JPH0613518B2 - Novel pyrimidopyrimidine derivative, process for producing the same, and pharmaceutical composition containing the compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel pyrimidopyrimidine derivative and a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition containing the compound as an active ingredient.

(Prior Art) It is known that in vivo chemical substances such as histamine, serotonin, and SRS-A, which are called chemical transmitters, play an important role in the development of various allergic symptoms in the human body. Therefore, antagonize these substances, and / or
Alternatively, since a drug that suppresses the release of these substances is useful as a therapeutic or prophylactic agent for allergic diseases, some compounds have been used for that purpose to date.

(Problems to be Solved by the Invention) An object of the present invention is to provide a compound which is useful for the treatment or prevention of various allergic diseases and has few side effects and high safety, a pharmaceutically acceptable salt thereof, a production method thereof, and Treatment of various allergic diseases containing the compound as an active ingredient,
To provide a preventive agent.

(Means for Solving the Problems) The inventors of the present invention have found that the pyrimidopyrimidine derivative of the present invention has an excellent antiallergic activity while researching drugs that act effectively on allergic diseases,
The present invention has been completed.

The compound of the present invention is a novel pyrimidopyrimidine derivative represented by the following general formula (I).

(In the formula, R ₁ and R ₂ are the same or different alkyl groups, R ₃ is an amino group or a lower alkylamino group, and R ₄ is hydrogen, an alkyl group, a phenyl group or an amino group.) More specifically, the above In the general formula (I), R ₁ , R ₂
Are the same or different, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-
Butyl, t-butyl, pentyl, hexyl, heptyl,
A linear or branched alkyl group having 1 to 10 carbon atoms such as octyl, nonyl and decyl, preferably methyl, ethyl,
It is a linear or branched lower alkyl group having 1 to 4 carbon atoms such as propyl or butyl.

R ₃ is an amino group, or, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec
It is an amino group substituted with a linear or branched lower alkyl group having 1 to 4 carbon atoms such as -butyl and t-butyl, preferably an amino group substituted with methyl or ethyl.

R ₄ is hydrogen, such as methyl, ethyl, n-propyl, i
-Propyl, n-butyl, i-butyl, sec-butyl,
Linear or branched alkyl group having 1 to 10 carbon atoms such as t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, preferably linear or branched such as methyl, ethyl, propyl or butyl. Is a lower alkyl group having 1 to 4 carbon atoms, phenyl group or amino group.

Among the compounds of the present invention, particularly preferable compounds are as follows.

5-Amino-1,3-dimethylpyrimido [4,5-d] pyrimidine-2,4-dione 5-amino-1,3-diethylpyrimido [4,5-d] pyrimidine-2,4-dione 5-amino-1-i-butyl-3-methylpyrimide [4,
5-d] pyrimidine-2,4-dione 5-amino-1,3,7-trimethylpyrimido [4,5-d] pyrimidine-2,4-dione 5-amino-1,3-dimethyl-7- Phenylpyrimido [4,5-d] pyrimidine-2,4-dione 5,7-diamino-1,3-dimethylpyrimido [4,5-d] pyrimidine-2,4-dione 5-methylamino-1 , 3-Dimethylpyrimido [4,5-d]
Pyrimidine-2,4-dione The pyrimidinepyrimidine derivative of the present invention has the above general formula (I).
Including pharmaceutically acceptable salts of compounds represented by, for example, lithium, sodium, potassium and other alkali metals, calcium, magnesium and other alkaline earth metals,
Other metal salts with aluminum or the like, or, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, inorganic acids such as boric acid, formic acid, acetic acid, haloacetic acid,
Organics such as propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid Examples thereof include acid addition salts with acids or salts with organic bases such as ammonia, trimethylamine, triethylamine, tris (hydroxymethyl) aminomethane.

These salts can be prepared from the free pyrimidopyrimidine derivative of the present invention by a known method, or can be converted into each other.

When an optical isomer is present in the compound of the present invention,
The present invention includes the d-form, the d-form and the-form.

Next, a method for producing the compound of the present invention will be described.

