JPS593479B2 - synkina pyridopyrimidine dione - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) ) A lower alkyl group substituted with a monohalogen atom, an alkoxy group, an acetoxy group, an alkoxycarbonyl group, an amino group, a vinyloxy group or a phenyl group, (
The present invention relates to a novel pyridopyrimidinedione derivative represented by (4) an alkenyl group or (5) an alkynyl group.

More specifically, a compound represented by the general formula () (in which R1 has the same meaning as above) is added to a compound represented by the general formula () (wherein, It means an atom or a lower alkoxy group, and XCOY means chlorocarbonate, dialkyl carbonate, phosgene, or 1.1'-carbonyldiimidazole.

The present invention relates to a method for producing a compound represented by the general formula (1) by reacting a compound represented by the formula (1).
To further explain R1 in the above general formulas (1) and (), the lower alkyl group of R1 is methyl, ethyl, n
-propyl, isopropyl, n-butyl, isobutyl,
Substituted lower alkyl groups include lower alkyl groups such as pentyl, mono-substituted lower alkyl groups with halogen atoms such as chlorine, bromine, fluorine, and iodine, or alkoxy groups such as methoxy, ethoxy, propoxy, and poxy, acetoxy groups,
A lower alkyl group substituted with an alkoxycarbonyl group, an amino group, a vinyloxy group or a phenyl group, an alkenyl group such as allyl, 3-methylallyl, 3,3-dimethylallyl, crotyl, etc., and an alkynyl group such as propargyl, etc. Represents an alkynyl group.

In addition, the compound represented by the general formula () specifically represents methyl chlorocarbonate, ethyl chlorocarbonate, dimethyl carbonate, diethyl carbonate, phosgene, or 1,1'-carbonyldiimidazole, and is used industrially. It is a raw material that is produced and readily available.

The starting material 2-(m-nitrophenyl)nicotinamide derivative is, for example, 2-(m-nitrophenyl)
It can be obtained in good yield by reacting nicotinic acid chloride droamines.

The present invention is represented by the following reaction formula. This reaction generally involves dimethylformamide, diglyme, tetrahydrofuran,
Although it is carried out in an organic solvent such as benzene, toluene, or xylene, it is also possible to use metal compounds such as sodium metal, sodium amide, sodium hydride, and sodium ethylate, organic bases such as trialkylamines, and inorganic bases such as alkali hydroxides and alkali carbonates. Preferably, it is carried out in the presence of a base,
In particular, when the above-mentioned metal compounds are used, the target compound can be obtained in extremely good yields.

The reaction temperature is not particularly limited and may be either room temperature or heating, but preferably heating to 50 to 120°C can shorten the reaction time.

A pure product can be obtained by distilling off the solvent from the generated reaction mixture and recrystallizing the residue using a solvent such as methanol, or by separating and purifying it by column chromatography.

The compound obtained by the present invention is a new compound that has not been described in any literature, and has remarkable anti-inflammatory, analgesic, and central nervous system depressing effects, and is an industrially useful compound as a pharmaceutical.

This will be demonstrated in pharmacological tests below.

Test method (1) Acute toxicity test The compound obtained according to the present invention and the comparative drug (hereinafter referred to as test compound) were added to a 0.5% CMC-saline solution (hereinafter referred to as 0.5% CMC-Saline). suspended,
The drug was administered intraperitoneally to male mice (body weight 16-24?).

The lethal concentration was evaluated from the presence or absence of animal death 24 hours after administration of the test compound.

(2) Central nervous system depressant effect test The test compound was suspended in 0.5% CMC-Saline,
It was administered intraperitoneally to Dd male mice (body weight 16-247), and the loss of righting reflex was observed.

The dose at which loss of righting reflex occurs is indicated by the evaluation method below.

9/I A test compound dissolved in 0.5% CMC-Saline was orally administered to each group of 5 animals.

0.5% ~ dissolved in distilled water for injection 30 minutes after oral administration
1.0% carrageenan was injected subcutaneously into the hind limb hopping. Three hours after the administration of carrageenan, carrageenan-induced edema was measured by the voluminous volume method, and the inhibition rate of the test compound was calculated from the edema rate of the control group. The display of inhibition rate is as follows.

