WO2005102344A1 - Pharmaceutical composition - Google Patents

Pharmaceutical composition Download PDF

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Publication number
WO2005102344A1
WO2005102344A1 PCT/JP2005/007966 JP2005007966W WO2005102344A1 WO 2005102344 A1 WO2005102344 A1 WO 2005102344A1 JP 2005007966 W JP2005007966 W JP 2005007966W WO 2005102344 A1 WO2005102344 A1 WO 2005102344A1
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WO
WIPO (PCT)
Prior art keywords
acceptable salt
bromide
anticholinergic
pharmacologically acceptable
hydrochloride
Prior art date
Application number
PCT/JP2005/007966
Other languages
French (fr)
Japanese (ja)
Inventor
Yuzuru Abe
Akiko Yoshimatsu
Ichiro Miki
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Publication of WO2005102344A1 publication Critical patent/WO2005102344A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a pharmaceutical composition and the like containing a phosphodiesterase IV inhibitor (PDE-IV inhibitor) and an anticholinergic.
  • PDE-IV inhibitor phosphodiesterase IV inhibitor
  • Patent Document 1 International Publication No. 02Z96463 pamphlet
  • Patent Document 2 International Publication No. 2003Z66044 pamphlet
  • Patent Document 3 International Publication No. 96Z36624 pamphlet
  • Patent Document 4 International Publication No.99Z16768 pamphlet
  • An object of the present invention is to provide 4-[(3,5-dichloro-4-pyridyl) potassium rubamoyl] -7-methoxy-2- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmacology.
  • Another object of the present invention is to provide a pharmaceutical composition containing a chemically acceptable salt and an anticholinergic. Means for solving the problem
  • the present invention relates to the following (1) to (44).
  • the pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • the pharmaceutical composition according to (2) which is cono or citrate.
  • composition according to (1) wherein the anticholinergic agent is piotothiopium bromide, pipato bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
  • Anticholinergic activity Tiotropium, iprat pium, oxitropium, tolterodine and The therapeutic and / or Z-prophylactic agent according to (5), which is a selected compound or a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • the therapeutic and / or Z preventive according to (6) which is cono or citrate.
  • kits comprising: a first component to be contained; and (b) a second component to contain an anticholinergic agent.
  • kits according to (9) which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • kits for treating and / or preventing COPD or asthma comprising a first component containing the first component and (b) a second component containing an anticholinergic.
  • Anticholinergic agent which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • the pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] —4-methoxy-spiro [1,3-benzodioxol-1,2′-cyclopentane described in (18) which is a succinate Or a pharmacologically acceptable salt thereof.
  • composition according to (21) which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
  • compositions according to (22) which is a hydrochloride, a methanesulfonate, a p-toluenesulfonate, a tartrate, an acetate, a cono, or a citrate.
  • Anticholinergic activity The method according to (25), wherein the compound is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine, and oxyptinin, or a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • Equation (I) 4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof
  • (b) CO characterized by administering an effective amount in combination with an anticholinergic agent
  • the pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • the pharmacologically acceptable salts of anticholinergic agents include hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, and acetic acid.
  • the pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • the pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate.
  • Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate and phosphate, acetate, and the like.
  • Organic acid salts such as methanesulfonate, ⁇ toluenesulfonate, succinate, maleate, fumarate, citrate, and tartrate are listed as pharmacologically acceptable metal salts.
  • Alkali metal salts such as calcium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, aluminum salts, zinc salts, etc. are listed as pharmacologically acceptable ammonium salts.
  • salts such as ammonium salts and tetramethylammonium salts.
  • Pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine.
  • Pharmacologically acceptable amino acids The salting, glycine, phenylene Ruaranin, lysine, Asuparagin acid addition salts such as glutamic acid and the like.
  • Compound (I) can be produced by the method described in W096Z36624 or W099Z16768.
  • Compound (I) may exist in stereoisomers such as tautomers, and the pharmaceutical composition of the present invention, COPD or asthma treatment and Z or prophylactic agent, kit, COPD or asthma treatment and Z Alternatively, for prophylactic kits and methods for treating and preventing or preventing COPD or asthma, all possible isomers and mixtures thereof, including these, can be used.
  • Compound (I) of the present invention includes: All possible isomers, including these, and mixtures thereof are included.
  • compound (I) When a salt of compound (I) is obtained, if compound (I) is obtained in the form of a salt, it may be purified as it is, or if compound (I) is obtained in a free form, compound (I) may be appropriately purified What is necessary is just to dissolve or suspend in a solvent, add an acid or a base, and isolate and purify.
  • Compound (I) and its pharmacologically acceptable salts may be present in the form of adducts with water or various solvents. These adducts may also be present in the pharmaceutical composition of the present invention, COPD or COPD. Or a therapeutic and / or prophylactic agent or kit for asthma, a kit for treating and / or preventing COPD or asthma, and a method for treating and / or prophylaxis of COPD or asthma. Or it is included in the pharmacologically acceptable salts thereof.
  • the anticholinergic agent may be any as long as it competitively antagonizes acetylcholine or muscarinic receptors and suppresses cholinergic nervous activity.
  • examples thereof include tiotropium represented by the following formula (A), Oxitropium represented by the following formula (B), pipium (ipratropium) represented by the following formula (C), pluium (flutropium) represented by the following formula (D), and flutropium represented by the following formula (E) ), Atropin represented by the following formula (F), scopolamine represented by the following formula (F), tolterodine represented by the following formula (G), and represented by the following formula (H) Oxybutynin, YM-905 (solifenacin succinate) represented by the following formula (J), LAS-34273 represented by the following formula (K), revatropate (revatropate) represented by the following formula (L), and the like.
  • these pharmacologically acceptable salts include, for example, the salts exemplified as the pharmacologically acceptable salts of the compound (I)) and Hydrates thereof may also be mentioned, and these may be used alone or in combination.
  • n 1 or 2
  • X _, X _, X— and X— are the same when n is 1.
  • the pharmaceutical composition of the present invention can be used, for example, for treating respiratory diseases, and more specifically, asthma, bronchial asthma, COPD, emphysema, chronic bronchitis, adult respiratory distress syndrome, It can be used to treat and prevent or prevent interstitial pneumonia, pulmonary fibrosis, eosinophilic pneumonia.
  • composition of the present invention or compound (I) or a pharmacologically acceptable salt thereof and an anticholinergic agent used in the treatment and / or the prophylactic agent for COPD or asthma are each of these.
  • a combination of two or more preparations is preferable even in the power that can be used or administered as a single agent (mixture) or as a combination of plural preparations.
  • these preparations for example, tablets, injections, or dry powder, aerosol, etc. It is preferably used as a form of an inhalant.
  • the dose ratio (weight Z weight) of compound (I) or a pharmacologically acceptable salt thereof to the anticholinergic agent is appropriately adjusted depending on the combination with the anticholinergic agent to be used, the efficacy of the anticholinergic agent, and the like.
  • 1Z50 (I-drug (I) or a pharmaceutically acceptable salt thereof Z anticholinergic agent) to 5000071 preferably 1Z30 to: LOOOOZl, more preferably lZ20 to 5000Zl, more preferably a ratio between 1/1 to 100/1.
  • the second component When administered as a combination of a plurality of preparations, for example, it contains (a) the first component containing compound (I) or a pharmaceutically acceptable salt thereof, and (b) an anticholinergic agent
  • the second component When administered as a combination of a plurality of preparations, for example, it contains (a) the first component containing compound (I) or a pharmaceutically acceptable salt thereof, and (b) an anticholinergic agent
  • Each of the second component and is separately formulated as described above and prepared as a kit, and each component is simultaneously or at a certain time using the kit, and is administered to the same subject by the same route or a different route. It can also be administered.
  • the material and shape of the kit are not particularly limited as long as it is a container that does not show, for example, denaturation of components as contents due to external temperature or light during storage, and elution of chemical components from the container.
  • Two or more containers e.g., vials, nogs, etc.
  • the contents also become active, and the contents of the first and second components are administered via separate routes (e.g., tubes, etc.) or via the same route
  • Those having a possible form are used.
  • Specific examples include kits for tablets, injections, inhalants, and the like. Inhalation kits can also be combined with commonly used metered dose inhalers (MDIs), powder inhalers, etc. to provide one or more of the above for the administration of the first and second components.
  • MDIs metered dose inhalers
  • the above-mentioned inhaler may be included.
  • one or more of the capsules containing the dry powder containing the effective dose unit of the first component and the capsule containing the dry powder containing the effective dose unit of the second component are compatible with the delivery of the dry powder from the capsule.
  • a dry powder suction device or the like may be included.
  • the kit also includes a multi-dose dry powder inhaler (MDPI) in which the drug storage portion comprises a drug storage portion containing the first component dry powder and a drug storage portion containing the second component dry powder.
  • MDPI multi-dose dry powder inhaler
  • the method for treating and preventing or preventing COPD or asthma relates to the compound (I) or the pharmacology thereof used in the pharmaceutical composition or the agent for treating and preventing COPD or asthma described above. Or use of chemically acceptable salts and anticholinergics It can be carried out in the same manner as the method. That is, the compound (I) or a pharmacologically acceptable salt thereof and an anticholinergic agent are formulated so as to contain the respective active ingredients. It can be carried out by administering two or more formulations in combination. When a plurality of preparations are administered in combination, these preparations can be administered simultaneously or separately at an interval, and can also be administered using a kit as described above.
  • Test Example 1 Effect of drug on electrical stimulation-induced bronchial smooth muscle contraction
  • the test was performed in the presence of 5 ⁇ mol ZL of indomethacin (Sigma-Aldrich, Missouri, USA).
  • the electrical stimulation was performed using a stimulator (SEN-3301, Nihon Kohden) with a rectangular pulse at a frequency of 8 Hz, a duration of 0.5 ms, a voltage of 30 V, and a stimulation time of 15 seconds.
  • a stimulator SEN-3301, Nihon Kohden
  • an aqueous solution of tiotropium bromide (Boehringer Ingelno, Im, Germany) was added to the Magnus tube so that the final concentration was lOnmolZL. Twenty minutes later, electrical stimulation was performed again (a group treated with palladium thionous bromide).
  • Electrical stimulation elicits a reproducible contractile response in two phases: an initial phase and a slow phase.
  • the change in tension with respect to each electrical stimulus in each treatment group was measured, and the contraction height in each phase was determined.
  • Table 1 shows the ratio of the height of contraction by the second stimulus to the contraction by the first stimulus. The values are shown as the standard error of the mean.
  • the pharmaceutical composition or the therapeutic and / or prophylactic agent for COPD or asthma used in the present invention comprises compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent, respectively.
  • compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent respectively.
  • it can be used, administered or manufactured as a single agent or as a combination of plural formulations.
  • these pharmaceutical compositions or the therapeutic and / or prophylactic agents for COPD or asthma are in a unit dosage form suitable for oral administration such as tablets or parenteral administration such as inhalants and injections.
  • they can be used or administered simultaneously or separately at an interval.
  • compositions each contain a pharmaceutically acceptable diluent, excipient, disintegrant, lubricant, binder, surfactant, water, physiological saline, vegetable oil solubilizer, etc. in addition to the active ingredient. It can be prepared by a conventional method using a Zhanging agent, a preservative, an antioxidant and the like as appropriate.
  • excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, surfactants such as fatty acid esters, and plasticizers such as glycerin. Agents and the like may be used in accordance with a conventional method.
  • water physiological saline
  • vegetable oil such as soybean oil
  • a solvent such as a solvent
  • a solubilizing agent such as soybean oil
  • an isotonic agent such as sodium bicarbonate
  • a preservative such as sodium bicarbonate
  • an antioxidant such as sodium bicarbonate
  • Inhalants are also prepared by powdering or liquidifying the active ingredient, dispersing it in an inhalation propellant or carrier, and filling an appropriate inhalation container.
  • an inhalation propellant When the active ingredient is a powder, an ordinary mechanical powder inhaler can be used, and when the active ingredient is a liquid, an inhaler such as a nebulizer can be used.
  • the inhalation propellant conventionally known ones can be widely used, and CFC-11, CFC-12, CFC-21, CFC-22, CFC113, CFC114, CFC123, CFC-142c, CFC-C.
  • chlorofluorocarbon 227 chlorofluorocarbon C318, fluorocarbon compounds such as 1,1,1,2-tetrafluoroethane, hydrocarbons such as propane, isobutane and n-butane, ethers such as getyl ether, Nitrogen gas, carbon dioxide gas, etc. Compressed gas. Further, if necessary, one or more diluents, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified above are selected. More auxiliary components can be added.
  • compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent are used or administered as a combination of a plurality of preparations for the above-mentioned purpose, the dose and the number of administrations of each compound should be Although it varies depending on the form, age, weight, symptoms, etc. of the patient, it is usually preferable to administer Compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent at the following doses per day.
