JP2662765B2 - Pharmaceutical composition containing pyrido [2,3-d] pyrimidine derivative - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition containing a pyrido [2,3-d] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. . 2. Description of the Related Art It is known that the production of chemical substances in vivo such as histamine, serotonin, SRS-A and the like, which are called chemical mediators, plays an important role in the manifestation of various allergic symptoms in the human body. I have. Therefore, since compounds that antagonize these substances and / or inhibit the release of these substances are useful for the treatment or prevention of allergic diseases, some compounds have been developed for that purpose to date. Has been used. [0003] The present inventors have studied drugs that effectively act on allergic diseases, and found that the pyrido [2,3-d] pyrimidine derivative of the present invention is an excellent antiallergic drug. The present invention has been found to have an effect, and the present invention has been completed. An object of the present invention is to provide a therapeutic or preventive agent for various allergic diseases, which contains a pyrido [2,3-d] pyrimidine derivative or a pharmaceutically acceptable salt thereof having an antiallergic activity as an active ingredient. [0004] The compound which is the active ingredient of the pharmaceutical composition of the present invention is a pyrido [2,3-d] pyrimidine derivative represented by the following general formula (I). Embedded image Wherein R ₁ and R ₂ are the same or different lower alkyl groups, and R ₃ and R ₄ are the same or different and are hydrogen, hydroxyl, halogen, nitro, amino, amino, lower alkylamino, hydroxy lower alkyl Represents an amino group, a lower alkenylamino group, a hydroxyamino group, a hydrazino group or an azido group. More specifically, in the general formula (I), R ₁ and R
₂ represents the same or different linear or branched lower alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl group, etc. . R ₃ and R ₄ may be the same or different and each may be a halogen such as hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, etc.
Preferably chlorine, nitro group, amino group, methylamino optionally having a hydroxyl group, dimethylamino, ethylamino,
A straight-chain or branched lower alkylamino group having 1 to 5 carbon atoms such as diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, and pentylamino;
Linear or branched C1-C5 such as vinyl, propenyl, isopropenyl, allyl, butenyl, pentynyl groups, etc.
Represents a lower alkenylamino group, a hydroxyamino group, a hydrazino group or an azido group. Among the compounds of the present invention, particularly preferred compounds are as follows. 1,3-dimethylpyrido [2,3-d] pyrimidine-
2,4-dione-5-hydroxy-1,3-dimethylpyrido [2,3-
d] pyrimidine-2,4-dione-5-chloro-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione-5-chloro-1,3-diethylpyrido [2,3-d]
Pyrimidine-2,4-dione-5-chloro-1-isobutyl-3-methylpyrido [2,3-d] pyrimidine-2,4-dione-6-nitro-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione-5-amino-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione-5-amino-1,3-diethylpyrido [2,3-d]
Pyrimidine-2,4-dione-5-amino-1-isobutyl-3-methylpyrido [2,3-d] pyrimidine-2,4-dione-6-amino-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione 7-amino-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione 7-amino-1-isobutyl-3-methylpyrido [2,3 -D] pyrimidine-2,4-dione-7-amino-5-hydroxy-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione-5-methylamino-1,3-dimethylpyrido [ Two, three
-D] pyrimidine-2,4-dione-5-methylamino-1,3-diethylpyrido [2,3
-D] pyrimidine-2,4-dione-5-ethylamino-1,3-dimethylpyrido [2,3
-D] pyrimidine-2,4-dione-5-propylamino-1,3-dimethylpyrido [2,
3-d] pyrimidine-2,4-dione-5-isopropylamino-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione-5-isopropylamino-1,3-diethylpyrido [2 3-d] pyrimidine-2,4-dione-5-butylamino-1,3-dimethylpyrido [2,3
-D] pyrimidine-2,4-dione 5-tert-butylamino-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione 5-tert-butylamino-1, 3-diethylpyrido [2,3-d] pyrimidine-2,4-dione-5-allylamino-1,3-dimethylpyrido [2,3
-D] pyrimidine-2,4-dione-5-hydroxyamino-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione-5- (2-hydroxyethyl) amino-1,3- Dimethylpyrido [2,3-d] pyrimidine-2,4-dione-5-hydrazino-1,3-dimethylpyrido [2,3-
d] pyrimidine-2,4-dione-5-azido-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione The pyrido [2,3-d] pyrimidine derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the above general formula (I). Metal salts such as potassium, alkaline metals such as calcium and magnesium, and other metal salts with aluminum or the like, or inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, and citric acid And acid addition salts with organic acids such as lactic acid, and salts with organic bases such as ammonia. These salts can be prepared by known methods using the free pyrido [4,3
