JPH10287655A - Pyrazole derivatives - Google Patents

Abstract

[PROBLEMS] To provide a compound useful for prevention and treatment of various eosinophil-related diseases and a medicament containing the same as an active ingredient, as well as an eosinophil inhibitor, an anti-allergy And anti-asthmatic agents. The general formula (I) [In the formula, n is 2, 3 or 4, R ¹ is a hydrogen atom, C _1-4
R ² such as an alkyl group and a C _2-5 alkoxyalkyl group;
_{Represents a} hydrogen atom, a _C2-5 aliphatic acyl group, an aromatic acyl group, etc.], a drug containing a pyrazole derivative or a salt thereof as an active ingredient, an eosinophil inhibitor, an antiallergic agent and an antiasthmatic agent .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrazole derivative or a salt thereof, and a medicament useful for preventing and treating various eosinophil-related diseases. Further, the present invention relates to an eosinophil inhibitor, an antiallergic agent and an antiasthmatic agent.

[0002]

2. Description of the Related Art Various diseases associated with eosinophils have been recognized, and drugs and steroids corresponding to the diseases have been used as therapeutic methods. For example, for the treatment of allergic diseases such as bronchial asthma, for which the involvement of eosinophils has been strongly suggested, histamine receptor antagonists, mediator release inhibitors from mast cells, leukotriene antagonists, thromboxane antagonists. Antiallergic agents such as synthetic inhibitors and steroids having an anti-inflammatory effect are used. For bronchial asthma, bronchodilators such as xanthine derivatives and β-exchange neuroreceptor stimulants are used in addition to the above agents.
However, none of the drugs target eosinophils, and only steroids having an anti-inflammatory effect have an eosinophil inhibitory effect. Currently, steroids are used as the most effective drugs for patients with eosinophilia diseases other than bronchial asthma. In eosinophilic pneumonia, eosinophilic fasciitis, allergic granulomatous vasculitis, etc., steroids are administered with an aim of reducing eosinophils.

[0003] As other treatment methods, for eosinophilic granuloma and the like, removal of a tumor mass and radiation therapy are performed. For eosinophilia, chemotherapeutic agents, anticoagulants and antiplatelet drugs, and leukocytes are further used. Removal and plasma exchange methods have also been attempted. However, the inhibitory effect of the steroids described above acts non-specifically not only on eosinophils but also on various cells, and steroid dependence and various side effects are problematic, which limits the use of steroids. Since it is well known, there is an urgent need for the development of a drug that specifically suppresses eosinophils and can be expected to reduce side effects in the treatment of eosinophil-related diseases.

[0004]

SUMMARY OF THE INVENTION In view of the current state of treatment and research on such eosinophil-related diseases, the present invention provides various eosinophils having an action of specifically inhibiting eosinophils. An object of the present invention is to provide compounds useful for the prevention and treatment of sphere-related diseases and medicaments containing them as active ingredients. Another object of the present invention is to provide an eosinophil inhibitor, an antiallergic agent and an antiasthmatic agent.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve these problems, and as a result, the pyrazole derivative of the present invention has an eosinophil-inhibiting action, and its specific activity is high. The present inventors have found that the present invention has an excellent therapeutic effect on eosinophil-related diseases by the action of suppressing eosinophils, and completed the present invention.

The present invention relates to a compound of the formula (I)

Embedded image (Wherein n is 2, 3 or 4; R ¹ is a hydrogen atom;
Alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 5 carbon atoms, a trifluoromethyl group or a halogen atom, a phenyl group optionally substituted by a nitro group or amino group, R ² is a hydrogen atom, a carbon An aliphatic acyl group having 2 to 5 carbon atoms, an aromatic acyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aralkyloxycarbonyl group, and 3 carbon atoms;
To 6 alkoxyoxalyl groups, aromatic sulfonyl groups or —C (＝ X) NHR ³ (where X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, an aralkyl group, an alkyl group having 1 to 4 carbon atoms) Group, aromatic acyl group, 5-7 carbon atoms
A cycloalkyl group having 2 to 5 carbon atoms, an alkylthiocarbonyl group having 2 to 5 carbon atoms, an alkenyloxycarbonyl group having 4 to 7 carbon atoms, an aralkyloxycarbonyl group, an alkoxy having 3 to 6 carbon atoms Carbonylalkyl group, aromatic sulfonyl group, naphthyl group or alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, halogen atom, trifluoromethyl group, trifluoro It is a phenyl group which may be substituted with a methoxy group, a carboxyl group, a nitro group, an amino group or an alkylthio group having 1 to 4 carbon atoms. ). Pharmaceuticals, eosinophil inhibitors, antiallergic agents and antiasthmatic agents comprising the pyrazole derivative represented by the formula (I) or a salt thereof as an active ingredient, and the general formula (I ')

Embedded image (Wherein n is 2, 3 or 4; R ¹ is a hydrogen atom;
Alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 5 carbon atoms, a trifluoromethyl group or a halogen atom, a phenyl group optionally substituted by a nitro group or amino group, R ² is a hydrogen atom, a carbon An aliphatic acyl group having 2 to 5 carbon atoms, an aromatic acyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aralkyloxycarbonyl group, and 3 carbon atoms;
To 6 alkoxyoxalyl groups, aromatic sulfonyl groups or —C (＝ X) NHR ³ (where X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, an aralkyl group, an alkyl group having 1 to 4 carbon atoms) Group, aromatic acyl group, 5-7 carbon atoms
A cycloalkyl group having 2 to 5 carbon atoms, an alkylthiocarbonyl group having 2 to 5 carbon atoms, an alkenyloxycarbonyl group having 4 to 7 carbon atoms, an aralkyloxycarbonyl group, an alkoxy having 3 to 6 carbon atoms Carbonylalkyl group, aromatic sulfonyl group, naphthyl group or alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, halogen atom, trifluoromethyl group, trifluoro It is a phenyl group which may be substituted with a methoxy group, a carboxyl group, a nitro group, an amino group or an alkylthio group having 1 to 4 carbon atoms. ). Where n is 3, R ¹ and R ²
Are both hydrogen atoms, n is 2, R ¹ has 1 to ¹ carbon atoms.
An alkyl group of 4, R ² is a hydrogen atom, and n is 3, R ¹ is a hydrogen atom, R ² is —C (＝ S) NHR ³ , and R ³ is a trifluoromethyl group, a methoxy group or Excludes phenyl groups substituted with methylthio groups. ) Or a salt thereof.