  • the compound (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic, per adult, respectively 0. 01 ⁇ : LOOOmg with 0. 1 8 to 50 Omg , Preferably 0.05 to 30011 ⁇ and 1 ) «8 to 20011 ⁇ , more preferably 0.1 to 200 mg and ⁇ : L0mg, usually once or several times a day, simultaneously or separately at different times Administer separately.
  • Compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent are administered in an amount of 1 ⁇ g to 100 mg and 0 mg / adult each. . 01 ⁇ g ⁇ 50mg, preferably a 5 ⁇ g ⁇ 30mg with 0. 1 ⁇ g ⁇ 20mg, more preferably 10 8-20111 8 with 0. 5 8 ⁇ 0. 5mg, typically once a day or several times Thus, they may be administered simultaneously or separately at intervals.
  • the dose and frequency of administration are determined by the dosage form, patient age, When used or administered as a combination of a plurality of the above-mentioned preparations, it is preferable to prepare, use, or administer as a single preparation at each dose when used or administered, depending on body weight, symptoms, and the like.
  • a tablet having the following composition is prepared by a conventional method.
  • Compound (I) 40 g, lactose 286.8 g and 60 g of potato starch is mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto.
  • This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • 1.2 g of magnesium stearate was added to the mixture and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having an 8 mm diameter punch. Containing).
  • a tablet having the following composition is prepared by a conventional method. 4 g of oxypeptinine hydrochloride, 300. Og of lactose and 68. Og of potato starch are mixed, and 200 g of a 10% aqueous solution of hydroxypropyl cellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. 8. Og of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) having a punch of 8 mm in diameter. Omg).
  • RT-15 type manufactured by Kikusui Co., Ltd.
  • a tablet having the following composition is prepared by a conventional method.
  • Compound (I) 40 g
  • oxypeptin hydrochloride 4 g
  • lactose L-sugar 286.0 g
  • potato powder 56.0 g
  • 120g 120g of 10% aqueous solution of Lulose.
  • the mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • Magnesium stearate 2.Og was added and mixed, and the mixture was compressed with a tableting machine (RT-15 type, manufactured by Kikusui) having an 8 mm diameter punch, and tablets (compound (1) 20 Omg and oxyptinin hydrochloride 2. containing Omg).
  • RT-15 type manufactured by Kikusui
  • An injection having the following composition is prepared by a conventional method.
  • Compound (I) lg is dissolved in purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection are added. This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion is aseptically filtered using a 0.2 ⁇ m disposable membrane filter, and then aseptically filled into glass vials in 2 mL increments, containing an injection (containing 2.Omg of active ingredient per vial). Get).
  • An injection having the following composition is prepared by a conventional method. 0.15 g of pipium bromide is dissolved in refined soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection are added. This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion is aseptically filtered using a 0.2-m disposable membrane filter, and aseptically filled into glass vials in a volume of 2 mL each to give an injection (0.3 mg of active ingredient per vial). Containing). Ipratropium bromide 0 3 mg purified soybean oil 20000 purified egg yolk lecithin 240 mg glycerin for injection 500 mg distilled water for injection 17 2 ml
  • An injection having the following composition is prepared by a conventional method.
  • Compound (I) lg and 0.15 g of iprat bromide are dissolved in purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of daliserine for injection are added. This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion was aseptically filtered using a 0.2-m disposable membrane filter, and aseptically filled into glass vials in 2 mL increments to give an injection (compound (1) 2.Omg per vial). And 0.3 mg of pipium in the mouth of iprat bromide).
  • a dry powder inhalant having the following compositional power is prepared.
  • the compound (I) is pulverized using a jet mill (volume average particle size: 5 to 20 m).
  • the obtained compound (I) powder and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) were mixed at a weight ratio of 1: 5.
  • the formulation can be administered with a conventional dry powder inhaler.
  • Dry powder inhalant (pium thiot mouth bromide monohydrate)
  • a dry powder inhalant having the following compositional power is prepared.
  • pulverized palladium thionite monohydrate is crushed (volume average particle size: 5 to 20 m).
  • the pulverized product of palladium monohydrate of thiotolipide bromide and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) are mixed at a weight ratio of 1: 249 to obtain a dry powder preparation.
  • the formulation can be administered with a conventional dry powder inhaler.
  • a dry powder inhalant having the following composition is prepared by a conventional method.
  • the compound (I) and palladium thionite monohydrate are pulverized (volume average particle diameter: both 5 to 20 ⁇ m).
  • the obtained compound (I), each pulverized product of palladium thionite bromide monohydrate and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) were mixed in a weight ratio of 82: 1: 417, and the resulting mixture was mixed with dry powder.
  • the formulation can be administered with a conventional dry powder inhaler.
  • a dry powder inhalant having the following composition is prepared by a conventional method. Pulverize oxytropium bromide using a jet mill (volume average particle size: 5 to 20 m). The obtained ground oxitropium bromide and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) are mixed at a weight ratio of 1:50 to obtain a dry powder preparation. The formulation can be administered with a conventional dry powder inhaler.
  • a dry powder inhalant having the following composition is prepared by a conventional method.
  • the compound (I) and oxotropium bromide are ground using a jet mill (volume average particle size: 5 to 20 m).
  • the obtained compound (I), crushed oxotropium bromide and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) are mixed at a weight ratio of 10: 1: 50 to obtain a dry powder preparation.
  • the formulation can be administered with a conventional dry powder inhaler.
  • a tablet having the following composition is prepared by a conventional method. 4 g of tolterodine tartrate, 300. Og of lactose and 68. Og of potato starch are mixed, and 200 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. 8. Og of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) having a punch of 8 mm in diameter. Omg). [Table 13]
  • Tolterodine tartrate 2.0 mg Lactose 15.0 mg Potato starch 34.0 mg Hydroxip-mouthed pinoresenolerose 10.0 mg Magnesium stearate 4.0 mg
  • a tablet having the following composition is prepared by a conventional method.
  • Compound (I) 40 g
  • tolterodine tartrate (4 g)
  • potato powder 56.Og
  • 120 g 120 g
  • a 10% aqueous solution of hydroxypropinolecellulose is added thereto.
  • the mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • Magnesium stearate 2.Og was added and mixed, and the mixture was compressed with a tableting machine (RT-15 type, manufactured by Kikusui) having an 8 mm diameter punch, and tablets (compound (1) 20 Omg and tolterodine tartrate 2. containing Omg)
  • composition containing 2- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof and an anticholinergic.

Abstract

Disclosed is a pharmaceutical composition containing (a) 4-[(3,5-dichloro-4-pyridyl)carbamoyl]-7-methoxy-2-(4-methylpiperazine-1-ylcarbonyl)benzofuran formula (I) or a pharmacologically acceptable salt thereof and (b) an anticholinergic agent. Also disclosed is such a pharmaceutical composition wherein the anticholinergic agent is a compound selected from the group consisting of tiotropium, ipratropium, oxitropium, tolterodine and oxybutynin, or a pharmacologically acceptable salt thereof.

Description

医薬組成物  Pharmaceutical composition
技術分野  Technical field
[0001] 本発明は、ホスホジエステラーゼ IV阻害剤（PDE— IV阻害剤）と抗コリン剤とを含 有する医薬組成物などに関する。  The present invention relates to a pharmaceutical composition and the like containing a phosphodiesterase IV inhibitor (PDE-IV inhibitor) and an anticholinergic.
背景技術  Background art
[0002] 従来、 PDE— IV阻害剤と抗コリン剤の併用投与が、喘息または慢性閉塞性肺疾患  [0002] Conventionally, combined administration of a PDE-IV inhibitor and an anticholinergic has been used for asthma or chronic obstructive pulmonary disease.
(COPD)などの閉塞性肺疾患に有用であることが知られている (特許文献 1、特許文 献 2参照)。  It is known to be useful for obstructive pulmonary diseases such as (COPD) (see Patent Document 1 and Patent Document 2).
[0003] 一方、 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4 —メチルビペラジン一 1—ィルカルボ-ル)ベンゾフランまたはその薬理学的に許容 される塩を PDE— IV阻害剤として用いることが知られている (特許文献 3、特許文献 4参照)。  [0003] On the other hand, 4-[(3,5-dichloro-14-pyridyl) potassium rubamoyl] —7-methoxy-12- (4-methylbiperazine-11-ylcarboyl) benzofuran or a pharmaceutically acceptable salt thereof is used. It is known to be used as a PDE-IV inhibitor (see Patent Documents 3 and 4).
特許文献 1：国際公開第 02Z96463号パンフレット  Patent Document 1: International Publication No. 02Z96463 pamphlet
特許文献 2：国際公開第 2003Z66044号パンフレット  Patent Document 2: International Publication No. 2003Z66044 pamphlet
特許文献 3：国際公開第 96Z36624号パンフレット  Patent Document 3: International Publication No. 96Z36624 pamphlet
特許文献 4:国際公開第 99Z16768号パンフレット  Patent Document 4: International Publication No.99Z16768 pamphlet
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] 本発明の目的は、 4— [ (3, 5—ジクロロ— 4—ピリジル）力ルバモイル]— 7—メトキ シ 2—（4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学 的に許容される塩と抗コリン剤とを含有する医薬組成物などを提供することにある。 課題を解決するための手段 [0004] An object of the present invention is to provide 4-[(3,5-dichloro-4-pyridyl) potassium rubamoyl] -7-methoxy-2- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmacology. Another object of the present invention is to provide a pharmaceutical composition containing a chemically acceptable salt and an anticholinergic. Means for solving the problem
[0005] 本発明は、以下の（1)〜 (44)に関する。 The present invention relates to the following (1) to (44).
(1) (a)式 (I)  (1) (a) Equation (I)
[化 1]
Figure imgf000004_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤とを含有する医薬組成物。 [Chemical 1]
Figure imgf000004_0001
4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof (b) a pharmaceutical composition containing an anticholinergic agent;
(2) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンお よびォキシプチニン力 なる群力 選ばれる化合物またはその薬理学的に許容され る塩である（1)記載の医薬組成物。  (2) Anticholinergic activity Tiotropium, iprat pium, oxitropium, tolterodine, and oxyptinin activity The pharmaceutical composition according to (1), which is a selected compound or a pharmacologically acceptable salt thereof.
(3) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコノ、ク酸塩である（2)記載の医薬組成物。  (3) The pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. The pharmaceutical composition according to (2), which is cono or citrate.
(4) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、 酒石酸トルテロジンまたは塩酸ォキシプチニンである（1)記載の医薬組成物。  (4) The pharmaceutical composition according to (1), wherein the anticholinergic agent is piotothiopium bromide, pipato bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
(5) (a)式（I)  (5) (a) Formula (I)
[化 2]  [Formula 2]
Figure imgf000004_0002
Figure imgf000004_0002
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤を有効成分とする同時にまたは時間を置いて別々に投与 するための COPDまたは喘息の治療および Zまたは予防剤。 4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof (b) A therapeutic or Z- or prophylactic agent for COPD or asthma, which is administered simultaneously or separately at intervals with an anticholinergic agent as an active ingredient.
(6) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンお よびォキシプチニン力 なる群力 選ばれる化合物またはその薬理学的に許容され る塩である（5)記載の治療および Zまたは予防剤。 (6) Anticholinergic activity: Tiotropium, iprat pium, oxitropium, tolterodine and The therapeutic and / or Z-prophylactic agent according to (5), which is a selected compound or a pharmacologically acceptable salt thereof.
(7) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコノ、ク酸塩である（6)記載の治療および Zまたは予防剤。  (7) The pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. The therapeutic and / or Z preventive according to (6), which is cono or citrate.
(8) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、 酒石酸トルテロジンまたは塩酸ォキシプチニンである（5)記載の治療および Zまたは 予防剤。  (8) The therapeutic and / or Z- or prophylactic agent according to (5), wherein the anticholinergic agent is piodium tiobromide, palladium pipium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
(9) (a)式 (I)  (9) (a) Equation (I)
[化 3] [Formula 3]
Figure imgf000005_0001
Figure imgf000005_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を含有する第 1成分と (b)抗コリン剤を含有する第 2成分を有することを特 徴とするキット。 4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt A kit comprising: a first component to be contained; and (b) a second component to contain an anticholinergic agent.
(10) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（9)記載のキット。 (10) Anticholinergic agent The kit according to (9), which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
(11) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（10)記載のキット。  (11) The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. The kit according to (10), which is a succinate.
