JP2005119976A - Inhalant comprising quinoline derivative as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an inhalant of a 7-aminoquinoline derivative exhibiting therapeutic or prophylactic effects on respiratory diseases to the maximum by making an active ingredient directly act on an affected part or the periphery of the affected part. <P>SOLUTION: The inhalant for treating the respiratory diseases comprises the 7-aminoquinoline derivative represented by general formula (I) (wherein, R<SB>1</SB>is a hydrogen atom or an alkyl group; R<SB>2</SB>and R<SB>3</SB>are each a group selected from a hydrogen atom, an acyl group, an alkyl group or an alkenyl group; and R<SB>4</SB>and R<SB>5</SB>are each a group selected from a hydrogen atom, an acyl group, an alkyl group, an alkenyl group or an aralkyl group) or/and a physiologically acceptable salt thereof as an active ingredient. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to 7-aminoquinolinone derivatives or / and physiologically acceptable salts thereof effective for the treatment of respiratory diseases, and inhaled steroids, anticholinergic agents, inhaled β2 stimulants, The present invention relates to an inhalant for treating respiratory diseases comprising a drug with at least one selected from an anti-asthma agent, an anti-allergic agent, an anti-inflammatory agent, an antibacterial agent and an antifungal agent.

Conventionally, a drug containing a 7-aminoquinolinone derivative, which is a main component in the present invention, as an active ingredient is used for allergic diseases such as immediate asthma, delayed asthma, bronchial asthma, childhood asthma, hypersensitivity pneumonitis, atopic Treatment of diseases such as dermatitis, allergic contact dermatitis, hives, eczema, allergic conjunctivitis, allergic rhinitis, hay fever, food allergy, allergic gastroenteritis, allergic colitis, drug allergy, autoimmune diseases Or it is known that it is useful for prevention (refer patent document 1). The patent document also describes powders, granules, tablets and the like as preparation methods of the compound.
In addition, as a formulation method for 7-aminoquinolinone derivatives, there is a description of capsules, coated granules, coated tablets, or sugar-coated tablets having a light-shielding property (see Patent Document 2), while antioxidants and / or lubricants. A capsule, coated granule, coated tablet, or sugar-coated tablet containing an agent and having a light-shielding property is also known (see, for example, Patent Document 3).
All of the above-mentioned documents describe the treatment or prevention of diseases targeted by oral administration. However, such 7-aminoquinolinone derivatives and / or physiologically acceptable salts thereof are effective. Inhalants as components, 7-aminoquinolinone derivatives and / or physiologically acceptable salts and inhaled steroids, anticholinergics, inhaled β2 stimulants, antiasthma agents, antiallergic agents, anti-inflammatory Asthma including immediate asthma, delayed asthma, bronchial asthma, and childhood asthma, allergic rhinitis, hypersensitivity using an inhalant combined with one or more drugs selected from agents, antibacterial agents and antifungal agents A therapeutic agent for respiratory diseases such as pneumonitis, chronic bronchitis, and emphysema has not been known.
Japanese Patent No. 2947725 Japanese Patent Application Laid-Open No. 11-255694 Japanese Patent Application Laid-Open No. 2001-72593

  The problem to be solved by the present invention is that the active ingredient is directly applied to the affected area or the periphery of the affected area, thereby making it possible to maximize the treatment or prevention effect for respiratory diseases, It is to provide an inhalant of a 7-aminoquinolinone derivative.

As a result of intensive studies in order to achieve the above-mentioned problems, the present inventors have obtained a specific aminoquinolinone derivative, or an aminoquinolinone derivative and an inhaled steroid, an anticholinergic agent, an inhaled β2 stimulant, It has been found that an inhalant comprising a combination of one or more drugs selected from anti-asthma, anti-allergic, anti-inflammatory, antibacterial and antifungal agents is extremely useful as a therapeutic agent for respiratory diseases, The present invention has been completed.
That is, the present invention
Formula (I)

（式中、Ｒ_１は水素原子、又はアルキル基であり、Ｒ_２とＲ_３は、各々水素原子、アシル基、アルキル基、又はアルケニル基から選ばれる基であり、Ｒ_４とＲ_５は、各々、水素原子、アシル基、アルキル基、アルケニル基、又はアラルキル基から選ばれる基である。）で表される７−アミノキノリノン誘導体、又は／及び、その生理学的に許容される塩を有効成分とする呼吸器系疾患治療用吸入剤に関する。
また、本発明は、上記７−アミノキノリノン誘導体、又は／及び、その生理学的に許容される塩と吸入ステロイド剤、抗コリン剤、吸入β２刺激剤、抗喘息剤、抗アレルギー剤、抗炎症剤、抗菌剤および抗真菌剤から選ばれる１種以上の薬剤を含有してなる呼吸器系疾患治療用吸入剤に関する。