-D] can be produced from pyrimidine derivatives or can be mutually converted. When an optical isomer is present in the compound of the present invention, the present invention includes any of its dl-, d- and l-forms. Next, a method for producing the compound of the present invention will be described. Using the uracil derivative represented by the following general formula (II) as a starting material, the compound of the present invention represented by the above general formula (I) can be produced by the following method. Embedded image [In the formula, R ₁ and R ₂ have the same meaning as in the general formula (I), X represents hydrogen, a methyl group or a cyanomethyl group, and Y represents an amino group or a dimethylaminomethyleneamino group. (1) A compound represented by the general formula (II) wherein X is a methyl group and Y is an amino group, and halogen such as phosphorus oxyhalide such as dimethylformamide (DMF) and phosphorus oxychloride and thionyl chloride. The compound of the present invention having halogen such as fluorine, chlorine, bromine and iodine at the 5-position by appropriately heating and reacting triphenylphosphine dihalogen such as thionyl halide or triphenylphosphine dichloride, triphenylphosphine dibromide or the like for 5 hours. Obtainable. Further, the 5-halogeno compound and ammonia,
Methylamine which may have a hydroxyl group, dimethylamine,
Ethylamine, diethylamine, propylamine, isopropylamine, butylamine, isobutylamine, s
ec-butylamine, tert-butylamine, straight-chain such as pentylamine group or branched straight-chain alkylamine having 1 to 5 carbon atoms, vinylamine, propenylamine, isopropenylamine, allylamine, butenylamine, pentynylamine, etc. Alternatively, by reacting with a branched lower alkenylamine having 1 to 5 carbon atoms, hydroxyamine, hydrazine, or sodium azide, a substitution reaction with a halogen at the 5-position is performed, and the compound having an amino group and a hydroxyl group at the 5-position. Straight or branched carbon number such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, etc. 1 to 5 lower alkylamino groups, vinylamino, Niruamino, isopropenyl amino can allylamino, Buteniruamino, linear or branched lower alkenyl group having 1 to 5 carbon atoms such as pentynyl group, hydroxyamino group, to introduce a hydrazino group or an azido group. This reaction can be carried out in an appropriate solvent such as alcohol such as methanol or ethanol or DMF at room temperature or by appropriately heating or refluxing, and reacting for several hours. However, when a substance having a low boiling point such as ammonia is used, it is necessary to seal the reaction system.
The 5-halogeno compound or the 5-azide compound obtained as described above can be prepared by a usual reduction method, for example, catalytic reduction using palladium-carbon or the like, and the compound of the present invention in which the 5-position is hydrogen or an amino group. It can be. Further, a compound represented by the general formula (II) wherein X is a methyl group and Y is an amino group, and dimethylformamide dimethyl acetal, dimethylformamide diethyl acetal or dimethylformamide dibutyl acetal are dissolved in a suitable solvent such as DMF. By appropriately heating and reacting for several hours, the compound of the present invention having a hydroxyl group at the 5-position can be obtained. The 5-hydroxy form is treated with a halogenating agent such as the above-mentioned phosphorus oxyhalide, thionyl halide or triphenylphosphine dihalogen to thereby perform a substitution reaction between the 5-position hydroxyl group and halogen, thereby converting the 5-halogeno form. It can also be manufactured. (2) The compound of the present invention having an amino group at the 7-position is obtained by reacting a compound represented by the general formula (II) wherein X is hydrogen and Y is an amino group with cyanomethylene triphenylphosphorane. Obtainable. This production method is an application of the Wittig reaction, and the reaction can be carried out by heating and refluxing in dry acetonitrile under a stream of an inert gas such as argon for several hours. (3) A compound represented by the general formula (II) wherein X is hydrogen and Y is a dimethylaminomethyleneamino group is reacted with nitromethane for several tens of minutes by appropriately heating in the presence of a base such as triethylamine. In this manner, the compound of the present invention having a nitro group at the 6-position can be obtained, and further reduced to a 6-amino form by a usual reduction method, for example, catalytic reduction using palladium-carbon or the like. Can be. (4) The compound represented by the general formula (II) wherein X is a cyanomethyl group and Y is an amino group is reacted with a base such as sodium carbonate as appropriate by heating or refluxing to react the compound for several hours to effect ring closure. The compound of the present invention having a hydroxyl group at the 5-position and an amino group at the 7-position can be obtained. The obtained compound of the present invention is purified by ordinary means such as distillation, chromatography, recrystallization and the like.