(12) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシブチュンである（9)記載のキット。  (12) The kit according to (9), wherein the anticholinergic agent is piodium thiotope bromide, pium iodide bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
(13) (a)式 (I) [化 4]
Figure imgf000006_0001
(13) (a) Equation (I) [Formula 4]
Figure imgf000006_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を含有する第 1成分と (b)抗コリン剤を含有する第 2成分を有することを特 徴とする COPDまたは喘息の治療および Zまたは予防用キット。 4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt A kit for treating and / or preventing COPD or asthma, comprising a first component containing the first component and (b) a second component containing an anticholinergic.
(14) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（13)記載のキット。  (14) Anticholinergic agent The kit according to (13), which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
(15) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（14)記載のキット。  (15) The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. The kit according to (14), which is a succinate.
(16) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシブチュンである（13)記載のキット。  (16) The kit according to (13), wherein the anticholinergic agent is piodium tiobromide, piodium pipromide, oxytropium bromide, tolterodine tartrate or oxybutun hydrochloride.
(17) 抗コリン剤と同時にまたは時間を置いて別々に投与するための式 (I)  (17) Formula (I) for administration simultaneously with or separately from an anticholinergic agent
[化 5] [Formula 5]
Figure imgf000006_0002
Figure imgf000006_0002
( I )  (I)
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩。 (18) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（ 17)記載の 4— [ (3, 5 ジクロロ一 4 ピリジル)力ルバモイル] - 7- メトキシ 2—（4ーメチルビペラジン 1ーィルカルボニル）ベンゾフランまたはその 薬理学的に許容される塩。 4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] —— 7-methoxy-12- (4-methylbiperazine 1-ylcarboyl) benzofuran or a pharmacologically acceptable salt thereof. (18) Anticholinergic activity The compound is selected from the group consisting of tiotropium, ipratophorium, oxitropium, tolterodine, and oxyptinin, or a pharmacologically acceptable salt thereof. (1-4 pyridyl) caprubayl] -7-methoxy-2- (4-methylbiperazine 1-ylcarbonyl) benzofuran or a pharmaceutically acceptable salt thereof.
(19) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（18)記載の 7— [2— (3, 5 ジクロロー 4 ピリジル）ー1ーォキ ソェチル]— 4—メトキシースピロ [1, 3 ベンゾジォキソールー 2, 1 '—シクロペンタ ン]またはその薬理学的に許容される塩。  (19) The pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] —4-methoxy-spiro [1,3-benzodioxol-1,2′-cyclopentane described in (18) which is a succinate Or a pharmacologically acceptable salt thereof.
(20) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシブチュンである（17)記載の 4 [ (3, 5 ジク ロロ一 4 ピリジル）力ルバモイル] 7—メトキシ一 2— (4—メチルビペラジン 1 ィ ルカルボニル)ベンゾフランまたはその薬理学的に許容される塩。 (20) The 4 [(3,5 dichloro-1-4 pyridyl) potassium thiolamine described in (17), wherein the anticholinergic agent is piodium tioto bromide, palladium pipato bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride. 7-Methoxy-1- (4-methylbiperazine 1-ylcarbonyl) benzofuran or a pharmacologically acceptable salt thereof.
(21) 抗コリン剤と同時にまたは時間を置いて別々に投与するための式 (I) (21) Formula (I) for administration simultaneously with or separately from an anticholinergic agent
[化 6]  [Formula 6]
Figure imgf000007_0001
Figure imgf000007_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を有効成分として含有する医薬組成物。 4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt Pharmaceutical composition containing as an active ingredient.
(22) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（21)記載の医薬組成物。  (22) The pharmaceutical composition according to (21), which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
(23) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコノ、ク酸塩である（22)記載の医薬組成物。 (23) Pharmaceutically acceptable salts of anticholinergic drugs include hydrochloride, hydrobromide and iodine. (22) The pharmaceutical composition according to (22), which is a hydrochloride, a methanesulfonate, a p-toluenesulfonate, a tartrate, an acetate, a cono, or a citrate.
(24) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシプチニンである（21)記載の医薬組成物。 (24) The pharmaceutical composition according to (21), wherein the anticholinergic agent is piodium thiotope bromide, palladium piodium bromide, oxitropium bromide, tolterodine tartrate or oxyptyninine hydrochloride.
(25) (a)式 (I) (25) (a) Equation (I)
[化 7] [Formula 7]
Figure imgf000008_0001
Figure imgf000008_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩および (b)抗コリン剤を同時にまたは時間を置いて別々に投与することを 特徴とする COPDまたは喘息の治療および Zまたは予防方法。 4-[(3,5-dichloro-1-pyridyl) potassium] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarboyl) benzofuran or its pharmaceutically acceptable salts and (b) A method for treating and preventing or preventing COPD or asthma, which comprises administering an anticholinergic agent simultaneously or separately at an interval.
(26) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（25)記載の方法。  (26) Anticholinergic activity The method according to (25), wherein the compound is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine, and oxyptinin, or a pharmacologically acceptable salt thereof.
(27) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（26)記載の方法。  (27) The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. (26) The method according to (26), which is a succinate.
(28) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシブチュンである（25)記載の方法。  (28) The method according to (25), wherein the anticholinergic agent is palladium tioto bromide, pium palladium bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
(29) (a)式 (I)
Figure imgf000009_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤との組み合わせの有効量を投与することを特徴とする CO(29) (a) Equation (I)
Figure imgf000009_0001
4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof (b) CO characterized by administering an effective amount in combination with an anticholinergic agent
PDまたは喘息の治療および Zまたは予防方法。 How to treat and prevent or prevent PD or asthma.
(30) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（29)記載の方法。  (30) Anticholinergic activity The method according to (29), which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
(31) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（30)記載の方法。  (31) The pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. (30) The method according to (30), which is a succinate.
(32) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシブチュンである（29)記載の方法。  (32) The method according to (29), wherein the anticholinergic agent is palladium tioto bromide, pium palladium bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
(33) COPDまたは喘息の治療および Zまたは予防剤の製造のための（a)式 (I) [化 9]  (33) Formula (a) for the manufacture of a therapeutic and / or prophylactic agent for COPD or asthma
Figure imgf000009_0002
Figure imgf000009_0002
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩および (b)抗コリン剤の使用。 4-[(3,5-dichloro-1-pyridyl) potassium] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarboyl) benzofuran or its pharmaceutically acceptable salts and (b) Use of anticholinergic agents.
(34) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（33)記載の使用。 (34) Anticholinergic drug activity Tiotropium, iprat mouth pium, oxitropium, tolterodine (33) The use according to (33), wherein the compound is a compound selected from the group consisting of oxyptinin power and group power, or a pharmacologically acceptable salt thereof.
[0012] (35) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（34)記載の使用。 (0012) The pharmacologically acceptable salts of anticholinergic agents include hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, and acetic acid. Use according to (34), which is a salt or a succinate.
(36) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシプチニンである（33)記載の使用。  (36) The use according to (33), wherein the anticholinergic agent is piodium tiobromide, pipium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
(37) (a)式 (I)  (37) (a) Equation (I)
[化 10]  [Formula 10]
Figure imgf000010_0001
Figure imgf000010_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤を同時にまたは時間を置いて別々に投与するための CO PDまたは喘息の治療および Zまたは予防剤の製造のための（a)および (b)の使用。 4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof (b) Use of (a) and (b) for the treatment of CO PD or asthma and for the manufacture of a Z or prophylactic agent for simultaneous or separate administration of anticholinergic agents.
(38) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である（37)記載の使用。 (38) Anticholinergic activity The use according to (37), which is a compound selected from the group consisting of tiotropium, ipratophium pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof.
(39) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（38)記載の使用。  (39) The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. Use according to (38), which is a succinate.
[0013] (40) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシプチニンである（37)記載の使用。  (40) The use according to (37), wherein the anticholinergic agent is piotothiopium bromide, pipato bromide, oxitropium bromide, tolterodine tartrate or oxyptyninine hydrochloride.
(41) (a)式 (I)  (41) (a) Equation (I)
[化 11]
Figure imgf000011_0001
[Formula 11]
Figure imgf000011_0001
( I  (I
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を含有する第 1成分と (b)抗コリン剤を含有する第 2成分を有する COPD または喘息の治療および Zまたは予防用キットの製造のための（a)および (b)の使用  4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt Use of (a) and (b) for the manufacture of a kit for the treatment and Z or prevention of COPD or asthma having a first component containing and (b) a second component containing an anticholinergic agent
(42) 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジン およびォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容さ れる塩である (41)記載の使用。 (42) Anticholinergic activity The use according to (41), which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine, and oxyptinin, or a pharmacologically acceptable salt thereof.
(43) 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ 化水素酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩また はコハク酸塩である（42)記載の使用。  (43) The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or acetate. Use according to (42), which is a succinate.
(44) 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム 、酒石酸トルテロジンまたは塩酸ォキシプチニンである (41)記載の使用。  (44) The use according to (41), wherein the anticholinergic agent is palladium tioto bromide, palladium pipium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
発明の効果  The invention's effect
[0014] 本発明により、 4— [ (3, 5 ジクロロ一 4—ピリジル）力ルバモイル]— 7—メトキシ一 2- (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的 に許容される塩と抗コリン剤とを含有する医薬組成物などが提供される。  According to the present invention, 4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] -7-methoxy-1- (4-methylbiperazine-1-ylcarboxy) benzofuran or a pharmacologically acceptable salt thereof is used. And a pharmaceutical composition containing the salt and an anticholinergic agent.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0015] 以下、式 (I) [0015] Hereinafter, the formula (I)
[化 12]
Figure imgf000012_0001
[Formula 12]
Figure imgf000012_0001
( I  (I
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルピペラジン 1ーィルカルボ-ル）ベンゾフランを化合物 (I)と 、う。 4-([3,5 dichloro- 1 -pyridyl) potassium rubamoyl]-7-methoxy-12- (4-methylpiperazine 1-ylcarbol) benzofuran is referred to as compound (I).
化合物 (I)の薬理学的に許容される塩は、薬理学的に許容される酸付加塩、金属 塩、アンモ-ゥム塩、有機アミン付加塩、アミノ酸付加塩などを包含する。  Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
化合物 (I)の薬理学的に許容される酸付加塩としては、塩酸塩、硫酸塩、臭化水素 酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩などの無機酸塩、酢酸塩、メタンススホン酸 塩、 ρ トルエンスルホン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、クェン酸塩、 酒石酸塩などの有機酸塩があげられ、薬理学的に許容される金属塩としては、ナトリ ゥム塩、カリウム塩などのアルカリ金属塩、マグネシウム塩、カルシウム塩などのアル カリ土類金属塩、アルミニウム塩、亜鉛塩などがあげられ、薬理学的に許容されるァ ンモ -ゥム塩としては、アンモ-ゥム塩、テトラメチルアンモ -ゥム塩などの塩があげら れ、薬理学的に許容される有機アミン付加塩としては、モルホリン、ピぺリジンなどの 付加塩があげられ、薬理学的に許容されるアミノ酸付加塩としては、グリシン、フエ二 ルァラニン、リジン、ァスパラギン酸、グルタミン酸などの付加塩があげられる。  Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate and phosphate, acetate, and the like. Organic acid salts such as methanesulfonate, ρtoluenesulfonate, succinate, maleate, fumarate, citrate, and tartrate are listed as pharmacologically acceptable metal salts. Alkali metal salts such as calcium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, aluminum salts, zinc salts, etc. are listed as pharmacologically acceptable ammonium salts. Are salts such as ammonium salts and tetramethylammonium salts.Pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine. Pharmacologically acceptable amino acids The salting, glycine, phenylene Ruaranin, lysine, Asuparagin acid addition salts such as glutamic acid and the like.
次に、化合物 (I)の製造方法について説明する。  Next, a method for producing the compound (I) will be described.
化合物（I)は、 W096Z36624または W099Z16768に記載の方法により製造す ることがでさる。  Compound (I) can be produced by the method described in W096Z36624 or W099Z16768.
化合物 (I)には、互変異性体などの立体異性体が存在し得るが、本発明の医薬組 成物、 COPDまたは喘息の治療および Zまたは予防剤、キット、 COPDまたは喘息 の治療および Zまたは予防用キットならびに COPDまたは喘息の治療および Zまた は予防方法には、これらを含め、全ての可能な異性体およびそれらの混合物を使用 することができ、本発明の化合物 (I)には、これらを含め、全ての可能な異性体およ びそれらの混合物が包含される。 化合物 (I)の塩を取得した 、とき、化合物 (I)が塩の形で得られるときはそのまま精 製すればよぐまた、遊離の形で得られるときは、化合物 (I)を適当な溶媒に溶解また は懸濁し、酸または塩基を加えて単離、精製すればよい。 Compound (I) may exist in stereoisomers such as tautomers, and the pharmaceutical composition of the present invention, COPD or asthma treatment and Z or prophylactic agent, kit, COPD or asthma treatment and Z Alternatively, for prophylactic kits and methods for treating and preventing or preventing COPD or asthma, all possible isomers and mixtures thereof, including these, can be used.Compound (I) of the present invention includes: All possible isomers, including these, and mixtures thereof are included. When a salt of compound (I) is obtained, if compound (I) is obtained in the form of a salt, it may be purified as it is, or if compound (I) is obtained in a free form, compound (I) may be appropriately purified What is necessary is just to dissolve or suspend in a solvent, add an acid or a base, and isolate and purify.
