WO2001089512A1

WO2001089512A1 - Drugs acting on the bronchi

Info

Publication number: WO2001089512A1
Application number: PCT/JP2001/004352
Authority: WO
Inventors: Yasuko Ashida; Mitsuru Shiraishi; Tatsumi Matsumoto; Kenichirou Kiyoshima
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 2000-05-26
Filing date: 2001-05-24
Publication date: 2001-11-29
Also published as: AU2001260611A1

Abstract

Drugs acting on the bronchi which contain quinone derivatives (Ia), hydroquinones derived therefrom, or salts thereof can exert the effects (including antiasthmatic effect) of the derivatives, the hydroquinones, or the salts specifically on the bronchi or the peripheral tissue thereof. Thus, the drugs permit topical administration in a minimal effective dose to thereby avoid systemic administration of the derivatives (Ia), the hydroquinones, or the salts in a large dose. (Ia) [In the general formula (Ia), R?1 and R2¿ are each methyl or methoxy, or alternatively R?1 and R2¿ may be united to form -CH=CH-CH=CH-; R3 is optionally substituted phenyl, naphthyl, or thienyl; R4 is carboxyl or a group which can be converted into carboxyl in vivo; and n is an integer of 3 to 15.]

Description

Description Bronchial agents Technical field

TECHNICAL FIELD The present invention relates to a bronchoactive agent comprising a quinone derivative or a hydroquinone derivative thereof. Background art

General formula (Ia)

Wherein either indicating each R ¹ and R ² are methyl or main butoxy group, bonded Ri and R ² together may indicate R ¹ and R ² in one CH = CH- CH two CH- R ³ represents an optionally substituted phenyl, naphthyl or phenyl group; R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo; and n represents an integer of 3 to 15. It is described that the quinone derivative represented by the formula or a compound containing a hydroquinone derivative thereof is useful as an anti-asthmatic agent, an anti-allergic agent or a cerebral circulatory system improving agent.

JP-A-63-101322 discloses that the compound (la) or a hydroquinone derivative thereof has a thromboxane A ₂ receptor antagonistic activity, and is an antithrombotic agent, an anti-vasoconstrictor, an anti-vasoconstrictor. It is described as being useful as an anti-hypertensive, anti-asthmatic or anti-atherosclerosis.

EP 645 137 describes that the compound (la) or its hydroquinone compound is useful as an antiallergic rhinitis agent.

EP 711 9552 describes that the compound (la) or its hydroquinone compound is useful as an anti-dermatitis agent. US Pat. No. 6,020,380 describes that the compound (la) or its hydroquinone is useful as a therapeutic agent for COPD.

Further, there has been a demand for the development of a preparation which can locally exert the action of the quinone derivative (la) or its hydroquinone derivative. Disclosure of the invention

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, by using the quinone derivative ( _Ia ) or its hydroquinone derivative as an inhalant or the like, the action of the derivative is locally applied to the bronchi. The present inventors have found that the present invention can be fully demonstrated, and as a result of conducting research based on these findings, they have completed the present invention.

That is, the present invention

(1) General formula (la):

(In the formula, R ¹ and R ² each represent a methyl group or a methoxy group, or Ri and R 2 may be bonded to each other to represent one CH = CH_CH = CH—, and R ³ may be substituted. R ⁴ represents a carboxyl group or a group capable of being converted into a carboxyl group in a living body, and n represents an integer of 3 to 15. A bronchoactive agent comprising a quinone derivative represented by the formula:

(2) The agent according to (1), wherein Ri and R ² are each a methyl group,

(3) R ³ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a halogen group, a hydroxyl group, a methyl group which may be substituted with methylenedioxy or trifluoromethyl. (1) the agent according to the above,

(4) The agent according to (1), wherein R ³ is a phenyl group which may be substituted with at least one substituent selected from a lower alkyl group and a halogen, (5) R3 is a phenyl group, a 3-phenololenophenyl group, a 4-phenololephenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-phenyl group or a 3-phenyl group; 1) The agent according to the above,

(6) The agent according to the above (1), wherein R ⁴ is a carboxyl group or a hydroxymethyl group,

(7) The agent according to (1), wherein n is an integer of 5 to 9,

(8) The agent according to the above (1), wherein the quinone derivative is 7_ (3,5,6_trimethyl-11,4-benzoquinone-12-yl) -17-phenylheptanoic acid,

(9) General formula (l a):

[Wherein, either R ¹ and R ² each represents a methyl group or main butoxy group, may indicate _CH = CH- CH = CH_ bonded to Ri and R ² together with R ¹ and R ^2, R ³ represents a phenyl, naphthyl or phenyl group which may be substituted, R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo, and n represents an integer of 3 to 15. Selected from the group consisting of quinone derivatives, their hydroquinone derivatives or salts thereof, anticholinergics, inhaled 02 stimulants, inhaled steroids, antiasthmatics, antiallergic agents, antiinflammatory agents, antibacterial agents and antifungal agents A bronchoactive agent in combination with one or more drugs

(10) Anti-asthmatic agent, Chronic obstructive pulmonary disease (COPD) prophylaxis / therapeutic agent, hypersensitivity pneumonitis prevention / therapeutic agent or eosinophilic pneumonia prevention / therapeutic agent (1) or (9) Agent described in item,

(11) The agent according to the above (1) or (9), which is a prophylactic or therapeutic agent for chronic obstructive pulmonary disease (COPD),

(1 2) The agent according to (1) or (9), which is a bronchial inhaler,

(13) The agent according to (12), which is a powder inhalant,

(1 4) Average particle diameter of about 0.1 to about ₂₀ μ ιη first (1 3) above, wherein the agent, (15) For the mammal's mouth or throat, general formula (la):

