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WO2009154246A1 - Agent thérapeutique pour un dysfonctionnement érectile - Google Patents

Agent thérapeutique pour un dysfonctionnement érectile Download PDF

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Publication number
WO2009154246A1
WO2009154246A1 PCT/JP2009/061071 JP2009061071W WO2009154246A1 WO 2009154246 A1 WO2009154246 A1 WO 2009154246A1 JP 2009061071 W JP2009061071 W JP 2009061071W WO 2009154246 A1 WO2009154246 A1 WO 2009154246A1
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Prior art keywords
alkyl
group
formula
hydrogen atom
hydroxy
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Ceased
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PCT/JP2009/061071
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English (en)
Japanese (ja)
Inventor
雅也 東岡
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Nippon Shinyaku Co Ltd
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Nippon Shinyaku Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present invention is a treatment for erectile dysfunction comprising, as an active ingredient, a heterocyclic derivative represented by the following general formula (1) (hereinafter referred to as “the present heterocyclic derivative (1)”) or a pharmaceutically acceptable salt thereof. It relates to the agent.
  • R 1 and R 2 are the same or different and are each a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy
  • R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl
  • R 5 represents a hydrogen atom, an alkyl or a halogen atom
  • Y represents N or N ⁇ O
  • A represents NR 6 and R 6 represents a hydrogen atom, alkyl, alkenyl or cycloalkyl
  • D represents alkylene or alkenylene optionally substituted with hydroxy, or A and D together represent a divalent group represented by the following formula (2); [In the formula (2), r represents
  • E represents phenylene or a single bond, or D and E together represent a divalent group represented by the following formula (3); [In the formula (3), u represents an integer of 0 to 2, and v represents 0 or 1. ] G represents O, S, SO or SO 2 ; Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or a group represented by the following formula (4).
  • R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 4) which may be substituted with 1 to 3 substituents selected from the group consisting of amino, dialkylamino, carboxy, cyano and nitro; 1) alkyl, 2) aryl, 3) Aryloxy, 4) A heterocyclic group. ]
  • Erectile dysfunction refers to a state in which satisfactory sexual intercourse cannot be performed because an effective erection cannot be obtained during sexual intercourse, and is positioned as one of so-called sexual dysfunctions. Erectile dysfunction tends to increase with age, but this increases with increasing age and increases the number of underlying diseases such as heart disease, diabetes, hypertension, hyperlipidemia, arteriosclerosis, and treats these underlying diseases. Therefore, the use of antihypertensives, hypoglycemic agents, etc. taken for this reason is also considered as a cause. Other causes are thought to be smoking, lack of exercise, and stress.
  • inhibitors of phosphodiesterase 5 are used as first-line drugs. Of patients receiving phosphodiesterase 5 inhibitors, 20-30% are ineffective. For patients inhibitors of phosphodiesterase 5 is invalid, intracavernosal injection of prostaglandin E 1 has been performed.
  • this heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof has already been reported to be useful as a PGI 2 receptor agonist in the treatment of pulmonary hypertension and obstructive arteriosclerosis (for example, see Patent Document 1).
  • An object of the present invention is mainly to provide a novel therapeutic agent for erectile dysfunction.
  • the present inventor has found that the present heterocyclic derivative (1) increases penile intracavernous pressure in rats, and has completed the present invention.
  • the erectile dysfunction therapeutic agent which contains this heterocyclic derivative (1) or its pharmaceutically acceptable salt as an active ingredient can be mentioned, for example.
  • FIG. 1 shows the variation of the value obtained by dividing the intracavernosal pressure by the blood pressure.
  • the vertical axis represents penile intracavernous pressure / blood pressure (ratio to pre-dose value;%), and the horizontal axis represents time (minutes) after administration.
  • the circles indicate the control group, and the squares indicate 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ acetic acid (hereinafter “compound A”).
  • FIG. 2 shows the variation of penile intracavernous pressure.
  • the vertical axis represents penile intracavernous pressure (ratio to pre-dose value;%), and the horizontal axis represents time (min) after administration.
  • a circle represents a control group
  • a square represents a group to which Compound A was administered
  • a triangle represents a group to which Compound B was administered.
  • R 1 and R 2 are the same or different and are phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy;
  • R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
  • R 5 is a hydrogen atom, Y is N,
  • A is NR 6 ,
  • R 6 is alkyl,
  • D is alkylene
  • E is a single bond,
  • G O,
  • Q is carboxy or a group represented by formula (4),
  • R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4) optionally substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino
  • Compound A and Compound B are preferable.
  • alkyl in the present invention is a linear or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. In particular, those having 1 to 4 carbon atoms are preferred.
  • Haloalkyl “Haloalkyl”, “arylalkyl”, “alkylthio”, “alkoxyalkyl”, “alkylsulfonyl”, “monoalkylamino”, “dialkylamino”, “monoalkylcarbazoyl” and “dialkylcarbamoyl” in the present invention
  • Examples of the moiety include the same alkyl groups as those described above.
  • alkoxy is a straight or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Examples include butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy and isohexyloxy. In particular, those having 1 to 4 carbon atoms are preferred.
  • alkoxy moiety of “alkoxycarbonyl” and “alkoxyalkyl” in the present invention include the same as the above alkoxy.
  • alkenyl is linear or branched having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples thereof include 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. In particular, those having 3 or 4 carbon atoms are preferred.
  • cycloalkyl in the present invention include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, those having 5 to 7 carbon atoms are preferred.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • aryl includes 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl. In particular, phenyl is preferred.
  • arylalkyl As the aryl moiety of “arylalkyl” and “aryloxy” in the present invention, the same aryl as the above aryl can be exemplified.
  • alkylene in the present invention, linear or branched ones having 1 to 8 carbon atoms such as methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, Examples include hexamethylene, heptamethylene, and octamethylene. In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.
  • alkenylene in the present invention, linear or branched ones having 2 to 8 carbon atoms such as ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1-heptenylene, 2- Examples include heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene and 7-octenylene. .
  • those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are preferred, and those
  • heterocyclic group examples include the following (1) or (2).
  • an atom or a sulfur atom such a nitrogen atom or sulfur atom may form an oxide.
  • piperidino, piperazinyl, 3-methylpiperazin-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, 2-tetrahydrofuranyl can be mentioned.
  • the present heterocyclic derivative (1) can be synthesized by the method described in Patent Document 1 (International Publication No. 02/088084 pamphlet).
  • the present heterocyclic derivative (1) can be used as a medicine as a free base or acid, but can also be used in the form of a medically acceptable salt by a known method.
  • a salt of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, or hydrobromic acid, or acetic acid, List organic acid salts of tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or camphorsulfonic acid Can do.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium
  • the present heterocyclic derivative (1) has geometric isomers (Z-form and E-form), and each geometric isomer and a mixture thereof are also included in the present heterocyclic derivative (1).
  • some of the heterocyclic derivatives (1) have asymmetric carbons, but each optical isomer and their racemates are also included in the heterocyclic derivatives (1).
  • the optical isomer is obtained from the racemate obtained as described above using its basicity and using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid), It can be optically resolved by a known method, or can be produced using a previously prepared optically active compound as a raw material.
  • erectile dysfunction examples include diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic surgery for prostatectomy, aging, There may be mentioned vascular erectile dysfunction associated with arteriosclerosis.
  • the therapeutic agent for erectile dysfunction according to the present invention preferably comprises the present heterocyclic derivative (1) in the range of 0.01 to 99.5% as it is or in a pharmaceutically acceptable non-toxic and inert carrier. Is contained in the range of 0.5 to 90%.
  • the carrier examples include solid, semi-solid or liquid diluents, fillers, and other formulation aids. One or more of these can be used.
  • the therapeutic agent for erectile dysfunction is a solid or liquid dosage unit, such as powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, lozenge and the like.
  • a parenteral preparation such as an oral preparation, an injection, an ointment, and a cream can be used. It may be a sustained-release preparation.
  • parenteral preparations are preferable, and injections, ointments and lotions are particularly preferable.
  • the powder can be produced by making the present heterocyclic derivative (1) fine.
  • the powder can be produced by making the present heterocyclic derivative (1) fine and then mixing it with a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol.
  • a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol.
  • flavor, etc. can be added arbitrarily.
  • Capsules are manufactured by first filling the powdered powdered powder or powder as described above into granules as described in the section of tablets, for example, into capsule shells such as gelatin capsules. can do.
  • Lubricants and fluidizers such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powder and powder, and then filled. It can also be manufactured.
  • disintegrators and solubilizers are added, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate
  • the fine powder of the present heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant and wrapped in a gelatin sheet to form a soft capsule.
  • Tablets are manufactured by adding excipients to the powdered heterocyclic derivative (1) to form a powder mixture, granulating or slugging, then adding a disintegrant or lubricant, and then tableting. can do.
  • the powder mixture can be produced by mixing the present heterocyclic derivative (1), which has been appropriately pulverized, with a diluent or a base.
  • a binder for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
  • a dissolution retardant for example, paraffin
  • a resorbent for example, a quaternary salt
  • An adsorbent for example, bentonite, kaolin or the like
  • the powder mixture can first be moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules.
  • a tablet can also be manufactured by directly compressing after mixing this heterocyclic derivative (1) with a fluid inert carrier, without going through the granulation and slagging steps as described above. it can. Film tablets and sugar coatings can be applied to the tablets thus produced.
  • a transparent or translucent protective coating made of a shellac hermetic coating, a coating of sugar or polymer material and a polishing coating made of wax can also be used.
  • oral dosage forms such as solutions, syrups, troches, and elixirs may also be in dosage unit form so that a given amount contains a certain amount of the heterocyclic derivative (1).
  • the syrup can be produced by dissolving the present heterocyclic derivative (1) in a suitable flavor aqueous solution.
  • An elixir can be produced by using a non-toxic alcoholic carrier.
  • the suspending agent can be produced by dispersing the present heterocyclic derivative (1) in a non-toxic carrier. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin), etc. may be added. it can.
  • solubilizers and emulsifiers for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives for example, peppermint oil, saccharin, etc.
  • a dosage unit formulation for oral administration can be microencapsulated.
  • the formulation can also be extended in action time or sustained release by being coated or embedded in a polymer, wax or the like.
  • the parenteral preparation can be a liquid dosage unit form for injection into subcutaneous, intramuscular, intravenous or intracavernosal bodies, for example, an injection having a solution or suspension form. Moreover, it can be made into the semi-solid form for applying to a penis, for example, an ointment, a lotion agent.
  • An injection having the form of a solution or suspension is obtained by suspending or dissolving a certain amount of the heterocyclic derivative (1) in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium.
  • a non-toxic liquid carrier suitable for injection purposes for example, an aqueous or oily medium.
  • the suspension or solution can then be sterilized.
  • Non-toxic salts and salt solutions can be added to make the injection solution isotonic.
  • stabilizers, preservatives, emulsifiers, and the like can be added.
  • the ointment can be produced, for example, by mixing the present heterocyclic derivative (1) and a base such as a hydrophobic base or a hydrophilic base. Moreover, a preservative, antioxidant, etc. can also be added.
  • the lotion can be produced, for example, by adding the present heterocyclic derivative (1) and a solvent, an emulsifier, a suspending agent and the like to an aqueous liquid such as normal water or purified water, and dissolving or dispersing it. A preservative or the like can also be added.
  • the dose of the therapeutic agent for erectile dysfunction according to the present invention varies depending on the patient's condition such as body weight and age, administration route, degree of symptom, etc.
  • the amount is suitably in the range of 0.001 mg to 100 mg per dose, more preferably in the range of 0.01 mg to 10 mg. In some cases, a lower dose may be sufficient, and vice versa.
  • Test example 1 (1) Test method The penile intracavernous pressure was measured according to the method of Teiweira et al. (The Journal of Pharmaceutical and Experimental Therapeutics, Vol. 315, p. 155-162, 2005). SD rats (male, 7 weeks old) (manufactured by SLC Japan) were anesthetized by subcutaneously administering 4 mL of 300 mg / mL urethane per 1 kg body weight of the rat, and fixed in the dorsal position.
  • MAP blood pressure
  • ICP Penile intracavernous pressure
  • the penile intracavernous pressure and blood pressure were recorded over time, and the values obtained by dividing the penile intracavernous pressure and penile intracavernous pressure by the blood pressure (ICP / MAP) were expressed as 100% before drug administration. did.
  • the penile intracavernous pressure and the value obtained by dividing the penile intracavernous pressure by the blood pressure are used as indicators of erectile activity (see The Journal of Pharmaceutical Therapies, Vol. 315, p. 155-162, 2005). ).
  • an aqueous solution containing Compound A at 3 mg / mL [medium: 5 w / v% glucose aqueous solution (manufactured by Otsuka Pharmaceutical Co., Ltd., the same shall apply hereinafter)]
  • an aqueous solution containing Compound B at 3 mg / mL (medium: 5 w / v% glucose aqueous solution) was used.
  • the control group was administered with 5 w / v% glucose aqueous solution as a vehicle. Four rats were used per group.

