JPH083164A - New pyridopyrimidine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject derivative shown by a prescribed formula, having both excellent bronchodilatory action and antiallergic action and a long prolonged time, useful for a therapeutic agent and a preventive for various allergic diseases and bronchial asthma. CONSTITUTION:This derivative is expressed by the formula (R1 and R2 are each an alkyl; X is H, an alkyl or an acyl; Y is an alkyl, a halogen, nitro, amino, hydroxy, benzyloxy, cyano, carboxy, an alkoxycarbonyl, an alkoxysulfonyl, aminosulfonyl, a dialkylaminosulfonyl or sulfo), in detail, such as 5-amino-1,3-diethyl-6-methylpyrido[2,3-d]pyrimidine-2,4-dione. The compound is obtained by dissolving 5-chloro-1,3-diethyl-6-methylpyrido[2,3-d]pyrimidine-2,4- dione as a starting substance and sodium azide in dimethylformamide and reacting.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrido [2,3-d] pyrimidine derivative useful as a medicine and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art In the modern society, the number of patients with bronchial asthma continues to increase due to the influence of dust and the like as the number of automobiles increases. Bronchial asthma is a disease in which bronchial smooth muscle spasms occur during an attack, and during an attack, a person suffers from extremely difficult breathing. It is classified into atopic type, infectious type, and mixed type depending on the trigger of seizure, but in general, acquired factors are added to constitutional factors such as increased airway hyperresponsiveness to chemical transmitters and other factors, so-called asthma. It is considered that a preparatory state is established, and in addition to this, inducing factors such as antigen stimulation are added to develop the condition.

As drugs for bronchial asthma, antiallergic agents, expectorants, corticosteroids, anti-anxiety agents and the like are used in addition to bronchodilators that directly act on and relax the contracted bronchi. There is. For example, an anti-allergic agent, which is one of the widely used drugs, means that a chemical mediator is a mechanism that acts by inhibiting the release or synthesis of chemical mediators such as histamine, which is involved in allergy, or by antagonizing them. It is used as a drug to prevent the development of related asthma symptoms. Therefore, a drug having an immediate bronchodilatory action and an antiallergic action that suppresses the onset of asthma symptoms and acts prophylactically is extremely useful as a drug for bronchial asthma. Further, from the viewpoint of compliance with drug administration by patients, it is desired to develop a drug having an appropriately long duration of action.

It is known that certain pyrido [2,3-d] pyrimidine derivatives have an antiallergic action based on the inhibitory action or antagonistic action of the release of chemical mediators such as histamine (Japanese Patent Laid-Open No. 63-63). 45279).
As a result of continuing research on a substance having an immediate bronchodilatory action and a preventive antiallergic action, the present inventors have both excellent pharmacological actions and, in addition, have a characteristic that the duration is long. New pyrido [2,3-
d] A pyrimidine derivative was found and the present invention was completed.

[0005]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel pyrido [2,3-, which has both bronchodilator action and antiallergic action and is useful as a therapeutic / preventive agent for various allergic diseases and bronchial asthma. d] Providing a pyrimidine derivative.

[0006]

The novel pyrido [2,
The 3-d] pyrimidine derivative is a compound represented by the following general formula (I).

Embedded image [Wherein, R ₁ and R ₂ each represent the same or different alkyl group, X represents hydrogen, an alkyl group or an acyl group, Y represents an alkyl group, a halogen, a nitro group, an amino group,
It represents a hydroxy group, a benzyloxy group, a cyano group, a carboxy group, an alkoxycarbonyl group, an alkoxysulfonyl group, an aminosulfonyl group, a dialkylaminosulfonyl group or a sulfo group. ]

In the above general formula (I), the alkyl group for R ₁ or R ₂ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-Butyl, pentyl, isopentyl, neopentyl, t
-A linear or branched alkyl group having 1 to 6 carbon atoms such as pentyl, hexyl, dimethylbutyl and the like.

The alkyl group in X is ethyl,
Propyl, isopropyl, butyl, isobutyl, sec
Examples of the acyl group include straight-chain or branched alkyl groups having 1 to 4 carbon atoms such as -butyl and t-butyl, and examples of the acyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, t-butyryl, and the like. Branched carbon number 1 to 4
The acyl group may be mentioned.