Identification was performed by R, NMR, UV, mass spectrum and the like. The following examples illustrate the invention in more detail. Embodiment 1 (1) 5.92 g of 5-acetyl-6-amino-1,3-dimethyluracil and 7.34 g of phosphorus oxychloride were added to 100 ml of DM
F and heated at 60 ° C. for 2 hours. After evaporating the solvent under reduced pressure, water was added and the precipitated crude crystals were collected by filtration and recrystallized from ethyl acetate to give 5.34 g of 5-chloro-1,3-dimethylpyrido [2,3-d] pyrimidine-2, 4-Dione (compound 1) was obtained. Yield: 79% Melting point: 175-177 ° C NMR (DMSO-d ₆ ) δ = 3.38 (3H, s), 3.55 (3H, s), 7.40 (1
H, d, J = 5 Hz), 8.55 (1H, d, J = 5 Hz) Similarly, 5-chloro-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione and 5-5 -Chloro-1-iso-butyl-3-methylpyrido [2,
3-d] Pyrimidine-2,4-dione was obtained. (2) 0.34 g of compound 1 was added to 100 ml of methanol.
And catalytic reduction was performed by adding palladium-carbon.
Decolorizing carbon was added to the reaction solution, and the mixture was heated and filtered, and the filtrate was distilled off under reduced pressure. Ethanol was added and the crude crystals were collected by filtration and recrystallized from ethanol to give 0.24 g of 1,3-dimethylpyrido [2,3-
d] Pyrimidine-2,4-dione (compound 2) was obtained. Yield: 84% Melting point: 160-161 ° C NMR (DMSO-d ₆ ) δ = 3.30 (3H, s), 3.55 (3H, s), 7.32 (1
H, dd, J = 5Hz, 7.5Hz), 8.35 (1H, dd, J = 2.5Hz, 7.5Hz), 8.68
(1H, dd, J = 2.5Hz, 5Hz) Embodiment 2 (1) 1.35 g of Compound 1 was dissolved in 10 ml of DMF, 0.52 g of 90% sodium azide was added, and the mixture was stirred at room temperature for 6 hours. After evaporating the solvent under reduced pressure, water was added and the precipitated crystals were collected by filtration.
1.16 g of 5-azido-1,3-dimethylpyrido [2,3
-D] pyrimidine-2,4-dione (compound 3) was obtained. Yield: 83% Melting point: 102-108 ° C (decomposition) IR (KBr): ν _max = 2110 (N ₃ ) Similarly, 5-azido-1,3-diethylpyrido [2,3-d] Pyrimidine-2,4-dione and 5-azido-1-iso-butyl-3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione were obtained. (2) 1.33 g of the compound 3 was added to 400 ml of methanol.
And 300 mg of palladium-carbon was added to perform catalytic reduction. Decolorizing carbon was added to the reaction solution, and the mixture was heated and filtered. After evaporating the filtrate under reduced pressure, ethanol was added and the precipitated crude crystals were collected by filtration and recrystallized from ethanol to give 0.87 g of 5-amino-ethanol.