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Abstract

L'invention porte sur agent thérapeutique pour un dysfonctionnement érectile contenant, à titre de composant efficace un dérivé hétérocyclique représenté par la formule générale (1) ou un sel pharmaceutiquement acceptable de celui-ci. Dans la formule (1), R1 et R2 peuvent être identiques ou différents, chacun représentant un groupe aryle facultativement substitué; R3 et R4 peuvent être identiques ou différents, chacun représentant un atome d'hydrogène ou un groupe alkyle; R5 représente un atome d'hydrogène, un groupe alkyle ou un atome d'halogène; Y représente N ou N→O; A représente NR6, où R6 représente un atome d'hydrogène, un groupe alkyle, entre autres; D représente un groupe alkylène ou alcénylène facultativement substitué par un groupe hydroxyle; E représente un groupe phénylène ou une simple liaison; G représente O, S, entre autres; Q représente un groupe carboxyle, un groupe alcoxycarbonyle, entre autres.
PCT/JP2009/061071 2008-06-19 2009-06-18 Agent thérapeutique pour un dysfonctionnement érectile Ceased WO2009154246A1 (fr)

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JP2008160225 2008-06-19

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010150865A1 (fr) 2009-06-26 2010-12-29 日本新薬株式会社 Cristaux
WO2011024874A1 (fr) * 2009-08-26 2011-03-03 日本新薬株式会社 Sels d'addition avec une base
KR20180081141A (ko) 2015-12-02 2018-07-13 니뽄 신야쿠 가부시키가이샤 2-｛4-[n-(5,6-디페닐피라진-2-일)-n-이소프로필아미노]부틸옥시｝-n-(메틸술포닐)아세트아미드를 함유하는 의약 조성물
WO2018162527A1 (fr) 2017-03-08 2018-09-13 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2019065792A1 (fr) 2017-09-28 2019-04-04 日本新薬株式会社 Cristaux
WO2019098300A1 (fr) 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
WO2021078835A1 (fr) 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2021152060A1 (fr) 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2022162163A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Procédé de fabrication d'un dérivé de diphénylpyrazine
WO2022162158A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant un dérivé de diphénylpyrazine
WO2023131608A1 (fr) 2022-01-04 2023-07-13 Actelion Pharmaceuticals Ltd Compositions à libération contrôlée
WO2023214059A1 (fr) 2022-05-06 2023-11-09 Actelion Pharmaceuticals Ltd Composés de diphénylpyrazine utilisés en tant que promédicaments
WO2024017964A1 (fr) 2022-07-20 2024-01-25 Actelion Pharmaceuticals Ltd Composition pharmaceutique injectable comprenant un dérivé de diphénylpyrazine
WO2024133620A1 (fr) 2022-12-22 2024-06-27 Actelion Pharmaceuticals Ltd Test de dissolution in vitro
WO2024194449A1 (fr) 2023-03-23 2024-09-26 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant un dérivé de diphénylpyrazine
WO2025196095A1 (fr) 2024-03-20 2025-09-25 Actelion Pharmaceuticals Ltd Composition pharmaceutique injectable pour le traitement de l'hypertension pulmonaire
US12427145B2 (en) 2019-02-03 2025-09-30 Innovate Therapeutics Llc Controlled release pharmaceutical composition of Selexipag or it's active metabolite

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JPH10152480A (ja) * 1996-09-25 1998-06-09 Takeda Chem Ind Ltd 三環性化合物、その製造法および剤
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Title
MIKHAILIDIS D. P. ET AL.: "Eicosanoids, impotence and pharmacologically induced erection", PROSTAGLANDINS, LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, vol. 40, no. 4, 1990, pages 239 - 242 *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3275871A1 (fr) 2009-06-26 2018-01-31 Nippon Shinyaku Co., Ltd. Cristaux
KR20240090716A (ko) 2009-06-26 2024-06-21 니뽄 신야쿠 가부시키가이샤 결정
KR20120109457A (ko) 2009-06-26 2012-10-08 니뽄 신야쿠 가부시키가이샤 결정
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