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WO2006075748A1 - Therapeutic agent for allergic conjunctival disease - Google Patents

Therapeutic agent for allergic conjunctival disease Download PDF

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Publication number
WO2006075748A1
WO2006075748A1 PCT/JP2006/300464 JP2006300464W WO2006075748A1 WO 2006075748 A1 WO2006075748 A1 WO 2006075748A1 JP 2006300464 W JP2006300464 W JP 2006300464W WO 2006075748 A1 WO2006075748 A1 WO 2006075748A1
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WO
WIPO (PCT)
Prior art keywords
allergic
pyridine
allergic conjunctivitis
therapeutic agent
conjunctival
Prior art date
Application number
PCT/JP2006/300464
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French (fr)
Japanese (ja)
Inventor
Daisuke Shii
Hideki Miyake
Original Assignee
Santen Pharmaceutical Co., Ltd.
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Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2006075748A1 publication Critical patent/WO2006075748A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to 9-cyclopentyl _ 7_ethyl _ 3_ (thiophene _ 2_ yl)-5, 6-dihydro 1 9H-pyrazo mouth [3, 4-c]-l, 2, 4_ triazolo Allergic conjunctival diseases containing [4, 3_a] pyridine, 2_ (3-chlorophenoxy) _ 3 _ [3 _ (3-hydroxypyridine -4-yl) propoxy] pyridin or their salts as active ingredients Related to the therapeutic agent.
  • Allergic conjunctival diseases are inflammatory diseases of the conjunctiva involving type I allergy, and allergens such as pollen, mites, house dust, fungi, pet hair, etc. are known. Allergic conjunctival diseases are roughly classified into allergic conjunctivitis, spring catarrh, and atopic keratoconjunctivitis. Allergic conjunctivitis is an allergic conjunctival disease in which no proliferative changes in the conjunctiva are observed, and seasonal symptoms are called seasonal allergic conjunctivitis. It is called allergic conjunctivitis.
  • Spring cataract is an allergic conjunctival disease in which the growth of the eyelid conjunctival nipples increases, conjunctival thickening, and swelling and swelling of the limbal conjunctiva.
  • Atopic keratoconjunctivitis is a chronic keratoconjunctival disease that occurs in association with atopic dermatitis.
  • the main symptoms of these allergic conjunctival diseases include edema and hyperemia.
  • Japanese Patent No. 3107827 Meito I 1 shows that substituted pyridines such as Tofimilast have PDE-IV inhibitory activity and TNF inhibitory activity, and are effective in diseases such as asthma, arthritis, bronchitis, and psoriasis.
  • substituted pyridine derivatives such as OS-0217 have PDE-IV inhibitory activity and show a strong bronchodilator action.
  • Tofimilast and OS-0217 have various pharmacological effects as pharmaceuticals, but finding an efficacy against allergic conjunctival disease as a new pharmacological effect is an interesting issue.
  • the present invention relates to 9-cyclopentyl-7 ethyl-3 (thiophene-2-inole) -5, 6 dihydro-9H pyrazo [3, 4-c] -l, 2, 4 triazolo [4, 3— a] Pyridine, 2- (3 Chlorophenoxy) 3- [3— (3-Hydroxypyridine-4-yl) propoxy] pyridine or a salt thereof as a therapeutic agent for allergic conjunctival disease provide.
  • the allergic conjunctival disease is, for example, allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis.
  • the allergic conjunctivitis is, for example, seasonal allergic conjunctivitis or perennial allergic conjunctivitis.
  • the therapeutic agent according to the present invention is preferably in the form of eye drops or eye ointment.
  • the present invention also relates to 9-cyclopentyl _7_ethyl _3_ (thiophene 2-yl) _5, 6-dihydro-9H_pyrazo mouth [3, 4_c] _l, 2, 4_triazolo [4, 3_a] Pyridine, 2 — (3-Chlorophenoxy) 3— [3-— (3-Hydroxypyridine-4-yl) propoxy] pyridine or a method for treating allergic conjunctival disease comprising administering an effective amount of a salt thereof to a patient I will provide a.
  • pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, and tartaric acid. And the like. More preferred salts are hydrochloride, acetate and fumarate.
  • quaternary ammonium salts, hydrates and solvates are also included in the pharmaceutically acceptable salts of the present invention.
  • geometric isomers, optical isomers, tautomers, polymorphs and the like are also included in the active ingredients of the present invention.
  • the therapeutic agent for allergic conjunctivitis, spring catarrh and atopic keratoconjunctivitis according to the present invention (hereinafter referred to as "allergic conjunctival disease therapeutic agent”) is a pharmaceutically acceptable additive as necessary.
  • a technique widely used as a single preparation or a combination preparation can be used to prepare a preparation.
  • the therapeutic agent for allergic conjunctival disease of the present invention can be administered either orally or parenterally.
  • Preferable dosage forms include eye drops, eye ointments, tablets and the like, and eye drops or eye ointments are more preferable. These can be formulated using widely used technologies.
  • the eye drop can be prepared by appropriately blending as an additive an isotonic agent, buffer, pH adjuster, solubilizer, thickener, stabilizer, preservative and the like.
  • a stable eye drop can be obtained by adding a pH adjuster, a thickener, a dispersant and the like to suspend the drug.
  • Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
  • Examples of the buffering agent include phosphoric acid, phosphate, citrate, acetic acid, ⁇ -amino force proacid, and the like.
  • Examples of the rhodium regulator include hydrochloric acid, citrate, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate and the like.
  • solubilizer examples include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000.
  • thickeners and dispersants include cellulose polymers such as hydroxypropyl methylcellulose and hydroxypropyl pill cellulose, polybulal alcohol, polybulurpyrrolidone, and the like.
  • stabilizers include edetic acid, Examples include sodium edetate.
  • preservatives examples include general-purpose sorbic acid, potassium sorbate, benzoleconium chloride, salt benzobentonium, methyl paraoxybenzoate, propyl parabenzoate, and chlorobutanol. Can be used in combination.
  • the eye drop containing the therapeutic agent for allergic conjunctival disease of the present invention it is desirable to set ⁇ to 4.0 to 8.5, and the osmotic pressure ratio may be set to around 1.0. desirable.
  • the dosage of the active ingredient when used as a therapeutic agent for allergic conjunctival disease is preferably 0.001 to 10% (w / v) as long as it is an eye drop that can be appropriately selected according to symptoms, age, dosage form, etc. More preferably, it may be instilled in an amount of 0 ⁇ 01 to 3% (w / v) at a dose of 1 to several drops once to several times a day (for example:: to 8 times). In the case of an eye ointment, a concentration of 0 ⁇ 001-10% (w / w), more preferably 0.01 to 3% (wZw) is preferably used once to several times a day (for example: ! ⁇ 4 times) Apply. In the case of an oral preparation, it is preferable to administer 1 mg to: 100 mg, more preferably 5 mg to 30 mg once to several times a day (for example:: to 3 times).
  • the dosage varies depending on various conditions, and therefore, an amount smaller than the above dosage may be sufficient or may be necessary beyond the range.
  • compound A 4, 3— a] pyridine (hereinafter referred to as “compound A”) and 2— (3 black phenoxy)
  • Compound B The inhibitory effect of (3-hydroxypyridine-l-yl) propoxy] pyridine (hereinafter referred to as “Compound B”) on conjunctival inflammation (edema / hyperemia) was examined.
  • Inhibition rate 100— ([mean value of conjunctival inflammation score of test compound] ⁇ [mean value of conjunctival inflammation score of control]) X 100
  • Table 2 shows the conjunctival inflammation score (average value) and inhibition rate (%) for compound A (16 subjects), and Table 3 shows the conjunctival inflammation score (average value) and inhibition rate (%) for compound B. Shown (18 eyes).
  • An eye drop of the following prescription is prepared using a widely used method.