[Wherein, either R ¹ and R ² each represents a methyl group or main butoxy group, may indicate _CH = CH- CH = CH_ bonded to Ri and R ² together with R ¹ and R ^2, R ³ represents a phenyl, naphthyl or phenyl group which may be substituted, R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo, and n represents an integer of 3 to 15. Asthma, chronic obstructive pulmonary disease (COPD), hypersensitivity, characterized by direct local administration of an effective amount of a bronchoactive agent comprising a quinone derivative represented by the formula: Prevention and treatment of pneumonitis or eosinophilic pneumonia,

(16) For the mammal's mouth or throat, the general formula (la):

Wherein R ¹ and R ² are either a methyl group or main butoxy group, attached R ¹ and R ² are each other show an CH = CH_CH = CH- by R ¹ and R2 consentration, R ³ represents a phenyl, naphthyl or phenyl group which may be substituted, R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo, and n represents an integer of 3 to 15. Quinone derivatives or their hydroquinone derivatives or salts thereof with anticholinergics, inhaled β2-agonists, inhaled steroids, antiasthmatics, antiallergic agents, antiinflammatory agents, antibacterial agents and antifungal agents Asthma, chronic obstructive pulmonary disease (COPD), irritable pneumonitis or eosinophilic pneumonia, characterized by the direct local administration of a drug in combination with one or more selected drugs Prevention and treatment of (17) General formula (la) for producing a preventive or therapeutic agent for asthma, chronic obstructive pulmonary disease (COPD), irritable pneumonitis or eosinophilic pneumonia:

Wherein either indicating each R ¹ and R ² are methyl or main butoxy group, may indicate R ¹ and one R ² CH = CH- CH = CH- attached Ri and R ² to each other R ³ represents an optionally substituted phenyl, naphthyl or phenyl group; R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo; and n represents an integer of 3 to 15. Use of a bronchoactive agent comprising a quinone derivative represented by the formula (I), a hydroquinone derivative thereof or a salt thereof, and

(18) General formula (la) for producing a preventive and therapeutic agent for asthma, chronic obstructive pulmonary disease (COPD), irritable pneumonia or eosinophilic pneumonia:

[In the formula, R ¹ and R ² each represent a methyl group or a methoxy group, or R ¹ and scale ² are bonded to each other to form 1 ^ and 1 ^ ² _〇11 =? 1_j 11 = j 11_, R ³ represents an optionally substituted phenyl, naphthyl or phenyl group, and R ⁴ represents a carbonyl group or a group capable of being converted to a carboxyl group in vivo. , N represents an integer of 3 to 15. A quinone derivative represented by the formula: Hydroquinone; selected from the body or its salts and anticholinergics, inhaled β2-agonists, inhaled steroids, antiasthmatics, antiallergic agents, antiinflammatory agents, antibacterial agents and antifungal agents The use of a broncho-active agent in combination with one or more other drugs is provided. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the correlation between the turntable rotation speed and the concentration of no Compound A in the suction chamber. The horizontal axis shows the turntable rotation speed, and the vertical axis shows the concentration of compound A in the suction chamber.

FIG. 2 shows the dose dependence of blood and lung tissue concentrations during inhaled administration of Compound A. The horizontal axis shows the concentration of Compound A in the inhalation chamber, and the vertical axis shows the concentration of Compound A in plasma (〇plasma) and lung tissue.

FIG. 3 shows the dose dependence of blood and lung tissue concentrations in oral administration of Compound A. The horizontal axis shows the oral dose of Compound A, and the vertical axis shows the concentration of Compound A in plasma (〇 plasma) and lung tissue (Qin lung).

FIG. 4 shows the inhibitory effect of inhaled administration of compound A on the airway constriction response induced by U-46619. The horizontal axis shows the turntable rotation speed, and the vertical axis shows the airway stenosis reaction (0 to 10 minutes after the end of inhalation: the area under the reaction curve for 10 minutes).

FIG. 5 shows the inhibitory effect of oral administration of compound A on the airway constriction response induced by U-46619. The horizontal axis shows the oral dose of Compound A, and the vertical axis shows the airway constriction reaction (0 to 10 minutes after the end of inhalation, the area under the reaction curve).

FIG. 6 shows the airway constriction response inhibitory effect and the blood and lung tissue concentrations after administration of Compound A by inhalation. The horizontal axis indicates the elapsed time after inhalation of Compound A, the vertical axis (left) indicates the inhibition rate of airway stenosis response, and the vertical axis (right) indicates plasma (A plasma) and lung tissue concentration of compound A (Qin lung). .

FIG. 7 shows the inhibitory effect of airway administration of Compound A on airway stenosis and blood and lung tissue concentrations. The horizontal axis shows the elapsed time after oral administration of Compound A, the vertical axis (left) shows the rate of inhibition of airway stenosis response, and the vertical axis (right) shows plasma (A plasma) and lung tissue concentration (lung) of compound A. Show.

FIG. 8 shows the inhibitory effect of inhaled administration of Compound A on the airway constriction response induced by antigen in sensitized guinea pigs. The horizontal axis shows the elapsed time after the antigen-induced, and the vertical axis shows the P enh increase rate.

FIG. 9 shows the inhibitory effect of oral administration of Compound A on the airway constriction response induced by antigen in sensitized guinea pigs. The horizontal axis shows the elapsed time after the antigen-induced, and the vertical axis shows the Penh increase rate. BEST MODE FOR CARRYING OUT THE INVENTION

In the general formula (la), preferably, R i and R ² are both methyl groups.