General formula (II) (Wherein R ₁ and R ₂ are the same or different alkyl groups, Y is an amino group, halogen or a di-lower alkylaminomethyleneamino group), and a uracil derivative represented by the general formula (III) H ₂ NZ (III) (In the formula, Z is (Where X is oxygen or NH, R ₄ is hydrogen, an alkyl group,
Represents a phenyl group or an amino group. ), A lower alkyl group or a hydroxyl group. ) By reacting with a compound represented by
When Z is a hydroxyl group, the compound of general formula (I) (In the formula, R ₁ and R ₂ are the same or different alkyl groups, R ₃ is an amino group or a lower alkylamino group, and R ₄ is hydrogen, an alkyl group, a phenyl group or an amino group.) The midopyrimidine derivative can be prepared.

In the above general formula (II), more specifically about Y, Y is an amino group, halogen, preferably chlorine, or an aminomethyleneamino group disubstituted with a lower alkyl group having 1 to 4 carbon atoms, preferably dimethylaminomethylene. Represents an amino group.

The method for producing the pyrimidopyrimidine derivative of the present invention can be roughly classified into the following three methods.

Process (I) 6- (amino or halogeno) -5-cyano-
A 5-amino-1,3,7-trisubstituted pyrimidopyrimidine derivative in which a 1,3-disubstituted uracil derivative is reacted with a carbamoyl derivative having a desired substituent or an amidine to introduce the substituent at the 7-position Production method.

The following general formula (IV) (In the formula, R ₁ and R ₂ are the same or different alkyl groups, and Y ′ represents an amino group or halogen.) And a 5-cyanouracil derivative represented by the general formula (V) (In the formula, X is oxygen or NH, R ₄ is hydrogen, an alkyl group,
Represents a phenyl group or an amino group. ) By reacting the compound represented by (Wherein R ₁ and R ₂ are the same or different alkyl groups, and R ₄ is hydrogen, an alkyl group, a phenyl group or an amino group.).

In the above reaction, when X is oxygen, the reaction is carried out for 1 to several hours under appropriate heating or reflux without using a suitable solvent. When X is NH,
The desired compound of the present invention can be obtained by reacting with an appropriate solvent, for example, a base such as metallic sodium in absolute ethanol, while appropriately heating or refluxing for 1 to several hours.

Process (2) A process for producing a 5-lower alkylamino-1,3-di-substituted pyrimidopyrimidine derivative by reacting a 5-cyano-6-di-lower alkylaminomethyleneaminouracil derivative with a lower amine.

General formula (VII) (In the formula, R ₁ and R ₂ are the same or different alkyl groups, and R ₅ is a lower alkyl group.) And a 5-cyano-6-di-lower alkylaminomethyleneaminouracil derivative represented by the general formula ( VIII) H ₂ N—R ₆ (VIII) (wherein, R ₆ represents a lower alkyl group) is reacted to produce the desired general formula (I
X) (In the formula, R ₁ and R ₂ are the same or different alkyl groups, and R ₆ is a lower alkyl group.) The compound of the present invention can be obtained.

In the above general formulas (VII), (VIII) and (IX), R ₅ and R
For more details on ₆ , R ₅ and R ₆ are, for example, methyl,
Ethyl, n-propyl, i-propyl, n-butyl, i
It is a linear or branched lower alkyl group having 1 to 4 carbon atoms such as -butyl, sec-butyl and t-butyl, preferably methyl and ethyl.

In the above reaction, the reaction is carried out in a suitable solvent such as methanol at room temperature or lower for several hours to several days.

Here, in the reaction of the compound of the general formula (VII) with the compound of the general formula (VIII), first, the following general formula (X) (Wherein R ₁ and R ₂ are the same or different alkyl groups and R ₆ is a lower alkyl group), and then R ₆ undergoes a dimross rearrangement to give a general formula (IX ) Is produced.

Production method (3) A method for producing a 5-amino-1,3-di-substituted pyrimidopyrimidine derivative by reacting a 5-cyano-6-di-lower alkylaminomethyleneaminouracil derivative with hydroxyamine and further reducing the same.

The compound of general formula (VII) is reacted with hydroxyamine, and the resulting compound is reduced to give the desired general formula (XI) (In the formula, R ₁ and R ₂ each represent the same or different alkyl group.) The compound of the present invention can be obtained.