(Wherein R ₁ is a hydrogen atom or an alkyl group, R ₂ and R ₃ are each a group selected from a hydrogen atom, an acyl group, an alkyl group, or an alkenyl group, and R ₄ and R ₅ are Each of which is a group selected from a hydrogen atom, an acyl group, an alkyl group, an alkenyl group, or an aralkyl group.) And / or a physiologically acceptable salt thereof. The present invention relates to an inhalant for treating respiratory diseases as a component.
The present invention also provides the 7-aminoquinolinone derivative or / and physiologically acceptable salt thereof and an inhaled steroid, anticholinergic agent, inhaled β2 stimulant, antiasthma agent, antiallergic agent, anti-inflammatory. The present invention relates to an inhalant for treating respiratory diseases, comprising one or more agents selected from agents, antibacterial agents and antifungal agents.

  The present invention relates to 7-aminoquinolinone derivatives or / and physiologically acceptable salts thereof, as well as 7-aminoquinolinone derivatives or / and physiologically acceptable salts thereof and inhaled steroids, By providing an inhalant comprising, as an active ingredient, a combination of one or more drugs selected from choline agents, inhaled β2 stimulants, anti-asthma agents, anti-allergic agents, anti-inflammatory agents, antibacterial agents and antifungal agents An inhalant for treating respiratory diseases, which makes it possible to maximize the therapeutic effect or preventive effect on respiratory diseases by acting the active ingredient directly on the affected area or around the affected area. Can be provided.

  The 7-aminoquinolinone derivative in the present invention has the general formula (I)

（式中、Ｒ_１は水素原子、又はアルキル基であり、Ｒ_２とＲ_３は、各々水素原子、アシル基、直鎖状でも分枝状でもよいアルキル基、又はアルケニル基から選ばれる基であり、Ｒ_４とＲ_５は、各々、水素原子、アシル基、アルキル基、アルケニル基、又はアラルキル基から選ばれる基である。）で示されるものであり、それを主要成分として含有することにより呼吸器系疾患治療用吸入剤として有効に作用する。
本発明にいう呼吸器系疾患とは、即時型喘息、遅延型喘息、気管支喘息、小児喘息を含む喘息、アレルギー性鼻炎、過敏性肺臓炎、慢性気管支炎、肺気腫であることを特徴とする。

(In the formula, R ₁ is a hydrogen atom or an alkyl group, and R ₂ and R ₃ are groups selected from a hydrogen atom, an acyl group, an alkyl group which may be linear or branched, or an alkenyl group, respectively. R ₄ and R ₅ are each a group selected from a hydrogen atom, an acyl group, an alkyl group, an alkenyl group, or an aralkyl group.) By containing it as a main component Effectively acts as an inhaler for the treatment of respiratory diseases.
The respiratory disease referred to in the present invention is characterized by immediate asthma, delayed asthma, bronchial asthma, asthma including childhood asthma, allergic rhinitis, hypersensitivity pneumonitis, chronic bronchitis, emphysema.

The alkyl group in R _{1 to} R ₅ of the 7-aminoquinolinone derivative of the general formula (I) may be a linear or branched alkyl group. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an n-pentyl group, a hexyl group, an octyl group, and a decyl group, preferably carbon. Examples thereof include an alkyl group having 1 to 10, more preferably 1 to 8 carbon atoms.

R ₂ and R ₃ in the general formula (I) are a hydrogen atom, an acyl group, an alkyl group, or an alkenyl group. Examples of the acyl group include an alkanoyl group and a benzoyl group represented by a formyl group, an acetyl group, a propionyl group, a butyryl group, and the like. The benzoyl group may have a substituent, and examples thereof include a p-hydroxybenzoyl group, a p-methoxybenzoyl group, a 2,4-dihydroxybenzoyl group, and a 2,4-dimethoxybenzoyl group. An alkanoyl group is preferred, and an acetyl group is particularly preferred.
Examples of the alkenyl group of R ₂ and R ₃ may be linear or branched alkenyl groups such as vinyl group, propenyl group, hexenyl group, octenyl group, prenyl group, geranyl group, etc., preferably carbon The alkenyl group of several 2-10 is mentioned.