The alkyl group in Y is methyl,
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl, and the halogen includes fluorine, chlorine, bromine, iodine and the like. Examples of the alkoxycarbonyl group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s.
Examples thereof include a carbonyl group to which a linear or branched C1-C4 alkoxy group such as ec-butoxy and t-butoxy is bonded, and the alkoxysulfonyl group may be the same linear or branched one as described above. Examples thereof include a sulfonyl group having an alkoxy group having 1 to 4 carbon atoms, and examples of the alkyl group in the dialkylaminosulfonyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and s.
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as ec-butyl and t-butyl.

Among the compounds of the present invention, particularly preferred compounds are as follows. 5-amino-1,3-diethyl-6-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 1) 5-amino-1,3-diethyl-6-fluoropyrido [2,3 -D] pyrimidine-2,4-dione (Compound 2) -5-amino-6-bromo-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 3) -5-amino -1,3-Diethyl-6-hydroxypyrido [2,3-d] pyrimidine-2,4-dione (Compound 4) 1,3-diethyl-5-isopropylamino-6-methylpyrido [2,3- d] pyrimidine-2,4-dione (Compound 5) -5-acetylamino-1,3-diethyl-6-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 6) -5-amino -6-benzyloxy-1 3-Diethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 7) 5-Amino-6-cyano-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione ( Compound 8) -5-amino-1,3-diethyl-6-ethoxycarbonylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 9) -5-amino-6-carboxy-1,3 -Diethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 10)

5-amino-1,3-diethyl-6-methoxysulfonylpyrido [2,3-d] pyrimidine-
2,4-dione (Compound 11) -5-amino-6-aminosulfonyl-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 12) -5-amino-1,3 -Diethyl-6-diethylaminosulfonylpyrido [2,3-d] pyrimidine-2,4-
Dione (Compound 13) 5-Amino-1,3-diethyl-6-sulfopyrido [2,3-d] pyrimidine-2,4-dione (Compound 1
4) 5-amino-1,3-diethyl-6-nitropyrido [2,3-d] pyrimidine-2,4-dione (Compound 1
5) ・ 5,6-Diamino-1,3-diethylpyrido [2,3
-D] pyrimidine-2,4-dione (Compound 16)-1,3-diethyl-5-formamido-6-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 17)

The novel 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), for example, hydrochloric acid, sulfuric acid, nitric acid, odor. Hydrofluoric acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranil Acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, and other acid addition salts; or alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; and aluminum. Mention may be made of salts with metals.

The novel pyrido [2,3-d] pyrimidine derivative of the present invention includes its metal complex compound, and examples thereof include complex compounds with zinc, nickel, cobalt, copper, iron and the like. These salts or metal complex compounds can be produced from the free pyrido [2,3-d] pyrimidine derivative of the present invention or converted into each other by a known method. Further, in the compound of the present invention, cis-trans isomer, optical isomer,
When stereoisomers such as conformational isomers exist or exist in the state of hydrates, the present invention includes any stereoisomers and hydrates thereof.

Regarding the method for producing the compound of the present invention, it can be produced according to the method described in JP-A-63-45279 or in accordance therewith. More specifically, the method for producing the compound of the present invention will be described below. Details are shown in the examples.

[0015]

【Example】

Reference example 1. (1) 3 g of 1-benzyl-5-chloropyrido [2,3
-D] Pyrimidine-2,4-dione and 1 g of sodium azide were dissolved in 30 ml of dimethylformamide (DMF), and the mixture was stirred at room temperature for 10 hours. The reaction solution was added to 400 ml of water, and the precipitated crystals were collected by filtration, dried, and dried to 150 m.
It was dissolved in 1 l of methanol, 0.5 g of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. The catalyst was removed, the filtrate was concentrated, the residue was dissolved in 1N hydrochloric acid, washed with chloroform, and the aqueous layer was neutralized with 20% sodium hydroxide. The precipitated crystals were extracted with chloroform, the organic layer was concentrated, and the obtained crystals were recrystallized from ethyl acetate to give 1.5 g of 5-amino-1-benzylpyrido [2,3-d] pyrimidine-2, 4-dione (mp: 291.5-292 ° C) was obtained.

(2) 5 g of 5-chloro-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione and 3.5 g of isopropylamine were dissolved in DMF (70 ml) and stirred at room temperature for 12 hours. . The reaction solution was added to ice water, and the precipitated crystals were collected by filtration, dried and purified on a silica gel column to give 4.9 g of 1,3-diethyl-5-isopropylaminopyrido [2,3-d] pyrimidine-. 2,4-dione (melting point: 118-119 ° C) was obtained.