1,3-dimethylpyrido [2,3-d] pyrimidine-
2,4-dione (compound 4) was obtained. Yield: 74% Melting point: 233-235 ° C NMR (DMSO-d ₆ ) δ = 3.20 (3H, s), 3.40 (3H, s), 6.40 (1
H, d, J = 6 Hz), 7.90 (1 H, d, J = 6 Hz), 7.90 (2H, br) The following compounds were obtained in the same manner. 5-Amino-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione (compound 5) Yield: 64.8% Melting point: 216-217 ° C NMR (CDCl ₃ ) δ = 1.29 (3H, t, J = 6Hz), 1.30 (3H, t, J = 6H
z), 4.12 (2H, q, J = 7Hz), 4.38 (2H, q, J = 7Hz), 6.31 (1H, d, J
= 6 Hz), 7.90 (1H, br), 8.08 (1H, d, J = 6 Hz) 5-amino-3-iso-butyl-1-methylpyrido [2,3-d] pyrimidine-2,4- Dione (Compound 6) Yield: 67% Melting point: 183-185 ° C NMR (DMSO-D ₆ ) δ = 0.87 (6H, d, J = 6Hz), 2.0-2.5 (1H,
m), 3.29 (3H, s), 4.08 (2H, d, J = 6Hz), 6.51 (1H, d, J = 6Hz),
7.90 (1H, br), 8.04 (1H, d, J = 6Hz) (1) 0.4 g of compound 1 and 1.86 g of methylamine (30% methanol solution) were added to 10 ml of DMF and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, water was added and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 0.23 g of 5-methylamino-1,3-dimethylpyrido [2,3-d] pyrimidine-2. , 4-dione (compound 7). Yield: 63% Melting point: 179-180 ° C NMR (DMSO-d ₆ ) δ = 2.85 (3H, d, J = 5Hz), 3.19 (3H, s),
3.40 (3H, s), 6.35 (1H, d, J = 6Hz), 8.05 (1H, d, J = 6Hz),
8.90 (1H, br) In the same manner, 5-methylamino-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione (compound 8) was obtained. Yield: 52% Melting point: 114 ° C NMR (CDCl ₃ ) δ = 1.25 (3H, t, J = 7Hz), 1.29 (3H, t, J = 7H
z), 4.10 (2H, q, J = 6Hz), 4.38 (2H, q, J = 6Hz), 6.29 (1H, d, J
= 6Hz), 8.15 (1H, d, J = 6Hz), 9.22 (1H, br) (2) The following compounds were used in the same manner as (1) using allylamine and isopropylamine instead of methylamine. I got 5-allylamino-1,3-dimethylpyrido [2,3-
d] Pyrimidine-2,4-dione (compound 9) Yield: 72% Melting point: 120-121 ° C NMR (CDCl ₃ ) δ = 3.40 (3H, s), 3.64 (3H, s), 3.93 (2H,
m), 4.25 (2H, m), 5.80 (1H, m), 6.30 (1H, d, J = 7Hz), 8.10
(1H, d, J = 7Hz), 9.38 (1H, br) 5-isopropyl-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione (compound 10) Yield: 77.9 % Melting point: 127-128 ° C NMR (DMSO-D ₆ ) δ = 1.23 (6H, d, J = 6Hz), 3.23 (3H,
s), 3.46 (3H, s), 3.82 (1H, m), 6.49 (1H, d, J = 6Hz), 8.05
(1H, d, J = 6 Hz), 9.07 (1 H, d, J = 8 Hz) (3) Using hydroxyamine hydrochloride in place of methylamine, 5-hydroxyamino- 1,3-Dimethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 11) was obtained. Yield: 84% Melting point: 118-120 ° C NMR (CDCl ₃ , DMSO-D ₆ ) δ = 3.39 (3H, s), 3.62 (3H,
s), 6.85 (1H, d, J = 6Hz), 8.15 (1H, d, J = 6Hz), 9.29 (1H, d, J = 6Hz)
s), 10.55 (1H, br) (4) Using hydrazine hydrate instead of methylamine,
1,3-dimethylpyrido [2,3-d] pyrimidine-
2,4-dione (compound 12) was obtained. Yield: 90% Melting point: 191-192 ° C NMR (DMSO-D ₆ ) δ = 3.24 (3H, s), 3.48 (3H, s), 4.72 (2
H, brs), 6.94 (1H, d, J = 6Hz), 8.12 (1H, d, J = 6Hz), 9.84 (1
(5) (5) Using ethanolamine hydrochloride instead of methylamine, 5- (2-hydroxyethyl) amino-1,3-dimethylpyrido [2,
3-d] Pyrimidine-2,4-dione (compound 13) was obtained. Yield: 68.8% Melting point: 163 ° C IR (KBr): 3300, 1685, 1645, 1590, 1570 cm ^-1 NMR (DMSO-D ₆ ) δ = 3.25 (3H, s), 3.48 (3H, s), 3.62 (2
H, ddd, J = 6Hz), 4.95 (2H, t, J = 5Hz), 6.48 (1H, d, J = 6Hz),
8.05 (1H, d, J = 6Hz), 9.26 (1H, t, J = 5Hz) Example 4.5 5-Acetyl-6-amino-
0.8 g of 1,3-dimethyluracil was dissolved in DMF, and 4 ml of dimethylformamide dibutyl acetal was added.