In the general formula (I), R ₄ and R ₅ are the same or different and are a hydrogen atom, an acyl group, an alkyl group, an alkenyl group, or an aralkyl group. Examples of the acyl group include an alkanoyl group represented by a formyl group, an acetyl group, a propionyl group, a butyryl group, a benzoyl group, a substituted benzoyl group, or an optionally substituted cinnamoyl group.
The substituted benzoyl group is, for example, a p-hydroxybenzoyl group, a p-methoxybenzoyl group, a 2,4-dihydroxybenzoyl group, a 2,4-dimethoxybenzoyl group, and the cinnamoyl group which may be substituted is For example, cinnamoyl group, 2-hydroxycinnamoyl group, 3-hydroxycinnamoyl group, 4-hydroxycinnamoyl group, 3,4-dihydroxycinnamoyl group, 4-hydroxy-3-methoxycinnamoyl group, 3-hydroxy- Examples include 4-methoxycinnamoyl group and 3,5-dimethoxy-4-hydroxycinnamoyl group. Preferably, an optionally substituted cinnamoyl group is used. As a quinolinone derivative having a cinnamoyl group having these substituents, 7- (3,5-dimethoxy-4-hydroxycinnamoylamino) -3-octyloxy-4-hydroxy-1-methyl-2 (1H) -quinolinone Is particularly preferred.

The alkenyl group of R ₄ and R ₅ may be a linear or branched alkenyl group, and examples thereof include a vinyl group, a propenyl group, a hexenyl group, an octenyl group, a prenyl group, and a geranyl group, preferably 2 carbon atoms. -10 alkenyl groups.
Examples of the aralkyl group of R ₄ and R ₅ include an aralkyl group of a benzyl group or a substituted benzyl group (for example, p-methoxybenzyl group, p-hydroxybenzyl group, etc.). In the present invention, a 7-aminoquinolinone derivative in which the substituents of R ₄ and R ₅ of the 7-aminoquinolinone derivative represented by the general formula (I) are the same substituents is also selected from the above group. Also included are 7-aminoquinolinone derivatives consisting of different combinations of groups.

The 7-aminoquinolinone derivative, which is an active ingredient of the therapeutic agent for respiratory system diseases of the present invention, can be produced by appropriately selecting a preferred production method depending on the intended 7-aminoquinolinone derivative. For example, it can be performed by the production method described in Japanese Patent No. 2943725 or US Pat. No. 6,136,822.
As an example, a method according to US Pat. No. 6,136,822 will be described.
Formula (II)

で表されるアミド誘導体と塩基性物質とを反応させ、分子内環化反応を行う。

Is reacted with a basic substance to carry out an intramolecular cyclization reaction.

（式中、Ｒ₆は水素原子、アルキル基、水酸基を有するアルキル基、アルケニル基、又はアリール基であり、Ｒ₇はアルキル基、アルケニル基、アリール基、又はアラルキル基であり、Ｒ₈は反応性カルボキシル基であり、Ｒ₉、Ｒ₁₀及びＲ₁₂は、水素原子であり、Ｒ₁₁は、Ｒ₁₃Ｒ₁₄Ｎ-(ここで、Ｒ₁₃とＲ₁₄は各々独立に、水素原子、アルキル基、アルケニル基、アラルキル基、又はアシル基を表わす）を表わす。)

Wherein R ₆ is a hydrogen atom, an alkyl group, an alkyl group having a hydroxyl group, an alkenyl group, or an aryl group, R ₇ is an alkyl group, an alkenyl group, an aryl group, or an aralkyl group, and R ₈ is a reaction R ₉ , R ₁₀ and R ₁₂ are hydrogen atoms, R ₁₁ is R ₁₃ R ₁₄ N— (wherein R ₁₃ and R ₁₄ are each independently a hydrogen atom or an alkyl group) Represents an alkenyl group, an aralkyl group, or an acyl group).