また、化合物 (I)およびその薬理学的に許容される塩は、水または各種溶媒との付 加物の形で存在することもある力 これらの付加物も本発明の医薬組成物、 COPDま たは喘息の治療および Zまたは予防剤、キット、 COPDまたは喘息の治療および Z または予防用キットならびに COPDまたは喘息の治療および Zまたは予防方法に使 用することができ、本発明の化合物 (I)またはその薬理学的に許容される塩に包含さ れる。  Compound (I) and its pharmacologically acceptable salts may be present in the form of adducts with water or various solvents. These adducts may also be present in the pharmaceutical composition of the present invention, COPD or COPD. Or a therapeutic and / or prophylactic agent or kit for asthma, a kit for treating and / or preventing COPD or asthma, and a method for treating and / or prophylaxis of COPD or asthma. Or it is included in the pharmacologically acceptable salts thereof.
抗コリン剤としては、アセチルコリンまたはムスカリン受容体において競合的に拮抗 し、コリン作動性神経活動を抑制するものであればいずれでもよいが、例えば下記式 (A)で表されるチォトロピウム（tiotropium)、下記式（B)で表されるォキシトロピウム (oxitropium)、下記式（C)で表されるィプラト口ピウム（ipratropium)、下記式（D) で表されるフルト口ピウム（flutropium)、下記式（E)で表されるアト口ピン（atropin) 、下記式 (F)で表されるスコポラミン（scopolamine)、下記式（G)で表されるトルテロ ジン（tolterodine)、下記式（H)で表されるォキシブチニン（oxybutynin)、下記式 (J)で表される YM— 905 (solifenacin succinate)、下記式（K)で表される LAS— 34273、下記式（L)で表されるレバトロペート（revatropate)など、およびそれらの 立体異性体 (例えば、鏡像異性体など)があげられる。また、これらの薬理学的に許 容される塩 (該薬理学的に許容される塩としては、前記化合物 (I)の薬理学的に許容 される塩として例示した塩などがあげられる）およびそれらの水和物などもあげられ、 これらを単独でまたは組み合わせて用いてもょ 、。 The anticholinergic agent may be any as long as it competitively antagonizes acetylcholine or muscarinic receptors and suppresses cholinergic nervous activity. Examples thereof include tiotropium represented by the following formula (A), Oxitropium represented by the following formula (B), pipium (ipratropium) represented by the following formula (C), pluium (flutropium) represented by the following formula (D), and flutropium represented by the following formula (E) ), Atropin represented by the following formula (F), scopolamine represented by the following formula (F), tolterodine represented by the following formula (G), and represented by the following formula (H) Oxybutynin, YM-905 (solifenacin succinate) represented by the following formula (J), LAS-34273 represented by the following formula (K), revatropate (revatropate) represented by the following formula (L), and the like. And their stereoisomers (e.g., enantiomers Etc.). In addition, these pharmacologically acceptable salts (the pharmacologically acceptable salts include, for example, the salts exemplified as the pharmacologically acceptable salts of the compound (I)) and Hydrates thereof may also be mentioned, and these may be used alone or in combination.
Figure imgf000014_0001
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0003
( ) (L)  () (L)
{式中、 nは 1または 2を表し、 X _、 X _、 X—および X—は、 nが 1のとき、それぞれ同  {Where, n represents 1 or 2, and X _, X _, X— and X— are the same when n is 1.
A B C D  A B C D
一または異なって、 F―、 Cl_、 Br", Γ、 CH SO 0_、 CH CH SO 0_、 CH OSO One or different, F-, Cl _ , Br ", CH, CH SO 0_, CH CH SO 0_, CH OSO
3 2 3 2 2 3 2 3 2 3 2 2 3 2
0_、 C H SO 0_または CH COO—を表し、 nが 2のとき [ (CH COO) ]2_を表す } 0_, CH SO 0_ or CH COO—, when n is 2, [(CH COO)] 2_ }
6 5 2 3 2 2  6 5 2 3 2 2
[0018] 本発明の医薬組成物は、例えば呼吸器疾患の治療などに使用することができ、より 具体的には喘息、気管支喘息、 COPD、肺気腫、慢性気管支炎、成人呼吸促迫症 候群、間質性肺炎、肺繊維症、好酸球性肺炎などの治療および Zまたは予防に使 用することができる。  The pharmaceutical composition of the present invention can be used, for example, for treating respiratory diseases, and more specifically, asthma, bronchial asthma, COPD, emphysema, chronic bronchitis, adult respiratory distress syndrome, It can be used to treat and prevent or prevent interstitial pneumonia, pulmonary fibrosis, eosinophilic pneumonia.
[0019] 本発明の医薬組成物、または COPDもしくは喘息の治療および Zもしくは予防剤 で使用される化合物 (I)またはその薬理学的に許容される塩と抗コリン剤は、これらそ れぞれの有効成分を含有するように製剤化したものであれば、単剤 (合剤）としてでも 複数の製剤の組み合わせとしてでも使用または投与することができる力 中でも 2つ 以上の製剤の組み合わせが好ま 、。複数の製剤の組み合わせとして使用または投 与する際には、同時にまたは時間を置いて別々に使用または投与することができる。 なお、これら製剤は、例えば錠剤、注射剤、またはドライパウダー、エアロゾルなどの 吸入剤などの形態として用いることが好ま 、。 The pharmaceutical composition of the present invention, or compound (I) or a pharmacologically acceptable salt thereof and an anticholinergic agent used in the treatment and / or the prophylactic agent for COPD or asthma are each of these. As long as it is formulated so as to contain the active ingredient of the above, a combination of two or more preparations is preferable even in the power that can be used or administered as a single agent (mixture) or as a combination of plural preparations. . When used or administered as a combination of multiple preparations, they can be used or administered simultaneously or separately at intervals. In addition, these preparations, for example, tablets, injections, or dry powder, aerosol, etc. It is preferably used as a form of an inhalant.
化合物 (I)またはその薬理学的に許容される塩と抗コリン剤との用量比 (重量 Z重 量）は、使用する抗コリン剤との組み合わせ、抗コリン剤の効力などに応じて適宜調 整すればよいが、具体的には例えば 1Z50 (ィ匕合物 (I)またはその薬理学的に許容 される塩 Z抗コリン剤）〜 5000071、好ましくは 1Z30〜： LOOOOZl、より好ましくは lZ20〜5000Zl、さらに好ましくは 1/10〜1000/1の間の比である。  The dose ratio (weight Z weight) of compound (I) or a pharmacologically acceptable salt thereof to the anticholinergic agent is appropriately adjusted depending on the combination with the anticholinergic agent to be used, the efficacy of the anticholinergic agent, and the like. Specifically, for example, 1Z50 (I-drug (I) or a pharmaceutically acceptable salt thereof Z anticholinergic agent) to 5000071, preferably 1Z30 to: LOOOOZl, more preferably lZ20 to 5000Zl, more preferably a ratio between 1/1 to 100/1.
[0020] 複数の製剤の組み合わせとして投与する際には、例えば (a)化合物 (I)またはその 薬理学的に許容される塩を含有する第 1成分と、（b)抗コリン剤を含有する第 2成分と を、それぞれ上記のように別途製剤化し、キットとして作成しておき、このキットを用い てそれぞれの成分を同時にまたは時間を置いて、同一対象に対して同一経路または 異なった経路で投与することもできる。  When administered as a combination of a plurality of preparations, for example, it contains (a) the first component containing compound (I) or a pharmaceutically acceptable salt thereof, and (b) an anticholinergic agent Each of the second component and is separately formulated as described above and prepared as a kit, and each component is simultaneously or at a certain time using the kit, and is administered to the same subject by the same route or a different route. It can also be administered.
該キットとしては、例えば保存する際に外部の温度や光による内容物である成分の 変性、容器力ゝらの化学成分の溶出などがみられない容器であれば材質、形状などは 特に限定されない 2つ以上の容器 (例えばバイアル、ノ ッグなど）と内容物力もなり、 内容物である上記第 1成分と第 2成分が別々の経路 (例えばチューブなど)または同 一の経路を介して投与可能な形態を有するものが用いられる。具体的には、錠剤、 注射剤、吸入剤などのキットがあげられる。吸入剤のキットにおいては、一般的に使 用される定量噴霧式吸入器 (MDI)、粉末吸入器などと組み合わせることもでき、上 記第 1成分と第 2成分の投与のための 1またはそれ以上の吸入装置が含まれていて もよい。例えば、上記第 1成分の有効用量単位を含むドライパウダーを含むカプセル および上記第 2成分の有効用量単位を含むドライパウダーを含むカプセルと共に、力 プセルからのドライパウダーの送達に適合する 1またはそれ以上のドライパウダー吸 入装置などが含まれていてもよい。また、薬剤貯蔵部分が上記第 1成分のドライバウ ダーを含む薬剤貯蔵部分と上記第 2成分のドライパウダーを含む薬剤貯蔵部分から なる多用量ドライパウダー吸入器 (MDPI)も当該キットに含まれる。  The material and shape of the kit are not particularly limited as long as it is a container that does not show, for example, denaturation of components as contents due to external temperature or light during storage, and elution of chemical components from the container. Two or more containers (e.g., vials, nogs, etc.) and the contents also become active, and the contents of the first and second components are administered via separate routes (e.g., tubes, etc.) or via the same route Those having a possible form are used. Specific examples include kits for tablets, injections, inhalants, and the like. Inhalation kits can also be combined with commonly used metered dose inhalers (MDIs), powder inhalers, etc. to provide one or more of the above for the administration of the first and second components. The above-mentioned inhaler may be included. For example, one or more of the capsules containing the dry powder containing the effective dose unit of the first component and the capsule containing the dry powder containing the effective dose unit of the second component are compatible with the delivery of the dry powder from the capsule. A dry powder suction device or the like may be included. The kit also includes a multi-dose dry powder inhaler (MDPI) in which the drug storage portion comprises a drug storage portion containing the first component dry powder and a drug storage portion containing the second component dry powder.
[0021] また、本発明の COPDまたは喘息の治療および Zまたは予防方法は、上記で記載 した医薬組成物または COPDもしくは喘息の治療および Zもしくは予防剤で使用さ れる化合物 (I)またはその薬理学的に許容される塩と抗コリン剤の使用または投与方 法と同様にして実施できる。つまり、化合物 (I)またはその薬理学的に許容される塩と 抗コリン剤を、それぞれの有効成分を含有するように製剤化し、例えば単剤としてま たは複数の製剤の組み合わせとして、好ましくは 2つ以上の製剤を組み合わせて投 与することにより実施できる。複数の製剤を組み合わせて投与する際には、これら製 剤は、同時にまたは時間を置いて別々に投与することができ、上記で記載したような キットを用いて投与することもできる。 [0021] Further, the method for treating and preventing or preventing COPD or asthma according to the present invention relates to the compound (I) or the pharmacology thereof used in the pharmaceutical composition or the agent for treating and preventing COPD or asthma described above. Or use of chemically acceptable salts and anticholinergics It can be carried out in the same manner as the method. That is, the compound (I) or a pharmacologically acceptable salt thereof and an anticholinergic agent are formulated so as to contain the respective active ingredients. It can be carried out by administering two or more formulations in combination. When a plurality of preparations are administered in combination, these preparations can be administered simultaneously or separately at an interval, and can also be administered using a kit as described above.
[0022] 次に、化合物 (I)またはその薬理学的に許容される塩および抗コリン剤を同時投与 することによる COPDまたは喘息の治療効果について試験例により具体的に説明す る。 Next, the therapeutic effect of COPD or asthma by co-administration of compound (I) or a pharmacologically acceptable salt thereof and an anticholinergic agent will be specifically described by test examples.