The reaction was performed at 8 ° C. for 8 hours. The solvent was distilled off under reduced pressure, separated by a silica gel column, and recrystallized from ethanol to give 0.59 g of 5
-Hydroxy-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione (compound 14) was obtained. Yield: 70.2% Melting point: 162-163 ° C NMR (DMSO-d ₆ ) δ = 3.30 (3H, s), 3.55 (3H, s), 6.78 (1
H, d, J = 6 Hz), 8.42 (1H, d, J = 6 Hz), 12.30 (1H, br) Example 5. 0.18 g of 6-amino-5-formyl-1,3-dimethyluracil And 0.45 g of cyanomethylenetriphenylphosphorane in 20 ml of dry acetonitrile
And heated to reflux for 12 hours under a stream of argon. After cooling, the precipitated crystals were collected by filtration, and 0.08 g of 7-amino-1,
3-dimethylpyrido [2,3-d] pyrimidine-2,4
-Dione (compound 15) was obtained. Yield: 39% Melting point: 290-295 ° C (sublimation) NMR (CF ₃ COOH) δ = 3.57 (3H, s), 3.84 (3H, s), 6.93 (1
H, d), 8.52 (1H, d) (1) 0.24 g of 5-formyl-6-dimethylaminomethyleneamino-1,3-dimethyluracil and 0.5 ml of triethylamine were added to 10 ml of nitromethane and heated at 80 ° C. for 2.5 hours. After evaporating the solvent under reduced pressure, ether was added to the residue, and the precipitated crude crystals were collected by filtration, recrystallized from ethanol to give 0.14 g
6-nitro-1,3-dimethylpyrido [2,3-d]
Pyrimidine-2,4-dione (compound 16) was obtained. Yield: 58.8% Melting point: 203-205 ° C NMR (DMSO-d ₆ ) δ = 3.63 (3H, s), 3.81 (3H, s), 8.61 (1
(H, d, J = 3 Hz), 9.43 (1 H, d, J = 3 Hz) (2) 0.08 g of the compound 14 was dissolved in methanol, and 100 mg of palladium-carbon was added thereto for catalytic reduction. Decolorizing charcoal was added, and the mixture was heated and filtered. The solvent is distilled off under reduced pressure,
Recrystallization from methanol gave 0.05 g of 6-amino-1,3.
-Dimethylpyrido [2,3-d] pyrimidine-2,4-
Dione (compound 17) was obtained. Yield: 71.6% Melting point: 219 - 220 ℃ NMR (DMSO -d 6) δ = 3.30 (3H, s), 3.50 (3H, s), 5.50 (2
H, s), 7.60 (1H, d, J = 3 Hz), 8.17 (1H, d, J = 3 Hz) Example 7.1.21 g of 6-amino-5- (2
-Cyanoacetyl) -1,3-dimethyluracil and 2.90
g of sodium carbonate was added to 20 ml of water, and the mixture was heated under reflux for 1 hour. After cooling, the deposited precipitate was collected by filtration, and 1.09 g of 7-amino-5-hydroxy-1,3-dimethylpyrido [2,
3-d] Pyrimidine-2,4-dione (compound 18) was obtained. Yield: 91% Melting point:> 300 ° C NMR (CF ₃ COOH) δ = 3.52 (3H, s), 3.81 (3H, s), 6.20 (1
H, s) Embodiment 8 (1) In the same manner as in Example 3, 5-tert-butylamino-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione (compound 19) was obtained. Melting point: 154 ° C. (2) 7-Amino-1-
Isobutyl-3-methylpyrido [2,3-d] pyrimidine-2,4-dione (compound 20) was obtained. Melting point: 152-154 ° C. Action The pyrido [2,3-d] pyrimidine derivative of the present invention is a compound having an excellent antiallergic effect.