Inhibition rate 15% or less: ± 16-30%: + 31-45%: + 46-60%: + 60% or more: Book (4) Analgesic effect test The test compound was suspended in 0.5% CMC-Sallne,
Orally administered to d-grandson male mice (body weight 18-207 cm).

One hour after administration, 0.6% acetic acid solution was applied at a rate of 0.6% per 10V of body weight.
It was administered intraperitoneally in a volume of 1 ml. Agony symptoms (Wri)
thingsyndrOme) was observed for 10 to 30 minutes after administration of the acetic acid solution. and 50% analgesic dose (ED5
O) and its 95% confidence limit were determined. Table 1 shows the results of each of the above tests.

Examples of the present invention are shown below.

Example 1 0.5y of 50% sodium hydride was added to a solution of 3.0f7 of 2-(m-nitroanilino)nicotinic acid-n-propylamide and 25ml of tetrahydrofuran, and the mixture was stirred at room temperature for 15 minutes.

Next, 5,4y of ethyl chlorocarbonate was added dropwise to the mixture under cooling, and the mixture was left to stand at room temperature for 1 hour, and then boiled under reflux for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol to give pale yellow prismatic crystals of 1-(m-nitrophenyl)-3-n-propylpyrid [2.3 -d]Pyrimidine-2.4(1H.3H)-
Zeon 2.5r was obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 184-185°C Elemental analysis value Cl6Hl4N4O4 Theoretical value C: 58.89H: 4.32 N: 17.17 Actual value C: 58.95H: 4.31 NZ17.09 Example 2 2-(m-nitroanilino) Nicotinic acid allylamide 3
．． Approximately 50% in a solution of 01 and 25ml of tetrahydrofuran
1.0 r of sodium hydride was added and stirred at room temperature for 3.0 minutes.

Next, 30% phosgene-toluene solution 16y was gradually added dropwise under cooling. After the addition, the mixture was stirred at room temperature for 1 hour, and then reacted under reflux for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from ethyl acetate to give colorless needle-like crystals of 1-(m-nitrophenyl)-3-
Allylpyrido[2.3-d]pyrimidine-2.4 (1H
-2.87 of 3H)-dione was obtained. The melting point and elemental analysis values of this substance were as follows. Melting point 188~
189°C Elemental analysis value C,6Hl2N4O4 Theoretical value C: 59.26H: 3.73 N: 17.28 Actual value C: 59.21H: 3.69 N: 17.34 Example 3 2-(m-nitroanilino) Nicotinic acid methylamide 2
．． To a solution of 7y and 20 m2 of dry diglyme were added 0.67 g of 50% sodium hydride and 5.97 g of diethyl carbonate, and the mixture was reacted under reflux for 12 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from methanol to obtain colorless prismatic crystals of 1-(m-nitrophenyl)-3-methylpyrid [2
・3-d] 2.6 g of pyrimidine-2.4(1H.3H)-dione was obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 234-235°C Example 4 2-(m-nitroanilino)nicotinic acid ethylamide 2
．． After dissolving 9g in 50ml of tetrahydrofuran, 50%
1 g of sodium hydride and 4.9 g of 1,1'-carbonyldiimidazole were added, stirred at room temperature for 1 hour, and then reacted under reflux for 5 hours.

After the reaction, the solvent was distilled off under reduced pressure, ice water was added to the residue, and the precipitated crystals were recrystallized from methanol to give colorless needle-like crystals of 1-(m-nitrophenyl)-3-ethylpyrid [2.
3-d]pyrimidine-2,4(1H,3H)-dione 2
．． 6g was obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point: 193-195°C Examples 5-25 According to the methods of Examples 1-4, the compounds shown in the following table were obtained in good yields.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is (1) a hydrogen atom, (2) a lower alkyl group, (3) a monohalogen atom, an alkoxy group, Lower alkyl group substituted with acetoxy group, alkoxycarbonyl group, amino group, vinyloxy group or phenyl group, (4
) alkenyl group, or (5) alkynyl group)
A compound represented by the general formula (wherein,
COY includes general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ that are characterized by reacting compounds represented by (meaning chlorocarbonate, dialkyl carbonate, phosgene, 1,1'-carbonyldiimidazole). A method for producing a novel pyridopyridinedione derivative represented by the formula (wherein R^1 has the same meaning as above).