Embodiment 1. (1) 1-Benzyl-5 in Reference Example 1 (1) above
-Chloropyrido [2,3-d] pyrimidine-2,4-dione instead of 5-chloro-1,3-diethyl-6-
A compound 1 was obtained by the same reaction as in Reference Example 1 (1) using methylpyrido [2,3-d] pyrimidine-2,4-dione. Melting point: 178-180 ° C NMR (DMSO-d ₆ ): 1.14 (t, 3H), 1.15 (t, 3H), 2.03 (s, 3H),
3.93 (q, 2H), 4.19 (q, 2H), 7.0 (bs, 1H), 7.91 (s, 1H), 8.
67 (bs, 1H).

(2) 5 in Reference Example 1 (2)
Instead of chloro-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione, 5-chloro-1,3
-Diethyl-6-methylpyrido [2,3-d] pyrimidine-2,4-dione was used to carry out the same reaction as in Reference Example 1 (2) to obtain Compound 5. Melting point: 119.5-120.0 ° C NMR (DMSO-d ₆ ): 1.14 (t, 3H), 1.16 (t, 3H), 1.20 (d, 6H),
2.29 (s, 3H), 3.93 (q, 2H), 4.19 (q, 2H), 4.2 (dq, 1H), 7.
94 (s, 1H), 9.71 (d, 1H).

Example 2.2.3 g of 5-amino-1,3
-Diethylpyrido [2,3-d] pyrimidine-2,4-
Dione was dissolved in 60 ml of tetrachloromethane and
76 ml of pyridine and 1.6 g of bromine were added, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction solution, water was added to the residue and the crystals were collected by filtration. After washing with water, recrystallization from ethanol gave 3.0 g of compound 3. Melting point: 154-155 ° C NMR (DMSO-d ₆ ): 1.15 (t, 3H), 1.18 (t, 3H), 3.93 (q, 2H),
4.17 (q, 2H), 7.18 (bs, 1H), 8.31 (s, 1H), 8.94 (bs, 1H).

Example 3. (1) Dissolve 3 g of Compound 1 in 10 ml of DMF,
8.3 ml of dimethylformamide dimethyl acetal was added, and the mixture was heated with stirring at 110 ° C. overnight. After concentrating the reaction solution, hexane was added to the residue, crystals were filtered off, and recrystallized from hexane to give 2.8 g of 1,3-diethyl-5-dimethylaminomethyleneamino-6-methylpyrido [2,3-
d] Pyrimidine-2,4-dione (melting point: 174-175 ° C)
I got

(2) The above product was treated with a silica gel column and then recrystallized from a mixed solvent of petroleum ether and benzene to obtain a compound 17. Melting point: 142-143 ° C.

(3) 2 g of compound 1 was added to 20 ml of acetic anhydride, and the mixture was heated under reflux overnight. After allowing to cool sufficiently, the precipitated crystals were added with ether, filtered and recrystallized from ethanol to obtain 1.6 g of compound 6. Melting point: 157-158 ° C NMR (DMSO-d ₆ ): 1.12 (t, 3H), 1.25 (t, 3H), 2.14 (s, 3H),
2.20 (s, 3H), 3.91 (q, 2H), 4.30 (q, 2H), 8.79 (s, 1H).

Example 4.6.2 g of 5-chloro-1,3
Diethyl-6-fluoropyrido [2,3-d] pyrimidine-2,4-dione and 50 ml of 28% ammonium hydroxide were heated in a simple polymerization apparatus at 150 ° C for 2 hours. After cooling, the mixture was extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off. The obtained crystals were recrystallized from ethanol to obtain 4.5 g of compound 2. Melting point: 201-202 ° C NMR (DMSO-d ₆ ): 1.15 (t, 3H), 1.16 (t, 3H), 3.92 (q, 2H),
4.18 (q, 2H), 7.69 (bs, 1H), 8.17 (d, 1H), 8.31 (bs, 1H).

5-chloro-1,3-diethyl-6-benzyloxypyrido [2,3-d] pyrimidine-2,4-
Compound 7 was obtained by treating the dione in the same manner as in the above production method. Melting point: 213-215 ° C NMR (DMSO-d ₆ ): 1.14 (t, 3H), 1.15 (t, 3H), 3.92 (q, 2H),
4.16 (q, 2H), 5.19 (s, 1H), 6.9-7.0 (bs, 1H), 7.3-7.6 (m,
5H), 7.94 (s, 1H), 8.3-8.4 (bs, 1H).