[0023] 試験例 1 電気刺激誘発気管支平滑筋収縮に対する薬物の作用  Test Example 1 Effect of drug on electrical stimulation-induced bronchial smooth muscle contraction
雄性 Hartley系モルモット（300— 450g)を二酸ィ匕炭素で窒息死させた後、主気管 支を摘出した。主気管支をリング状に切り分け、軟骨部分でリングを切り開き、標本を 作成した。標本は、一端は白金電極付き支持棒に、他端はアイソメトリック ·トランスデ ユーサー (TB— 611T、日本光電）に取り付け、栄養液（37°C)の入ったマグヌス管 中に懸垂した。栄養液としては、 95%0 + 5%COガスを 30分以上通気したクレブ  Male Hartley guinea pigs (300-450 g) were suffocated and killed with carbon dioxide and the main bronchus was removed. The main bronchus was cut into a ring, and the ring was cut open at the cartilage to prepare a specimen. The specimen was attached to a support rod with a platinum electrode at one end, and attached to an isometric transducer (TB-611T, Nihon Kohden) at the other end, and suspended in a Magnus tube containing a nutrient solution (37 ° C). Kleb with 95% 0 + 5% CO gas for more than 30 minutes
2 2  twenty two
ス-ヘンゼライト（Krebs— Henseleit)液 [組成： NaCl 119mmol/L, KC1 4. 7m mol/L, MgSO 1. 2mmol/L, CaCl 2. 5 mmol/L, KH PO 1. 2mmo  S-Henseleit solution [Composition: NaCl 119 mmol / L, KC1 4.7 mmol / L, MgSO 1.2 mmol / L, CaCl 2.5 mmol / L, KH PO 1.2 mmo
4 2 2 4  4 2 2 4
1/L, NaHCO 25mmol/Lおよびグルコース（glucose) 11. 7mmol/L]を  1 / L, NaHCO 25mmol / L and glucose (11.7mmol / L)
3  Three
用いた。標本に 0. 3gの静止張力をカ卩え、圧ひずみアンプ (AP— 621G、日本光電） を用いて張力変化を測定した。  Using. A 0.3 g static tension was applied to the sample, and the change in tension was measured using a pressure-strain amplifier (AP-621G, Nihon Kohden).
試験は、 5 μ molZLのインドメタシン（シグマアルドリッチ社製、ミズーリ、 USA)存 在下で行った。電気刺激は、刺激装置（SEN— 3301、日本光電)を用いて、矩形波 パルスにより、頻度 8Hz、持続 0. 5ミリ秒、電圧 30V、刺激時間 15秒間の条件で行つ た。 1回目の電気刺激を行った後、臭化チオト口ピウム（tiotropium bromide；ベー リンガーインゲルノ、ィム社製、ドイツ）の水溶液を、最終濃度が lOnmolZLになるよう にマグヌス管中に添加し、 20分後、再び電気刺激を行った (臭化チオト口ピウム処置 群)。同様に、化合物（I)のジメチルスルホキシド溶液を、最終濃度 10 /z molZLにな るようにマグヌス管中に添加し、 20分後、再び電気刺激を行った (化合物 (I)処置群） 。さらに、臭化チオト口ピウムおよびィ匕合物 (I)それぞれの最終濃度が lOnmolZLお よび 10 /z molZLとなるように、同様に双方の上記薬物溶液を添カ卩し、 20分後、再び 電気刺激を行った (併用処置群)。また、各薬物を溶解した溶媒 (蒸留水およびジメ チルスルホキシド）を添加し同様に電気刺激を行う群を設けた (溶媒処置群)。 The test was performed in the presence of 5 μmol ZL of indomethacin (Sigma-Aldrich, Missouri, USA). The electrical stimulation was performed using a stimulator (SEN-3301, Nihon Kohden) with a rectangular pulse at a frequency of 8 Hz, a duration of 0.5 ms, a voltage of 30 V, and a stimulation time of 15 seconds. After the first electrical stimulation, an aqueous solution of tiotropium bromide (Boehringer Ingelno, Im, Germany) was added to the Magnus tube so that the final concentration was lOnmolZL. Twenty minutes later, electrical stimulation was performed again (a group treated with palladium thionous bromide). Similarly, a dimethyl sulfoxide solution of compound (I) was added to a Magnus tube so as to have a final concentration of 10 / z molZL, and after 20 minutes, electrical stimulation was performed again (compound (I) treated group). . Furthermore, both the above drug solutions were similarly added so that the final concentrations of the pium bromide and the conjugated product (I) would be lOnmolZL and 10 / zmolZL, respectively, and after 20 minutes, the mixture was added again. Electrical stimulation was performed (combination treatment group). In addition, a group in which a solvent (distilled water and dimethyl sulfoxide) in which each drug was dissolved was added and electric stimulation was similarly performed was provided (solvent treatment group).
電気刺激により、初期相と緩徐相の二相性の再現可能な収縮反応が惹き起こされ る。それぞれの処置群における各回の電気刺激に対する張力変化を測定し、各相に おける収縮高を求めた。 1回目の刺激による収縮に対する 2回目の刺激による収縮 高の割合を第 1表に示す。値は平均値士標準誤差で示した。  Electrical stimulation elicits a reproducible contractile response in two phases: an initial phase and a slow phase. The change in tension with respect to each electrical stimulus in each treatment group was measured, and the contraction height in each phase was determined. Table 1 shows the ratio of the height of contraction by the second stimulus to the contraction by the first stimulus. The values are shown as the standard error of the mean.
[表 1] [table 1]
第 1表  Table 1
処 1回目の収縮力に対する 2回目の収縮力の割合（％) The ratio of the second contractile force to the first force of contraction treatment (%)
初期相 緩徐相  Initial phase Slow phase
溶媒 5 109.8 土 2.9 109.4土 11.3 臭化チ才トロピウム 5 52.6土 9.9** 101.3土 6.2 化合物 （ I ) 5 95.8土 4.2* 51.8土 3.6** 併用 5 32.3 士 8.4*** 35.8士 7.5  Solvent 5 109.8 Sat 2.9 109.4 Sat 11.3 Tropium bromide 5 52.6 Sat 9.9 ** 101.3 Sat 6.2 Compound (I) 5 95.8 Sat 4.2 * 51.8 Sat 3.6 ** 5 32.3 8.4 *** 35.8 7.5
**, **, ***： p<0.01, 0.01, 0.001 vs. 溶媒処置群 (Student't t- test) 臭化チオト口ピウム処置群では初期相の収縮が抑制された。化合物 (I)処置群では 初期相および緩徐相の収縮が抑制された。臭化チオト口ピウムとィ匕合物 (I)の併用処 置群では、臭化チオト口ピウム処置群よりも初期相の収縮が強く抑制され、化合物 (I) 処置群よりも緩徐相の収縮が強く抑制された。  **, **, ***: p <0.01, 0.01, 0.001 vs. Solvent-treated group (Student't t-test) In the group treated with palladium thiotobromide, contraction of the initial phase was suppressed. In the compound (I) treatment group, contraction in the initial phase and the slow phase was suppressed. In the group treated with the combination of palladium thiotobromide and i-conjugate (I), the contraction of the initial phase was suppressed more strongly than in the group treated with palladium tiotobromide, and the contraction in the slower phase than in the group treated with compound (I). Was strongly suppressed.
初期相は副交感神経力 放出されたアセチルコリンによって、緩徐相は不随知覚 神経力 放出されるサブスタンス Pや-ユーロキュンなどのタキキュンによって惹起さ れることが報告されて 、る（ブリティッシュ ·ジャーナル ·ォブ ·ファーマコロジー（Br. J . Pharmacol) , 1996年、 117卷、 p. 967)。  It has been reported that the initial phase is triggered by parasympathetic nerve released acetylcholine, and the slow phase is induced by involuntary sensory nerves released by substances such as substance P and tachycun such as eurocun. Pharmacology (Br. J. Pharmacol), 1996, Vol. 117, p. 967).
アセチルコリンとタキキュンによって惹起される収縮反応の双方を抑制することは、 COPDや喘息などの呼吸器疾患の治療に有効と考えられている (カレント'オビ-ォ ン 'イン 'ケミカル'バイオロジー（Curr. Opin. Chem. Biol. ) , 2000年、 4卷、 p. 4 12 ;ョ一口ピアン'ジャーナル'ォブ 'ファーマコロジー（Eur. J. Pharmacol. 200 1年、 429卷、 p. 239)。 [0025] 上記試験の結果、 COPDまたは喘息などの呼吸疾患に対し、化合物 (I)と抗コリン 剤とを併用して用いることにより、それぞれの薬剤を単独で用いた場合より、より有効 な治療効果が得られると考えられる。 Suppressing both the contractile response elicited by acetylcholine and tachycun is thought to be effective in treating respiratory diseases such as COPD and asthma (current 'obion' in 'chemical' biology (Curr Opin. Chem. Biol.), 2000, vol. 4, p. 412; Epp. Pian 'Journal of Obb' Pharmacology (Eur. J. Pharmacol. 2001, Vol. 429, p. 239). [0025] As a result of the above test, the combined use of compound (I) and an anticholinergic agent for respiratory diseases such as COPD or asthma results in more effective treatment than when each agent is used alone. It is considered that an effect can be obtained.
[0026] 上述したように、本発明に使用される医薬組成物または COPDもしくは喘息の治療 および Zもしくは予防剤は、化合物 (I)またはその薬理学的に許容される塩と抗コリン 剤それぞれの有効成分を含有するように製剤化したものであれば、単剤としてでも複 数の製剤の組み合わせとしてでも使用、投与または製造することができる。これらの 医薬組成物または COPDもしくは喘息の治療および Zもしくは予防剤は、錠剤など の経口的投与または吸入剤、注射剤などの非経口的投与に対して適する単位服用 形態にあることが望ましい。また、複数の製剤の組み合わせとして使用または投与す る際には、同時にまたは時間を置いて別々に使用または投与することができる。 これら製剤は、それぞれ有効成分の他に製剤学的に許容される希釈剤、賦形剤、 崩壊剤、滑沢剤、結合剤、界面活性剤、水、生理食塩水、植物油可溶化剤、等張ィ匕 剤、保存剤、抗酸化剤などを適宜用いて常法により作成することができる。  [0026] As described above, the pharmaceutical composition or the therapeutic and / or prophylactic agent for COPD or asthma used in the present invention comprises compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent, respectively. As long as it is formulated so as to contain the active ingredient, it can be used, administered or manufactured as a single agent or as a combination of plural formulations. It is desirable that these pharmaceutical compositions or the therapeutic and / or prophylactic agents for COPD or asthma are in a unit dosage form suitable for oral administration such as tablets or parenteral administration such as inhalants and injections. When used or administered as a combination of a plurality of preparations, they can be used or administered simultaneously or separately at an interval. These preparations each contain a pharmaceutically acceptable diluent, excipient, disintegrant, lubricant, binder, surfactant, water, physiological saline, vegetable oil solubilizer, etc. in addition to the active ingredient. It can be prepared by a conventional method using a Zhanging agent, a preservative, an antioxidant and the like as appropriate.
錠剤の調製にあたっては、例えば乳糖などの賦形剤、澱粉などの崩壊剤、ステアリ ン酸マグネシウムなどの滑沢剤、ヒドロキシプロピルセルロースなどの結合剤、脂肪酸 エステルなどの界面活性剤、グリセリンなどの可塑剤などを常法に従って用いればよ い。  In preparing tablets, for example, excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, surfactants such as fatty acid esters, and plasticizers such as glycerin. Agents and the like may be used in accordance with a conventional method.
[0027] 注射剤の調製にあたっては、水、生理食塩水、大豆油などの植物油、溶剤、可溶 ィ匕剤、等張化剤、保存剤、抗酸化剤などを常法により用いればよい。  [0027] In preparing the injection, water, physiological saline, vegetable oil such as soybean oil, a solvent, a solubilizing agent, an isotonic agent, a preservative, an antioxidant, and the like may be used in a conventional manner.
また、吸入剤は活性成分を粉末または液状にして、吸入噴射剤または担体中に配 合し、適当な吸入容器に充填することにより製造される。また上記活性成分が粉末の 場合は通常の機械的粉末吸入器を、液状の場合はネブライザ一などの吸入器をそ れぞれ使用することもできる。ここで吸入噴射剤としては従来公知のものを広く使用 でき、フロン一 11、フロン一 12、フロン一 21、フロン一 22、フロン 113、フロン一 11 4、フロン一 123、フロン一 142c、フロン一 134a、フロン一 227、フロン一 C318、 1,1 , 1,2—テトラフルォロェタンなどのフロン系化合物、プロパン、イソブタン、 n—ブタン などの炭化水素類、ジェチルエーテルなどのエーテル類、窒素ガス、炭酸ガスなど の圧縮ガスなどがあげられる。さらに必要に応じて、上記に例示した希釈剤、防腐剤 、フレーバー類、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤など力ゝら選 択される 1種もしくはそれ以上の補助成分を添加することもできる。 Inhalants are also prepared by powdering or liquidifying the active ingredient, dispersing it in an inhalation propellant or carrier, and filling an appropriate inhalation container. When the active ingredient is a powder, an ordinary mechanical powder inhaler can be used, and when the active ingredient is a liquid, an inhaler such as a nebulizer can be used. Here, as the inhalation propellant, conventionally known ones can be widely used, and CFC-11, CFC-12, CFC-21, CFC-22, CFC113, CFC114, CFC123, CFC-142c, CFC-C. 134a, chlorofluorocarbon 227, chlorofluorocarbon C318, fluorocarbon compounds such as 1,1,1,2-tetrafluoroethane, hydrocarbons such as propane, isobutane and n-butane, ethers such as getyl ether, Nitrogen gas, carbon dioxide gas, etc. Compressed gas. Further, if necessary, one or more diluents, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified above are selected. More auxiliary components can be added.