  • An eye ointment having the following formulation is prepared using a widely used method.

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  • Life Sciences & Earth Sciences (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel pharmacological efficacy (pharmaceutical usage) of 9-cyclopentyl-7-ethyl-3-(thiophen-2-yl)-5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine. These substituted pyridine derivatives without exception exhibit excellent allergic conjunctival symptom suppressing effects on allergic conjunctival models, so that they are useful as a therapeutic agent for allergic conjunctival diseases, such as allergic conjunctivitis, spring catarrh and atopic keratoconjunctivitis.

Description

明 細 書  Specification
アレルギー性結膜疾患治療剤  Allergic conjunctival disease treatment
技術分野  Technical field
[0001] 本発明は、 9—シクロペンチル _ 7_ェチル _ 3_ (チォフェン _ 2_ィル） - 5, 6 —ジヒドロ一 9H—ピラゾ口 [3, 4-c] - l, 2, 4_トリァゾロ [4， 3_a]ピリジン、 2_ ( 3 -クロロフエノキシ） _ 3 _ [3 _ (3—ヒドロキシピリジン一 4 _ィル）プロポキシ]ピリジ ンまたはそれらの塩類を有効成分として含有するアレルギー性結膜疾患の治療剤に 関する。  [0001] The present invention relates to 9-cyclopentyl _ 7_ethyl _ 3_ (thiophene _ 2_ yl)-5, 6-dihydro 1 9H-pyrazo mouth [3, 4-c]-l, 2, 4_ triazolo Allergic conjunctival diseases containing [4, 3_a] pyridine, 2_ (3-chlorophenoxy) _ 3 _ [3 _ (3-hydroxypyridine -4-yl) propoxy] pyridin or their salts as active ingredients Related to the therapeutic agent.
背景技術  Background art
[0002] アレルギー性結膜疾患は、 I型アレルギーが関与する結膜の炎症性疾患であり、そ の原因として花粉、ダニ、ハウスダスト、真菌、ペットの毛などのアレルゲンが知られて いる。アレルギー性結膜疾患は、アレルギー性結膜炎、春季カタル、アトピー性角結 膜炎に大別される。アレルギー性結膜炎は、結膜の増殖性変化が認められないァレ ルギー性結膜疾患であり、症状の発現が季節性のものを季節性アレルギー性結膜 炎と呼び、また、通年性のものを通年性アレルギー性結膜炎と呼んでいる。春季カタ ノレは、眼瞼結膜の乳頭の増殖'増大、結膜肥厚、輪部結膜の腫脹や隆起などの増 殖性変化がみられるアレルギー性結膜疾患である。また、アトピー性角結膜炎とは、 アトピー性皮膚炎に合併して起こる慢性角結膜疾患である。これらのアレルギー性結 膜疾患の主症状として、浮腫および充血が挙げられる。  [0002] Allergic conjunctival diseases are inflammatory diseases of the conjunctiva involving type I allergy, and allergens such as pollen, mites, house dust, fungi, pet hair, etc. are known. Allergic conjunctival diseases are roughly classified into allergic conjunctivitis, spring catarrh, and atopic keratoconjunctivitis. Allergic conjunctivitis is an allergic conjunctival disease in which no proliferative changes in the conjunctiva are observed, and seasonal symptoms are called seasonal allergic conjunctivitis. It is called allergic conjunctivitis. Spring cataract is an allergic conjunctival disease in which the growth of the eyelid conjunctival nipples increases, conjunctival thickening, and swelling and swelling of the limbal conjunctiva. Atopic keratoconjunctivitis is a chronic keratoconjunctival disease that occurs in association with atopic dermatitis. The main symptoms of these allergic conjunctival diseases include edema and hyperemia.
[0003] 一方、 9—シクロペンチル _ 7_ェチル _ 3 _ (チォフェン一 2—ィル） _ 5， 6—ジヒ ドロ _ 9H_ピラゾ口 [3, 4-c] - l , 2, 4_トリァゾロ [4， 3_a]ピリジン（Tofimilast) および 2_ (3—クロロフエノキシ） _ 3 _ [3 _ (3—ヒドロキシピリジン一 4 _ィル）プロ ポキシ]ピリジン (OS-0217)は、いずれも置換ピリジン誘導体である。  On the other hand, 9-cyclopentyl _ 7_ ethyl _ 3 _ (thiophene 2-yl) _ 5, 6-dihydro _ 9H_ pyrazo mouth [3, 4-c]-l, 2, 4_ triazolo [4,3_a] pyridine (Tofimilast) and 2_ (3-chlorophenoxy) _ 3 _ [3 _ (3-hydroxypyridine mono 4- yl) propoxy] pyridine (OS-0217) are both substituted pyridines Is a derivative.
[0004] 特許第 3107827号明糸田書 1には、 Tofimilastなどの置換ピリジン類は PDE— IV阻害 活性や TNF阻害活性を有し、喘息、関節炎、気管支炎、乾癬などの疾患に有効で あること力 S記載され、また、 WO 00/20391号には、 OS-0217などの置換ピリジン誘 導体は PDE— IV阻害活性を有し、強い気管支拡張作用を示すことが記載されてい る。 [0004] Japanese Patent No. 3107827 Meito I 1 shows that substituted pyridines such as Tofimilast have PDE-IV inhibitory activity and TNF inhibitory activity, and are effective in diseases such as asthma, arthritis, bronchitis, and psoriasis. In addition, WO 00/20391 describes that substituted pyridine derivatives such as OS-0217 have PDE-IV inhibitory activity and show a strong bronchodilator action. The
[0005] しかし、上記文献には、これらの化合物の眼疾患、とりわけアレルギー性結膜疾患 に対する作用につレ、ては全く検討されてレ、なレ、。  [0005] However, in the above literature, the effects of these compounds on eye diseases, particularly allergic conjunctival diseases, have been completely studied.
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
[0006] 上記したように、 Tofimilastや OS-0217は、医薬として種々の薬理効果を有するが、 さらに新たな薬理効果としてアレルギー性結膜疾患に対する有効性を見い出すこと は興味ある課題である。 [0006] As described above, Tofimilast and OS-0217 have various pharmacological effects as pharmaceuticals, but finding an efficacy against allergic conjunctival disease as a new pharmacological effect is an interesting issue.
課題を解決するための手段  Means for solving the problem
[0007] 本発明者等は、 9—シクロペンチル _7_ェチル _3_ (チォフェン _2_ィル） -5 , 6—ジヒドロ一 9H_ピラゾ口 [3, 4_c]_l, 2, 4_トリァゾロ [4, 3_a]ピリジン（Tof imilast)および 2_(3_クロロフエノキシ） _3_[3_ (3—ヒドロキシピリジン _4—ィ ノレ)プロボキシ]ピリジン (OS-0217)の新たな医薬用途を探索すべく鋭意研究を行なつ たところ、アレルギー性結膜炎モデルを用いた結膜炎症状抑制試験において、これ らの置換ピリジン誘導体が優れたアレルギー性結膜炎症状 (浮腫 ·充血)抑制効果を 発揮することを見い出し、本発明に至った。  [0007] The present inventors, 9-cyclopentyl _7_ ethyl _3_ (thiophene _2_yl) -5, 6-dihydro 1 9H_ pyrazo mouth [3, 4_c] _l, 2, 4_ triazolo [4, 3_a ] Intensive research to explore new pharmaceutical uses of pyridine (Tof imilast) and 2_ (3_chlorophenoxy) _3_ [3_ (3-hydroxypyridine _4—ynole) propoxy] pyridine (OS-0217) As a result, in a conjunctival inflammation suppression test using an allergic conjunctivitis model, it was found that these substituted pyridine derivatives exhibited an excellent allergic conjunctival inflammation (edema / hyperemia) suppression effect, and the present invention was achieved.