Example 5 5.5 g of compound 7 was suspended in 300 ml of methanol and 500 mg of 10% palladium-
Catalytic reduction was performed at room temperature in the presence of carbon. About an hour later,
When the crystals of benzyloxy compound (Compound 7) disappeared, the catalyst was removed and the solvent was distilled off. The residual crystals were recrystallized from ethanol to obtain 1.4 g of compound 4. Melting point: 213-215 ° C NMR (DMSO-d ₆ ): 1.14 (t, 3H), 1.15 (t, 3H), 3.92 (q, 2H),
4.16 (q, 2H), 6.5-7.0 (bs, 1H), 7.71 (bs, 1H), 7.9-8.3 (b
s, 1H), 9.63 (s, 1H).

Example 6 To 30 g of DMF was added to 4.2 g of potassium cyanide, 0.7 g of palladium diacetate and 3.3 g of toluphenylphosphine, and the mixture was stirred for 30 minutes at room temperature under an argon atmosphere, then 10 g of bromo compound was added. 20 ml of a DMF solution of (Compound 3) was added. 90 ℃ reaction solution
After stirring for 24 hours, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off, the residue was purified by a silica gel column, and recrystallized from benzene to obtain 3.5 g of compound 8. Melting point: 193-195 ° C NMR (DMSO-d ₆ ): 1.15 (t, 3H), 1.17 (t, 3H), 3.92 (q, 2H),
4.20 (q, 2H), 8.04 (bs, 1H), 8.54 (s, 1H), 9.06 (bs, 1H).

Example 7. (1) Raney nickel was added to 1 g of an ethanol solution of 5-amino-1,3diethyl-6-ethoxycarbonyl-7-methylthiopyrido [2,3-d] pyrimidine-2,4-dione, and the mixture was heated under reflux for 5 hours. did. The filtrate obtained by removing the catalyst using Celite was concentrated, the residue was purified by a silica gel column, and the obtained crystals were recrystallized from ethanol to give 6.0 g.
Compound 9 of was obtained. Melting point: 144-145 ° C NMR (DMSO-d ₆ ): 1.16 (t, 3H), 1.18 (t, 3H), 1.32 (t, 3H),
3.93 (q, 2H), 4.23 (q, 2H), 4.30 (q, 2H), 8.49 (d, 1H), 7.
86 (s, 1H), 9.36 (d, 1H).

(2) 0.56 g of compound 9 was added to a mixture of 10 ml of ethanol, 1 g of potassium hydroxide and 10 ml of water, and the mixture was heated under reflux for 10 minutes. The reaction solution was made acidic with acetic acid, and the precipitated crystals were collected by filtration and washed with water to obtain 0.46 g of compound 10. Melting point: 264-266 ° C NMR (DMSO-d ₆ ): 1.16 (t, 3H), 1.18 (t, 3H), 1.32 (t, 3H),
3.93 (q, 2H), 4.23 (q, 2H), 8.70 (d, 1H), 8.72 (s, 1H), 9.
28 (d, 1H).

Example 8. (1) 1 g of 5-amino-1,3 diethylpyrido [2,
3-d] pyrimidine-2,4-dione was added to 3 ml of chlorosulfuric acid and stirred at 100 ° C for 2 hours. The reaction solution was added to ice water, and the precipitated crystals were collected by filtration and washed with water to give 1.1 g of 5-
Amino-6-chlorosulfonyl-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione was obtained.

(2) 3 g of the above product was dissolved in 30 ml of tetrahydrofuran and 20 ml of methanol to obtain 3
Sodium methoxide solution prepared from 00 mg sodium and 10 ml methanol was added and stirred for 30 minutes. After acetic acid was added to the reaction solution to make it acidic, the solvent was distilled off. Water was added to the residue and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue is purified by a silica gel column and then recrystallized from methanol to obtain 2.
1 g of compound 11 was obtained. Melting point: 156-157 ° C NMR (DMSO-d ₆ ): 1.16 (t, 3H), 1.20 (t, 3H), 3.77 (s, 3H),
3.93 (q, 2H), 4.24 (q, 2H), 7.28 (bs, 1H), 8.55 (s, 1H),
9.51 (bs, 1H).