As the naphthyl group represented by R ³ , a 1- or 2-naphthyl group is used, and as the phenyl group, 2- or 3-phenyl is used.

R ³ is preferably an optionally substituted phenyl or phenyl group, more preferably a phenyl group.

Each of the phenyl, naphthyl and chelyl groups represented by R ³ may have 1 to 3 substituents at any position on the ring. Examples of such a substituent include a lower alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, etc.), a lower alkoxy group having 1 to 4 carbon atoms. (Eg, methoxy, ethoxy, n-propoxy, i-propoxy, etc.), halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, etc.), hydroxyl group, methylenedioxy group, trifluoromethyl group, etc. Can be As the substituent, a lower alkyl group and a halogen atom are particularly preferable, and a fluorine atom and a methyl group are more preferable.

R ³ is particularly preferably a phenyl group, a 3_ or 4-methylphenyl group, a 3- or 4-monofluorophenyl group, a 2-phenyl group or a 3-phenyl group.

The group convertible to a carboxyl group in vivo represented by R ^4, for example, methylation group, an optionally substituted arsenide Dorokishimechiru group, the carboxyl group which may be esterified or amino-de-reduction used .

Examples of the optionally substituted hydroxymethyl group include, in addition to an unsubstituted hydroxymethyl group, for example, a methoxymethyloxy group, an acetyloxymethyl group, a nitroxymethyl group, and an aminoaminocarbonyloxymethyl group.

Examples of the esterified carboxyl group include a lower phenolic phenol group having 2 to 8 carbon atoms (eg, methoxycarbonyl, ethoxycarbinole, benzyloxycarbonyl, bivaloyloxymethoxycarbonyl, etc.). Is used.

Examples of the carboxyl group which may be amidated include, for example, an aminocarbonyl group, a hydroxyaminocarbonyl group, and a monoalkylamino having 2 to 4 carbon atoms. Carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl, etc.), dialkylaminocarbonyl group of 3 to 5 carbon atoms (eg, dimethylaminocarbon, etc.), cyclic aminocarbonyl group (eg, morpholinocarbonyl, And thiomorpholinocarbonyl.

R ⁴ is preferably a carboxyl group or a hydroxymethyl group. The hydroquinone compound of the compound represented by the general formula (la) is represented by the general formula (lb):

Wherein each symbol is as defined above. ] The compound represented by these is shown.

Of the above compounds (la) or (lb), R 3 is phenyl, 3 _ or 4 -methinolepheny ^ /, 3-or 4 -fluorophenyl, 2-ceynole or 3 _ phenyl, and R ⁴ is A compound having a carboxyl group or hydroxymethyl and the number (n) of methylene groups is an integer of 5 to 9 is more preferable as the compound used as an active ingredient in the present invention. In particular, 7- (3,5,6-trimethyl-11,4-benzoquinone-12-yl) -17-phenylheptanoic acid is preferred.

The compound represented by the general formula (la) or (lb) has an R-form and an S-form, and the present invention includes both isomers. When R ³ is an aryl group such as phenyl or naphthyl, the R-form is preferred from the viewpoint of efficacy.

Examples of the salt of the compound represented by the general formula (Ia) or (lb) include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid And the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolanolamine, cyclohexanolamine, dicyclohexanolamine. And salts with N, N'-dibenzylethylenediamine and the like. With inorganic acids Preferred examples of the salt include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, conodic acid, malic acid, methanesulfonic acid, Salts with benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like. Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salts. ,

Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.) or an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.) , Ammonium salts, etc., and when the compound has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid And salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid. The compound (Ia), (lb) or a salt thereof used as an active ingredient of the present invention is described in JP-A-61-0444840 or JP-A-63-101322, and is described therein. It can be manufactured by the method of (1).

For example, compound (lb) can be converted to the corresponding hydroquinone compound without an asymmetric side chain in the presence of an acid catalyst by the formula:

CH (OH) R _3- (CH ₂ ) nR ⁴

By reacting with a compound represented by the formula:

Compound (la) can be produced by oxidizing compound (lb).

The quinone derivative represented by the above formula (la) is biochemically interchangeable with the hydroquinone derivative represented by the formula (lb) in vivo, and these compounds are physiologically It can be considered equivalent in terms of physical significance.

The compounds (la) and (lb) used as the active ingredient in the present invention have a bulky group at the carbon at the alpha () position of the side chain of the quinone nucleus or the hydroquinone nucleus. It has a chiral center. In this action, one of the optical isomers based on the chiral center exhibits a specific strong activity. However, even a racemic compound does not cause any problem in the efficacy.

The compound used as an active ingredient in the present invention is less susceptible to inactivation reaction due to metabolism in vivo due to the structure having a bulky group at the carbon at the alpha position of the side chain, and has a longer effective drug concentration in blood. It can be maintained for a long time and shows excellent efficacy at low doses.

The bronchoactive agent of the present invention does not cause the above-mentioned quinone derivative (la), its hydroquinone derivative or its salt to act on the whole body, but specifically acts on the bronchi. Further, the preparation of the present invention may act on tissues surrounding the bronchi, for example, may act on the trachea, lungs and the like.

The preparation of the present invention may be any preparation as long as it can exert the local action of the quinone derivative (la), its hydroquinone derivative or a salt thereof. Is preferred.

For example, when the preparation of the present invention is used as an inhalant, the additive for the inhalant may be any additive that is generally used in inhalation preparations. Agents, solid excipients such as sucrose, lactose, glucose, mannitol, sorbitol, liquid excipients such as inert liquids such as propylene glycol, methylcellulose, hydroxypropylcellulose, polybutylpyrrolidone, polyethylene glycol, sucrose Binders such as magnesium stearate, light caffeic anhydride, talc, sodium lauryl sulfate, etc., flavoring agents such as citric acid, menthol, glycyrrhizin ammonium salt, glycine, orange powder, benzoic acid Sodium, sodium bisulfite, methyl paraben, propyl paraben Preservatives, stabilizers such as cunic acid and sodium citrate, suspending agents such as methylcellulose, polyvinylpyrrolidone, lecithin, sonolevitan trioleate, dispersants such as surfactants, and solvents such as water For example, an isotonic agent such as sodium chloride, a pH adjusting agent such as sulfuric acid and hydrochloric acid, and a solubilizing agent such as ethanol are used.

As the propellant, a liquefied gas propellant, a compressed gas, or the like is used. Liquefied gas injection As the propellant, for example, fluorinated hydrocarbons (eg, HCFC 22, HCFC-123, HCFC-134a, HCFC 142, etc.), liquefied fossil oil, dimethyl ether, etc. are used. . As the compressed gas, for example, a soluble gas (eg, carbon dioxide gas, nitrous oxide gas, etc.), an insoluble gas (eg, nitrogen gas, etc.) and the like are used.

Further, the preparation of the present invention may contain a pharmaceutically active ingredient other than the quinone derivative (Ia) or its hydroquinone derivative as an active ingredient. Such pharmaceutically active ingredients include, for example, anticholinergic agents (eg, iprat bromide, furtium bromide, oxitropium bromide, tiotropium bromide), inhaled j82 stimulants (eg, phenotheronore, subtamol, formotero) Inhaled steroids, inhaled steroids (eg, beclomethasone, flutizone, budesonide), anti-asthmatics (eg, theophylline, propoterol, ketotifen, azelastine, etc.), anti-allergic agents (eg, ketotifen, Terfenadine, azelastine, epinastine, etc.), anti-inflammatory agents (eg, diclofenac sodium, ibuprofen, indomethacin, etc.), antibacterial agents (eg, cefixime, cefujiel, ofloxacin, tosfloxacin, etc.), antifungal agents (eg, Conazole, such as Lee Torakona tetrazole), and the like. Further, these pharmaceutical ingredients can be used in combination with the preparation of the present invention.

These components are not particularly limited as long as the object of the present invention is achieved, and can be used in an appropriate mixing ratio or combination ratio.

In the preparation of the present invention, the content of the quinone derivative (la), its hydroquinone derivative or its salt varies depending on the target disease, the age and sex of the target patient, the state of the disease, and the like. It is about 0.01 to 99.9% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight. The content of various additives such as excipients for inhalants varies depending on the target disease, the age and gender of the target patient, the symptoms of the disease, etc., but is usually about 0.1 to 99% by weight, preferably about the whole preparation. Is about 10 to 99% by weight, more preferably about 50 to 99% by weight, particularly preferably about 70 to 99% by weight.

Quinone derivatives (la), other pharmaceutical compounds other than the hydroquinone derivative or its salts Although the content of the minute component varies depending on the target disease, the age and gender of the target patient, the state of the disease, etc., it is usually about 0.01 to 99.9% by weight, preferably about 0.1% by weight, based on the whole preparation. :! To 50% by weight, more preferably about 0.5 to 20% by weight. When the formulation of the present invention is used as an inhalant, it is converted into a powder inhaler, inhaler suspension, inhalation solution or capsule inhaler by a method known per se, and is applied using an appropriate inhaler at the time of use. In particular, powder inhalants are preferably used. The average particle size of the powder inhalant of the present invention is not particularly limited, but is preferably about 0.1 to about 20 m, particularly preferably about 1 to about 5 μm.

The particle size of the powdered inhalant of the present invention is not particularly limited, but the amount of particles having a size of about 25 m or more is preferably about 5% or less, particularly preferably about 1% or less. Further, the preparation of the present invention can be used as an aerosol. In the case of aerosols, the contents inside the can are completely free from contamination during the period of use, so the inside of the aerosol can is always kept in a pressurized state, and contamination of substances from the outer periphery is prevented. There is no feature.

Aerosols usually consist of five components: container, valve, button, contents and propellant, and are classified into two-phase, three-phase, and diaphragm (dual container) systems. As the container, those specified by the High Pressure Gas Control Law are used, but as the material, metal (eg, tin, aluminum), glass or plastic is used. There are three types of metal containers: three-piece side seam cans, two-piece seamless cans, and one-piece monoblock cans. Glass containers have excellent solvent resistance and corrosion resistance, and are easy to process. Valves are the ones that have the greatest influence on the jetting characteristics and sealing properties of azoles. The valve usually consists of a mountain cup, a stem, a housing, a spring, a dip tube, and a gasket rubber. In the valve mechanism, when the stem is pushed, the stem hole that was closed by the gasket rubber, which is a hermetic seal, communicates with the inside of the container, and the contents are released by being released.

Buttons include a straight button, a brake gap button, a foam button, and a long nozzle button. As the contents, the above-mentioned topical agent (inhalant) of the present invention is used. As the propellant, the same as described above is used.

In a two-phase aerosol using a liquefied gas propellant as the propellant, the propellant dissolves with the suspension containing the quinone derivative (Ia) or its hydroquinone derivative (stock solution) to form a uniform liquid phase. However, the interior of the vessel is composed of two phases: a liquid phase and a gas phase in which the propellant is vaporized in the upper space. In this system, fine particles can be obtained due to the vaporization crushing force when the propellant liquefied under pressure in the container is ejected under normal pressure through a valve. In the case of a compressed gas, it is compressed in the upper space and only presses the undiluted solution. In the three-phase system, the liquid phase forms a two-phase emulsified state, and there is an emulsified system consisting of this and the gas phase in the upper space, and a suspension system consisting of the powder / liquefied gas phase consisting of the gas phase in the upper space. The diaphragm system is a form in which the undiluted solution is spouted as it is. Using a double container, the undiluted solution is filled into the inner container in which the propellant is passed through the valve to the outer container, and only the undiluted solution is ejected.