In the above reaction, the reaction is carried out for 1 to several hours under reflux with a base such as triethylamine in a suitable solvent such as ethanol, and then the obtained compound is reduced by a usual method to obtain the desired compound. The compound of the present invention can be obtained.

In the reaction of the compound of the general formula (VII) with hydroxylamine, first, the 6-position N- represented by the following general formula (XII)
An oxide form is obtained.

(In the formula, R ₁ and R ₂ each represent the same or different alkyl group.) Then, the compound of the general formula (XII) is reduced by heating with, for example, triphenylphosphine under a nitrogen stream to give the general formula The compound of the present invention represented by (XI) is produced.

General formula (VII) used in the above production methods (2) and (3)
The 5-cyano-6-di-lower alkylaminomethyleneaminouracil derivative of is represented by the following general formula (XIII) (In formula, R < ₁ >, R < ₂ > respectively represents the same or different alkyl group.) The 6-amino-5-cyano uracil derivative represented by these,
It can be easily obtained by reacting di-lower alkylformamide dialkyl acetal.

In the reaction, the compound of the general formula (XIII) is heated in a suitable solvent such as dimethylformamide in a suitable solvent such as dimethylformamide dimethyl acetal, dimethylformamide diethyl acetal, diethylformamide diethyl acetal and the like under heating under reflux with 1 to 4 lower alkylformamide dialkyl acetal. The purpose can be achieved by reacting for several hours.

The compound of the general formula (VII) may be isolated and purified after the reaction, but can also be directly used in the next reaction.

The obtained compound of the present invention is subjected to distillation, chromatography,
It was purified by a usual means such as recrystallization and identified by elemental analysis, melting point measurement, IR, NMR, MS and the like.

(Example) Hereinafter, an example of a method for producing the compound of the present invention will be described with reference to Examples.

Example 1. 6-amino-5-cyano-1,3-dimethyluracil 0.3 g
Was added to formamide (2 ml) and the mixture was heated under reflux for 2 hours. 10 ml of water
The precipitated crystals were collected by filtration to give 5-amino-1,3-dimethylpyrimido [4,5-d] pyrimidine-2,4-dione (Compound 1) 0.2 g (yield 58%). .

Melting point:> 300 ℃ Elemental analysis: As C ₈ H ₉ N ₅ O ₂ NMR (CF ₃ COOH) δ = 3.57 (s, 3H), 3.83 (s, 3H), 8.48 (b
rs, 1H), 8.68 (s, 1H), 9.80 (br.s, 1H) 6-amino-5-cyano-1,3-dimethyl 6-amino-5-cyano-1,3-diethyl instead of uracil The following compounds were similarly obtained using uracil and 6-amino-5-cyano-1-i-butyl-3-methyluracil. still,
The parentheses after the compound name indicate reaction temperature, reaction time, and yield, respectively. The recrystallization solvent is shown in the parentheses after the melting point.

5-Amino-1,3-diethylpyrimido [4,5-d] pyrimidine-2,4-dione (compound 2) (reflux, 4 hours, 64%) Melting point: 200-202 ° C (methanol) Elemental analysis : As C ₁₀ H ₁₃ N ₅ O ₂ NMR (CDCl ₃ ) δ = 1.26 (t, 3H, J = 7Hz), 1.30 (t, 3H, J = 7H
z), 4.09 (q, 2H, J = 7Hz), 4.32 (q, 2H, J = 7Hz), 6.63 (br.s, 1
H), 8.39 (s, 1H), 8.63 (br.s, 1H) 5-amino-1-i-butyl-3-methylpyrimide [4,
5-d] pyrimidine-2,4-dione (compound 3) (reflux, 4 hours, 83%) Melting point: 192-193 ° C (methanol) Elemental analysis: as C ₁₁ H ₁₅ N ₅ O ₂ NMR (CDCl ₃ ) δ = 0.94 (d, 6H, J = 7Hz), 2.26 (m, 1H), 3.4
1 (s, 3H), 4.11 (d, 2H, J = 7Hz), 6.13 (br.s, 1H), 8.40 (s, 1H),
8.58 (br.s, 1H) Example 2. 6-chloro-5-cyano-1,3-dimethyluracil 0.5 g
And 0.473 g of acetamidine hydrochloride were added to 50 ml of absolute ethanol in which 0.24 g of metallic sodium was dissolved. The reaction solution was heated under reflux for 1 hour, and the precipitated crystals were collected by filtration, washed with water and dried.
Recrystallization from acetic acid yielded 0.44 g (yield 80%) of 5-amino-1,3,7-trimethylpyrimido [4,5-d] pyrimidine-2,4-dione (Compound 4).

Melting point: 267 ° C Elemental analysis: As C ₉ H ₁₁ N ₅ O ₂ NMR (CF ₃ COOH) δ = 2.78 (s, 3H), 3.56 (s, 3H), 3.82 (s,
3H) Using benzamidine hydrochloride and guanidine nitrate instead of acetamidine hydrochloride, the following compounds were similarly obtained.

5-Amino-1,3-dimethyl-7-phenylpyrimido [4,5-d] pyrimidine-2,4-dione (Compound 5)
(Reflux, 1 hour, 61%) Melting point: 260-266 ° C. (acetic acid) Elemental analysis: as C ₁₄ H ₁₃ N ₅ O ₂ NMR (CF ₃ COOH) δ = 3.60 (s, 3H), 3.97 (s, 3H), 7.70 (m,
3H), 8.30 (m, 2H) 5,7-diamino-1,3-dimethylpyrimido [4,5-d] pyrimidine-2,4-dione (compound 6) (reflux, 2 hours, 36%) Points:> 300 ° C (acetic acid) Elemental analysis: As C ₈ H ₁₀ N ₆ O ₂ NMR (CF ₃ COOH) δ = 3.53 (s, 3H), 3.71 (s, 3H) Example 3. 6-amino-5-cyano-1,3-dimethyluracil 3.6g
And 9.36 g of dimethylformamide dimethylacetal are added to 36 ml of dimethylformamide, and the mixture is heated under reflux for 30 minutes.
The solvent was distilled off under reduced pressure, crystallized with ether, collected by filtration, and recrystallized from ethyl acetate to obtain 5.68 g of 5-cyano-6-dimethylaminomethyleneamino-1,3-dimethyluracil (compound 7). . (Yield 99%) Melting point: 174-175 ° C. Elemental analysis: As C ₁₀ H ₁₃ N ₅ O ₂ NMR (DMSO-d ₆ ) δ = 3.10 (s, 3H), 3.15 (s, 3H), 3.23 (s,
3H), 3.27 (s, 3H), 8.26 (s, 1H) 0.47 g of the above compound 7 was dissolved in 11 ml of methanol, and 1 ml of methylamine (30% methanol solution) was added dropwise under cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and recrystallized from ligroin to give 5-methylamino-1,3-
There was obtained 0.38 g (yield 85%) of dimethylpyrimido [4,5-d] pyrimidine-2,4-dione (Compound 8).

Melting point: 178-179 ° C. Elemental analysis: as C ₉ H ₁₁ N ₅ O ₂ NMR (CF ₃ COOH) δ = 3.39 (d, 3H, J = 5Hz), 3.57 (s, 3H),
3.85 (s, 3H), 6.80 (br.s, 1H), 8.65 (s, 1H) Example 4. 0.235 g of compound 7, 0.138 g of hydroxylamine hydrochloride,
0.243 g of triethiamine is added to 3 ml of ethanol and heated under reflux for 3 hours. After cooling, 5 ml of water was added and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 5-amino-1,3-dimethylpyrimido [4,5-d] pyrimidine-2,4.
0.223 g (yield 85%) of -on-6-oxide was obtained.

Melting point: 297 ℃ Elemental analysis: As C ₈ H ₉ N ₅ O ₃ NMR (CF ₃ COOH) δ = 3.58 (s, 3H), 3.82 (s, 3H), 8.27 (b
rs, 1H), 8.87 (s, 1H), 9.78 (br.s, 1H) Next, 0.1 g of the compound obtained above is heated with 0.5 g of triphenylphosphine for 30 minutes at 150 ° C. under a nitrogen stream and cooled. After that, it was washed with ether and recrystallized from acetic acid to obtain 0.037 g of Compound 1 (yield 40%).

The compound of the present invention can be made into a medicine by combining with a suitable medicinal carrier or diluent, and can be formulated by any ordinary method. It can be solid, semisolid, liquid or gas for oral or parenteral administration. Can be formulated into a dosage form of

In the formulation, 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, and a compounding agent with another pharmaceutically active ingredient can be used. May be

As a preparation for oral administration, as it is or as a suitable additive,
For example, together with conventional excipients such as lactose, mannitol, corn starch, potato starch, etc., crystalline cellulose, cellulose derivatives, gum arabic, corn starch, binders such as gelatin, corn starch,
Tablets, powders, granules or capsules by appropriately combining disintegrating agents such as potato starch and sodium carboxymethyl cellulose, lubricants such as talc and magnesium stearate, and other fillers, wetting agents, buffers, preservatives, and flavors. It can be an agent.

The ointment can be formulated by combining with an ointment base such as petrolatum, paraffin, plastibase, single ointment, single lead ointment, hydrophilic ointment, hydrophilic petrolatum, hydrophilic plastibase.

Further, the compound of the present invention is mixed with various bases, for example, an oleaginous base such as cacao butter, an emulsion base, or a water-soluble base such as macrogol, a hydrophilic base, etc. to produce a suppository. be able to.

The injection can be 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.

For use as inhalants, aerosols, the compounds according to the invention are in the form of solutions, suspensions or finely divided powders, together with gas or liquid propellants and, if desired, customary auxiliaries such as wetting or dispersing agents. Along with filling the aerosol container. The compound of the present invention may be in a non-pressurized dosage form such as a nebulizer or an atomizer.

For formulation as an eye drop, a solution or suspension can be prepared using an aqueous solvent such as sterile purified water or physiological saline or a non-aqueous solvent for injection.

As a poultice, a peppermint oil, concentrated glycerin, kaolin or the like can be mixed and formulated.

Although the desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc., in order to obtain a desired effect, generally 1 to 1,000 mg of the compound of the present invention per day for an adult, Preferably, 10 to 500 mg can be orally administered, and a unit preparation containing an appropriate amount of the compound of the present invention can be administered 1 to several units per day.

In the case of parenteral administration (eg, injection), the daily dose is preferably a dose level of 3 to 1/10 of the above dose.

Formulation examples of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below, but the present invention is not limited thereto.

Prescription example 1. (tablet) Prescription example 2. (Capsule) Prescription example 3. (Injection) Prescription example 4. (Ointment) Prescription example 5. (Suppository) Prescription example 6. (Inhalant) (Action) The compound pyrimidopyrimidine derivative of the present invention is a compound having an excellent antiallergic action.

The pharmacological action of the compound of the present invention will be described below.

(1) Acute toxicity A group of 10 male ddY mice was used to examine the acute toxicity of the compound of the present invention using the probit method based on the mortality rate for 7 days after administration of the test drug.

An example of the results is shown in Table 1.

(2) Antiallergic action The antiallergic action of the compound of the present invention was based on rat PCA reaction as an index.

Anti-DN diluted with physiological saline at four intradermal sites on the back of 10 Wister male rats (6 weeks old) with shaved back
Passive sensitization was performed by administering P-Asc serum. One hour after oral administration of the test drug, a DNP-Asc solution (5 m
(g / ml) and an equivalent mixture of a 2% Evans blue solution were intravenously administered to induce a PCA reaction. After 30 minutes, the blood was decapitated and sacrificed, the blue spot was cut off, and the amount of leaked pigment was measured. That is, the skin was dissolved with a 2N potassium hydroxide aqueous solution, a 2N phosphoric acid aqueous solution and acetone were added, the mixture was centrifuged, and the amount of the dye was measured by the absorbance at 620 nm of the obtained supernatant.

Table 2 shows an example of the results.

(Effect of the invention) As is clear from the results of the pharmacological experiment, the pyrimidopyrimidine derivative of the present invention exhibits excellent antiallergic activity comparable to other drugs such as theophylline, and since it has lower toxicity, It is highly safe and extremely useful when used as a medicine. That is, it is useful as a therapeutic and prophylactic agent for various allergic diseases such as bronchial asthma, urticaria, allergic rhinitis, allergic skin diseases, and allergic conjunctivitis. Since the compound of the present invention can be administered orally, it is particularly useful when applied to chronic diseases.

