21.84 (%) Example 1O 1.10 g of 2-amino-6-(N-methylamino)-3-nitropyridine was hydrogenated in the same manner as in Example 3, followed by 12 ml of 4N-hydrochloric acid. Sierra acid 0.59g
The reaction was carried out in the same manner as in Reference Example 1 to obtain 0.75 g of 6-(N-methylamino)-pyrido(2,3-b)pyrazine-2,3-dione hydrochloride.

NMR (DMSO-d, δ from TMS): 2.
78 (s, 3H) + 6.36 (d, IH), 6.
96 (br, IH), 7.30 (d, IH).

11.86 (br, 2H) MS (FAB); 193 (M”+1) m, p,
;)300℃(DMF-H,O)E,A, ;(C,H
, N, 02・HCI) Calcd, : C-42,0
3: H-3, 97: N= 24.50: C1,
15,51C%) Found, : C942,15:
H, 3,92; N, 24.54; C1,15
, 55 (%) Example 11 6-medoxyviride (2,3-b) pyrazine-2,3-
Suspend 0.25 g of dione in 48% hydrobromic acid,
The mixture was heated to reflux overnight. Dilute the reaction solution with 10 mt of water.

The crystals obtained by filtering the suspension were washed with water.

Recrystallized from N,N'-dimethylformamide-water system.

By drying under reduced pressure, (5H)-pyrido(2゜3-
b) 0.16g of pyrazine-2,3,6-trione was obtained.

NMR (DMSO-d6: δfrom TMS);
6.41 (d, IH).

7.38 (d, IH), 10.65 (br, IH
), 11.77 (s, IH).

12.69 (s, IH) MS (FAB); 180 (M”+1)m,
p, ;>300'C(DMF-H2O)E, A,
;C7)(,N, 01Calcd, :C,46
,94; H,2,81:N, 23.46 (%)F
ound, : C, 46,50; H, 2,90;
N, 22.83 (%) Example 12゜5-nitro-2,3-diaminopyridine 0.6 g, 4N
- 12 rnl of hydrochloric acid water and 0.39 g of oxalic acid were reacted in the same manner as in Reference Example 1, and 7-nitropyride (2,3
-b) 0.53g of pyrazine-2,3-dione was obtained.

NMR (DMSO-d, δ from TMS);
8.40(d, IH).

8.86 (d, IH), 12.21 (IH), ]
, 2.93 (IH) MS (EI): 208 (M) m, p; > 300 °C (DMF-H2O) E, A,;
C? H4N404 Calcd: C,40,40: H,1,94:
N, 26.92 (%) Found, : C, 4
0,20: H, 1,95; N+ 26.92 (%)
Example 13 7-nitropyride (2,3-b) pyrazine-2,3
590 mg of -dione was suspended in 6 ml of sulfolane, 530 rr of nitronium-tetrafluoroborate was added, and the mixture was stirred at 130°C for 2 hours. When the temperature returned to room temperature, the reaction solution was poured into ice water, and crystals were precipitated after a while. This was separated and recrystallized from water to obtain 320 μ of 6,7-sinitropyrid (2,3-b) pyrazine-2°3-dione.

NMR (DMSO-do, δfrom TMS); 8
．． 12(s, IH).

12.60(s, IH), 13.30(s, IH
) MS (EI); 253 (M) m, p,; 265 °C (dec,) (H2O)E,
A, : C7Hs Ns 0aCal'cd, : C
,33,21:H,1,19:N, 27.67 (%
) Found, : C, 32, 98; H, 1, 27:
N, 27.47 (%) Example 14゜2-amino-6-morpholino-3-nitropyridine 1.
74 g in 30 ml of acetic acid-methanol (3:1) solution 1K
l! I! After adding 0.17 g of platinum oxide, the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. Filter the reaction solution,
Solution F was concentrated under reduced pressure. 4N = 18 mt of hydrochloric acid solution,
The mixture was reacted with 0.70 g of shiulic acid in the same manner as in Reference Example 1 to obtain 0.55 g of 6-morpholinopyrido[2,3-b]]pyrazine-2,3-dio.