In the above general formulas (I) and (I ′), the “alkyl group having 1 to 4 carbon atoms” includes methyl, ethyl, n-propyl, isopropyl, n-
Butyl group, isobutyl group, sec-butyl group, tert
-Butyl group and the like. Preferred are a methyl group and an ethyl group. As the “C 2-5 alkoxyalkyl group”, a methoxymethyl group, an ethoxymethyl group,
Examples thereof include an n-propoxymethyl group and an n-butoxymethyl group. Preferably it is a methoxymethyl group. As the "C2-5 aliphatic acyl group", a formyl group,
Examples include an acetyl group, an n-propionyl group, and an n-butyryl group. Preferably it is an acetyl group. Examples of the "aromatic acyl group" include a benzoyl group and a toluoyl group. Preferably it is a benzoyl group. The “alkoxycarbonyl group having 2 to 5 carbon atoms” includes methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group, tert
-Butoxycarbonyl group and the like. Preferred are an ethoxycarbonyl group and a tert-butoxycarbonyl group. As the "aralkyloxycarbonyl group",
A benzyloxycarbonyl group; Examples of the "alkoxyoxalyl group having 3 to 6 carbon atoms" include a methoxyoxalyl group, an ethoxyoxalyl group, an n-propoxyoxalyl group, and a tert-butoxyoxalyl group. Examples of the “aromatic sulfonyl group” include a phenylsulfonyl group and a toluenesulfonyl group. Preferably, it is a toluenesulfonyl group. Examples of the “aralkyl group” include a benzyl group. Examples of the "C5-7 cycloalkyl group" include a cyclohexyl group and a cyclopentyl group. Preferably it is a cyclohexyl group. Examples of the "alkylthiocarbonyl group having 2 to 5 carbon atoms" include a methylthiocarbonyl group, an ethylthiocarbonyl group, an n-propylthiocarbonyl group, an n-butylthiocarbonyl group, and a tert-butylthiocarbonyl group. "C 4-7
Examples of the "alkenyloxycarbonyl group" include an allyloxycarbonyl group. Examples of the "alkoxycarbonylalkyl group having 3 to 6 carbon atoms" include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, an n-propoxycarbonylmethyl group, an n-butoxycarbonylmethyl group and the like. Preferred is an ethoxycarbonylmethyl group. "Alkoxy group having 1 to 4 carbon atoms"
Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group and a tert-butoxy group. Preferred are a methoxy group and an ethoxy group. Examples of the "alkylthio group having 1 to 4 carbon atoms" include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, and a tert-butylthio group. Preferably it is a methylthio group. Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferred are a chlorine atom and a bromine atom.

The compounds represented by the general formulas (I) and (I ') of the present invention are represented by the following general formulas (I ") or (I"')
), Any of those compounds are also included in the present invention.

Embedded image

The salts of the pyrazole derivatives of the present invention include:
There is no particular limitation as long as it is pharmacologically acceptable. For example, salts with inorganic acids such as hydrochloride, hydrobromide, phosphate, sulfate, acetate, trifluoroacetate, and succinate Acid salts, salts with organic acids such as maleate, fumarate, malate, tartrate, salts with alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium and calcium salts. And the like.

Specific examples of the pyrazole derivative of the present invention represented by the general formula (I) are shown in Table 1 below. However, the present invention is not limited to these exemplified compounds.

[0011]

[Table 1]

[Table 2]

[Table 3]

[0012]

[Production method A]

Embedded image (Wherein, n, R ¹ , X and R ³ are the same as described above;
R ⁴ represents an alkoxycarbonyl group having 2 to 5 carbon atoms or an aralkyloxycarbonyl group. (A) Method for producing a compound of the formula (I) in which R ² is an alkoxycarbonyl group or an aralkyloxycarbonyl group having 2 to 5 carbon atoms: a compound represented by the formula (II) is treated with hydrazine in an inert solvent. By reacting, the compound represented by the general formula (Ia) can be produced. The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.
Cyclohexane, benzene, aliphatic or aromatic hydrocarbons such as toluene, diethyl ether, diisopropyl ether, dioxane, ethers such as tetrahydrofuran, acetonitrile, nitriles such as propionitrile, alcohols such as methanol, ethanol, propanol or Water or a mixture of these organic solvents and water is mentioned. In this reaction, 1 to 5 mol of hydrazine is used per 1 mol of the compound represented by the general formula (II). This reaction proceeds even in the absence of a base, but a base can be used if necessary. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and sodium hydride, and organic bases such as pyridine, triethylamine, and DBU. The reaction temperature is usually -90 to 200C, preferably,
0-120 ° C. The reaction time may be appropriately selected from the range of 1 to 15 hours.

(B) Method for producing a compound of the general formula (I) wherein R ² is a hydrogen atom The compound of the general formula (Ia) is reacted with an acid to produce a compound of the general formula (Ib) can do. Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as toluenesulfonic acid, trifluoromethanesulfonic acid, acetic acid, and trifluoroacetic acid. This reaction uses 1 to 10 mol of the acid per 1 mol of the compound represented by the general formula (Ia). This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, and examples thereof include hexane, cyclohexane, benzene, and aliphatic or aromatic hydrocarbons such as toluene, diethyl ether, and diisopropyl hydrocarbon. Ethers such as ether, dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; alcohols such as methanol, ethanol and propanol; and halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane. The reaction temperature is usually -90 to 2
00 ° C, preferably 0 to 120 ° C. The reaction time may be appropriately selected from the range of 0.5 to 15 hours.