(3) Similarly, the product of (1) above was treated with ammonia, diethylammonium and sodium hydroxide to obtain compounds 12, 13 and 14, respectively. (Compound 12) Melting point: 236-238 ° C NMR (DMSO-d ₆ ): 1.16 (t, 3H), 1.18 (t, 3H), 3.94 (q, 2H),
4.22 (q, 2H), 7.19 (bs, 1H), 7.61 (bs, 2H), 8.50 (s, 1H),
9.41 (bs, 1H). (Compound 13) Melting point: 168-169 ° C NMR (DMSO-d ₆ ): 1.07 (tx2,3Hx2), 1.15 (t, 3H), 1.19 (t, 3
H), 3.25 (qx2,2Hx2), 3.92 (q, 2H), 4.23 (q, 2H), 7.34 (b
s, 1H), 8.49 (s, 1H), 9.39 (bs, 1H). (Compound 14) Melting point:> 320 ° C NMR (DMSO-d ₆ ): 1.13 (t, 3H), 1.15 (t, 3H), 3.92 (q, 2H),
4.19 (q, 2H), 7.46 (d, 1H), 8.30 (s, 1H), 8.87 (d, 1H).

Example 9. (1) A mixed solution of 40 ml of nitric acid and 40 ml of concentrated sulfuric acid was cooled in an ice bath, and 10 g of 5-amino-1,3 diethylpyrido [2,3-d] pyrimidine-2,4-dione was added. The reaction solution is returned to room temperature and stirred for 1 hour, and further 50 ° C.
After stirring for 1 hour, the mixture was added to ice water and extracted with chloroform. The organic layer was dried over sodium sulfate, the solvent was distilled off, and the obtained crystal was recrystallized from methanol to obtain 9.1 g of 1,3.
-Diethyl-5-nitroaminopyrido [2,3-d] pyrimidine-2,4-dione was obtained.

(2) 5.3 g of the above product was dissolved in 20 ml of sulfuric acid and stirred at 50 ° C. for 3 hours. The reaction mixture was added to ice water, neutralized with 28% aqueous ammonia, and extracted with chloroform. The organic layer was dried over sodium sulfate, the solvent was distilled off, and the obtained crude crystals were recrystallized from methanol to obtain 3.
3 g of compound 15 was obtained. Melting point: 169-170 ° C NMR (DMSO-d ₆ ): 1.17 (t, 3H), 1.20 (t, 3H), 3.94 (q, 2H),
4.26 (q, 2H), 8.81 (bs, 1H), 9.15 (s, 1H), 9.94 (bs, 1H).

(3) 2.9 g of Compound 15 was dissolved in 60 ml of ethyl acetate, 0.5 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The filtrate from which the catalyst was removed using Celite was concentrated, and the precipitated crystals were recrystallized from methanol to obtain 1.6 g of compound 16. Melting point: 198-199 ° C NMR (DMSO-d ₆ ): 1.14 (tx2,3Hx2), 3.92 (q, 2H), 4.15 (q,
2H), 4.62 (bs, 1H), 7.64 (s, 1H), 6.5-8.5 (bs, 2H).

[0035]

Next, the pharmacological action of the novel pyrido [2,3-d] pyrimidine derivative of the present invention will be described in detail. (1) Bronchodilation action A guinea pig was exsanguinated and killed, the trachea was extracted, and four tracheal sections with a width of about 1 mm, which were cut along the tracheal cartilage, were connected with silk thread to prepare a tracheal smooth muscle sample. Approximately 0.5g of the sample was filled with Tyrode's solution and placed in a 5ml Magnus tank (31 ° C), which was aerated with a mixed gas of 95% oxygen and 5% carbon dioxide.
Suspended by applying the tension of. After allowing the baseline to stabilize for 0.5-1 hour, histamine dihydrochloride was applied and its isotonic contractions were recorded via isotonic transducers.

In the examination of the bronchodilator effect of the test drug, the relaxation effect on the continuous contractile response by the contractile agent was used as an index.
That is, after the continuous contraction reaction of smooth muscle by 10 ⁻⁴ M histamine dihydrochloride reached a certain level, the test drug was ^treated with 10 ⁻⁵ M.
It acts at a concentration to determine the relaxation rate for continuous contraction height,
The activity was evaluated by the strength of this relaxation rate. The relaxation rate was defined as the value obtained by dividing the length of the contracted bronchial smooth muscle when the histamine dihydrochloride was allowed to act and the length of the relaxed effect of the test drug.

Table 1 below shows an example of the experimental results.