[0008] すなわち、本発明は、 9ーシクロペンチルー 7 ェチルー 3 （チォフェンー2—ィ ノレ）ー5, 6 ジヒドロー 9H ピラゾ口 [3, 4-c]-l, 2, 4 トリァゾロ [4, 3— a]ピリ ジン、 2— (3 クロロフエノキシ） 3— [3— (3 ヒドロキシピリジン一 4—ィル）プロボ キシ]ピリジンまたはそれらの塩類を有効成分として含有するアレルギー性結膜疾患 の治療剤を提供する。  That is, the present invention relates to 9-cyclopentyl-7 ethyl-3 (thiophene-2-inole) -5, 6 dihydro-9H pyrazo [3, 4-c] -l, 2, 4 triazolo [4, 3— a] Pyridine, 2- (3 Chlorophenoxy) 3- [3— (3-Hydroxypyridine-4-yl) propoxy] pyridine or a salt thereof as a therapeutic agent for allergic conjunctival disease provide.
[0009] アレルギー性結膜疾患は、たとえばアレルギー性結膜炎、春季カタルまたはアトピ 一性角結膜炎である。  [0009] The allergic conjunctival disease is, for example, allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis.
[0010] アレルギー性結膜炎は、たとえば季節性アレルギー性結膜炎または通年性アレル ギー性結膜炎である。  [0010] The allergic conjunctivitis is, for example, seasonal allergic conjunctivitis or perennial allergic conjunctivitis.
[0011] 本発明による治療剤は、好ましくは点眼剤または眼軟膏の形態である。  [0011] The therapeutic agent according to the present invention is preferably in the form of eye drops or eye ointment.
[0012] 本発明はまた、 9—シクロペンチル _7_ェチル _3_ (チォフェン一 2—ィル） _5 , 6—ジヒドロ一 9H_ピラゾ口 [3, 4_c]_l, 2, 4_トリァゾロ [4, 3_a]ピリジン、 2 — (3—クロロフエノキシ） 3— [3— (3—ヒドロキシピリジン一 4—ィル）プロポキシ]ピ リジンまたはそれらの塩類の有効量を患者に投与することからなるアレルギー性結膜 疾患の治療方法を提供する。 [0012] The present invention also relates to 9-cyclopentyl _7_ethyl _3_ (thiophene 2-yl) _5, 6-dihydro-9H_pyrazo mouth [3, 4_c] _l, 2, 4_triazolo [4, 3_a] Pyridine, 2 — (3-Chlorophenoxy) 3— [3-— (3-Hydroxypyridine-4-yl) propoxy] pyridine or a method for treating allergic conjunctival disease comprising administering an effective amount of a salt thereof to a patient I will provide a.
[0013] 9—シクロペンチル _ 7_ェチル _ 3 _ (チォフェン一 2—ィル）_ 5, 6—ジヒドロ一 9H ピラゾ口 [3， 4_ c] _ l , 2, 4_トリァゾロ [4, 3 _&]ピリジン（丁01¾ 3 ぉょび 2- (3 クロロフエノキシ） _ 3 _ [3— (3—ヒドロキシピリジン一 4—ィノレ）プロポキシ] ピリジン (OS-0217)は、後述するアレルギー性結膜炎モデルを用いた結膜炎症状抑 制試験の結果から明らかなように、アレルギー性結膜疾患に対して優れた結膜炎症 状 (浮腫 ·充血)抑制作用を有する。  [0013] 9-cyclopentyl _ 7_ ethyl _ 3 _ (thiophene 2-yl) _ 5, 6-dihydro 1H pyrazo mouth [3, 4_ c] _ l, 2, 4_ triazolo [4, 3 _ & ] Pyridine (Cho 01¾ 3 Chobi 2- (3 Chlorophenoxy) _ 3 _ [3- (3-Hydroxypyridine-1-4-inole) propoxy] Pyridine (OS-0217) is a model for allergic conjunctivitis described below. As is evident from the results of the conjunctival inflammation suppression test used, it has excellent conjunctival inflammation suppression (edema / hyperemia) suppression for allergic conjunctival diseases.
[0014] 本発明において、医薬として許容される塩類は、特に制限はなぐ塩酸、硝酸、硫 酸等の無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、酒石酸等の有機酸と の塩などが挙げられる。より好ましい塩は、塩酸塩、酢酸塩およびフマル酸塩である。 また、第四級アンモニゥム塩、水和物および溶媒和物も本発明の医薬として許容され る塩類に包含される。さらに、幾何異性体、光学異性体、互変異性体、多形体なども 本発明の有効成分に包含される。  [0014] In the present invention, pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, and tartaric acid. And the like. More preferred salts are hydrochloride, acetate and fumarate. In addition, quaternary ammonium salts, hydrates and solvates are also included in the pharmaceutically acceptable salts of the present invention. Furthermore, geometric isomers, optical isomers, tautomers, polymorphs and the like are also included in the active ingredients of the present invention.
[0015] 本発明のアレルギー性結膜炎、春季カタルおよびアトピー性角結膜炎の治療剤（ 以下、これらを「アレルギー性結膜疾患治療剤」とする）は、必要に応じて、医薬として 許容される添加剤を加え、単独製剤または配合製剤として汎用されている技術を用 レ、て製剤化することができる。  [0015] The therapeutic agent for allergic conjunctivitis, spring catarrh and atopic keratoconjunctivitis according to the present invention (hereinafter referred to as "allergic conjunctival disease therapeutic agent") is a pharmaceutically acceptable additive as necessary. In addition, a technique widely used as a single preparation or a combination preparation can be used to prepare a preparation.
[0016] 本発明のアレルギー性結膜疾患治療剤は、経口でも、非経口でも投与することが できる。好ましい投与剤型としては、点眼剤、眼軟膏、錠剤等が挙げられるが、より好 ましくは点眼剤または眼軟膏である。これらは汎用されている技術を用いて製剤化す ること力 Sできる。例えば、点眼剤は、添加物として、等張化剤、緩衝剤、 pH調節剤、可 溶化剤、増粘剤、安定化剤、保存剤等を適宜配合して、調製することができる。また 、 pH調節剤、増粘剤、分散剤などを添加し、薬物を懸濁化させることによって、安定 な点眼剤を得ることもできる。  [0016] The therapeutic agent for allergic conjunctival disease of the present invention can be administered either orally or parenterally. Preferable dosage forms include eye drops, eye ointments, tablets and the like, and eye drops or eye ointments are more preferable. These can be formulated using widely used technologies. For example, the eye drop can be prepared by appropriately blending as an additive an isotonic agent, buffer, pH adjuster, solubilizer, thickener, stabilizer, preservative and the like. In addition, a stable eye drop can be obtained by adding a pH adjuster, a thickener, a dispersant and the like to suspend the drug.
[0017] 等張化剤としては、例えばグリセリン、プロピレングリコール、塩化ナトリウム、塩化力 リウム、ソルビトール、マンニトール等を挙げることができる。 [0018] 緩衝剤としては例えば、リン酸、リン酸塩、クェン酸、酢酸、 ε -ァミノ力プロン酸等を 挙げること力 Sできる。 [0017] Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like. [0018] Examples of the buffering agent include phosphoric acid, phosphate, citrate, acetic acid, ε-amino force proacid, and the like.
[0019] ρΗ調節剤としては、例えば塩酸、クェン酸、リン酸、酢酸、水酸化ナトリウム、水酸 化カリウム、ホウ酸、ホウ砂、炭酸ナトリウム、炭酸水素ナトリウム等を挙げることができ る。  [0019] Examples of the rhodium regulator include hydrochloric acid, citrate, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate and the like.
[0020] 可溶化剤としては、例えばポリソルベート 80、ポリオキシエチレン硬化ヒマシ油 60、 マクロゴール 4000等を挙げることができる。  [0020] Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and macrogol 4000.
[0021] 増粘剤、分散剤としては、例えばヒドロキシプロピルメチルセルロース、ヒドロキシプ 口ピルセルロースなどのセルロース系高分子、ポリビュルアルコール、ポリビュルピロ リドン等を、また、安定化剤としては、例えばェデト酸、ェデト酸ナトリウム等を挙げるこ とができる。 [0021] Examples of thickeners and dispersants include cellulose polymers such as hydroxypropyl methylcellulose and hydroxypropyl pill cellulose, polybulal alcohol, polybulurpyrrolidone, and the like. Examples of stabilizers include edetic acid, Examples include sodium edetate.
[0022] 保存剤（防腐剤）としては、例えば汎用のソルビン酸、ソルビン酸カリウム、塩化ベン ザノレコニゥム、塩ィ匕べンゼトニゥム、パラォキシ安息香酸メチル、パラォキシ安息香酸 プロピル、クロロブタノール等が挙げられ、これらの保存剤を組み合わせて使用する ことちできる。  [0022] Examples of preservatives (preservatives) include general-purpose sorbic acid, potassium sorbate, benzoleconium chloride, salt benzobentonium, methyl paraoxybenzoate, propyl parabenzoate, and chlorobutanol. Can be used in combination.
[0023] 本発明のアレルギー性結膜疾患治療剤を含有する点眼剤は、 ρΗを 4. 0〜8. 5に 設定することが望ましぐまた、浸透圧比を 1. 0付近に設定することが望ましい。  [0023] In the eye drop containing the therapeutic agent for allergic conjunctival disease of the present invention, it is desirable to set ρΗ to 4.0 to 8.5, and the osmotic pressure ratio may be set to around 1.0. desirable.
[0024] アレルギー性結膜疾患治療剤として用いる場合の有効成分の投与量は症状、年令 、剤型等によって適宜選択できる力 点眼剤であれば好ましくは 0. 001〜10% (w /v)、より好ましくは 0· 01〜3% (w/v)の濃度のものを 1回量 1〜数滴を 1日 1〜数 回（例えば、：!〜 8回）点眼すればよい。また、眼軟膏であれば好ましくは 0· 001 - 1 0% (w/w)、より好ましくは 0. 01〜3% (wZw)の濃度のものを 1日 1〜数回（例え ば、：!〜 4回）塗布すればよレ、。経口剤であれば、好ましくは lmg〜： 100mg、より好ま しくは 5mg〜30mgを 1日 1〜数回（例えば、：!〜 3回）投与すればよい。  [0024] The dosage of the active ingredient when used as a therapeutic agent for allergic conjunctival disease is preferably 0.001 to 10% (w / v) as long as it is an eye drop that can be appropriately selected according to symptoms, age, dosage form, etc. More preferably, it may be instilled in an amount of 0 · 01 to 3% (w / v) at a dose of 1 to several drops once to several times a day (for example:: to 8 times). In the case of an eye ointment, a concentration of 0 · 001-10% (w / w), more preferably 0.01 to 3% (wZw) is preferably used once to several times a day (for example: ! ~ 4 times) Apply. In the case of an oral preparation, it is preferable to administer 1 mg to: 100 mg, more preferably 5 mg to 30 mg once to several times a day (for example:: to 3 times).
[0025] もちろん前記したように、投与量は、種々の条件によって変動するので、上記投与 量より少ない量で十分な場合もあるし、また範囲を越えて必要な場合もある。  [0025] Of course, as described above, the dosage varies depending on various conditions, and therefore, an amount smaller than the above dosage may be sufficient or may be necessary beyond the range.