(C) In the general formula (I), R ² is -C
(= X) Method for producing compound represented by NHR ³ A compound represented by the general formula (Ic) is reacted with a compound represented by the general formula (Ib) in an inert solvent to give a compound represented by the general formula (Ic). Can be manufactured. The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, and examples thereof include hexane, cyclohexane, benzene, and aliphatic or aromatic hydrocarbons such as toluene and diethyl ether. And ethers such as diisopropyl ether, dioxane and tetrahydrofuran. In this reaction, 1 mol of the compound represented by the general formula (III) is used per 1 mol of the compound represented by the general formula (Ib). This reaction proceeds even in the absence of a base, but a base can be used if necessary. As the base, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, inorganic bases such as sodium hydride or pyridine, triethylamine,
Organic bases such as DBU can be mentioned. The reaction temperature is usually
The temperature is from 90 to 200C, preferably from 0 to 120C. The reaction time may be appropriately selected from the range of 0.5 to 15 hours.

[Production method B] Production method of a compound in which R ³ is a hydrogen atom in the general formula (I)

Embedded image (In the formula, n, R ¹ and X are the same as described above, and R ⁵ represents an alkoxycarbonyl group or an aralkyloxycarbonyl group having 2 to ⁵ carbon atoms.) A compound represented by the general formula (Id) is a base By subjecting the compound to a hydrolysis reaction in an inert solvent in the presence of the compound, the compound represented by the general formula (Ie)
Can be produced. Examples of the base used include inorganic bases such as sodium hydroxide and potassium hydroxide. The amount of the base is 1 to 10 mol per 1 mol of the compound represented by the general formula (Id). The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.For example, dioxane, ethers such as tetrahydrofuran, alcohols such as methanol, ethanol, and propanol, or water or Mixtures of these organic solvents and water are mentioned. Reaction temperature is usually 0 to 200 ° C,
Preferably, it is 20 to 120 ° C. Reaction time is 1 to 1
What is necessary is just to select suitably from the range of 5 hours.

[Production method C] Production method of a compound of the formula (I) wherein R ² is an aliphatic acyl group having 2 to 5 carbon atoms, an aromatic acyl group or an alkoxyoxalyl group having 3 to 6 carbon atoms.

Embedded image (In the formula, n and R ¹ are the same as described above, and R ⁶ represents an aliphatic acyl group having 2 to 5 carbon atoms, an aromatic acyl group, or an alkoxyoxalyl group having 3 to 6 carbon atoms.) The compound represented by the general formula (If) can be produced by reacting the compound represented by Ib) with an acid anhydride or an acid halide in the presence of a base. The base used is not particularly limited as long as it normally acts as a base, and examples thereof include tertiary amine organic bases such as triethylamine and pyridine. In this reaction, 1 mol of the acid anhydride or acid halide is used per 1 mol of the compound represented by the general formula (Ib). This reaction proceeds even without solvent, but a solvent can be used if necessary. The solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, and examples thereof include hexane, cyclohexane, benzene, and aliphatic or aromatic hydrocarbons such as toluene, diethyl ether, and diisopropyl hydrocarbon. Examples include ethers such as ether, dioxane, and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; and halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane. The reaction temperature is usually -90 to 200C,
Preferably, it is 0 to 120 ° C. The reaction time is 0.5-
What is necessary is just to select suitably from the range of 15 hours.

[Production method D] Production method of a compound of the formula (I) wherein R ² is an aromatic sulfonyl group

Embedded image (In the formula, n and R ¹ are the same as described above, and R ⁷ represents an aromatic sulfonyl group.) By reacting a compound represented by the general formula (IV) with hydrazine in an inert solvent, The compound represented by Ig) can be produced. The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.
Cyclohexane, benzene, aliphatic or aromatic hydrocarbons such as toluene, diethyl ether, diisopropyl ether, dioxane, ethers such as tetrahydrofuran, acetonitrile, nitriles such as propionitrile, alcohols such as methanol, ethanol, propanol or Water or a mixture of these organic solvents and water is mentioned. In this reaction, 1 to 5 mol of hydrazine is used per 1 mol of the compound represented by the general formula (IV). This reaction proceeds even in the absence of a base, but a base can be used if necessary. As the base, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,
An inorganic base such as sodium hydride or an organic base such as pyridine, triethylamine, DBU and the like can be mentioned. The reaction temperature is usually -90 to 200C, preferably 0 to 12C.
0 ° C. The reaction time may be appropriately selected from the range of 1 to 15 hours.

[Production Method E] Production method of a compound of the formula (I) wherein R ³ is a phenyl group substituted with an amino group.

Embedded image (In the formula, n, R ¹ and X are the same as described above.) By subjecting the compound represented by the general formula (Ih) to a reduction reaction in an inert solvent, the compound represented by the general formula (Ii) is obtained. Can be manufactured. This reaction can use a conventional means of reducing a nitro group to an amino group, but it is preferable to carry out the reaction from neutral to weakly acidic using a metal such as tin, zinc, iron, and platinum. Examples include a method using zinc and calcium chloride, platinum oxide or iron and acetic acid. The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.For example, hexane, cyclohexane, benzene,
Aliphatic or aromatic hydrocarbons such as toluene, diethyl ether, diisopropyl ether, dioxane,
Ethers such as tetrahydrofuran, acetonitrile, nitriles such as propionitrile, methanol,
Examples thereof include alcohols such as ethanol and propanol, water, and mixtures of these organic solvents and water.
The reaction temperature is usually -90 to 200C, preferably 0 to 1C.
20 ° C. The reaction time may be appropriately selected from the range of 1 to 15 hours.

[Production method F] Production method of compound of formula (I) wherein R ¹ is a phenyl group substituted with an amino group

Embedded image (In the formula, n and R ² are the same as described above.) A compound represented by the general formula (Ik) is produced by subjecting the compound represented by the general formula (Ij) to a reduction reaction in an inert solvent. be able to. This reaction can use a conventional means of reducing a nitro group to an amino group, but it is preferable to carry out the reaction from neutral to weakly acidic using a metal such as tin, zinc, iron, and platinum. Examples include a method using zinc and calcium chloride, platinum oxide or iron and acetic acid. The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.For example, hexane, cyclohexane, benzene,
Aliphatic or aromatic hydrocarbons such as toluene, diethyl ether, diisopropyl ether, dioxane,
Ethers such as tetrahydrofuran, acetonitrile, nitriles such as propionitrile, methanol,
Examples thereof include alcohols such as ethanol and propanol, water, and mixtures of these organic solvents and water.
The reaction temperature is usually -90 to 200C, preferably 0 to 1C.
20 ° C. The reaction time may be appropriately selected from the range of 1 to 15 hours.