Examples of the basic substance include various compounds such as alkali metal, alkali metal alkoxide, alkaline earth metal alkoxide, alkali metal hydride, alkaline earth metal hydride, and alkali metal amide.
For example, an alkali metal such as sodium or potassium is used as the alkali metal, and a basic substance such as methoxy sodium, ethoxy sodium, t-butoxy sodium or t-butoxy potassium is used as the alkaline earth metal alkoxide as the alkali metal alkoxide. Examples thereof include methoxymagnesium, ethoxymagnesium, t-butoxymagnesium, methoxycalcium, ethoxycalcium, t-butoxycalcium, methoxybarium, ethoxybarium, and t-butoxybarium.
Examples of the alkali metal hydride include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, and examples of the alkaline earth metal hydride include alkaline earth metal hydrides such as calcium hydride. be able to. Furthermore, examples of the alkali metal amide include lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.

  Moreover, although the quantity of the basic substance required for cyclization reaction can be normally used 1-5 times mole with respect to the amide derivative made to react, 2-3 times mole is preferable. For example, when sodium hydride, t-butoxypotassium, or lithium diisopropylamide is used as the basic substance, it is usually sufficient to use twice the amount of the amide derivative.

Reaction in the manufacturing method of said 7-amino quinolinone derivative is performed in the organic solvent which does not inhibit reaction. Examples of the organic solvent used here include hydrocarbon solvents such as benzene and toluene, alcohol solvents such as methanol, ethanol, propanol, isopropanol, and t-butanol, diethyl ether, tetrahydrofuran, and 1,2-dimethoxyethane. Examples include ether solvents, amide solvents such as N, N-dimethylformamide and 1-methyl-2-pyrrolidinone.
The preferred organic solvent varies depending on the type of basic substance to be used. For example, in the case of an alkali metal alkoxide, an alcohol solvent is generally preferred. When an alkali metal amide such as lithium amide, sodium amide, or potassium amide is used, Ammonia can be used as a solvent.

  While the reaction temperature varies depending on the basic substance used and the type of reaction solvent, it is generally -80 ° C to 100 ° C, preferably -50 ° C to 50 ° C, and the reaction time is usually 1 to 5 hours. .

  Specific examples of the 7-aminoquinolinone derivative represented by the general formula (I) of the present invention thus obtained include compounds shown in the following table.

The present invention also includes physiologically acceptable salts of these compounds.
The physiologically acceptable salt as used herein is an alkaline addition salt having no toxicity with respect to those having a hydroxyl group at the 3-position and / or 4-position among the compounds shown above, for example, Non-toxic salts such as sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, non-toxic amine salt and the like can be mentioned. These can be produced by known conventional methods.
For those having no hydroxyl group, the amino group of the aromatic ring is replaced with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or various organic acids such as acetic acid, propionic acid, succinic acid, tartaric acid, maleic acid. Examples of fumaric acid and sulfonic acids include non-toxic addition salts such as methanesulfonic acid, and these can be produced by a known and conventional method.

The respiratory disease in the present invention refers to immediate asthma, delayed asthma, bronchial asthma, asthma including childhood asthma, allergic rhinitis, irritable pneumonitis, chronic bronchitis and emphysema. Quinolinone derivatives have been shown to be effective against these diseases (Patent Document 1 and Patent Document 4 described above). For example, as shown in (Reference Example 1) described in Patent Document 1, high efficacy has been confirmed in an orally administered guinea pig asthma model, and the acute toxicity test in mice described in Patent Document 1 As shown in the results, the 50% lethal dose (LD ₅₀ : mg / kg) is 1000 mg / kg, and extremely high safety has been confirmed.
Such a preparation method of 7-aminoquinolinone derivative, or a physiologically acceptable salt thereof, which has been confirmed to be effective and safe, has been conventionally used as a tablet, capsule, granule, fine granule, powder, lozenge. , Sublingual tablets, injections, emulsions, suspensions, syrups and the like (see Patent Document 1, Patent Document 2, Patent Document 3, or Patent Document 4), and these are active ingredients throughout the body. It has the characteristic of expressing an effect by acting. However, in the inhalant in the present invention, the effect is expressed at the minimum effective amount by causing the drug to act locally on or around the affected part, and compared with the drug acting on the whole body, By reducing the amount of exposure, it is possible to reduce the burden on the patient and to exhibit excellent effects.