[0028] 上記の目的で、化合物 (I)またはその薬理学的に許容される塩と抗コリン剤を複数 の製剤の組み合わせとして使用または投与する場合には、それぞれの用量および投 与回数は投与形態、患者の年齢、体重、症状などにより異なるが、通常一日当たり、 化合物 (I)またはその薬理学的に許容される塩と抗コリン剤を、それぞれ以下の用量 で投与するのが好ましい。 [0028] When compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent are used or administered as a combination of a plurality of preparations for the above-mentioned purpose, the dose and the number of administrations of each compound should be Although it varies depending on the form, age, weight, symptoms, etc. of the patient, it is usually preferable to administer Compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent at the following doses per day.
経口的に、例えば錠剤として投与する場合、化合物 (I)またはその薬理学的に許容 される塩と抗コリン剤を、成人一人当たり、それぞれ 0. 01〜： LOOOmgと 0. 1 8〜50 Omg、好ましくは 0. 05〜30011^と1 )« 8〜20011^、さらに好ましくは 0. l〜200mg と 〜： L0mg、通常一日一回ないし数回にわけて、同時にまたは時間を置いて別 々に投与する。 Orally, for example when administered as a tablet, the compound (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic, per adult, respectively 0. 01~: LOOOmg with 0. 1 8 to 50 Omg , Preferably 0.05 to 30011 ^ and 1 ) «8 to 20011 ^, more preferably 0.1 to 200 mg and ~: L0mg, usually once or several times a day, simultaneously or separately at different times Administer separately.
非経口的に、例えば注射剤または吸入剤として投与する場合、化合物 (I)またはそ の薬理学的に許容される塩と抗コリン剤を、成人一人当たり、それぞれ 1 μ g〜100m gと 0. 01 μ g〜50mg、好ましくは 5 μ g〜30mgと 0. 1 μ g〜20mg、さらに好ましくは 10 8〜201118と0. 5 8〜0. 5mg、通常一日一回ないし数回にわけて、同時にま たは時間を置いて別々に投与する。 When administered parenterally, for example, as an injection or inhalant, Compound (I) or a pharmaceutically acceptable salt thereof and an anticholinergic agent are administered in an amount of 1 μg to 100 mg and 0 mg / adult each. . 01 μ g~50mg, preferably a 5 μ g~30mg with 0. 1 μ g~20mg, more preferably 10 8-20111 8 with 0. 5 8~0. 5mg, typically once a day or several times Thus, they may be administered simultaneously or separately at intervals.
また上記の目的で、化合物 (I)またはその薬理学的に許容される塩と抗コリン剤を 単剤として使用または投与する場合には、それぞれの用量および投与回数は投与 形態、患者の年齢、体重、症状などにより異なるが、上記の複数の製剤の組み合わ せとして使用または投与する場合のそれぞれの用量で 1つの製剤として調製し、使用 または投与するのが好ま 、。  In addition, when Compound (I) or a pharmacologically acceptable salt thereof and an anticholinergic agent are used or administered as a single agent for the above purpose, the dose and frequency of administration are determined by the dosage form, patient age, When used or administered as a combination of a plurality of the above-mentioned preparations, it is preferable to prepare, use, or administer as a single preparation at each dose when used or administered, depending on body weight, symptoms, and the like.
[0029] 以下に、本発明の態様を実施例で説明する力 本発明の範囲はこれら実施例によ り限定されることはない。 [0029] Hereinafter, the power of explaining embodiments of the present invention with examples will not limit the scope of the present invention.
実施例 1  Example 1
[0030] 錠剤 (化合物 (1) ) [0030] Tablet (Compound (1))
常法により、次の組成からなる錠剤を調製する。化合物 (I) 40g、乳糖 286. 8gおよ び馬鈴薯澱粉 60gを混合し、これにヒドロキシプロピルセルロースの 10%水溶液 120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆 粒とする。これにステアリン酸マグネシウム 1. 2gをカ卩えて混合し、径 8mmの杵をもつ た打錠機 (菊水社製 RT— 15型)で打錠を行って、錠剤（1錠あたり活性成分 20mgを 含有する）を得る。 A tablet having the following composition is prepared by a conventional method. Compound (I) 40 g, lactose 286.8 g and 60 g of potato starch is mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. 1.2 g of magnesium stearate was added to the mixture and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having an 8 mm diameter punch. Containing).
[表 2]  [Table 2]
処方 化合物 （I ) 2 0 m g Formulation compound (I) 20 mg
乳糖 4 3 4 m g  Lactose 4 3 4 mg
3 0 m g  3 0 mg
ヒ ドロキシプロピノレセノレロース 6 m g  Hydroxypropinoresenolerose 6 mg
ステアリン酸マグネシゥム ϋ 6 m g  Magnesium stearate ϋ 6 mg
2 0 0 m g  2 0 0 mg
実施例 2 Example 2
錠剤（塩酸ォキシブチュン） Tablet (Oxybutun hydrochloride)
常法により、次の組成からなる錠剤を調製する。塩酸ォキシプチニン 4g、乳糖 300 . Ogおよび馬鈴薯澱粉 68. Ogを混合し、これにヒドロキシプロピルセルロースの 10% 水溶液 200gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整 粒し打錠用顆粒とする。これにステアリン酸マグネシウム 8. Ogを加えて混合し、径 8 mmの杵をもった打錠機 (菊水社製 RT— 15型)で打錠を行って、錠剤（1錠あたり活 性成分 2. Omgを含有する）を得る。  A tablet having the following composition is prepared by a conventional method. 4 g of oxypeptinine hydrochloride, 300. Og of lactose and 68. Og of potato starch are mixed, and 200 g of a 10% aqueous solution of hydroxypropyl cellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. 8. Og of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) having a punch of 8 mm in diameter. Omg).
[表 3] [Table 3]
塩酸ォキシブチニン 2 . 0 m g  Oxybutynin hydrochloride 2.0 mg
乳糖 5 0 . 0 m g  Lactose 50.0 mg
馬鈴薯澱粉 3 4 0 m g  Potato starch 3 4 0 mg
ヒ ドロキシプロピノレセノレロース 1 0 0 m g  Hydroxypropinoresenololose 100 mg
ステアリン酸マグネシゥム 4 0 m g  Magnesium stearate 40 mg
2 0 0 m g  2 0 0 mg
実施例 3 Example 3
錠剤 (化合物 (I)と塩酸ォキシプチニンの単剤） Tablets (Compound (I) and oxyptinin hydrochloride alone)
常法により、次の組成からなる錠剤を調製する。化合物 (I) 40g、塩酸ォキシプチ- ン 4g、孚 L糖 286. 0gおよび馬鈴薯滅粉 56. 0gを混合し、これにヒドロキシプロピノレセ ルロースの 10%水溶液 120gをカ卩える。この混合物を常法により練合し、造粒して乾 燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム 2. Ogを加え て混合し、径 8mmの杵をもった打錠機 (菊水社製 RT— 15型)で打錠を行って、錠剤 ( 1錠あたり化合物 (1) 20. Omgおよび塩酸ォキシプチニン 2. Omgを含有する）を得 る。 A tablet having the following composition is prepared by a conventional method. Compound (I) (40 g), oxypeptin hydrochloride (4 g), lactose L-sugar (286.0 g) and potato powder (56.0 g) were mixed, and the mixture was mixed with hydroxypropinolose. Calculate 120g of 10% aqueous solution of Lulose. The mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Magnesium stearate 2.Og was added and mixed, and the mixture was compressed with a tableting machine (RT-15 type, manufactured by Kikusui) having an 8 mm diameter punch, and tablets (compound (1) 20 Omg and oxyptinin hydrochloride 2. containing Omg).
[表 4]  [Table 4]
化合物 （I ) 2 0 . 0 m g 塩酸ォキシブチニン 2 . 0 m g 乳糖 1 4 3 . 0 m g 馬鈴薯澱粉 2 8 . 0 m g ヒ ドロキシプロピノレセノレロース 6 . 0 m g ステアリン酸マグネシゥム 1 . 0 m g  Compound (I) 2.0 mg oxybutynin hydrochloride 2.0 mg lactose 143.0 mg potato starch 28.0 mg hydroxypropinoresenololose 6.0 mg magnesium stearate 1.0 mg
2 0 0 m g  2 0 0 mg
実施例 4  Example 4
[0033] 注射剤 (化合物 (I) ) [0033] Injection (Compound (I))
常法により、次の組成からなる注射剤を調製する。化合物 (I) lgを精製大豆油に溶 解させ、精製卵黄レシチン 12gおよび注射用グリセリン 25gを加える。この混合物を 常法により注射用蒸留水で lOOOmLとして練合 '乳化する。得られた分散液を 0. 2 μ mのデイスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイァ ルに 2mLずつ無菌的に充填して、注射剤（1バイアルあたり活性成分 2. Omgを含有 する）を得る。 処方 化合物 （I )  An injection having the following composition is prepared by a conventional method. Compound (I) lg is dissolved in purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection are added. This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion is aseptically filtered using a 0.2 μm disposable membrane filter, and then aseptically filled into glass vials in 2 mL increments, containing an injection (containing 2.Omg of active ingredient per vial). Get). Prescription compound (I)
精製大豆油 2 0  Refined soybean oil 2 0
精製卵黄レシチン 2  Purified egg yolk lecithin 2
注射用グリセリン 5  Glycerin for injection 5
注射用蒸留水
Figure imgf000021_0001
Distilled water for injection
Figure imgf000021_0001
2 . 0 0 m L  2.0 mL
実施例 5  Example 5
[0034] 注射剤 (臭化ィプラト口ピウム）  [0034] Injection (iprat bromide)
常法により、次の組成からなる注射剤を調製する。臭化ィプラト口ピウム 0. 15gを精 製大豆油に溶解させ、精製卵黄レシチン 12gおよび注射用グリセリン 25gを加える。 この混合物を常法により注射用蒸留水で lOOOmLとして練合 '乳化する。得られた分 散液を 0. 2 mのデイスポーザブル型メンブランフィルターを用いて無菌濾過後、ガ ラスバイアルに 2mLずつ無菌的に充填して、注射剤（1バイアルあたり活性成分 0. 3 mgを含有する）を得る。 臭化ィプラトロピウム 0 3 m g 精製大豆油 2 0 0 0 m g 精製卵黄レシチン 2 4 0 m g 注射用グリセリン 5 0 0 m g 注射用蒸留水 1 7 2 m L An injection having the following composition is prepared by a conventional method. 0.15 g of pipium bromide is dissolved in refined soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection are added. This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion is aseptically filtered using a 0.2-m disposable membrane filter, and aseptically filled into glass vials in a volume of 2 mL each to give an injection (0.3 mg of active ingredient per vial). Containing). Ipratropium bromide 0 3 mg purified soybean oil 20000 purified egg yolk lecithin 240 mg glycerin for injection 500 mg distilled water for injection 17 2 ml
2 . 0 0 m L  2.0 mL
実施例 6  Example 6
[0035] 注射剤 (化合物 (I)と臭化ィプラト口ピウムの単剤）  [0035] Injection (Compound (I) and iprat bromide single agent)
常法により、次の組成からなる注射剤を調製する。化合物 (I) lgおよび臭化ィプラト 口ピウム 0. 15gを精製大豆油に溶解させ、精製卵黄レシチン 12gおよび注射用ダリ セリン 25gを加える。この混合物を常法により注射用蒸留水で lOOOmLとして練合' 乳化する。得られた分散液を 0. 2 mのデイスポーザブル型メンブランフィルターを 用いて無菌濾過後、ガラスバイアルに 2mLずつ無菌的に充填して、注射剤（1バイァ ルあたり化合物 (1) 2. Omgおよび臭化ィプラト口ピウム 0. 3mgを含有する）を得る。  An injection having the following composition is prepared by a conventional method. Compound (I) lg and 0.15 g of iprat bromide are dissolved in purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of daliserine for injection are added. This mixture is kneaded and emulsified with distilled water for injection to 100 mL in a conventional manner. The resulting dispersion was aseptically filtered using a 0.2-m disposable membrane filter, and aseptically filled into glass vials in 2 mL increments to give an injection (compound (1) 2.Omg per vial). And 0.3 mg of pipium in the mouth of iprat bromide).