[Process G] Process for preparing a compound of formula (I) wherein R ³ is a phenyl group substituted by a carboxyl group.

Embedded image (In the formula, n, R ¹ and X are the same as described above, and R ⁸ represents an alkyl group having 1 to 4 carbon atoms.) In an inert solvent, a compound represented by the general formula (Il) is added in the presence of a base. By subjecting the compound to the hydrolysis reaction, the compound represented by the general formula (Im)
Can be produced. Examples of the base used include inorganic bases such as sodium hydroxide and potassium hydroxide. The base is used in an amount of 1 to 10 mol per 1 mol of the compound represented by the general formula (Il). The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.For example, dioxane, ethers such as tetrahydrofuran, alcohols such as methanol, ethanol, and propanol, or water or Mixtures of these organic solvents and water are mentioned. Reaction temperature is usually 0 to 200 ° C,
Preferably, it is 20 to 120 ° C. Reaction time is 1 to 1
What is necessary is just to select suitably from the range of 5 hours.

All of the compounds produced by the above-mentioned production methods can be isolated and purified by a conventional method. The compound produced by the production method A, E or F may be in the form of a salt such as hydrochloride, hydrobromide or trifluoroacetate depending on the type of reaction compound, reaction conditions or isolation and purification conditions. Can be taken. In such a case, it can be used as a free compound by using it in the form of a salt in the next reaction or by adding an inorganic base such as sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide or an aqueous solution thereof.

In the general formula (I), a compound wherein n is 3, R ¹ and R ² are both hydrogen atoms is represented by PMQuan, Louis
According to D. Quin, J. Org. Chem., 31, 2487 (1966), n is 2, R ¹
Is an alkyl group having 1 to 4 carbon atoms, and a compound wherein R ² is a hydrogen atom is disclosed in JP-B-49-20783.
Further, n is 3, R ¹ is a hydrogen atom, and R ² is -C (= S) N
Compounds which are HR ³ and R ³ is a phenyl group substituted by a trifluoromethyl group, a methoxy group or a methylthio group are commercially available as reagents. However, there is no disclosure suggesting that any of them has an eosinophil inhibitory action.

The pyrazole derivative of the present invention or a salt thereof has an excellent eosinophil inhibitory activity and can be used as an eosinophil inhibitor, antiallergic agent or antiasthmatic agent as an active ingredient. It can be widely applied to the prevention and treatment of various eosinophil-related diseases. Examples of the eosinophil-related diseases include the following AD. A. Allergic diseases: for example, chronic bronchial asthma, allergic rhinitis, skin diseases and conjunctivitis, hay fever, drug and food allergies, allergic bronchopulmonary mycosis,
Allergic granulomatous vasculitis and the like. B. Pulmonary eosinophilia: for example, pulmonary eosinophilia associated with fungal and parasitic infections, central bronchial granulomatosis,
Drug-induced pneumonia, simple pulmonary eosinophilia, chronic and acute eosinophilic pneumonia, sarcoidosis, etc. C. Skin diseases causing eosinophilia: eg, autoimmune bullous disease, collagen diseases and related diseases, animal skin diseases such as parasitic infection, pregnancy-related skin diseases such as gestational herpes, granulomatous and tumorous Skin diseases and the like. D. Hematopoietic tumors with eosinophilia: for example, acute and chronic myeloid leukemia, acute lymphocytic leukemia, Hodgkin's disease,
Non-Hodgkin's lymphoma, Kimura's disease (eosinophilic lymphoid follicle-like structure-growth granuloma), etc. E. FIG. Other eosinophil-related diseases: eosinophilic angioedema, eosinophilic cystitis, spring catarrh, autoimmune diseases with eosinophil infiltration, eosinophilic fasciitis, multiple periarterial Such as fire.

The medicament of the present invention can be widely applied to these eosinophil-related diseases, and it is necessary to suppress eosinophils at present or in the future even for diseases not exemplified here. If so, the medicament of the present invention can be applied.

The medicament of the present invention can be administered orally or parenterally, and may be systemically administered or locally administered. Also, the dosage form is not particularly limited and can be appropriately selected according to the administration route. For example, tablets,
Capsules, dragees, granules, fine granules, inhalants, suppositories,
Solutions, syrups, dry syrups, suspensions, emulsions, lotions, ointments, patches, sprays, gels, nasal drops,
Examples include eye drops and injections. If desired, these preparations may contain organic or inorganic solid or liquid excipients,
Auxiliary substances, stabilizers, wetting agents, emulsifiers, buffers and other pharmacologically acceptable additives can be incorporated.

The dose of the medicament of the present invention to humans depends on the purpose of treatment or prevention, the sex, weight, age, health condition,
It is appropriately determined according to various conditions such as the type and degree of disease, dosage form, administration route, administration period, and the like. The daily dose of the pyrazole derivative of the present invention is generally about 0.01 to 100 m.
g / kg range.

The medicament of the present invention can be used for livestock, pet animals,
It may be used to treat eosinophil-related diseases in captive or warm-blooded animals such as wildlife. The dosage form and dosage in this case can be determined with reference to the dosage form and dosage for humans.

[0028]

The compounds of the present invention and the production method thereof will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the present invention. The melting point was measured by MP-500D (manufactured by Yanagimoto Seisakusho), and ¹
H-NMR spectrum is tetramethylsilane (TMS)
Was used as an internal standard and measured with a JNM-EX270 type spectrum meter (270 MHz, manufactured by JEOL Ltd.), and the δ value was shown in ppm.

Example 1a Preparation of 4- (3-aminopropyl) -3-hydroxypyrazole 4- (3-aminopropyl)-according to the method disclosed in J. Org. Chem., 31, 2487 (1966). 3-Hydroxypyrazole was obtained. ¹ H-NMR (D ₂ O) δ value: 1.60-1.75 (2H, m), 2.15-
2.25 (2H, m), 2.75-2.85 (2H, m), 7.07 (1H, s).

