JPS584032B2 - Synkina Pyridopyrimidinedione - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel pyridopyrimidinedione derivative represented by the general formula (I) (wherein R represents a hydrogen atom or a lower alkyl group).

More specifically, 1-(m-nitrophenyl)pyrido(2.
3-d] pyrimidine-2,4(1H,3H)dione with the general formula (■) (wherein, X is an oxygen atom, a carbonyldioxy group (-O
-CO-O-), sulfinyldioxy group (-O-S
The present invention relates to a method for producing a compound represented by the general formula (■) by reacting a compound represented by O-O-) with R having the same meaning as above.

To explain R in the above general formulas (I) and (■) in more detail, the lower alkyl group of R is a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, etc. , represents.

The present invention is illustrated by the following reaction formula.

To carry out the present invention, in an organic solvent such as methanol, ethanol, dimethylformamide, tetrahydrofuran,
It is carried out in the presence of organic bases such as pyridine, trimethylamine, and triethylamine, inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, and metal compounds such as sodium hydride, sodium amide, and sodium alcoholate, and at room temperature. The reaction will proceed even if it is left to stand, but desirably it will proceed in a short time when heated to 50 to 150°C.

A pure product can be obtained by distilling off the solvent from the generated reaction mixture under reduced pressure and recrystallizing the residue from an organic solvent such as methanol, or 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 pharmacological effects such as remarkable analgesic effect, anti-inflammatory effect, and central nervous system depressing effect, and is an industrially useful compound as a pharmaceutical.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

This will be demonstrated in pharmacological tests below.

Comparative test on the pharmacological action of the compound obtained by the method of the present invention and the exemplified compounds (similar compounds) of each reference Test method (1) Anti-inflammatory action test Wistar male rats weighing 100 to 150 g were used in groups of 5 rats. The test compound dissolved in 0.5% CMC-saline was orally administered.

0.5% ~ dissolved in distilled water for injection 30 minutes after oral administration
1.0% carrageenan was injected subcutaneously into the hind paw print.

Three hours after carrageenan administration, carrageenan-induced edema was measured by the volumetric 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: ± 16mg 30%: + 31mg 45%: ++ 46% or more: +++ (2) Analgesic effect test The test compound was suspended in 0.5% CMC-saline,
The drug was administered sealed to DD male mice (body weight: 18 mg, 20 g).

One hour after administration, a 0.6% acetic acid solution was added at a rate of 0.6% per 101 body weight.
It was injected intraperitoneally to a total volume of 1 ml.

Writhing syndrome was observed for 10 to 30 minutes after administration of the acetic acid solution.

The inhibition rate of this compound was expressed as the inhibition rate relative to the control group.

The display of inhibition rate is as follows.

Inhibition rate 25% or less: ± 26 mg 50%: + 51 mg 75%: ++ 76% or more: +++ (3) 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 mg, 24 g), and the loss of righting reflex was observed.

The dose at which loss of righting reflex occurs is shown in Evaluation Method 1 below.

1000mg/ky or more:- 1000-300mg/kg:± 300-100mg/kg:+ 100-30mg/kg:++ 30mg/kg or less: +++ The above test results are shown in Table 1.

Example 1 After dissolving 2.8 g of 1-(m-nitrophenyl)pyrido[2.3-)d]pyrimidine-2.4(1H.3H) monodione in 30 ml of dimethylformamide, 9.53 P of 55% sodium hydride was added. The temperature was raised to 150°C, and 0.97g of ethylene carbonate was added thereto.
After reacting for an hour, the solvent was distilled off under reduced pressure.

Next, water was added to the residue and the precipitated crystals were recrystallized from methanol to produce pale yellow prismatic crystals of 1-(m-nitrophenyl)-3-(2-hydroxyethyl)pyrid [2.・
3-d]pyrimidine-2,4(1H,3H)-dione 2
．． I got 8g.

The melting point and elemental analysis values of this substance were as follows.

Melting point 212-213°C Elemental analysis value C15H12N4O5 Theoretical value C: 54.88H: 3.68 N: 17.07 Actual value C: 54.93H: 3.65 N: 17.16 Example 2 1-(m-nitrophenyl ) Pyrido[2.3-d]pyrimidine-2.4(1H.3H)-dione 1.4 g, glycol sulfite 1.6 g, triethylamine 5 ml
A mixture of 15 ml of dimethylformamide and 15 ml of dimethylformamide was reacted at 100° C. 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-(2-hydroxyethyl)pyrido. [2.3-d]Pyrimidine-2.4
1.3 g of (IH·3H)-dione was obtained.

The melting point of this material was 212-213°C.

Example 3 After dissolving 2.8 g of 1-(m-nitrophenyl)pyrido[2.3-d]pyrimidine-2.4(1H.3H) monodione in 30 ml of dimethylformamide, 0.53 g of 55% sodium hydride was added. In addition, the temperature was raised to 130℃,
3.1 g of propylene carbonate was added thereto, and after reacting for 1 hour, the solvent was distilled off under reduced pressure.

Next, the residue was extracted with chloroform, dehydrated and concentrated, adsorbed on a column packed with alumina, and eluted with ethyl acetate for isolation and purification, resulting in pale yellow prismatic crystals of 1-(m-nitrophenyl)-3-(2-hydroxypropylene). Bill) Pirid [2.
3-d] pyrimidine-2,4(1H,3H)-dione 2
．． I got 6ta.

The melting point and elemental analysis values of this substance were as follows. Melting point: 203-204°C Elemental analysis value: ctct H14 N4 o5 Theoretical value: C
:56.14 H:4.12N:16.37 Actual value C:56.29 H:4.09N:16.4
4

Claims (1)

[Scope of Claims] 1-(m-nitrophenyl)pyrid [2.
3-d] Pyrimidine-2,4(1H,3H)-dione with the general formula (wherein, X is an oxygen atom, carbonyldioxy group, or sulfinyldioxy group, and R is a hydrogen atom or a lower alkyl group) A method for producing a novel pyridopyrimidinedione derivative represented by the general formula (wherein R has the same meaning as above), which comprises reacting a compound represented by the following formula: