JP2013177351A - Asthma therapeutic agent comprising pgd2 antagonist and leukotriene antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an asthma therapeutic agent exhibiting more strong pharmacological action by using both a PGD2 receptor antagonist and a leukotriene receptor antagonist.SOLUTION: An asthma therapeutic agent combines a compound expressed by chemical formula (I), or its pharmaceutically allowable salt, at least one compound selected from the group consisting of montelukast, zafirlukast and pranlukast, its pharmaceutical allowable salt, or their solvates.

Description

  The present invention relates to a therapeutic agent for asthma. More specifically, the present invention relates to a therapeutic agent for asthma characterized by combining a specific PGD2 receptor antagonist and a specific leukotriene receptor antagonist.

  Prostaglandin D2 (PGD2), which is a product of the cyclooxygenase cycle of arachidonic acid metabolism, has a strong bronchoconstrictive action and induces increased vascular permeability and migration of inflammatory cells such as eosinophils. Receptor antagonists are known to be useful for the treatment of allergic diseases (eg, asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, etc.).

  For example, the present applicant has reported a sulfonamide derivative having antagonist activity at the DP receptor, which is one of the PGD2 receptors, as a therapeutic agent for allergic diseases (see Patent Document 1).

  Patent Document 2 also includes a PGD2 receptor antagonist and a leukotriene (LT) receptor antagonist, which is also a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, and a component that shows a different mechanism of action against asthma. It has been reported that a synergistic effect on anti-asthma is exhibited when used in combination.

  Patent Document 3 reports that the combined use of a PGD2 receptor antagonist and a histamine H1 receptor antagonist and / or an LTD4 receptor antagonist is useful for allergic rhinitis, and mepyramine is used as an antihistamine. On the other hand, examples of anti-LT agents include montelukast, zafirlukast, and pranlukast.

  For the treatment of asthma, LT receptor antagonists (eg, montelukast sodium, zafirlukast, pranlukast hydrate), LT synthesis inhibitors (eg, zileuton), PDE IV inhibitors (eg, roflumilast), xanthine derivatives (eg, Theophylline), corticosteroids (eg fluticasone), β2 agonists (eg salmeterol), anti-IgE antibody formulations (eg omalizumab), Th2 cytokinin inhibitors (eg IPD), histamine H1 receptor antagonists (eg loratadine) ) Etc. are used.

WO2007 / 037187 pamphlet WO2006 / 118169 pamphlet WO2001 / 078697 pamphlet

  The subject of this invention is providing the therapeutic agent for asthma which shows a more powerful pharmacological action by using together a PGD2 receptor antagonist and a LT receptor antagonist.

  The present inventors combined a specific compound (compound II-74) among the PGD2 receptor antagonists described in Patent Document 1 with a specific LT receptor antagonist, respectively, compared with the case where each is administered as a single agent. Newly found to suppress more powerful asthma symptoms.

That is, the present invention
(1) Formula (I):

Or a pharmaceutically acceptable salt thereof,
The present invention relates to a therapeutic agent for asthma characterized by combining at least one compound selected from the group consisting of montelukast, zafirlukast, and pranlukast, a pharmaceutically acceptable salt thereof, or a solvate thereof.

More specifically, it relates to the following (2) to (8).
(2) The therapeutic agent according to (1) above, wherein the asthma is bronchial asthma, acute bronchitis or chronic bronchitis.
(3) The therapeutic agent according to (1) or (2) above, which is an orally administered agent.
(4) A combination of 10 to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and 2.5 to 10 mg of montelukast or a pharmaceutically acceptable salt thereof. (1) The therapeutic agent in any one of (3).
(5) A combination of 50 to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and 4 to 10 mg of montelukast or a pharmaceutically acceptable salt thereof (1) The therapeutic agent according to any of (3) to (3).
(6) 10 to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and 5 to 40 mg of zafirlukast or a pharmaceutically acceptable salt thereof in combination (1 The therapeutic agent according to any of (3) to (3).
(7) A combination of 50 to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and 10 to 40 mg of zafirlukast or a pharmaceutically acceptable salt thereof (1) The therapeutic agent according to any of (3) to (3).
(8) 10-200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and 7-450 mg of pranlukast, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic agent according to any one of (1) to (3) above, which is combined.
(9) 50-100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and 10-450 mg of pranlukast, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic agent according to any one of (1) to (3) above, which is combined.
(10) Formula (I):

Or a pharmaceutically acceptable salt thereof,
An asthma treatment combination comprising at least one compound selected from the group consisting of montelukast, zafirlukast, and pranlukast, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(11) The therapeutic mixture according to the above (10), wherein the asthma is bronchial asthma, acute bronchitis or chronic bronchitis.
(12) The asthma treatment mixture according to (10) or (11), which is an orally administered agent.
(13) A combination of 10 to 200 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and 2.5 to 10 mg of montelukast or a pharmaceutically acceptable salt thereof. (10) The combination for treating asthma according to any one of (12).
(14) A combination of 50 to 100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and 4 to 10 mg of montelukast or a pharmaceutically acceptable salt thereof (10) ) To (12) asthma treatment combination.
(15) 10 to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and 5 to 40 mg of zafirlukast or a pharmaceutically acceptable salt thereof in combination (10 ) To (12).
(16) A combination of 50 to 100 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and 10 to 40 mg of zafirlukast or a pharmaceutically acceptable salt thereof (10) ) To (12).
(17) 10 to 200 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and 7 to 450 mg of pranlukast, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic combination according to any one of (10) to (12) above, which is combined.
(18) 50-100 mg of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and 10-450 mg of pranlukast, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic combination according to any one of (10) to (12) above, which is combined.

By using a PGD2 receptor antagonist represented by the formula (I) and a leukotriene receptor antagonist in combination, a synergistic therapeutic effect is exerted on asthma, and safety is high. It is useful as a therapeutic and / or prophylactic agent for asthma.

It is a figure which shows airway ventilation pressure in a rat airway chronic inflammation model. It is a figure which shows the cell number in an airway alveolar lavage fluid in a rat airway chronic inflammation model. It is a figure which shows the mucin amount in an airway alveolar lavage fluid in a rat airway chronic inflammation model.

The therapeutic agent for asthma according to the present invention comprises (A) Formula (I) as an active ingredient:

Or a pharmaceutically acceptable salt thereof,
(B) It is selected from the group consisting of montelukast, zafirlukast, and pranlukast, or is used in combination with at least one compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(A) PGD2 receptor antagonist The PGD2 receptor antagonist used in the present invention is a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  The compound represented by the formula (I) is [2- (Oxazol-2-yl) -5- (4- {4-[(propan-2-yl) oxy] phenylsulfonyl} piperazin-1-yl) phenoxy]. It is an acetic acid and has antagonist activity at the DP receptor, which is one of the PGD2 receptors.

  The compound represented by the formula (I) can be synthesized according to a known method, for example, the method described in WO2007 / 037187 pamphlet or WO2008 / 123349 pamphlet.

(B) LT receptor antagonist Examples of the LT receptor antagonist used in the present invention include montelukast, zafirlukast, pranlukast and the like.

  Montelukast is described in JP 2,501,385 or US 5,565,473 and may form pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts include sodium montelukast, (+)-1-[[[(R) -3-[(E) -2- (7-Chloro-2-quinolyl) vinyl] -α- [2 -(1-hydroxy-1-methylethyl) phenethyl] benzyl] thio] methyl] cyclopropaneacetic acid monosodium salt. With montelukast alone, as montelukast sodium, 10 mg per day for an adult is administered once a day before going to bed.

  Zafirlukast is described in JP 1,955,810 or US 4,859,692, and Cyclopentyl 3- (2-methoxy-4-[{2-toylsulfonyl} carbamoyl] benzoyl) -1-methylindole-5-carbamate is described. Can be mentioned. A pharmaceutically acceptable salt may be formed. In the case of zafirlukast alone, 20 mg per adult is administered twice daily as zafirlukast.

  Pranlukast is described in JP 1,741,466 or US 4,780,469 and 4-Oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl)- 4H-1-benzopyran hemihydrate. A pharmaceutically acceptable salt may be formed. Pranlukast alone is administered as pranlukast hydrate, 450 mg per day for an adult divided into two doses per day.

  The LT receptor antagonist may be synthesized according to a known method, or a commercially available product may be used.

  In the present specification, the “pharmaceutically acceptable salt” includes basic salts such as alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metals such as calcium salt, magnesium salt and barium salt. Salt: transition metal salt such as zinc salt and iron salt; ammonium salt; aliphatic such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, ethylenediamine salt, meglumine salt, brocaine salt Amine salts; Aralkylamine salts such as N, N-dibenzylethylenediamine; Heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, Benji Triethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, quaternary ammonium salts such as tetrabutylammonium salts; arginine salts, basic amino acid salts such as lysine salts. Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide, perchlorate; formate , Acetate, propionate, trifluoroacetate, citrate, lactate, tartrate, oxalate, maleate, fumarate, mandelate, glutarate, malate, benzoate Organic salts such as phthalate and ascorbate; Methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, etc .; Aspartate, glutamic acid Examples thereof include acidic amino acid salts such as salts.

  Solvates include organic solvates that coordinate any number of organic solvent molecules and hydrates that coordinate any number of water molecules. The “solvate” in the present specification is 1 selected from the group consisting of a solvate of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, montelukast, zafirlukast, and pranlukast. Or a solvate of a compound or a pharmaceutically acceptable salt thereof, for example, a monosolvate, a disolvate, a monohydrate, a dihydrate, etc. It is done. In particular, hydrates of pranlukast are mentioned.

  Pharmaceutically acceptable salts and solvates can be synthesized according to known methods.

  The asthma therapeutic agent of the present invention is not particularly limited as long as it is a combination of the above components (A) and (B), and can contain other active ingredients as long as the effects of the present invention are not impaired. . For example, leukotriene receptor antagonists (eg, leukotriene B4 receptor antagonists), leukotriene synthesis inhibitors (eg, zileuton), PDE IV inhibitors (eg, theophylline, silomilast, roflumilast), corticosteroids (eg, prednisolone, fluticasone, Budesonide, ciclesonide), β2 agonist (eg, salbutamol, salmeterol, formoterol), anti-IgE antibody formulation (eg, omalizumab), histamine H1 receptor antagonist (eg, cetirizine, fexofenadine, loratadine, chlorpheniramine), immune Inhibitors (eg, protopic, cyclosporine, etc.), thromboxane A2 receptor antagonists (eg, ramatroban), chemokine receptors (particularly CCR-1, CR-2, CCR-3) antagonists, other prostanoid receptor antagonists (eg PGD2 receptor antagonists, CRTH2 antagonists), adhesion molecule antagonists (eg VLA-4 antagonists), cytokine antagonists (eg , Anti-IL-4 antibody, anti-IL-3 antibody), non-steroidal anti-inflammatory drug (for example, propionic acid derivative; ibuprofen, ketoprofen, naproxen, etc., acetic acid derivative; indomethacin, diclofenac, etc., salicylic acid; acetylsalicylic acid, etc., cyclooxygenase 2 Inhibitors; celecoxib, etoroxib, etc.) may be used in combination or as a combination. Furthermore, antitussives (eg, codeine, hydrocodeine, etc.), cholesterol lowering agents (eg, lovastatin, simvastatin, fluvastatin, rosuvastatin, etc.), anticholinergic agents (eg, tiotropium, ipratropium, flutropium, oxitropium, etc.) It is done. These contents are not particularly limited.

  In addition, other pharmaceutical ingredients include excipients, binders, disintegrants, lubricants, sweeteners, flavoring agents, preservatives, chelating agents, antioxidants, cooling agents, coating agents, stabilizers, fluids Agents, thickeners, solubilizers, thickeners, buffers, fragrances, colorants, adsorbents, wetting agents, moisture-proofing agents, antistatic agents, plasticizers, antifoaming agents, surfactants, emulsifiers, etc. An additive may be contained. Specifically, binders (for example, corn starch), fillers (for example, lactose, microcrystalline cellulose, etc.), disintegrants (for example, sodium starch glycolate), lubricants (for example, magnesium stearate) Etc.). These contents are not particularly limited.

  The asthma therapeutic agent of the present invention is not particularly limited as long as it combines the above components (A) and (B), and can be prepared according to methods known to those skilled in the art. Further, the shape and size of the therapeutic agent are not particularly limited, but oral preparations are preferable, and solid preparations are more preferable. The solid dosage forms include tablets (including intraoral quick disintegrating tablets, chewable tablets, effervescent tablets, jelly-like drops, etc.), lozenges, granules, pills, powders (including fine granules). And capsules (including hard capsules and soft capsules). In preparing these, granulation may or may not be performed, and coating treatment may be performed by a known method.

  When the therapeutic agent for asthma according to the present invention is a tablet, for example, a mixture obtained by adding and mixing desired raw materials for the above components (A) and (B) is prepared as it is or according to a known method. After granulation, it can be prepared by a method of putting into a tableting machine and molding.

  The therapeutic agent for asthma according to the present invention is characterized by combining the component (A) and the component (B) as active ingredients, and the use form thereof is prepared separately for each of the component (A) and the component (B). A mode in which the prepared single agent is used simultaneously, a mode in which the single agent separately prepared for each of the component (A) and the component (B) is separately used, and the component (A) and the component (B) are formulated together. And an embodiment used as a preparation (mixture) prepared in the above manner. In this invention, the aspect used as a mixture from the viewpoint of a patient's QOL (Quality of life) is mentioned.

  The dosage of component (A) and component (B) when used as an asthma treatment agent depends on the dosage form, patient symptoms, age, weight, sex, or other concomitant drugs (if any) Unlikely, it is ultimately left to the judgment of the doctor. For example, when (B) component is montelukast, the aspect which 10-200 mg of (A) component and 2.5-10 mg of (B) component are orally administered per day of an adult is mentioned. Furthermore, the aspect which orally administers 50-100 mg of (A) component and 5-10 mg of (B) component is mentioned.

  For example, when the component (B) is zafirlukast, an embodiment in which 10 to 200 mg of the component (A) and 5 to 40 mg of the component (B) are orally administered per day for an adult. Furthermore, the aspect which orally administers 50-100 mg of (A) component and 10-40 mg of (B) component is mentioned.

  For example, when (B) component is pranlukast, the aspect which orally administers 10-200 mg of (A) component and 7-450 mg of (B) component per adult day is mentioned. Furthermore, the aspect which orally administers 50-100 mg of (A) component and 10-450 mg of (B) component is mentioned.

  Such dose may be administered at once or divided.

  The therapeutic agent of the present invention is excellent in the effect of suppressing asthma symptoms due to the synergistic effect of the components (A) and (B), but can be administered as a prophylactic agent for the prevention of asthma symptoms. In this specification, “asthma therapeutic agent” is a drug having a therapeutic or / and preventive effect on bronchial asthma, bronchitis or airway hypersensitivity, bronchodilator, airway hypersensitivity inhibitor, mucus secretion Inhibitors or airway inflammatory cell infiltration inhibitors are mentioned. The “synergistic effect” means a case where the combined effect of two or more (usually two) drugs is significantly greater than the sum of the single effects of each drug.

EXAMPLES Hereinafter, although this invention is demonstrated based on an Example, this invention is not limited at all by these Examples.

Test Example 1 Airway hypersensitivity test for rat airway inflammation model Male rat (BN / CrlCrlj, manufactured by Charles River Japan) induces airway inflammation by the following method to produce a rat chronic airway inflammation model did. Specifically, on the first day (day 0), 1 mL of OVA solution prepared to 0.1 mg / mL with 1 mg / mL aluminum hydroxide solution was intraperitoneally administered to rats. After 12, 19, 26, and 33 days (day 12, 19, 26, and 33), prepare a 1% OVA solution, and spontaneously inhale the rats in the chamber with a nebulizer (NE-U17, Omron) for 30 minutes to stimulate the antigen. As a result, a rat airway inflammation model in which airway inflammation was induced was prepared. The control group as a control was prepared by intraperitoneal administration of physiological saline instead of intraperitoneal administration of the OVA solution.

  The obtained rat airway inflammation model was divided into groups shown in Table 1 below. That is, group 1: Control group (group in which only vehicle is administered to guinea pigs in which airway inflammation is not induced), Group 2: Vehicle group (group in which only vehicle is administered to airway inflammation model), Group 3: represented by formula (I) 0.1 mg / kg administration group, group 4: montelukast (Mont) 10 mg / kg administration group, group 5: Formula (I) 0.1 mg / kg and Mont 10 mg / kg administration groups were prepared.

Next, on the 33rd, 34th and 35th days (day 33, 34 and 35), the test substances shown in Table 1 were orally administered once a day using a 0.5% methylcellulose (MC) solution as a vehicle. The administration on day 33 (day 33) was carried out 1 hour before the OVA exposure.
Further, in preparation for measurement of airway contraction and administration of acetylcholine, rats were anesthetized with pentobarbital sodium (80 mg / kg body weight, ip, Dainippon Sumitomo Pharma Co., Ltd.) on day 36 (day 36). A cannula was attached to the vein. Connect a respirator (SN-480-7, Shinano Manufacturing Co., Ltd.) that delivers 3 mL of air 60 times per minute, and the air pressure that overflows from the side branch of the suction pipe is converted into a pressure transducer (TP-400T, Nihon Kohden) ) Was recorded on a thermal recording device (WT-645G, Nihon Kohden) through a strain pressure amplifier (AP-601G, Nihon Kohden). This air pressure was used as airway ventilation pressure, and airway hypersensitivity was evaluated by administering acetylcholine while increasing the dose every 5 minutes (3.9, 7.8, 15.6, 31.3, 62.5, 125, 250 and 500 μg / kg) from the area under the dose-response curve of airway ventilation pressure. The acetylcholine used here was prepared by diluting a commercially available acetylcholine (Nacalai Tesque) to 500 μg / mL with physiological saline and further diluting it twice before measuring the airway reactivity. It was.
Moreover, the comparison between groups is performed by a one-sided t-test, and the inhibition rate for group 2 (vehicle group) is expressed by the following formula:
Inhibition rate (%) = (A−B) / (A−C) × 100
A: Area under the dose-response curve of the airway ventilation pressure of the group 2 B: Area under the dose-response curve of the airway ventilation pressure of the group to which the test substance was administered did. The results are shown in FIG.

  From FIG. 1, the combined administration group (group 5) of the formula (I) (0.1 mg / kg) and montelukast (10 mg / kg) showed 81% suppression, and the formula (I) 0.1 mg / kg single agent administration The inhibition was stronger than 63% (the sum of 36% and 27%), which is the sum of the inhibition rate of the group (group 3) and the inhibition rate of the montelukast monotherapy group (group 4).

Test Example 2 Cell number measurement test in airway alveolar lavage fluid for rat airway inflammation model A test was performed using rats after airway hypersensitivity measurement. That is, an excessive amount of pentobarbital was intraperitoneally administered to rats after airway hypersensitivity measurement and euthanized. Thereafter, the airway lumen of the rat was washed 3 times with 5 mL of cooled physiological saline. This was used as airway alveolar lavage fluid (BAL), stained with Turku, and the number of cells was counted with a microscope using a hemocytometer. The results are shown in FIG. Moreover, the suppression rate (%) with respect to the group 2 (Vehicle group) of the number of infiltrated cells was calculated using the same method as in Test 1.
Furthermore, after fixing the cell on the slide glass using Cytospin 3 (Shandon), May-Grunwald-Giemsa staining was performed to identify the type of the cell. For each cell type, the inhibition rate (%) relative to group 2 (vehicle group) was calculated using the same method as in test 1. The results are shown in Table 2.

  From FIG. 2, the combined administration group (group 5) of formula (I) (0.1 mg / kg) and montelukast (10 mg / kg) showed 46% suppression, and the formula (I) 0.1 mg / kg single agent administration The inhibition was stronger than 17% (sum of 20% and -3%) which is the sum of the inhibition rate of the group (group 3) and the inhibition rate of the montelukast single agent administration group (group 4). Also, by cell, the effect of the combined use was more than the sum of the suppression of the single agent in any of macrophages, eosinophils, neutrophils and lymphocytes (Table 2).

Test Example 3 Mucin content measurement test in airway alveolar lavage fluid for rat airway inflammation model BAL solution obtained in Test Example 2 was centrifuged at 1000 rpm, 4 ° C (8800, Kubota) for 10 minutes, and then the supernatant The mucin amount was quantified using jacalin which is a mucin-binding lectin. That is, a 96-well plate was coated with BAL solution or mucin standard (Sigma), allowed to stand at 37 ° C. for 2 hours, and then blocked with Block-Ace (Dainippon Sumitomo Pharma). Thereafter, the plate was washed with a phosphate buffer containing 0.05% Tween 20 (Calbiochem), and 2.5 μg / mL biotinylated jacalin (Vector Laboratories) was added and treated at 37 ° C. for 1 hour. The plate was washed again with a phosphate buffer containing 0.05% Tween 20 (Calbiochem), and streptavidin-conjugated alkaline phosphatase (Jackson ImmunoResearch Laboratories) diluted to 1/1000 was added and allowed to react at room temperature for 30 minutes. Further, after washing the plate with a phosphate buffer containing 0.05% Tween 20 (Calbiochem), p-nitrophenyl phosphate liquid substrate (Sigma) was added, and then 3N sodium hydroxide was added to stop the reaction. Absorbance at 405 nm was measured with a multilabel reader (EnVisionTM 2103, Wallac), and the amount of mucin in the airway alveolar lavage fluid was calculated from a calibration curve based on a mucin standard. In addition, the inhibition rate (%) with respect to group 2 (vehicle group) was calculated using the same method as in test 1. The results are shown in FIG.

  From FIG. 3, the combination administration group (group 5) of the formula (I) (0.1 mg / kg) and montelukast (10 mg / kg) showed 70% suppression, and the formula (I) 0.1 mg / kg single agent administration It showed stronger inhibition than -3% (sum of 3% and -6%), which is the sum of the inhibition rate of the group (group 3) and the inhibition rate of the montelukast single agent administration group (group 4).

  From the above results, the combined use of formula (I), which is a prostaglandin D2 receptor antagonist, and montelukast, an LT receptor antagonist, may be more effective than each single agent treatment for asthma treatment. It was suggested.

  Since the effect of the therapeutic agent for asthma of the present invention exceeds the sum of the effects of administration of each drug alone for asthma, it is useful as a therapeutic agent for asthma having a strong pharmacological effect.

Claims (5)

Formula (I):

Or a pharmaceutically acceptable salt thereof,
A therapeutic agent for asthma, comprising a combination of at least one compound selected from the group consisting of montelukast, zafirlukast, and pranlukast, a pharmaceutically acceptable salt thereof, or a solvate thereof.   The therapeutic agent according to claim 1, wherein the asthma is bronchial asthma, or acute bronchitis or chronic bronchitis.   The therapeutic agent of Claim 1 or 2 which is an oral administration agent. Formula (I):

Or a pharmaceutically acceptable salt thereof,
An asthma treatment combination comprising at least one compound selected from the group consisting of montelukast, zafirlukast, and pranlukast, a pharmaceutically acceptable salt thereof, or a solvate thereof.   The therapeutic combination according to claim 4, wherein the asthma is bronchial asthma, or acute bronchitis or chronic bronchitis.

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