Example 1b Preparation of ethyl N '-[3- (3-hydroxy-4-pyrazolyl) propyl] thioureidocarboxylate

Embedded image 4- (3-Aminopropyl) -3 obtained in Example 1a
-200 mg of hydroxypyrazole in 24 m of dioxane
of ethoxycarbonyl isothiocyanate at room temperature. After stirring at 65 ° C. for 2 hours, the solvent was distilled off under reduced pressure until crystals precipitated. The obtained solid was washed with ethanol, and ethyl N ′-[3- (3
-Hydroxy-4-pyrazolyl) propyl] thioureidocarboxylate (292 mg) was obtained. Melting point: 170-172 ° C ¹ H-NMR (DMSO-d ₆ ) δ value: 1.22 (3H, t), 1.7
6 (2H, dt), 2.27 (2H, t), 3.45-3.70 (2H, m), 4.15 (2H,
q), 7.23 (1H, s).

Hereinafter, Examples 2 to 4 were carried out in the same manner as in Example 1b.
3 was produced. Table 2 shows the physical property values of the obtained compound.

[Table 4]

[Table 5]

[Table 6]

Example 44 Preparation of tert-butyl N '-[2- (3-hydroxy-5-methyl-4-pyrazolyl) ethyl] carbamate

Embedded image 2.0 g of ethyl 2-acetyl-4-tert-butoxycarbonylaminobutanoate was dissolved in 20 ml of ethanol, and 0.43 ml of hydrazine hydrate was added dropwise. 65
After stirring at 3 ° C. for 3 hours, the solvent was distilled off under reduced pressure until crystals precipitated. The obtained solid is washed with benzene, and tert-butyl N '-[2- (3-hydroxy-5-methyl-4
1.8 g of [-pyrazolyl) ethyl] carbamate were obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.37 (9H, s), 2.0
3 (3H, s), 2.29 (2H, t), 2.90-2.95 (2H, m), 6.60-6.80
(1H, m).

Example 45 Preparation of 4- (2-aminoethyl) -3-hydroxy-5-methylpyrazole trifluoroacetate

Embedded image To 500 mg of the compound obtained in Example 44, 0.6 ml of trifluoroacetic acid was added dropwise at room temperature. After stirring for 1 hour, trifluoroacetic acid was distilled off under reduced pressure to obtain 4- (2-aminoethyl) -3-hydroxy-5-methylpyrazole as a trifluoroacetic acid salt. ¹ H-NMR (DMSO-d ₆ ) δ value: 2.15 (3H, s), 2.5
6 (2H, t), 2.75-3.00 (2H, m).

Example 46 3-Hydroxy-5-methyl-4- [2- [N '-(3
-Trifluoromethylphenyl) thioureido] ethyl] pyrazole

Embedded image 530 mg of the compound obtained in Example 45 was added to ethanol 5
and dissolved at room temperature in triethylamine 0.42 ml.
And 0.25 ml of 3-trifluoromethylphenyl isothiocyanate were added dropwise. After stirring for 15 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and methanol-chloroform (1: 4) was used.
9) 3-Hydroxy-5-methyl-4- [2-
324 mg of [N ′-(3-trifluoromethylphenyl) thioureido] ethyl] pyrazole were obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 2.08 (3H, s), 2.4
0-2.65 (2H, m), 3.40-3.70 (2H, m), 7.39 (1H, d), 7.52
(1H, t), 7.67 (1H, dd), 7.99 (1H, s).

Thereafter, Examples 47 to 62 were produced in the same manner as in Examples 44, 45 and 46. Table 3 shows the physical property values of the obtained compound.

[Table 7]

[Table 8]

Example 63 Preparation of 3-hydroxy-4- (3-thioureidopropyl) pyrazole

Embedded image To 150 mg of the compound obtained in Example 1b, 1.9 ml of a 1N aqueous sodium hydroxide solution was added. After heating under reflux for 2 hours, a 1N aqueous hydrochloric acid solution was added to make the mixture acidic, and the mixture was extracted with ethyl acetate. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. Then, the residue was recrystallized from ethyl acetate-hexane to give 3-hydroxy-4- (3
-Ureidopropyl) pyrazole 31 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.60-1.80 (2H,
m), 2.24 (2H, t), 3.20-3.60 (2H, m), 7.22 (1H, s).

Example 64 Preparation of 4- (3-acetylaminopropyl) -3-hydroxypyrazole

Embedded image 4- (3-Aminopropyl) -3 obtained in Example 1a
300 mg of -hydroxypyrazole was dissolved in 6 ml of pyridine, and 0.24 ml of acetic anhydride was added at room temperature. After stirring for 2 hours, pyridine was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 169 mg of 4- (3-acetylaminopropyl) -3-hydroxypyrazole from a methanol-chloroform (1: 4) fraction. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.56 (2H, dt), 1.
79 (3H, s), 2.22 (2H, t), 2.95-3.05 (2H, m), 7.19 (1H,
s).

Example 65 Preparation of 4- (3-benzoylaminopropyl) -3-hydroxypyrazole

Embedded image 4- (3-aminopropyl) -5 obtained in Example 1a
Using 4-hydroxypyrazole and benzoic anhydride, 4- (3-benzoylaminopropyl) -3-hydroxypyrazole was obtained in the same reaction as in Example 64. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.71 (2H, dt), 2.
29 (2H, t), 3.20-3.45 (2H, m), 7.23 (1H, s), 7.35-7.6
5 (3H, m), 7.70-7.90 (2H, m), 8.30-8.55 (1H, m).

Example 66 Preparation of ethyl N '-[3- (3-hydroxy-4-pyrazolyl) propyl] oxamate

Embedded image 4- (3-Aminopropyl) -3 obtained in Example 1a
Dissolve 100 mg of hydroxypyrazole in 6 ml of pyridine, then add 116 mg of ethyl chloroglyoxylate.
Was dissolved in 2 ml of 1,2-dichloroethane and added dropwise at room temperature. After stirring for 2 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl N'-
[3- (3-hydroxy-4-pyrazolyl) propyl]
81 mg of oxamate was obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.27 (3H, t), 1.6
4 (2H, dt), 2.23 (2H, t), 3.00-3.30 (2H, m), 4.22 (2H,
q), 7.21 (1H, s).

Example 67 Preparation of 3-hydroxy-5-methyl- [3- (4-methylphenylsulfonylamino) propyl] pyrazole

Embedded imageEthyl 2-acetyl-5- (4-methylphenylsul
Same as Example 44 using (honylamino) pentanate
3-hydroxy-5-methyl- [3-
(4-methylphenylsulfonylamino) propyl] pi
Lazole was obtained. ¹ H-NMR (DMSO-d₆) Δ value: 1.43 (2H, dt), 1.
96 (3H, s), 2.12 (2H, t), 2.38 (3H, s), 2.55-2.75 (2H,
 m), 7.38 (2H, d), 7.65 (2H, d).

Example 68 4- [3- [N '-(3-aminophenyl) ureido]
Production of propyl] -3-hydroxypyrazole

Embedded image 50 mg of the compound obtained in Example 37 was dissolved in methanol, 3.8 mg of platinum oxide was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours, followed by filtration of insolubles, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and from a methanol-chloroform (1: 4) fraction, 4- [3-
[N '-(3-aminophenyl) ureido] propyl]
35 mg of -3-hydroxypyrazole were obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.59 (2H, dt), 2.
26 (2H, t), 3.00-3.15 (2H, m), 4.80-5.00 (2H, br s),
6.02-6.11 (2H, m), 6.49 (1H, d), 6.60-6.70 (1H, m),
6.81 (1H, t), 7.22 (1H, s), 8.10 (1H, s).

Example 69 Benzyl N '-[3- [5- (3-aminophenyl)
Production of [-3-hydroxy-4-pyrazolyl] carbamate

Embedded image 100 mg of the compound obtained in Example 57 was dissolved in methanol, 12 mg of platinum oxide was added, and the mixture was stirred for 5 hours under a hydrogen atmosphere, followed by filtration of insolubles, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and methanol-chloroform (3:97) was subjected to benzyl distillation.
65 mg of N '-[3- [5- (3-aminophenyl) -3-hydroxy-4-pyrazolyl] carbamate were obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.50-1.65 (2H,
m), 2.37 (2H, t), 2.90-3.10 (2H, m), 4.99 (2H, s), 6.
45-6.70 (3H, m), 6.90-7.40 (6H, m).

Example 70 Preparation of 4- [N '-[3- (3-hydroxy-4-pyrazolyl) propyl] ureido] benzoic acid

Embedded image To 150 mg of the compound obtained in Example 39, 1.9 ml of a 1N aqueous sodium hydroxide solution was added. After heating under reflux for 2 hours, a 1N aqueous hydrochloric acid solution was added to make the mixture acidic. The precipitated crystals are washed with water and benzene, and 4- [N '-[3- (3-
Hydroxy-4-pyrazolyl) propyl] ureido] benzoic acid 109 mg was obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.62 (2H, dt), 2.
27 (2H, t), 3.10 (2H, dd), 6.31 (1H, dd), 7.22 (1H,
s), 7.48 (2H, d), 7.80 (2H, d), 8.31 (1H, s).

Test Examples Next, test examples will be described in which the pyrazole derivative of the present invention has an excellent eosinophil inhibitory activity and its activity is eosinophil-specific. About the compound of the present invention, (1) EPO (Eosinophil Peroxydase) release inhibitory action from guinea pig eosinophils,
(2) direct action on enzymatic activity of guinea pig eosinophil EPO, (3) action on histamine release from rat mast cells, (4) action on guinea pig immediate asthma model,
(5) A test was performed on the growth inhibitory effect on guinea pig airway epithelial cells. The test methods and results are described below.

Test Example 1: EPO from guinea pig eosinophils
Release inhibitory effect Sephadex G-200 (Pharmacia) (3 mg / kg)
Was intravenously administered and eosinophils were induced. The eosinophils collected by a Parcoll density gradient centrifugation method after washing the alveoli of male Hartley guinea pigs were used for the test. Eosinophils were added to Hanks (H.) at 5 × 10 ⁵ cells / 200 μl.
anks) After preparation with buffer, the test substance was added thereto, and
Incubated at 5 ° C for 5 minutes. Then, fMLP (Fo
(rmyl-methionyl leucil phenylalanine) 1 μM (final concentration) was added and reacted for 10 minutes. Thai Road (Ty
rode) solution (without Ca ²⁺ and Mg ²⁺ ) was added to stop the reaction, and the centrifuged supernatant was pre-incubated. Thereafter, 200 μl of a 10 mM Mo-phenylenediamine (OPD) solution containing 1% hydrogen peroxide was added to carry out an enzyme reaction. Five minutes later, 133.3 μl of 4N sulfuric acid was added to stop the reaction, and the absorbance at a wavelength of 492 nm was measured using a spectrophotometer (Dainippon Pharmaceutical Co., Ltd.). Eosinophil 10 from absorbance
^The amount of EPO released per ⁶ cells was calculated, and the EPO release inhibition rate (%) of the test substance was calculated using the amount of EPO released from eosinophils stimulated by fMLP as a control. Table 4 shows the results.

[0046]

[Table 9] From the results of Test Example 1, it was confirmed that the compound of the present invention strongly suppressed the release of EPO from guinea pig eosinophils.

Test Example 2: Direct action of guinea pig eosinophils on the enzymatic activity of EPO Eosinophils obtained in the same manner as in Test Example 1 were treated with 5 × 10 ⁶ c
cells / ml cell suspension, frozen at -20 ° C,
After re-thawing, the centrifuged supernatant was used as a guinea pig eosinophil EPO enzyme preparation. 100 μl of the enzyme standard solution was dispensed into a test tube, and after adding the test substance, 200 μl of a 10 mM MOPD solution containing 1% hydrogen peroxide was added to carry out the enzyme reaction. Five minutes later, 133.3 μl of 4N sulfuric acid was added to stop the reaction, the absorbance was measured in the same manner as in Test Example 1, and the EPO enzyme activity inhibition rate (%) by the test substance was calculated. The test substance has a final concentration of 10
μM, and 3-amino-1,2,4-triazole (abbreviated as ATA) (final concentration 3 mM) was used as a positive control. Table 5 shows the results.