[表 7]  [Table 7]
化合物 （I ) 2 . 0 m g  Compound (I) 2.0 mg
臭化ィプラトロピウム 0 . 3 m g  0.3 mg of ipratropium bromide
精製大豆油 2 0 0 . 0 m g  Refined soybean oil 20.0 mg
精製卵黄レシチン 2 4 . 0 m g  Purified egg yolk lecithin 24.0 mg
注射用グリセリン 5 0 · 0 m g  Glycerin for injection 500 mg
注射用蒸留水 1 . 7 2 m L  1.7 2 mL of distilled water for injection
2 . 0 0 m L  2.0 mL
実施例 7  Example 7
[0036] ドライパウダー吸入剤 (化合物 (I) )  [0036] Dry powder inhalant (Compound (I))
常法により、次の組成力もなるドライパウダー吸入剤を調製する。ジェットミルを用い て、化合物 (I)を粉砕する (体積平均粒子径： 5〜20 m)。得られた化合物 (I)の粉 砕物と乳糖 (Pharmatose 325M ;登録商標、 DMV社製）とを重量比 1： 5で混合し 、ドライパウダー製剤を得る。該製剤は慣用のドライパウダー吸入器により、投与が可 能である。 According to a conventional method, a dry powder inhalant having the following compositional power is prepared. The compound (I) is pulverized using a jet mill (volume average particle size: 5 to 20 m). The obtained compound (I) powder and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) were mixed at a weight ratio of 1: 5. To obtain a dry powder formulation. The formulation can be administered with a conventional dry powder inhaler.
[表 8]  [Table 8]
処方 化合物 （I) 1 6. 7 m g  Formulation compound (I) 16.7 mg
乳糖 83. _J _m_g  Lactose 83._J_m_g
100. 0 m g  100.0 mg
実施例 8  Example 8
[0037] ドライパウダー吸入剤（臭化チオト口ピウム一水和物）  [0037] Dry powder inhalant (pium thiot mouth bromide monohydrate)
常法により、次の組成力もなるドライパウダー吸入剤を調製する。ジェットミルを用い て、臭化チオト口ピウム一水和物を粉砕する（体積平均粒子径： 5〜20 m)。得られ た臭化チオト口ピウム一水和物の粉砕物と乳糖 (Pharmatose 325M;登録商標、 DMV社製)とを重量比 1:249で混合し、ドライパウダー製剤を得る。該製剤は慣用 のドライパウダー吸入器により、投与が可能である。  According to a conventional method, a dry powder inhalant having the following compositional power is prepared. Using a jet mill, pulverized palladium thionite monohydrate is crushed (volume average particle size: 5 to 20 m). The pulverized product of palladium monohydrate of thiotolipide bromide and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) are mixed at a weight ratio of 1: 249 to obtain a dry powder preparation. The formulation can be administered with a conventional dry powder inhaler.
[表 9]  [Table 9]
処方 臭化チオト口ピウム一水和物 0. 4 m g  Formulation Thiotodium bromide pium monohydrate 0.4 mg
1 00. 0 m g  1 00.0 mg
実施例 9  Example 9
[0038] ドライパウダー吸入剤 (化合物 (I)と臭化チオト口ピウム一水和物の単剤）  [0038] Dry powder inhalant (Compound (I) and single dose of Pt monobromide monohydrate)
常法により、次の組成カゝらなるドライパウダー吸入剤を調製する。ジェットミルを用い て、化合物 (I)と臭化チオト口ピウム一水和物をそれぞれ粉砕する (体積平均粒子径: 共に 5〜20 μ m)。得られた化合物 (I)と臭化チオト口ピウム一水和物のそれぞれの 粉砕物と乳糖（Pharmatose 325M;登録商標、 DMV社製）とを重量比 82: 1 :417 で混合し、ドライパウダー製剤を得る。該製剤は慣用のドライパウダー吸入器により、 投与が可能である。  A dry powder inhalant having the following composition is prepared by a conventional method. Using a jet mill, the compound (I) and palladium thionite monohydrate are pulverized (volume average particle diameter: both 5 to 20 μm). The obtained compound (I), each pulverized product of palladium thionite bromide monohydrate and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) were mixed in a weight ratio of 82: 1: 417, and the resulting mixture was mixed with dry powder. Obtain the formulation. The formulation can be administered with a conventional dry powder inhaler.
[表 10]  [Table 10]
処方 化合物 （I) 1 6. 4 m g  Formulation compound (I) 16.4 mg
臭化チォト口ピウム一水和物 0. 2 m g 乳糖 83. 4 _m g  Ptium monobromide monohydrate 0.2 mg Lactose 83.4 _mg
1 00. 0 m g  1 00.0 mg
実施例 10 [0039] ドライパウダー吸入剤（臭化ォキシトロピウム） Example 10 [0039] Dry powder inhalant (Oxytropium bromide)
常法により、次の組成カゝらなるドライパウダー吸入剤を調製する。ジェットミルを用い て、臭化ォキシトロピウムを粉砕する (体積平均粒子径: 5〜20 m)。得られた臭化 ォキシトロピウムの粉砕物と乳糖 (Pharmatose 325M；登録商標、 DMV社製）とを 重量比 1 : 50で混合し、ドライパウダー製剤を得る。該製剤は慣用のドライパウダー吸 入器により、投与が可能である。  A dry powder inhalant having the following composition is prepared by a conventional method. Pulverize oxytropium bromide using a jet mill (volume average particle size: 5 to 20 m). The obtained ground oxitropium bromide and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) are mixed at a weight ratio of 1:50 to obtain a dry powder preparation. The formulation can be administered with a conventional dry powder inhaler.
[表 11]  [Table 11]
処方 臭化ォキシトロピウム 1 , 9 m g  Prescription Oxytropium bromide 1, 9 mg
乳糖 9 8 . 1 m g  Lactose 9 8.1 mg
1 0 0 . 0 m g  1 0 0 .0 mg
実施例 11  Example 11
[0040] ドライパウダー吸入剤 (化合物 (I)と臭化ォキシトロピウムの単剤）  [0040] Dry powder inhalant (Compound (I) and oxotropium bromide alone)
常法により、次の組成カゝらなるドライパウダー吸入剤を調製する。ジェットミルを用い て、化合物 (I)と臭化ォキシトロピウムを粉砕する (体積平均粒子径: 5〜20 m)。得 られた化合物（I)と臭化ォキシトロピウムの粉砕物と乳糖 (Pharmatose 325M ;登 録商標、 DMV社製)とを重量比 10 : 1 : 50で混合し、ドライパウダー製剤を得る。該 製剤は慣用のドライパウダー吸入器により、投与が可能である。  A dry powder inhalant having the following composition is prepared by a conventional method. The compound (I) and oxotropium bromide are ground using a jet mill (volume average particle size: 5 to 20 m). The obtained compound (I), crushed oxotropium bromide and lactose (Pharmatose 325M; registered trademark, manufactured by DMV) are mixed at a weight ratio of 10: 1: 50 to obtain a dry powder preparation. The formulation can be administered with a conventional dry powder inhaler.
[表 12]  [Table 12]
処方 化合物 （ I ) 1 6 . 4 m g  Prescription compound (I) 16.4 mg
臭化ォキシトロピウム 1 . 6 m g 乳糖 8 2 . 0 m g  Oxitropium bromide 1.6 mg Lactose 82.0 mg
1 0 0 . 0 m g  1 0 0 .0 mg
実施例 12  Example 12
[0041] 錠剤 (酒石酸トルテロジン） [0041] Tablets (tolterodine tartrate)
常法により、次の組成からなる錠剤を調製する。酒石酸トルテロジン 4g、乳糖 300. Ogおよび馬鈴薯澱粉 68. Ogを混合し、これにヒドロキシプロピルセルロースの 10% 水溶液 200gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整 粒し打錠用顆粒とする。これにステアリン酸マグネシウム 8. Ogを加えて混合し、径 8 mmの杵をもった打錠機 (菊水社製 RT— 15型)で打錠を行って、錠剤（1錠あたり活 性成分 2. Omgを含有する）を得る。 [表 13] A tablet having the following composition is prepared by a conventional method. 4 g of tolterodine tartrate, 300. Og of lactose and 68. Og of potato starch are mixed, and 200 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. 8. Og of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) having a punch of 8 mm in diameter. Omg). [Table 13]
酒石酸トルテロジン 2 . 0 m g 乳糖 1 5 0 . 0 m g 馬鈴薯澱粉 3 4 . 0 m g ヒ ドロキシプ口ピノレセノレロース 1 0 . 0 m g ステアリン酸マグネシゥム 4 . 0 m g  Tolterodine tartrate 2.0 mg Lactose 15.0 mg Potato starch 34.0 mg Hydroxip-mouthed pinoresenolerose 10.0 mg Magnesium stearate 4.0 mg
2 0 0 m g  2 0 0 mg
実施例 13  Example 13
[0042] 錠剤 (化合物 (I)と酒石酸トルテロジンの単剤）  [0042] Tablet (Compound (I) and tolterodine tartrate as a single agent)
常法により、次の組成からなる錠剤を調製する。化合物 (I) 40g、酒石酸トルテロジ ン 4g、孚 L糖 286. Ogおよび馬鈴薯滅粉 56. Ogを混合し、これにヒドロキシプロピノレセ ルロースの 10%水溶液 120gをカ卩える。この混合物を常法により練合し、造粒して乾 燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム 2. Ogを加え て混合し、径 8mmの杵をもった打錠機 (菊水社製 RT— 15型)で打錠を行って、錠剤 (1錠あたり化合物 (1) 20. Omgおよび酒石酸トルテロジン 2. Omgを含有する）を得る  A tablet having the following composition is prepared by a conventional method. Compound (I) (40 g), tolterodine tartrate (4 g), L-sugar L-sugar (286.Og) and potato powder (56.Og) are mixed, and 120 g of a 10% aqueous solution of hydroxypropinolecellulose is added thereto. The mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Magnesium stearate 2.Og was added and mixed, and the mixture was compressed with a tableting machine (RT-15 type, manufactured by Kikusui) having an 8 mm diameter punch, and tablets (compound (1) 20 Omg and tolterodine tartrate 2. containing Omg)
[表 14] [Table 14]
化合物 （ I ) 2 0 . 0 m g 酒石酸トルテロジン 2 . 0 m g 乳糖 1 4 3 . 0 m g 馬鈴薯澱粉 2 8 . 0 m g ヒ ドロキシ: /口ピノレセノレロース 6 . 0 m g ステアリン酸マグネシゥム 1 . 0 m g  Compound (I) 2.0 mg tolterodine tartrate 2.0 mg lactose 143.0 mg potato starch 28.0 mg hydroxy: / mouth pinoresenorelose 6.0 mg magnesium stearate 1.0 mg
2 0 0 m g 産業上の利用可能性  200 mg Industrial availability
[0043] 本発明により、 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一  [0043] According to the present invention, 4-[(3,5-dichloro-1-4-pyridyl) potassium rubamoyl] -7-methoxy-1
2- (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的 に許容される塩と抗コリン剤とを含有する医薬組成物などが提供される。  There is provided a pharmaceutical composition containing 2- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof and an anticholinergic.

Claims

請求の範囲  The scope of the claims
(a)式 (I)  (a) Formula (I)
[化 14]  [Formula 14]
Figure imgf000026_0001
Figure imgf000026_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— 4— [(3,5 dichloro- 1 4 pyridyl) rubamoyl] — 7—methoxy-1 2—
(4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤とを含有する医薬組成物。 A pharmaceutical composition comprising (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmacologically acceptable salt thereof and (b) an anticholinergic.
[2] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 1記載の医薬組成物。 [2] The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[3] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 2記載の医薬組成物。 [3] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 3. The pharmaceutical composition according to claim 2, which is a citrate.
[4] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシプチニンである請求項 1記載の医薬組成物。  [4] The pharmaceutical composition according to claim 1, wherein the anticholinergic agent is palladium tioto bromide, palladium palladium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
[5] (a)式 (I)  [5] Equation (a) (I)
[化 15]  [Formula 15]
Figure imgf000026_0002
Figure imgf000026_0002
( I )  (I)
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤を有効成分とする同時にまたは時間を置いて別々に投与 するための慢性閉塞性肺疾患 (COPD)または喘息の治療および Zまたは予防剤。 4-[(3,5-dichloro-1-pyridyl) potassium) represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmacologically acceptable A therapeutic and / or Z- or prophylactic agent for chronic obstructive pulmonary disease (COPD) or asthma, which is separately or simultaneously administered at an interval comprising an acceptable salt and (b) an anticholinergic agent as active ingredients.