When the preparation of the present invention is used as an aerosol, it is preferable to use a powder aerosol.

The production of aerosols usually consists of two steps: a contents preparation step and a contents and propellant filling step.

The content can be prepared using a method known per se. (1) A quinone derivative (la), its hydroquinone derivative or its salt, and an adjuvant and a solvent are mixed and stirred to form a uniform suspension. (2) a method of kneading a quinone derivative (Ia), its hydroquinone derivative or its salt with a surfactant to form a powder, and (3) a quinone derivative (la), its hydroquinone derivative or its salt. A method is used in which a water-soluble inhalant additive is mixed, stirred, heated, and then cooled to form an emulsion. Filling the contents and propellant usually consists of cleaning the container, filling the contents, degassing the container, filling the propellant, and installing a valve device. For the propellant filling, cooling filling, pressure filling, under-cup filling and the like are used.

After filling, check the crimp condition to see if the valve is properly installed. In addition, a hot water test is performed to check for product leakage, and water droplets are removed. In addition, flame length tests and aging tests (eg, tests for weight loss, injection characteristics, container corrosion, valve function, internal pressure, etc.) will be performed to confirm the safety of the aerosol during storage and use.

When the formulation of the present invention is used, a commercially available inhaler may be used as a device used for application. For example, VENTOLIN ROTACAPS (Daraxo), Spinhera (registered Trademarks, Fujisawa Pharmaceutical Co., Ltd.), INTAL SPINCAPS (Fuisonzu), AtoVent and BEROTEC INHALETTEN (ATROVENT AND BEROTEC INHALETTEN; Boehringer 'Ingelheim), Foradir

(FORADIL; Ciba), BENTODISKS (Daraxo), Publyzer (registered trademark, Teijin Limited), BRICANYL TURBUHALER (Astra), MIAT INSUFFLATOR (MIAT INSUFFLATOR) ).

The compound used as an active ingredient in the present invention has low toxicity, for example, (Sat) -17- (3,5,6-trimethyl-11,4-benzoquinone-12-yl) -17-phenylheptanoic acid Was orally administered to five groups of 5-week-old ICR male mice in a group at 100 mg / kg, but no deaths were observed for 7 days.

The topical agent of the present invention can cause the quinone derivative (Ia) or its hydroquinone derivative to specifically act on the bronchi or its surrounding tissues by local injection into the mouth, throat and the like. In this way, the local administration of the quinone derivative (la), its hydroquinone derivative or a salt thereof allows the administration of a minimally effective amount, thereby avoiding systemic multiple administration. Therefore, even children can easily and safely take it. In particular, when used as an inhalant or aerosol, it can exert a special local effect.

As described above, the preparation of the present invention provides an anti-asthmatic agent or an anti-asthma agent that is safe for mammals (eg, humans, mice, rats, cats, dogs, higgs, pomas, pests, monkeys, etc.). PAF agents, antiallergic agents, eosinophil chemotactic inhibitors, diseases involving eosinophil infiltration (eg, urticaria, atopic dermatitis, allergic rhinitis, irritable pneumonitis, etc.)

: Skin disease such as unisexual disease, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrome) and respiratory diseases such as chronic obstructive pulmonary disease (COPD) can be used as preventive and therapeutic agents. In particular, anti-asthmatics, chronic obstructive pulmonary disease

(COPD) Prevention · Therapeutic agent, Irritable pneumonitis prevention · Therapeutic agent or eosinophilic pneumonia prevention · It is useful as a therapeutic agent.

The dosage of the formulation of the present invention varies depending on the target disease, age, body weight, symptoms, administration route, number of administrations, and the like. For example, when the particle size is about 0.1 to 20 μm, In general, it is preferable to administer about 0.1 to 1 OmgZ human 3 to 4 times a day in terms of the active ingredient (quinone derivative (la), its hydroquinone derivative or its salt) at a time. Les ,. In addition, when the particle size is about 0.5 to 5 im, it is usually about 0.5 to 5 mg as an active ingredient (quinone derivative (Ia) or its hydroquinone derivative) once per adult. Humans should be given 3 to 4 times a day.

As the administration route, it is usually preferable to inhale directly into the mouth using an inhalation device.

Since the preparation of the present invention can be directly administered to the local respiratory tract, the effects of the quinone derivative (la), the hydroquinone derivative or a salt thereof to be incorporated are immediately exerted. Therefore, the preparation of the present invention is useful not only as a preventive agent before the onset of the disease state but also as a therapeutic agent after the onset of the disease state.