Table 5 << Example Inhibition rate (%) >> 1a 4.0 1b 4 3.328 3.7 40 5.4 49 4.5 ATA 95.1

From the results of Test Example 2, it was found that the compound of the present invention
At a concentration clearly having a PO release inhibiting effect, no direct effect on the enzyme activity of guinea pig eosinophil EPO was observed. Therefore, it was confirmed that the compound of the present invention suppressed the release of EPO from eosinophils without directly suppressing the EPO enzyme.

Test Example 3: Effect on histamine release from rat peritoneal mast cells Mast cells were collected from the peritoneal cavity of Wistar male rats (about 200 g in weight) to which anti-DNP-OA (ovalbumin) rat serum was intraperitoneally administered. 0.1% B
3.75 × 10 ⁵ cells / m with SA Tyrode's solution
After the mixture was dispensed in 400 μl aliquots and incubated at 37 ° C. for 10 minutes, the test substance was added and reacted for 30 seconds. 50 μl of an antigen solution (DNP-OA) was added thereto and reacted at 37 ° C. for 10 minutes, and then Tyrode solution (Ca ²⁺ , Mg 2
^The reaction was stopped by immersing in 1 ml of ice water. The centrifuged supernatant was subjected to alkali extraction with 4N sodium hydroxide and then to butanol extraction. This butanol layer is 0.1N
After placing in a hydrochloric acid solution and shaking, 500 ml of a hydrochloric acid layer was obtained. 0.4 ml of 1N sodium hydroxide was added thereto, and 1
0.1 ml of a% o-phthalaldehyde (OPT) solution was added, shaken, and then immersed in ice water. After 45 minutes, 0.2 ml of 2M citric acid was added to stop the reaction. This was measured with a fluorometer (EX: 351, EM: 441, manufactured by Hitachi, Ltd.), and the amount of histamine released was calculated. The histamine release rate (%) was determined from the total histamine amount (T), the histamine amount not stimulated by the antigen (Sp) and the histamine amount stimulated by the antigen (H) according to the following formula. Histamine release rate (%) = (H-Sp) / T Furthermore, the histamine release rate of the test substance-free group was 100%.
%, And the histamine release inhibition rate of the test substance added group (%)
Was calculated. DSCG 10 μM was used as a positive control. Table 6 shows the results.

Table 6 ──────────────────────── Example concentration (μM) inhibition rate (%) ────────── {1b 0.3 33.9 1 37.1 3 34.9 10 41.6 DSCG 10 86.9} ────────────

From Test Example 3, it was confirmed that the compound of the present invention did not show a strong inhibitory effect on histamine release from rat peritoneal mast cells. Therefore, it has been clarified that the compound of the present invention specifically suppresses eosinophils without suppressing the activation of cells involved in the initial defense mechanism of a living body such as mast cells.

Test Example 4: Effect on guinea pig immediate asthma model Antigen (1% OA) was given to guinea pigs passively sensitized on the day before the test.
Was inhaled for 3 minutes. Measure the airway resistance for 3-6 minutes after the end of inhalation, and average the value near the maximum value (more than 20 breaths)
Was defined as an airway resistance value during an immediate asthmatic reaction. The test substance was administered from the ear vein 5 minutes before inhalation of the antigen. The inhibition rate was calculated from the difference in the airway resistance increase between the solvent administration group and the drug administration group. Table 7 shows the results.

Table 7 Example Dose (mg / kg) Immediate asthma response inhibition rate (%) ─────────────────────────────── 1b 0.1 22.0 0.3 33.1 1.0 53.0 ───────────────────────────────

From Test Example 4, it was confirmed that the compound of the present invention having an eosinophil function inhibitory action had a strong anti-asthmatic action in a guinea pig immediate asthma model.

Test Example 5: Growth Inhibitory Effect on Guinea Pig Airway Epithelial Cells Guinea pig trachea was treated with protease to obtain guinea pig airway epithelial cells. 3 × 10 ⁴ cells in 199 medium
As a cell suspension of s / ml, 0.1 ml of the cell suspension was seeded on a 96-well plate, and cultured in a 5% CO ₂ incubator. After 72 hours of culture, the test substance (1
0-0.1 mg / ml) was added to each well. The cells were cultured for 72 hours in a 5% CO ₂ incubator, and cell proliferation was measured by the MTT method. For the test results, the average absorbance of the blank was determined and subtracted from the absorbances of the control and the test substance to calculate the respective average values and 2SD. The test result was judged to be cytostatic if (mean value of test substance + 2SD) −mean value of control <0 and (mean value of test substance−2SD) −mean value of control <0. . As a result, it was confirmed that the compound of Example 1b had no inhibitory effect on the growth of guinea pig airway epithelial cells at a dose of 0.1 to 10 mg / ml, and had no cytotoxicity.

[Formulation Examples] Formulation examples of the compound of the present invention are shown below, but the formulation is not limited thereto. Formulation Example 1: Tablet A tablet containing 10 mg of the active ingredient per tablet was prepared according to the following formulation. Compound of Example 1b 10 mg Starch 40 mg Lactose 30 mg Crystalline cellulose 15 mg Methylcellulose 3 mg Magnesium stearate 2 mg Total amount 100 mg

Formulation Example 2: Capsules 1 containing 10 mg of active ingredient according to the following formulation
Capsules were prepared by filling 00 mg of the mixed ingredients into capsules. Compound of Example 1b 10 mg Starch 30 mg Lactose 50 mg Crystalline cellulose 8 mg Magnesium stearate 2 mg Total amount 100 mg

Formulation Example 3: Liquid preparation A liquid preparation containing 100 mg of the active ingredient was prepared according to the following formulation. Compound of Example 1b 100 mg Citric acid monohydrate 7.8 mg Sodium citrate dihydrate 18.5 mg EDTA / 2Na dihydrate 3.72 mg NaCl 900 mg Distilled water for injection qs ─────────────────────────── Total volume 10 ml

Formulation Example 4: Inhalant An inhalant containing 10 mg of the active ingredient was prepared according to the following formulation. Compound of Example 1b 10 mg Citric acid monohydrate 7.8 mg Sodium citrate dihydrate 18.5 mg EDTA / 2Na dihydrate 3.72 mg Sodium chondroitin sulfate 500 mg NaCl 900 mg Appropriate volume of distilled water for injection ─────────────────────────── total volume 10 ml