[6] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 5記載の治療および Zまたは予防剤。 [6] The therapeutic and / or Z- or prophylactic agent according to claim 5, which is a compound selected from the group consisting of tiotropium, ipratophium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[7] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 6記載の治療および Zまたは予防剤。 [7] The pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 7. The therapeutic and / or Z preventive agent according to claim 6, which is a citrate.
[8] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシプチニンである請求項 5記載の治療および Zまたは 予防剤。 [8] The therapeutic and / or Z- or prophylactic agent according to claim 5, wherein the anticholinergic agent is piodium thiotope bromide, pium iodide bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
[9] (a)式 (I) [9] (a) Formula (I)
[化 16]  [Formula 16]
Figure imgf000027_0001
Figure imgf000027_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を含有する第 1成分と (b)抗コリン剤を含有する第 2成分を有することを特 徴とするキット。  4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt A kit comprising: a first component to be contained; and (b) a second component to contain an anticholinergic agent.
[10] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 9記載のキット。  [10] The kit according to claim 9, wherein the kit is a compound selected from the group consisting of tiotropium, ipratophium pium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[11] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 10記載のキット。 [12] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシブチュンである請求項 9記載のキット。 [11] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 11. The kit according to claim 10, which is a citrate. [12] The kit according to claim 9, wherein the anticholinergic agent is piodium thiotope bromide, palladium oxalate bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
[13] (a)式 (I)  [13] Equation (a) (I)
[化 17]  [Formula 17]
Figure imgf000028_0001
Figure imgf000028_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を含有する第 1成分と (b)抗コリン剤を含有する第 2成分を有することを特 徴とする COPDまたは喘息の治療および Zまたは予防用キット。  4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt A kit for treating and / or preventing COPD or asthma, comprising a first component containing the first component and (b) a second component containing an anticholinergic.
[14] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 13記載のキット。 14. The kit according to claim 13, which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine, and oxyptinin, or a pharmacologically acceptable salt thereof.
[15] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 14記載のキット。 [15] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 15. The kit according to claim 14, which is a citrate.
[16] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシブチュンである請求項 13記載のキット。 [16] The kit according to claim 13, wherein the anticholinergic agent is piodium thiotope bromide, pium iodide bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
[17] 抗コリン剤と同時にまたは時間を置いて別々に投与するための式 (I) [17] Formula (I) for simultaneous or separate administration with an anticholinergic
[化 18]  [Formula 18]
Figure imgf000028_0002
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩。
Figure imgf000028_0002
4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] —— 7-methoxy-12- (4-methylbiperazine 1-ylcarboyl) benzofuran or a pharmacologically acceptable salt thereof.
[18] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 17記載の 4 [ (3, 5 ジクロロー 4 ピリジル）力ルバモイル]ー7—メト キシ 2—（4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理 学的に許容される塩。  [18] The anticholinergic activity of the compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxyptinin, or a pharmacologically acceptable salt thereof. Pyridyl) pothamboilyl] -7-methoxy-2- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof.
[19] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 18記載の 4 [ (3, 5 ジクロロー 4 ピリジル)力ルバモイル] 7—メトキシ 2—（4ーメチルビペラジン 1ーィルカルボニル）ベンゾフランまたはそ の薬理学的に許容される塩。  [19] The pharmacologically acceptable salt of the anticholinergic agent is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 19. The 4 [(3,5 dichloro-4-pyridyl) potassium rubamoyl] 7-methoxy-2- (4-methylbiperazine-1-ylcarbonyl) benzofuran or a pharmaceutically acceptable salt thereof according to claim 18, which is a citrate salt. .
[20] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシブチュンである請求項 17記載の 4 [ (3, 5 ジクロ 口一 4 ピリジル）力ルバモイル] 7 メトキシ一 2— (4 メチルビペラジン 1 ィ ルカルボニル)ベンゾフランまたはその薬理学的に許容される塩。  [20] The method according to claim 17, wherein the anticholinergic agent is selected from the group consisting of piotothiopium bromide, pipium bromide, oxitropium bromide, tolterodine tartrate, and oxybutun hydrochloride. Rubamoyl] 7 Methoxy-1- (4-methylbiperazine 1-ylcarbonyl) benzofuran or a pharmaceutically acceptable salt thereof.
[21] 抗コリン剤と同時にまたは時間を置いて別々に投与するための式 (I)  [21] Formula (I) for simultaneous administration with or separately from an anticholinergic agent
[化 19]  [Formula 19]
Figure imgf000029_0001
Figure imgf000029_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を有効成分として含有する医薬組成物。  4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt Pharmaceutical composition containing as an active ingredient.
抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 21記載の医薬組成物。 Anticholinergic activity Tiotropium, iprat mouth pium, oxitropium, tolterodine and 22. The pharmaceutical composition according to claim 21, which is a compound selected from the group consisting of oxiptinin and group, or a pharmacologically acceptable salt thereof.
[23] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 22記載の医薬組成物。 [23] The pharmacologically acceptable salt of the anticholinergic agent may be hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 23. The pharmaceutical composition according to claim 22, which is a citrate.
[24] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシプチニンである請求項 21記載の医薬組成物。 [24] The pharmaceutical composition according to claim 21, wherein the anticholinergic agent is palladium tioto bromide, palladium palladium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
[25] (a)式 (I) [25] (a) Equation (I)
[化 20]  [Formula 20]
Figure imgf000030_0001
Figure imgf000030_0001
( I  (I
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩および (b)抗コリン剤を同時にまたは時間を置いて別々に投与することを 特徴とする COPDまたは喘息の治療および Zまたは予防方法。  4-[(3,5-dichloro-1-pyridyl) potassium] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarboyl) benzofuran or its pharmaceutically acceptable salts and (b) A method for treating and preventing or preventing COPD or asthma, which comprises administering an anticholinergic agent simultaneously or separately at an interval.
[26] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 25記載の方法。 [26] The method according to claim 25, wherein the compound is a compound selected from the group consisting of tiotropium, ipratophium pium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[27] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 26記載の方法。 [27] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 27. The method of claim 26 which is a citrate.
[28] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシブチュンである請求項 25記載の方法。 [28] The method according to claim 25, wherein the anticholinergic agent is piodium tiobromide, pipium bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
[29] (a)式 (I) [29] (a) Equation (I)
[化 21] [Formula 21]
Figure imgf000031_0001
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤との組み合わせの有効量を投与することを特徴とする CO
Figure imgf000031_0001
4-[(3,5-dichloro-1-pyridyl) potassium rubamoyl] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or a pharmaceutically acceptable salt thereof (b) CO characterized by administering an effective amount in combination with an anticholinergic agent
PDまたは喘息の治療および Zまたは予防方法。 How to treat and prevent or prevent PD or asthma.
[30] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 29記載の方法。 [30] The method according to claim 29, which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[31] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 30記載の方法。 [31] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 31. The method of claim 30, which is a citrate.
[32] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシブチュンである請求項 29記載の方法。 32. The method according to claim 29, wherein the anticholinergic agent is piodium tiobromide, pipium bromide, oxitropium bromide, tolterodine tartrate or oxybutun hydrochloride.
[33] COPDまたは喘息の治療および Zまたは予防剤の製造のための（a)式 (I) [33] Formula (a) for the manufacture of a therapeutic and / or prophylactic agent for COPD or asthma
[化 22]  [Formula 22]
Figure imgf000031_0002
Figure imgf000031_0002
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩および (b)抗コリン剤の使用。  4-[(3,5-dichloro-1-pyridyl) potassium] represented by the formula: 7-Methoxy-12- (4-methylbiperazine 1-ylcarboyl) benzofuran or its pharmaceutically acceptable salts and (b) Use of anticholinergic agents.
抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 33記載の使用。 Anticholinergic activity Tiotropium, iprat mouth pium, oxitropium, tolterodine and 34. The use according to claim 33, which is a compound selected from the group consisting of oxiptinin and group, or a pharmacologically acceptable salt thereof.
[35] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 34記載の使用。 [35] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 35. Use according to claim 34 which is a citrate.
[36] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシプチニンである請求項 33記載の使用。 [36] The use according to claim 33, wherein the anticholinergic agent is piodium thiotope bromide, palladium oxalate bromide, oxitropium bromide, tolterodine tartrate or oxyptyninine hydrochloride.
[37] (a)式 (I) [37] Equation (a) (I)
[化 23]  [Formula 23]
Figure imgf000032_0001
Figure imgf000032_0001
( I  (I
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— 4— [(3,5 dichloro- 1 4 pyridyl) rubamoyl] — 7—methoxy-1 2—
(4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩と (b)抗コリン剤を同時にまたは時間を置いて別々に投与するための CO(4-methylbiperazine 1-ylcarbol) benzofuran or its pharmacologically acceptable salt and (b) CO for the simultaneous or separate administration of anticholinergic agents
PDまたは喘息の治療および Zまたは予防剤の製造のための（a)および (b)の使用。 Use of (a) and (b) for the treatment of PD or asthma and for the manufacture of a Z or prophylactic agent.
[38] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 37記載の使用。 [38] The use according to claim 37, which is a compound selected from the group consisting of tiotropium, ipratophium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[39] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 38記載の使用。 [39] The pharmacologically acceptable salt of the anticholinergic is hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 39. Use according to claim 38 which is a citrate.
[40] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシプチニンである請求項 37記載の使用。 [40] The use according to claim 37, wherein the anticholinergic agent is piodium tiobromide, pipium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
[41] (a)式 (I) [41] (a) Equation (I)
[化 24]
Figure imgf000033_0001
[Formula 24]
Figure imgf000033_0001
( I  (I
で表わされる 4— [ (3, 5 ジクロロ一 4 ピリジル）力ルバモイル]— 7—メトキシ一 2— (4ーメチルビペラジン 1ーィルカルボ-ル）ベンゾフランまたはその薬理学的に許 容される塩を含有する第 1成分と (b)抗コリン剤を含有する第 2成分を有する COPD または喘息の治療および Zまたは予防用キットの製造のための（a)および (b)の使用  4-((3,5-dichloro-1-pyridyl) potassium rubamoyl) —7-methoxy-12- (4-methylbiperazine 1-ylcarbol) benzofuran or its pharmaceutically acceptable salt Use of (a) and (b) for the manufacture of a kit for the treatment and Z or prevention of COPD or asthma having a first component containing and (b) a second component containing an anticholinergic agent
[42] 抗コリン剤力 チォトロピウム、ィプラト口ピウム、ォキシトロピウム、トルテロジンおよび ォキシプチニン力もなる群力も選ばれる化合物またはその薬理学的に許容される塩 である請求項 41記載の使用。 [42] The use according to claim 41, which is a compound selected from the group consisting of tiotropium, iprat pium, oxitropium, tolterodine and oxiptinin, or a pharmacologically acceptable salt thereof.
[43] 抗コリン剤における薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、ヨウ化水素 酸塩、メタンスルホン酸塩、 p トルエンスルホン酸塩、酒石酸塩、酢酸塩またはコハ ク酸塩である請求項 42記載の使用。 [43] The pharmacologically acceptable salt of the anticholinergic agent may be hydrochloride, hydrobromide, hydroiodide, methanesulfonate, p-toluenesulfonate, tartrate, acetate or potassium salt. 43. Use according to claim 42 which is a citrate.
[44] 抗コリン剤が、臭化チオト口ピウム、臭化ィプラト口ピウム、臭化ォキシトロピウム、酒石 酸トルテロジンまたは塩酸ォキシプチニンである請求項 41記載の使用。 [44] The use according to claim 41, wherein the anticholinergic agent is piodium tiobromide, pipium bromide, oxitropium bromide, tolterodine tartrate or oxyptinin hydrochloride.
PCT/JP2005/007966 2004-04-27 2005-04-27 Pharmaceutical composition WO2005102344A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016768A1 (en) * 1997-10-01 1999-04-08 Kyowa Hakko Kogyo Co., Ltd. Benzofuran derivatives
WO2002096463A1 (en) * 2001-05-25 2002-12-05 Pfizer Inc. A pde 4 inhibitor and an anti-cholinergic agent in combination for treating obstructive airways diseases
WO2003011274A2 (en) * 2001-07-27 2003-02-13 Glaxo Group Limited Use of a pde4 inhibitor in combination with an anticholinergic agent for the treatment of pulmonary disease such as asthma

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016768A1 (en) * 1997-10-01 1999-04-08 Kyowa Hakko Kogyo Co., Ltd. Benzofuran derivatives
WO2002096463A1 (en) * 2001-05-25 2002-12-05 Pfizer Inc. A pde 4 inhibitor and an anti-cholinergic agent in combination for treating obstructive airways diseases
WO2003011274A2 (en) * 2001-07-27 2003-02-13 Glaxo Group Limited Use of a pde4 inhibitor in combination with an anticholinergic agent for the treatment of pulmonary disease such as asthma

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