  The inhalant for treating respiratory diseases according to the present invention includes not only inhalers containing 7-aminoquinolinone derivatives and / or physiologically acceptable salts thereof as active ingredients, but also 7-aminoquinolinone derivatives. And / or a physiologically acceptable salt thereof and an inhaled steroid, an anticholinergic agent, an inhaled β2 stimulant, an antiasthma agent, an antiallergic agent, an antiinflammatory agent, an antibacterial agent and an antifungal agent It also includes an inhalant formed by combining the above drugs. Examples of the drugs used in combination include anticholinergic drugs such as ipratropium bromide, oxytropium bromide, and flutropium bromide, inhaled β2 stimulants such as fenoterol, subtamol, procaterol, and formoterol, beclomethasone, fluticasone, budesonide Such as inhaled steroids, theophylline, ketotifen, anti-asthmatic agents such as azelastine, anti-allergic agents such as ketotifen, terfenadine, azelastine, epinastine, anti-inflammatory agents such as diclofenac sodium, ibuprofen, indomethacin, cefixime, cefdinir, ofloxacin, tosufloxacin, etc. Antifungal agents such as antibacterial agents, itraconazole, fluconazole and the like can be mentioned, but are not limited thereto. Moreover, these chemical | medical agents can be used with a suitable compounding ratio suitably.

The inhalant according to the present invention comprises a preparation containing an additive in addition to the above main components. As the additive at that time, an additive generally used for an inhalation preparation can be used.
Such additives include, for example, non-toxic excipients, binders, disintegrants, lubricants, preservatives, antioxidants, isotonic agents, dispersants, buffers that are commonly used for this type of drug. It can be formulated by a known method using additives such as a corrigent, a stabilizer, a propellant and a colorant. Specific examples of these non-toxic additives are listed below, but are not limited thereto.
First, as excipients, starch and derivatives thereof (dextrin, carboxymethyl starch, etc.), cellulose and derivatives thereof (methyl cellulose, hydroxypropylmethyl cellulose, etc.), sugars (lactose, sucrose, glucose etc.), silicic acid and silicates (Natural aluminum silicate, magnesium silicate, etc.), carbonates (calcium carbonate, magnesium carbonate, sodium bicarbonate, etc.), aluminum hydroxide / magnesium, synthetic hydrotalcite, polyoxyethylene derivatives, glyceryl monostearate, monoolein Examples include acid sorbitan.

As binders, starch and derivatives thereof (pregelatinized starch, dextrin, etc.), cellulose and derivatives thereof (ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, etc.), gum arabic, tragacanth, gelatin, sugars (glucose, sucrose, etc.), Examples include ethanol and polyvinyl alcohol.
Disintegrators include starch and derivatives thereof (carboxymethyl starch, hydroxypropyl starch, etc.), cellulose and derivatives thereof (sodium carboxymethylcellulose, crystalline cellulose, hydroxypropylmethylcellulose, etc.), carbonates (calcium carbonate, calcium bicarbonate, etc.), Examples include tragacanth, gelatin, and agar.

  Lubricants include stearic acid, calcium stearate, magnesium stearate, talc, silicic acid and salts thereof (light anhydrous silicic acid, natural aluminum silicate, etc.), titanium oxide, calcium hydrogen phosphate, dry aluminum hydroxide gel, Examples include macro goals.

  Preservatives include paraoxybenzoates, sulfites (sodium sulfite, sodium pyrosulfite, etc.), phosphates (sodium phosphate, calcium polyphosphate, sodium polyphosphate, sodium metaphosphate, etc.), alcohols (chlorobutanol, Benzyl alcohol, etc.), benzalkonium chloride, benzethonium chloride, phenol, cresol, chlorocresol, dehydroacetic acid, sodium dehydroacetate, glycerin sorbate, saccharides and the like.

Antioxidants include sulfites (sodium sulfite, sodium bisulfite, etc.), Rongalite, erythorbic acid, L-ascorbic acid, cysteine, thioglycerol, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, ascorbyl palmitate, dl-α-tocopherol and the like.
Examples of isotonic agents include sodium chloride, sodium nitrate, potassium nitrate, dextrin, glycerin, glucose and the like.

Examples of the buffer include sodium carbonate, hydrochloric acid, boric acid, phosphate (such as sodium hydrogen phosphate) and the like.
Examples of the corrigent include sugars (glucose, sucrose, lactose, etc.), sodium saccharin, sugar alcohols and the like.
Examples of the dispersant include gum arabic, tragacanth, cellulose derivatives (such as methylcellulose), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, sorbitan fatty acid esters, and the like.
Examples of the stabilizer include sulfites (such as sodium bisulfite), nitrogen, carbon dioxide and the like.