[Table 1]

(2) Antiallergic action The antiallergic action of the compound of the present invention was evaluated by the rat passive cutaneous anaphylaxis (PCA) reaction. A group of 6 Wistar male rats (6 weeks old) with shaved backs were treated with anti-DNP-A diluted in physiological saline at 4 intradermal sites on the back.
Passive sensitization was performed by administering sc (2,4-dinitrophenyl-ascaris) solution. One hour after oral administration of the test drug, DNP-Asc solution (5 mg / ml) and 2
% Evans Blue Solution Equivalent Mixture IV
CA reaction was evoked. 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, the skin is dissolved with a 2N potassium hydroxide aqueous solution,
After adding N phosphoric acid aqueous solution and acetone and centrifuging, the dye amount was measured by the absorbance of the obtained supernatant at 620 nm, and the inhibition rate of dye leakage was determined. As a result, in the oral administration group of the compound of the present invention 20 mg / kg, a significant inhibitory effect on dye leakage was observed as compared with the control group.

(3) Inhibitory effect on LTD ₄ -induced bronchoconstriction reaction The inhibitory effect of the compound of the present invention on LTD ₄ -induced bronchoconstrictor reaction was measured by Konze using Hartley male guinea pigs.
Measured according to a modification of the tt and Rossler method [Japan. J.
Pharmacol., Vol. 30, 537 (1980)]. As a result, LTD
Against the bronchoconstriction reaction of the guinea pig induced by ₄ , even after 5 hours after the oral administration of the compound of the present invention,
A strong inhibitory effect equivalent to 1 hour after administration was observed. However, in the case of the known compound having no substituent at the 7-position of the compound of the present invention, almost no bronchoconstriction inhibitory action was observed 5 hours after administration. The effect of extending this action duration is
It was considered to be due to the structural characteristic of the compound of the present invention having a substituent at the 7-position.

[0040]

[Effect] As is clear from the results of the above-mentioned pharmacological experiments, the novel pyrido [2,3-d] pyrimidine derivative of the present invention has excellent bronchodilation and antiallergic activity, and has a long duration. Also has. Thus, the compound of the present invention, in addition to being able to suppress and prevent the development of asthma symptoms involving chemical mediators such as histamine, directly act on the contracted tracheal smooth muscle to relax it, resulting in dyspnea symptoms during an asthma attack. It can also be used for immediate treatment to relieve
It can be used for the treatment of various bronchial asthma such as extrinsic asthma and dust asthma. In addition, the pyrido [2,3-d] of the present invention
Since the pharmacological action of the pyrimidine derivative lasts for a long time, it has many advantages such as reducing the number of times of medication and the amount of medication per day, such as allergic rhinitis, allergic conjunctivitis, urticaria, and allergic skin diseases. It is very useful as a drug for allergic diseases and bronchial asthma.

[0041]

EXAMPLES The compound of the present invention can be made into a medicine by combining it with a suitable pharmaceutical carrier or diluent, and can be formulated by any ordinary method. It can be solid or semisolid for oral or parenteral administration. , Liquid or gas 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.

The preparation for oral administration may be used as it is or together with suitable additives, for example, conventional excipients such as lactose, mannitol, corn starch and potato starch.
Crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin and other binders, corn starch, potato starch, carboxymethyl cellulose potassium and other disintegrants, talc, magnesium stearate and other lubricants, other extenders, wetting agents Tablets, powders, granules or capsules can be prepared by appropriately combining buffers, preservatives, perfumes and the like.

The injection may be an aqueous solvent or a non-aqueous solvent such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol solution or suspension. it can. Further, depending on the patient's condition and the type of disease, it is possible to appropriately formulate a dosage form other than the above which is most suitable for the treatment, for example, an inhalant, an aerosol, a suppository, an ointment, a poultice, an eye drop, etc. is there.

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, but in order to obtain the desired effect, it is usually administered to an adult at a daily dose of 1 day.
To 1000 mg, preferably 5 to 500 mg, can be orally administered in one to several divided doses. In the case of parenteral administration of injections and the like, a dose level of 3 to 1/10 of the above oral dose is preferable due to the influence of absorption and the like.

Claims (1)

[Reference number] PC-233 [Claims] 1. A novel pyrido [2,3-d] pyrimidine derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. Embedded image [Wherein, R ₁ and R ₂ each represent the same or different alkyl group, X represents hydrogen, an alkyl group or an acyl group, Y represents an alkyl group, a halogen, a nitro group, an amino group,
It represents a hydroxy group, a benzyloxy group, a cyano group, a carboxy group, an alkoxycarbonyl group, an alkoxysulfonyl group, an aminosulfonyl group, a dialkylaminosulfonyl group or a sulfo group. ]