In addition, when the preparation of the present invention is used in combination with a quinone derivative (la) or a pharmaceutical ingredient other than the hydroquinone derivative thereof (hereinafter abbreviated as concomitant drug), the administration time of the preparation of the present invention and the concomitant drug is limited. Instead, the preparation of the present invention and the concomitant drug may be administered to a subject to be administered simultaneously or at an interval. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

The administration form of the preparation of the present invention and the concomitant drug is not particularly limited, as long as the preparation of the present invention and the concomitant drug are combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing the preparation of the present invention and a concomitant drug, and (2) separate preparation of the preparation of the present invention and the concomitant drug. (3) Simultaneous administration of the two formulations obtained by the same route of administration, and (3) the time difference of the two formulations obtained by separately formulating the formulation of the present invention and the concomitant drug in the same route of administration. Being (4) Simultaneous administration of two types of preparations obtained by separately preparing the preparation of the present invention and the concomitant drug by different administration routes, (5) Separate preparation of the preparation of the present invention and the concomitant drug Administration of the two preparations obtained in different times with different administration routes (for example, administration in the order of the preparation of the present invention → concomitant drug, or administration in the reverse order). Hereinafter, the present invention will be more specifically described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example

Example 1 Suspension for inhalation

(1) (Sat) 1 7— (3,5,6-trimethyl-1,4,1 ^ -quinzoquinone

— 2-yl) — 7_phenylheptanoic acid 20.0mg

(2) HC F C-1 23 1 56 O.Omg

(3) HC F C-1 34 a 240 O.Omg

(4) Sorbitan trioleate 2 O.Omg

The above are mixed to obtain a suspension for inhalation. Use a metering valve that blows out 50 μ1 each time.

Example 2 Inhalation solution

(1) (±) — 7— (3,5,6-trimethyl-1,4-benzoquinone

— 2-yl) _ 7-phenylheptanoic acid 2 O.Omg

(2) Purified water 1000.0 g

The above are mixed to obtain a solution for inhalation. This inhalation solution is applied using a nebulizer (trade name).

Example 3 Powder Inhalant

(1) (±) — 7— (3,5,6-trimethyl-1,4-benzoquinone

— 2-yl) 1 7-phenylheptanoic acid 25.0 g

(2) Lactose 250.0 g

The above ingredients are mixed to obtain a powder inhalant.

Example 4 Capsule Inhalant (1) (Sat) 1 7- (3,5,6-trimethyl-11,4-benzoquinone 1-2 l) -7-phenylheptanoic acid 25.0 g

(2) Lactose 250.0 g

The above components are mixed and filled in No. 2 capsule so as to contain 2.5 mg of the compound of Reference Example 4 in one capsule to obtain 10,000 capsule inhalants. This force-based inhaler is applied using a spin-herler (Fujisawa Pharmaceutical Co., Ltd.) as a small injector.

Experimental Example 1 Inhibition of airway constriction response (1)

(1) Thromboxane A ₂ agonist U-466 19 Inhalation-induced airway constriction response

Lactose of (Sat) -17- (3,5,6-trimethyl-1,4-benzoquinone-12-yl) -17-phenylheptanoic acid (hereinafter abbreviated as Compound A) in male Hartley guinea pigs 300 Inhalation is performed in a nasal exposure device (Shibata Kagaku Co., Ltd.) (exhaust flow 30 L Zmin) under spontaneous breathing for 10 minutes, or a 0.5% MC suspension of Compound A orally Was administered. After a certain period of time after the administration, the animals are placed in an acrylic box, and an aerosolized U-46619 solution (10 μgZml) is inhaled with an ultrasonic nebulizer for 1 minute to induce an airway constriction reaction. did. As for the respiratory function, PenMenhanced pause) was measured as an index of airway stenosis using a respiratory function measuring device (manufactured by Buxco).

(2) Preparation of sample for compound A concentration measurement

10 minutes after inhalation administration of Compound A or 1 hour after oral administration, blood was collected from the abdominal aorta under ether anesthesia to prepare plasma. In addition, the lung was perfused with 25 ml of physiological saline and then extracted, immersed in a four-fold volume of physiological saline, homogenized with a polytron, and the homogenate was used as a sample for measuring tissue concentration.

The concentration of Compound A in the suction chamber was measured by sampling a fixed amount (10 L) of air in the suction chamber, extracting Compound A attached to the sampling filter, and measuring.

(3) Result

(i) Correlation between the turntable rotation speed and the concentration of compound A in the suction chamber Figure 1 shows the relationship. In this nose exposing device, a groove is formed on the turntable, and the compound filled in the groove is suctioned and supplied into the suction chamber. The animal is fixed in the holder and only the nose is exposed inside the inhalation chamber. The concentration of Compound A in the suction chamber depends on the turntable rotation speed. In this nose exposing device, it was found that the turntable rotation speed was proportional to the concentration of Compound A in the inhalation chamber.

(ii) Compound A 300-fold powder was inhaled at a turntable rotation speed of 90, 200 and 600 for 10 minutes.After 10 minutes, plasma and lung tissue were prepared, and the compound A concentration was measured. The result is shown in figure 2. It was found that the concentration of Compound A in the inhalation chamber was proportional to the concentration of Compound A in plasma and lung tissue.

In addition, plasma and lung tissues were prepared 1 hour after oral administration of Compound A at a ratio of 0.03, 0.1 and 0.3 mg / kg, and the results of measurement of Compound A concentration are shown in FIG. It was found that the oral dose of Compound A was proportional to the concentration of Compound A in plasma and lung tissue.

As described above, in the case of inhaled administration of compound A lactose trituration using this nasal exposure device, there is a proportional relationship between the dose and compound A concentration in plasma and lung tissue, as in oral administration. I understood.

(^) Inhalation of compound 300-fold powder at each turntable rotation speed for 10 minutes, and airway constriction when inhaling U-46661 (10 μg / m 1) 10 minutes later The reaction is shown in FIG. It was found that the airway constriction reaction was most strongly suppressed at a turntable rotation speed of 600. In addition, FIG. 5 shows the airway constriction response when compound A was orally administered at each dose and one hour later, U-46619 (10 g / m 1) was inhaled. It was found that oral administration of the compound A could suppress the airway constriction reaction caused by U-46619.