  When the preparation containing the additive of the present invention is used as an inhalant, it is converted into a powder inhaler, a capsule inhaler, a solution inhaler, a suspension inhaler, or a jet inhaler by a known method. Although it can be applied using an appropriate inhaler at the time of use, a powdery inhalant is particularly preferable. The average particle size of the powdered inhalant in the present invention is not particularly limited, but is preferably about 0.1 to about 10 μm, particularly preferably about 1 to about 5 μm. In inhalation, for example, administration can be performed using an inhaler such as a spin heller, a disk heller, a tabu heller, a jet heller, or a jet slicer.

  As for the capsule inhaler, the above powder inhaler can be enclosed in a capsule container usually used for inhalation preparations and administered using a small inhaler such as a spin heller, jet heller, jet ricer or the like according to a conventional method.

Moreover, the solution-form inhalant or suspension inhaler of this invention can be used for the inhalation therapy by a nebulizer. The solution inhalant can be adjusted according to a conventional method, and the active ingredient may be dissolved in a liquid carrier. Examples of the liquid carrier include water, salt water, organic solvent, and the like, but water is preferred. In addition, polyethylene glycol having a molecular weight of 200 to 5,000, polyoxyethylene (20) sorbitan monooleate, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like can be appropriately added upon dissolution. The suspension inhalant can be adjusted according to a conventional method, and the active ingredient may be suspended in a liquid carrier. Examples of the carrier include commonly used water, salt water, and organic solvents. Water is preferred.
Nebulizers are classified into jet (pressurized) nebulizers and ultrasonic nebulizers, but the preparations of the present invention can be used for either nebulizer, and these do not require synchronization with inhalation, so infants and elderly The present invention is also useful for the treatment of a person under further artificial respiration management without spontaneous breathing.

Further, as the injection type inhalant, the above-mentioned drug can be used as a so-called aerosol agent. An aerosol agent is a device that adds a drug together with a dispersing agent or the like into liquid chlorofluorocarbon gas that is a propellant, fills it in a small portable container as a suspension, and generates an aerosol when released from the container. The components of the aerosol agent are a content liquid and a device. The content liquid is composed of the aforementioned medicine and propellant, and the device portion is composed of a container, a metering valve and an actuator. The manufacture of an aerosol is usually composed of two steps: a content preparation step, a content, and a propellant filling step. . Aerosols are excellent in portability and can be used quickly in emergencies such as seizures.
Examples of such propellants include liquefied gas propellants and compressed gases. As the liquefied gas propellant, for example, fluorinated hydrocarbons such as CFC-11, CFC-12, CFC-114, HCFC-123, HCFC-134a, liquefied petroleum, dimethyl ether and the like are used. As the compressed gas, for example, a soluble gas such as carbon dioxide gas or nitrous oxide gas, an insoluble gas such as nitrogen gas, or the like can be used.

The content of the 7-aminoquinolinone derivative represented by the above general formula and / or physiologically acceptable salt thereof in the inhalant of the present invention varies depending on the dosage form, but is generally 0. It is desirable to contain it at a concentration of 01 to 100% by weight, preferably 0.01 to 50% by weight.
The amount of the inhalant of the present invention to be administered as a therapeutic agent for respiratory diseases can vary widely depending on the type of warm-blooded animals including human beings, the severity of symptoms, and judgment of a doctor. In general, the effective ingredient is 0.01 to 50 mg per person per day, preferably 0.1 to 10 mg.

  Next, although an Example and a reference example demonstrate this invention concretely, the range of this invention is not limited by the range of this Example from the first.

(Reference Example 1) (Pharmacological action of the compound of the present invention)
In order to clarify the pharmacological action of the compound of the present invention,
The result of the medicinal effect test by the antigen-induced immediate type and delayed type respiratory tract reaction by oral administration as described in FIG. This test is an animal test model for asthma. Test method: Using an ultrasonic nebulizer (NE-U12, OMRON Corporation) in a guinea pig, OVA (1%) was inhaled for 10 minutes a day for 8 consecutive days for sensitization. One week after the final sensitization, OVA (2%) was inhaled for 5 minutes using an ultrasonic nebulizer. Metyrapon (10 mg / kg) was administered intravenously 24 hours before and 1 hour before the challenge, and pyrilamine (10 mg / kg) was administered intraperitoneally 30 minutes before the challenge. Measurement is performed using an airway resistance measuring device (Pulmos-I, MIPS Co., Ltd.) 1 minute after induction, 2, 4, 5, 6, 7 and 8 hours, and further once every 23-24 hours for 1 minute each. did. The test substance was orally administered twice 1 hour before the antigen challenge and 3 hours after the antigen challenge. The positive control substance (prednisolone) was orally administered twice 16 hours before and 2 hours before. The results of this reference example were calculated as inhibition rate (%) by comparison with the solvent control group and are shown in Table-19. In the test, 8 guinea pigs per group were used.