Formulation Example 5: Ointment An ointment containing 100 mg of the active ingredient was prepared according to the following formulation. Compound of Example 1b 100 mg Collagen 10 mg Liquid paraffin 200 mg White petrolatum 700 mg PBS appropriate amount ─────────────────────── total amount 1.1 g

Formulation Example 6: Injection An injection containing 10 mg of the active ingredient was prepared according to the following formulation. Compound of Example 1b 10 mg hydroxyapatite 10 mg distilled water for injection qs ─────────────────────── total volume 10 ml

[0063]

Industrial Applicability The pyrazole derivative of the present invention and a medicament containing the same as an active ingredient have an action of specifically inhibiting eosinophils and prevent various eosinophil-related diseases while reducing side effects. Treatment can be given. Further, the eosinophil inhibitor, antiallergic agent and antiasthmatic agent of the present invention are useful for various eosinophil-related diseases.

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Tsutomu Nakamura 14 Shinomiya Minami-Kawaramachi, Yamashina-ku, Kyoto-shi, Kyoto Prefecture Within Kaken Pharmaceutical Co., Ltd. (72) Inventor Mitsuru Watanuki 14 Shinomiya Minami-Kawara-cho, Yamashina-ku, Kyoto, Kyoto, Japan Kaken Pharmaceutical Co., Ltd. (72) Inventor Kyoko Fujimoto Kyoto Prefecture, Kyoto City Kaken Pharmaceutical Co., Ltd.

Claims (7)

[Claims] 1. A compound of the general formula (I) (Wherein n is 2, 3 or 4; R ¹ is a hydrogen atom;
Alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 5 carbon atoms, a trifluoromethyl group or a halogen atom, a phenyl group optionally substituted by a nitro group or amino group, R ² is a hydrogen atom, a carbon An aliphatic acyl group having 2 to 5 carbon atoms, an aromatic acyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aralkyloxycarbonyl group, and 3 carbon atoms;
To 6 alkoxyoxalyl groups, aromatic sulfonyl groups or —C (＝ X) NHR ³ (where X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, an aralkyl group, an alkyl group having 1 to 4 carbon atoms) Group, aromatic acyl group, 5-7 carbon atoms
Cycloalkyl group having 2 to 5 carbon atoms, alkoxythiol group having 2 to 5 carbon atoms, alkenyloxycarbonyl group having 4 to 7 carbon atoms, aralkyloxycarbonyl group, alkoxy having 3 to 6 carbon atoms Carbonylalkyl group, aromatic sulfonyl group, naphthyl group or alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, halogen atom, trifluoromethyl group, trifluoro It is a phenyl group which may be substituted with a methoxy group, a carboxyl group, a nitro group, an amino group or an alkylthio group having 1 to 4 carbon atoms. ). A pharmaceutical comprising the pyrazole derivative represented by the formula (1) or a salt thereof as an active ingredient. 2. An eosinophil inhibitor comprising the pyrazole derivative represented by the general formula (I) according to claim 1 or a salt thereof as an active ingredient. 3. An anti-allergic agent comprising the pyrazole derivative represented by the general formula (I) according to claim 1 or a salt thereof as an active ingredient. 4. An anti-asthmatic agent comprising the pyrazole derivative represented by the general formula (I) according to claim 1 or a salt thereof as an active ingredient. 5. A compound of the formula (I ') (Wherein n is 2, 3 or 4; R ¹ is a hydrogen atom;
Alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 5 carbon atoms, a trifluoromethyl group or a halogen atom, a phenyl group optionally substituted by a nitro group or amino group, R ² is a hydrogen atom, a carbon An aliphatic acyl group having 2 to 5 carbon atoms, an aromatic acyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aralkyloxycarbonyl group, and 3 carbon atoms;
To 6 alkoxyoxalyl groups, aromatic sulfonyl groups or —C (＝ X) NHR ³ (where X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, an aralkyl group, an alkyl group having 1 to 4 carbon atoms) Group, aromatic acyl group, 5-7 carbon atoms
Cycloalkyl group having 2 to 5 carbon atoms, alkoxythiol group having 2 to 5 carbon atoms, alkenyloxycarbonyl group having 4 to 7 carbon atoms, aralkyloxycarbonyl group, alkoxy having 3 to 6 carbon atoms Carbonylalkyl group, aromatic sulfonyl group, naphthyl group or alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, halogen atom, trifluoromethyl group, trifluoro It is a phenyl group which may be substituted with a methoxy group, a carboxyl group, a nitro group, an amino group or an alkylthio group having 1 to 4 carbon atoms. ). Where n is 3, R ¹ and R ²
Are both hydrogen atoms, n is 2, R ¹ has 1 to ¹ carbon atoms.
An alkyl group of 4, R ² is a hydrogen atom, and n is 3, R ¹ is a hydrogen atom, R ² is —C (＝ S) NHR ³ , and R ³ is a trifluoromethyl group, a methoxy group or Excludes phenyl groups substituted with methylthio groups. Or a salt thereof. 6. The compound of the formula (I ′) wherein n is 3,
¹ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R ² is an aromatic acyl group or —C (＝ X) NHR ³ (where X is an oxygen atom or a sulfur atom, R ³ is an aralkyl group, an alkyl group having 1 to 4 carbon atoms, an aromatic acyl group,
C5-C7 cycloalkyl group, C2-C5 alkoxycarbonyl group, C4-C7 alkenyloxycarbonyl group, aralkyloxycarbonyl group, C3-C3
6 alkoxycarbonylalkyl group, aromatic sulfonyl group, naphthyl group or C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trifluoromethyl group ,
Trifluoromethoxy group, carboxyl group, nitro group,
A phenyl group which may be substituted with an amino group or an alkylthio group having 1 to 4 carbon atoms. The pyrazole derivative according to claim 5, or a salt thereof. 7. The compound of the formula (I ′) wherein R ² is —C (=
7. The pyrazole derivative or a salt thereof according to claim 6, wherein S) is NHR ³ and R ³ is an ethoxycarbonyl group.