As described above, Compound A 3 0 0 times variance inhalation administration, like oral administration, has been found to be able to suppress airway constriction reaction by Toro Nbokisan A ₂ Agonisu bets. Experimental Example 2 Inhibition of airway constriction response (2)

(1) thromboxane A ₂ Agonisuto U- 4 6 6 1 9 inhalation challenge with airway constriction reaction Hartley male guinea pigs were inhaled with Compound A lactose 300 times powder inhaled by spontaneous breathing for 10 minutes in a nasal exposing device (Shibata Kagaku Co., Ltd.) (exhaust flow 30 LZin). A 0.5% MC suspension was orally administered. After the administration is completed, the animal is placed in an acrylic box for a certain period of time, and a U-46619 solution (10 μgZm1) aerosolized by an ultrasonic nebulizer is inhaled for 1 minute to restrict airway stenosis A reaction was elicited. As for the respiratory function, Penh (enhanced pause) was measured as an index of airway stenosis using a respiratory function measuring device (manufactured by Buxco).

(2) Preparation of sample for compound A concentration measurement

Ten minutes after inhalation administration of Compound A or one hour after oral administration, blood was collected from the abdominal aorta under ether anesthesia to prepare plasma. Further, the lung was perfused with 25 ml of a physiological saline solution and then excised, immersed in a four-fold volume of a physiological saline solution, homogenized with a polytron, and the homogenate was used as a sample for measuring the concentration in tissue.

(3) Result

(i) After inhaling Compound A 300 times powder at a turntable rotation speed of 600 for 10 minutes, 5, 10, 30, and 60 minutes later, plasma and lung tissue were prepared, and the Compound A concentration was measured. . Fig. 6 shows the rate of suppression of the airway constriction reaction when U-46619 (10 ^ g / m1) was inhaled at the same time. Compound A plasma and lung tissue concentrations were highest 5 minutes after inhalation and then decreased sharply. The plasma and lung tissue concentrations of Compound A after 5 minutes were 5.26 ng / 1 and 26.34 ng / g tissue, respectively. In addition, Compound A inhalation suppressed the airway constriction response due to U_46619 up to 30 minutes after inhalation, but it was found that the inhibitory effect disappeared 60 minutes after inhalation.

(ii) Compound A was orally administered at a rate of 0.3 mg / kg, and plasma, lung tissue was prepared 1, 2, 4, 8 and 24 hours later, and the concentration of Compound A was measured. Fig. 7 shows the airway narrowing response when inhaling U-46619 (10 µg / m1) at the same time. Compound A plasma and lung tissue concentrations are highest 2 hours after oral administration It was high and then gradually decreased, but remained high even after 24 hours. One hour after administration, the concentrations in plasma and lung tissue were 53.89 ng Zml and 37.25 ng / g tissue, respectively. In addition, oral administration of Compound A suppressed the airway constriction reaction caused by U-46619 even 24 hours after administration, with an inhibition rate of 55%.

As described above, it was found that inhalation administration of Compound A 300 times powder could suppress airway constriction reaction similarly to oral administration, while keeping plasma concentration low. Experimental example 3 Airway constriction response inhibitory action (3)

(1) Airway constriction response induced by inhalation of antigen in sensitized guinea pigs

Guinea pigs were sensitized by the following method. Hartley male guinea pigs were placed in an atrial box, a 1% ovalbumin solution was converted into an aerosol with an ultrasonic nebulizer, and the aerosol was inhaled twice at weekly intervals for 10 minutes to sensitize. One week after the final sensitization, sensitized guinea pigs were inhaled with 30-fold compound A lactose in a nasal exposure device (Shibata Kagaku Co., Ltd.) (exhaust flow 30 L min) for 10 minutes under spontaneous breathing Alternatively, a 0.5% MC suspension of Compound A was orally administered. At the time of inhalation administration, immediately after the end of administration, and at the time of oral administration, one hour after administration, the animal is placed in an acrylic box, and a 2% ovalbumin solution aerosolized by an ultrasonic nebulizer is inhaled for 5 minutes. An airway constriction response was elicited. As for the respiratory function, Penh (enhancedpause) was measured as an index of airway stenosis using a respiratory function measuring device (manufactured by Buxco).

(2) Result

Figure 8 shows the airway constriction response when inhaling Compound A 30-fold at a turntable rotation speed of 200 or 600 for 10 minutes and immediately inhaling the antigen aerosol for 5 minutes. Compound A inhalation was able to suppress antigen-induced airway constriction response.

In addition, FIG. 9 shows the airway narrowing reaction when compound A was orally administered at a rate of 1 or 3 mg / kg, and one hour later, the antigen aerosol was inhaled for 5 minutes. It was found that oral administration of Compound A can suppress antigen-induced airway constriction response. As described above, inhalation administration of Compound A30-fold powder is similar to oral administration, It was found that antigen-induced airway constriction reaction in guinea pigs can be suppressed. Industrial applicability

The preparation of the present invention can cause the anti-asthmatic effect of the quinone derivative (la), its hydroquinone derivative or its salt, etc., to act specifically on the bronchi or its surrounding tissues. Therefore, topical administration can avoid the systemic administration of the quinone derivative (la), its hydroquinone derivative or its salt in large amounts, since the administration of the minimum effective amount is sufficient.

Claims

Claims General formula (la)

Wherein either indicating each R ¹ and R ² are methyl or main butoxy group, may indicate attached R ¹ and R2 together with Ri and R2 one CH CH- CH = CH-, R ³ Represents a phenyl, naphthyl or phenyl group which may be substituted, R ⁴ represents a hydroxyl group or a group capable of being converted to a carboxyl group in a living body, and n represents an integer of 3 15. ] A bronchoactive agent comprising a quinone derivative represented by the formula: or a hydroquinone derivative or a salt thereof.