NMR (DMSO-d, δfrom TMS);
3.35-3.41 (m.

4H), 3.65-3.75 (m, 4H), 6.
60 (d, IH), 7.33 (d, IH), 1
1.71 (s, IH), 12.01 (s, IH)
MS (FAB);249(M+1)m,p,;
) 300°C (DMF-H2O) E, A,; C,, H
,2N403・0.6H,0Calcd, :C,
51,00; H, 5,14; N, 21.63 (%)
Found, :C,51,16;H,5,02:N,
21.46 (%) Example 15゜2-amino-6-methylthio-3-nitropyridino 1.
68 g of Ra was used instead of palladium carbon in Example 3.
-Hydrogenation using Ni, followed by 4N-hydrochloric acid water 18
rnl, 0.82 g of shiulic acid was reacted in the same manner as in Reference Example 1 to obtain 090 g of 6-methylthiopyrido[2,3-'b]pyrazine-2,3-dione.

NMR (DMSO-d6; δfrom TMS); 3
．． 32(s, 3H).

7.02 (d, IH), 7.37 (d, IH),
11.90 (s, IH).

12.31 (s, IH) MS (FAB); 210 (M”+1 >m, p,
; >300'C(DMF-H2O)E, A, :C
8H7N302S Calcd: C, 45, 92: H, 3, 37;
N, 20.08; S, 15.33 (%) Fou
nd,: C, 45, 74; H, 3, 39: N, 2
0.10:S, 15.17 (%) Example 16 029 g of 6-morpholinopyrido[2,3-b]]pyrazine-23-dione was suspended in 3 ml of concentrated sulfuric acid.

While cooling the reaction solution to 0°C, add 0.12 g of potassium nitrate.
was added, the temperature was raised to 70°C, and then allowed to cool to room temperature. The reaction solution was poured into ice water and the precipitated crystals were separated, then recrystallized from a N,N'-dimethylformamide-water system and dried under reduced pressure to give 6-morpholino-7-nitroviride [2,3-b Co pyrazine-2,3-dione 0.15
I got g.

NMR (DMSO-d, :δfrom TMS)
: 3.33 (br, 4 H) + 3.70 (m,
4H), 8.01 (s, LH), 11.86 (
s, 1)I).

12.57 (a, IH) MS (FAB); 294 (M”+1) m, p
;) 300°C (DMF-H2O)' ”: Co
H+ r Ns 0sCalcd, : C,43,
34; H, 4, 22; N, 22.81 (%) Fou
nd, : C, 43, 52: H, 4, 16: N, 2
2.52 (%) 6-methylthiopyrido [2,3-b
] ] 020 g of pyrazine-23-dione in 2 m of acetic acid
30% hydrogen peroxide aqueous solution 0.36 rn
1 was added thereto, and the mixture was stirred at room temperature overnight. 15mt in reaction solution
of water, the suspension was separated, recrystallized from a N,N'-dimethylformamide-water system, and dried under reduced pressure to obtain 6-methylsulfonylpyrid[2,3-b]pyrazine-2, 0.12g of 3-dione was obtained.

NMR(DMS O-da *δfrom TMS
): 3.22 (a, 3H).

7.62 (d, IH), 7.78 (d, IH),
12.51 (br, 2H) MS (FAB): 2
42 (M”+1)m, p-; > 300°C (DMF
-H2O) E, A, : C, H, N304S Calcd, : C, 39,83; H, 2,92: N
, 17.42 SS, 13.29 (%) Foun
d, : C, 39, 75: H, 2, 89: N, 1
7.40: S, 13.31 (%) Patent applicant
Yamanouchi Pharmaceutical Co., Ltd. Representative Patent Attorney Sho Nagai Representative Patent Attorney Taku Mori 1)

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ means the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or it represents a pyridine ring shown by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R
^1 is a nitro group, mono- or di-lower alkylamino group, morpholino group, hydroxyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfonyl group, lower alkyl group, and R^2 is a hydrogen atom or R^ It has the same meaning as 1. ) or a salt thereof.