As the test results show, it is clear that the compound of the present invention has an inhibitory effect on immediate and delayed asthma that is almost equal to or higher than that of prednisolone.

(Example 1) (Preparation of pulverized product)
17 kg of Compound 551 was pulverized with a single track jet mill (STJ-200, Seishin Enterprise) to obtain 15.6 kg of pulverized product having an average particle size of 4.2 μm.
Grinding conditions Nozzle pressure (MPa): 0.15
Used air volume (m ³ / min): 0.8
Supply amount (kg / hr): 3.0

Example 2 (Solution Inhalant)
(1) Compound 551 40.0 mg
(2) Polyoxyethylene (20) sorbitan monooleate 2.0 g
(3) Purified water 1000.0 g
Compound 551 pulverized in Example 1 and polyoxyethylene (20) sorbitan monooleate of the above components were mixed with purified water to prepare a 0.2% w / w aqueous solution, and compound 551 was further mixed. An inhalation solution was obtained. This inhalation solution is applied using a nebulizer according to standard methods.

(Example 3) (Suspension inhalant)
(1) Compound 551 20.0 mg
(2) HCFC-123 1560.0 mg
(3) HCFC-134a 2400.0 mg
(4) Sorbitan trioleate 20.0 mg
Compound 551 pulverized in Example 1 and the above components were mixed to obtain a suspension for inhalation. This inhalation suspension is made into an aerosol according to a conventional method and applied.

Example 4 (powdered inhalant)
(1) Compound 551 30.0 g
(2) Lactose 270.0 g
Compound 551 pulverized in Example 1 and the above components were mixed to obtain a powder inhaler. This powder inhaler is applied using a small inhaler such as a disc heller or tabuherer according to a conventional method.

Example 5 (capsule inhalant)
(1) Compound 551 30.0 g
(2) Lactose 270.0 g
Compound 551 pulverized in Example 1 and the above components were mixed, and 30 mg of the mixture was filled into No. 2 capsules in one capsule to obtain a capsule inhalant. This capsule inhalant is applied using a small inhaler such as a spin heller, jet heller, jet ricer or the like according to a conventional method.

  7-aminoquinolinone derivative of the present invention or / and physiologically acceptable salt thereof, and 7-aminoquinolinone derivative or / and physiologically acceptable salt thereof and inhaled steroid, anticholine An inhalant comprising as an active ingredient a combination of one or more drugs selected from agents, inhaled β2 stimulants, anti-asthma agents, anti-allergic agents, anti-inflammatory agents, antibacterial agents and antifungal agents is used for respiratory diseases It can be used medically as a therapeutic agent.

Claims (24)

Formula (I)