Hereinafter, the pharmacological action of the compound of the present invention will be described. (1) Acute toxicity A group of five ICR male mice was used to examine the acute toxicity of the compound of the present invention by the Richfield-Wilkoxon method from the mortality rate of 14 days after oral administration of the test drug. Table 1 shows an example of the results. [Table 1] (2) Anti-allergic action The anti-allergic action of the compound of the present invention was determined by using the rat PCA reaction as an index. Passive sensitization was performed by administering an anti-DNP-Asc solution diluted with physiological saline to four sites in the back skin of a group of 6 male Wister rats (6 weeks old) whose backs were shaved. One hour after oral administration of the test drug, DNP-As
An equivalent mixture of solution c (5 mg / ml) and 2% Evans blue solution was administered intravenously to elicit a PCA reaction. Thirty minutes later, the blood was decapitated and sacrificed, the blue spot was cut off, and the amount of the leaked pigment was measured. That is, after dissolving the skin with a 2N aqueous potassium hydroxide solution, adding a 2N aqueous phosphoric acid solution and acetone, and centrifuging, the amount of the dye was measured by the absorbance of the obtained supernatant at 620 nm, and the inhibition rate of dye leakage was determined. . An example of the results is shown in Table 2. [Table 2] As is clear from the results of the above pharmacological experiments, the pyrido [2,3-d] pyrimidine derivative of the present invention exhibits an antiallergic effect superior to or better than theophylline and has low toxicity. Therefore, it is useful when used as a medicine. That is, it is useful as a therapeutic or preventive agent for various allergic diseases such as bronchial asthma, urticaria, allergic rhinitis, allergic conjunctivitis, allergic skin disease and the like. The compounds of the present invention can be administered orally, which is particularly advantageous when adapting to chronic diseases. Further, as a result of examining phosphodiesterase inhibitory activity as an index of antiallergic activity different from the PCA reaction, the compound of the present invention inhibited phosphodiesterase activity at a very low concentration. Since the compound of the present invention has an excellent phosphodiesterase inhibitory activity, the compound of the present invention can be expected to be used not only as a therapeutic agent for allergic diseases but also as a cardiotonic agent, a bronchodilator and the like. The compound of the present invention can be made into a medicament in combination with a suitable medicament carrier or diluent, can be formulated by any conventional method, and can be used as a solid, semi-solid, or solid for oral or parenteral administration. It can be formulated in liquid or gaseous dosage forms. In formulating, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, or a combination with another pharmaceutically active ingredient. It may be. For example, a combination with a bronchodilator, an antihistamine, a tranquilizer, and a tranquilizer may be mentioned. The preparation for oral administration may be used as it is or together with appropriate additives such as conventional excipients such as lactose, mannitol, corn starch, potato starch and the like.
Binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin, disintegrants such as corn starch, potato starch, sodium carboxymethylcellulose, lubricants such as talc, magnesium stearate, other bulking agents, wetting agents , Buffers, preservatives, tablets and powders by appropriately combining flavors, etc.
Granules or capsules can be prepared. Further, the compound of the present invention, various bases, for example, an oily base such as cocoa butter, an emulsion base, or a water-soluble base such as macrogol,
Suppositories can be prepared by mixing with a hydrophilic base or the like. As an injection, an aqueous solvent or a non-aqueous solvent,
For example, a solution or suspension of distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, or the like can be used. For use as inhalants, aerosols, the compounds according to the invention in the form of solutions, suspensions or finely divided powders, together with gas or liquid propellants, and optionally conventional adjuvants such as wetting or dispersing agents Together with the aerosol container. The compound of the present invention may be in a non-pressurized dosage form such as a nebulizer or an atomizer. Depending on the type of the disease, it can be formulated into a dosage form other than the above, which is optimal for the treatment, for example, eye drops, ointments, cataplasms and the like. The desired dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period and the like. To obtain the desired effect, the compound of the present invention is generally administered to an adult daily for 1 to 3 days. 1,000 mg, preferably 10 to 500 mg, can be administered orally, and a unit preparation containing an appropriate amount of the compound of the present invention can be administered one to several units per day. In the case of parenteral administration (for example, injection), the daily dose is preferably at a dose level of 3 to 1/10 of the above dose. [0049] Formulation examples of a pharmaceutical composition containing the compound of the present invention as an active ingredient are shown below, but the present invention is not limited thereto. [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location // C07D 471/04 118 C07D 471/04 118Z (72) Inventor Norihiko Kitamura Shatocho, Kato-gun, Hyogo 442-1, Kawakitayama, Kinashi-sha Nippon Organ Pharmaceutical Co., Ltd.

Claims (1)

(57) [Reference number] PC-219 [Claims] An agent for treating or preventing various allergic diseases, comprising as an active ingredient at least one of a pyrido [2,3-d] pyrimidine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image Wherein R ₁ and R ₂ are the same or different lower alkyl groups, and R ₃ and R ₄ are the same or different and are hydrogen, hydroxyl, halogen, nitro, amino, amino, lower alkylamino, hydroxy lower alkyl Represents an amino group, a lower alkenylamino group, a hydroxyamino group, a hydrazino group or an azido group. ] 2. Claim 1 which is an agent for treating and preventing bronchial asthma
The drug according to Item. 3. The drug according to claim 1, which is an agent for treating and preventing urticaria. 4. The drug according to claim 1, which is an agent for treating or preventing allergic rhinitis. 5. The drug according to claim 1, which is an agent for treating or preventing allergic conjunctivitis. 6. The drug according to claim 1, which is an agent for treating or preventing atopic dermatitis.