2. The agent according to claim 1, wherein Ri and R ² are each a methyl group.

3. The agent according to claim 1, wherein R3 is a lower alkyl group having 14 carbon atoms, a lower alkoxy group having 14 carbon atoms, a phenyl group which may be substituted with halogen, a hydroxyl group, methylenedioxy or trifluoromethyl.

4. The agent according to claim 1, wherein R ³ is a phenyl group which may be substituted with at least one substituent selected from a lower alkyl group and a halogen.

5. R ³ is a phenyl group, a 3-phenyl phenol group, a 4-phenyl phenol group, a 3-methylphenyl group, a 4-methyl phenyl group, a 2-phenyl group, a 2-phenyl group, or a 3-phenyl group. 2. The agent according to claim 1, which is a nyl group.

6. The agent according to claim 1, wherein R ⁴ is a carboxyl group or a hydroxymethyl group.

7. The agent according to claim 1, wherein n is an integer of 59.

8. The agent according to claim 1, wherein the quinone derivative is 7- (3,5,6-trimethyl-l, 4-benzoquinone_2-inole) -17-phenylheptanoic acid.

9. General formula (la):

Wherein either indicating each R ¹ and R ² are methyl or main butoxy group, attached R ¹ and R ² are each other also exhibit R ¹ and R ² in one CH = CH- CH = CH- R ³ represents a phenyl, naphthyl or phenyl group which may be substituted, R ⁴ represents a carbonyl group or a group capable of being converted to a carboxyl group in vivo, and n represents an integer of 3 to 15. Selected from the group consisting of quinone derivatives, their hydroquinone derivatives or salts thereof, anticholinergics, inhaled 02 stimulants, inhaled steroids, antiasthmatics, antiallergic agents, antiinflammatory agents, antibacterial agents and antifungal agents A bronchial agent consisting of one or more drugs.

10. The agent according to claim 1 or 9, which is an anti-asthmatic agent, a preventive / therapeutic agent for chronic obstructive pulmonary disease (COPD), a preventive / therapeutic agent for irritable pneumonitis or a preventive / therapeutic agent for eosinophilic pneumonia.

1 1. The agent according to claim 1 or 9, which is an agent for preventing and treating chronic obstructive pulmonary disease (COPD).

12. The agent according to claim 1 or 9, which is a bronchial inhaler.

13. The agent according to claim 12, which is a powder inhalant.

14. The agent according to claim 13, wherein the average particle size is about 0.1 to about 20 µm.

15. For the mammal's mouth or throat, the general formula (la):

Wherein R ¹ and R ² are either a methyl group or main butoxy group, also shows the attached R ¹ and R ² together R ¹ and R ² in one CH = CH- CH = CH_ R ³ is an optionally substituted phenyl, naphthyl or phenyl group, and R ⁴ is A ruboxyl group or a group that can be converted into a carboxyl group in vivo, and n represents an integer of 3 to 15. Asthma, chronic obstructive pulmonary disease (COPD), hypersensitivity, characterized by direct local administration of an effective amount of a bronchoactive agent comprising a quinone derivative represented by the formula: Prevention and treatment of pneumonitis or eosinophilic pneumonia.

1 6. For the mammal's mouth or throat, the general formula (la):

Wherein either indicating each R ¹ and R ² are methyl or main butoxy group, may indicate R ¹ and one R ² CH = CH- CH = CH- attached Ri and R ² to each other R ³ represents an optionally substituted phenyl, naphthyl or phenyl group; R ⁴ represents a carboxyl group or a group capable of being converted to a carboxyl group in vivo; and n represents an integer of 3 to 15. Selected from quinone derivatives, their hydroquinones or their salts and anticholinergics, inhaled J32 stimulants, inhaled steroids, antiasthmatics, antiallergic agents, antiinflammatory agents, antibacterial agents and antifungal agents For the treatment of asthma, chronic obstructive pulmonary disease (COPD), irritable pneumonitis or eosinophilic pneumonia, characterized by the direct local administration of a drug in combination with one or more drugs. Prevention · treatment methods.

1 7. General formula (la) for producing a preventive / therapeutic agent for asthma, chronic obstructive pulmonary disease (COPD), irritable pneumonitis or eosinophilic pneumonia:

Wherein either indicating each R ¹ and R ² are methyl or main butoxy group, attached R ¹ and R ² are each other also exhibit R ¹ and R ² in one CH = CH- CH = CH- R ³ is an optionally substituted phenyl, naphthyl or phenyl group, and R ⁴ is A ruboxyl group or a group that can be converted into a carboxyl group in vivo, and n represents an integer of 3 to 15. ] The use of a bronchoactive agent comprising a quinone derivative represented by the formula: or a hydroquinone derivative or a salt thereof.

1 8. General formula (la) for producing a preventive and therapeutic agent for asthma, chronic obstructive pulmonary disease (COPD), irritable pneumonitis or eosinophilic pneumonia:

Wherein either R ¹ and R ² each represents a methyl group or main butoxy group, may indicate Ri and R2 are bonded to Ri one and R2 CH = CH- CH = CH- each other, R ³ Represents an optionally substituted phenyl, naphthyl or phenyl group, R ⁴ represents a carboxyl group or a group capable of being converted into a carboxyl group in vivo, and n represents an integer of 3 to 15. Selected from quinone derivatives, their hydroquinone derivatives or salts thereof, anticholinergics, inhaled β2-agonists, inhaled steroids, antiasthmatics, antiallergic agents, antiinflammatory agents, antibacterial agents and antifungal agents Use of bronchial agents in combination with one or more drugs.