(Wherein R ₁ is a hydrogen atom or an alkyl group, R ₂ and R ₃ are each a group selected from a hydrogen atom, an acyl group, an alkyl group, or an alkenyl group, and R ₄ and R ₅ are Each is a group selected from a hydrogen atom, an acyl group, an alkyl group, an alkenyl group, or an aralkyl group.)
An inhalant for the treatment of respiratory diseases, comprising as an active ingredient a 7-aminoquinolinone derivative represented by the formula: and / or a physiologically acceptable salt thereof. The 7-aminoquinolinone derivative or / and physiologically acceptable salt thereof according to claim 1, wherein R ₁ is a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms. An inhalant for treating respiratory diseases as a component. R ₂ and R ₃ are each a hydrogen atom, an acyl group, a linear or branched alkyl group having 1 to 10 carbon atoms, or a linear or branched alkenyl group having 2 to 10 carbon atoms. An inhalant for treating respiratory diseases, comprising the 7-aminoquinolinone derivative or / and physiologically acceptable salt thereof as an active ingredient. R ₄ and R ₅ are each a hydrogen atom, an acyl group, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkenyl group having 2 to 10 carbon atoms, or an aralkyl group. An inhalant for treating respiratory diseases, comprising the 7-aminoquinolinone derivative according to claim 1 and / or a physiologically acceptable salt thereof as an active ingredient. R ₁ is a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms, and R ₂ and R ₃ are each a hydrogen atom, an acyl group, a linear or branched carbon atom having 1 to 10 carbon atoms. An alkyl group, or a linear or branched alkenyl group having 2 to 10 carbon atoms, wherein R ₄ and R ₅ are each a hydrogen atom, an acyl group, a linear or branched alkyl group having 1 to 10 carbon atoms, Or a straight-chain or branched alkenyl group having 2 to 10 carbon atoms or an aralkyl group, or the 7-aminoquinolinone derivative according to any one of claims 1 to 4, and / or a physiologically acceptable product thereof. An inhalant for the treatment of respiratory diseases, comprising a salt as an active ingredient. The R ₂ is a hydrogen atom, and the R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms or a linear or branched alkenyl group having 2 to 10 carbon atoms. 7. -An inhalant for treating respiratory diseases, comprising an aminoquinolinone derivative and / or a physiologically acceptable salt thereof as an active ingredient. The R ₂ is a linear or branched alkyl group having 1 to 10 carbon atoms or a linear or branched alkenyl group having 2 to 10 carbon atoms, and R ₃ is a hydrogen atom. 7. -An inhalant for treating respiratory diseases, comprising an aminoquinolinone derivative and / or a physiologically acceptable salt thereof as an active ingredient. R ₄ is a hydrogen atom, R ₅ is a hydrogen atom, an acyl group, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkenyl group having 2 to 10 carbon atoms, or an aralkyl. An inhalant for treating respiratory diseases comprising the 7-aminoquinolinone derivative according to any one of claims 6 to 7 and / or a physiologically acceptable salt thereof as an active ingredient. 9. An inhalant for treating respiratory diseases, comprising as an active ingredient the 7-aminoquinolinone derivative according to claim 8, wherein R ₅ is an acyl group, and / or a physiologically acceptable salt thereof. Respiration containing as an active ingredient a 7-aminoquinolinone derivative according to claim 9 and / or a physiologically acceptable salt thereof, wherein R ₅ is an acyl group comprising a cinnamoyl group which may have a substituent. Inhalant for treatment of systemic diseases. The 7-aminoquinolinone derivative according to claim 10, wherein R ₅ is a 4-hydroxy-3-methoxycinnamoyl group or a 3,5-dimethoxy-4-hydroxycinnamoyl group, and / or a physiological thereof An inhalant for the treatment of respiratory diseases comprising a salt acceptable as an active ingredient. The 7-aminoquinolinone derivative is 7- (3,5-dimethoxy-4-hydroxycinnamoylamino) -3-octyloxy-4-hydroxy-1-methyl-2 (1H) -quinolinone, The inhalant for treating respiratory diseases according to claim 1. The 7-aminoquinolinone derivative according to claim 1 and / or a physiologically acceptable salt thereof, an inhaled steroid, an anticholinergic agent, an inhaled β2 stimulant, an antiasthma agent, an antiallergic agent, an antiallergic agent, An inhalant for treating respiratory diseases, comprising a combination of one or more agents selected from inflammatory agents, antibacterial agents and antifungal agents. The respiratory system disease therapeutic agent according to claim 1, wherein the respiratory system disease inhaler is a powdered inhaler. The therapeutic agent for respiratory system diseases according to claim 14, wherein the powder inhalant has an average particle size of about 0.1 to about 10 µm. The respiratory system disease therapeutic agent according to claim 1, wherein the respiratory system disease inhalant is an aerosol. The respiratory system disease therapeutic agent according to claim 1, wherein the respiratory system disease inhalant is a liquid inhalant. The respiratory system disease therapeutic agent according to claim 1, wherein the respiratory system disease inhaler is a suspended inhalant. 14. The therapeutic agent for respiratory system diseases according to claim 1, wherein the inhalation agent for respiratory system disease treatment is a capsule inhalation agent. The respiratory system disease inhaler according to any one of claims 1 to 19, wherein the respiratory disease is asthma including immediate asthma, delayed asthma, bronchial asthma, and childhood asthma. The respiratory system disease treatment inhalant according to claim 1, wherein the respiratory system disease is allergic rhinitis. The respiratory system disease inhaler according to claim 1, wherein the respiratory system disease is hypersensitivity pneumonitis. The respiratory system disease inhaler according to claim 1, wherein the respiratory system disease is chronic bronchitis. The respiratory system disease inhaler according to claim 1, wherein the respiratory system disease is pulmonary emphysema.