Further, regarding the method for producing the pyrimidopyrimidine derivative of the present invention, according to the above-mentioned production method (1), an amino group is present at the 5-position, which is difficult to synthesize by the conventional method, and hydrogen or an arbitrary substituent is present at the 7-position. A pyrimidopyrimidine derivative having a group can be easily synthesized in one step. That is, a 5-cyanouracil derivative, which is a starting material that can be easily synthesized, is reacted with various readily available raw material carbamoyl derivatives or various amidines to introduce an amino group at the 5-position and, at the same time, to an arbitrary substituent at the 7-position. Can be introduced. Conventionally, a method of introducing an amino group at the 5-position has been reported, but the reaction of introducing an amino group at the 5-position and hydrogen or an arbitrary substituent at the 7-position at the same time as ring closure as in this method is novel. . In addition, the 5-cyanouracil derivative as the starting material is easily synthesized in good yield, and various raw material carbamoyl derivatives and amidine are also easily available.
The method of the present invention is extremely useful.

The production methods (2) and (3) are novel methods for obtaining a pyrimidopyrimidine derivative having a lower alkylamino group or an amino group at the 5-position. That is, a 5-cyano-6-di-lower alkylaminomethyleneaminouracil derivative which can be easily synthesized from a 6-amino-5-cyanouracil derivative is reacted with various amines to give an alkylamino group or an amino group at the 5-position. Can be easily introduced. Although a method of introducing an amino group at the same time as ring closure has been reported, the method of introducing a lower alkylamino group or an amino group as in this method is novel.

Claims (14)

[Claims] 1. A novel pyrimidopyrimidine derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. (In the formula, R ₁ and R ₂ are the same or different alkyl groups, R ₃ is an amino group or a lower alkylamino group, and R ₄ is hydrogen, an alkyl group, a phenyl group or an amino group.) 2. General formula (II) (Wherein R ₁ and R ₂ are the same or different alkyl groups, Y is an amino group, halogen or a di-lower alkylaminomethyleneamino group), and a uracil derivative represented by the general formula (III) H ₂ NZ (III) (In the formula, Z is (Where X is oxygen or NH, R ₄ is hydrogen, an alkyl group,
Represents a phenyl group or an amino group. ), A lower alkyl group or a hydroxyl group. ) The compound represented by the general formula (I) is characterized by further reacting with a compound represented by (In the formula, R ₁ and R ₂ are the same or different alkyl groups, R ₃ is an amino group or a lower alkylamino group, and R ₄ is hydrogen, an alkyl group, a phenyl group or an amino group.) A method for producing a midopyrimidine derivative. 3. A therapeutic and prophylactic agent for various allergic diseases, which comprises, as an active ingredient, at least one of a novel pyrimidopyrimidine derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. (In the formula, R ₁ and R ₂ are the same or different alkyl groups, R ₃ is an amino group or a lower alkylamino group, and R ₄ is hydrogen, an alkyl group, a phenyl group or an amino group.) 4. The therapeutic and prophylactic agent for allergic diseases according to claim 3, which is a therapeutic and prophylactic agent for bronchial asthma. 5. The therapeutic or prophylactic agent for allergic diseases according to claim 3, which is a therapeutic or prophylactic agent for urticaria. 6. The therapeutic and prophylactic agent for allergic diseases according to claim 3, which is a therapeutic and prophylactic agent for allergic rhinitis. 7. The therapeutic and prophylactic agent for allergic diseases according to claim 3, which is a therapeutic and prophylactic agent for allergic skin diseases. 8. The therapeutic or prophylactic agent for allergic diseases according to claim 3, which is a therapeutic or prophylactic agent for allergic conjunctivitis. 9. Claims 3 to 8 in the form of tablets.
A therapeutic or prophylactic agent for allergic diseases according to item. 10. The third aspect of the present invention in the form of capsule.
10. A therapeutic or prophylactic agent for allergic diseases according to item 8. 11. The therapeutic or prophylactic agent for allergic diseases according to claim 3, which is in the form of an injection. 12. The therapeutic or prophylactic agent for allergic diseases according to claim 3, which is in the form of an ointment. 13. The therapeutic or prophylactic agent for allergic diseases according to claim 3, which is in the form of suppositories. 14. The therapeutic or prophylactic agent for allergic diseases according to claim 3, which is in the form of an inhalant.