発明の効果  The invention's effect
[0026] 後述するように、結膜炎症状抑制試験を実施したところ、 9ーシクロペンチルー 7— ェチル 3— (チォフェン一 2—ィル） 5, 6 ジヒドロ一 9H ピラゾ口 [3, 4— c]— 1 , 2, 4 トリァゾロ [4, 3— a]ピリジン（Tofimilast)および 2— (3 クロロフエノキシ） 3—[3—（3—ヒドロキシピリジンー4 ィル）プロポキシ]ピリジン (OS-0217)は、ァレ ルギー性結膜炎モデルにぉレ、てアレルギー性結膜疾患の主症状である浮腫 ·充血 に対して優れた抑制効果を発揮するので、アレルギー性結膜炎、春季カタル、アトピ 一性角結膜炎などのアレルギー性結膜疾患の治療剤として有用である。 [0026] As will be described later, when a conjunctival inflammation state suppression test was performed, 9-cyclopentyl 7- Ethyl 3- (thiophene 2-yl) 5, 6 Dihydro-one 9H Pyrazo mouth [3, 4— c] — 1, 2, 4 Triazolo [4, 3— a] pyridine (Tofimilast) and 2— (3 chloroph Enoxy) 3- [3 -— (3-Hydroxypyridine-4-yl) propoxy] pyridine (OS-0217) is an edema that is a major symptom of allergic conjunctival disease in the allergic conjunctivitis model. Since it exhibits an excellent suppressive effect on hyperemia, it is useful as a therapeutic agent for allergic conjunctival diseases such as allergic conjunctivitis, spring catarrh, and atopic keratoconjunctivitis.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0027] 以下に、薬理試験および製剤例を示すが、これらの例は本発明をよりよく理解する ためのものであり、本発明の範囲を限定するものではない。 [0027] Pharmacological tests and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
[0028] [薬理試験] [0028] [Pharmacological test]
アレルギー性結膜炎モデルを用いた結膜炎症状抑制試験  Conjunctival inflammation suppression test using allergic conjunctivitis model
アレルギー性結膜炎モデルを用いて、 9ーシクロペンチルー 7—ェチルー 3—（チォ フェンー2—ィノレ） 5, 6 ジヒドロー 9H ピラゾ口 [3, 4 - c] - l , 2, 4 トリァゾロ [ Using an allergic conjunctivitis model, 9-cyclopentyl-7-ethyl-3- (thiophene-2-ynole) 5, 6 dihydro-9H pyrazo mouth [3, 4-c]-l, 2, 4 triazolo [
4, 3— a]ピリジン（以下「ィ匕合物 A」とする）および 2— (3 クロ口フエノキシ）一3— [34, 3— a] pyridine (hereinafter referred to as “compound A”) and 2— (3 black phenoxy)
— (3—ヒドロキシピリジン一 4—ィル)プロボキシ]ピリジン（以下「ィ匕合物 B」とする）の 結膜炎症状 (浮腫 ·充血）に対する抑制作用を検討した。 — The inhibitory effect of (3-hydroxypyridine-l-yl) propoxy] pyridine (hereinafter referred to as “Compound B”) on conjunctival inflammation (edema / hyperemia) was examined.
[0029] (実験方法） [0029] (Experimental method)
生理食塩液に水酸化アルミニウムゲル吸着ォブアルブミンを懸濁（20 μ g/mL) し、 5週齢の雄性 Hartley系モルモットの両眼球結膜下に、それぞれ 100 μ Lずつ注 射し、能動感作を行った。感作後 14日目、 15日目に、ォブアルブミン 1. 0%(W/V) の生理食塩液を 10 眼ずつ両眼に点眼投与して、アレルギー性結膜炎を惹起 した。  Suspend aluminum hydroxide gel adsorbed ovalbumin in physiological saline (20 μg / mL), and inject 100 μL each into the conjunctiva of 5-week-old male Hartley guinea pigs for active sensitization. went. On days 14 and 15 after sensitization, 10% ovalbumin physiological saline was administered to both eyes to induce allergic conjunctivitis.
[0030] 感作後 15日目のォブアルブミン点眼投与の 60分、 30分前 (合計 2回）に、 0. 1 %ヒ ドロキシプロピルメチルセルロース含有生理食塩液 (W/V)に懸濁した化合物 A1. 0 %懸濁液 (W/V)または化合物 B1. 0%懸濁液 (W/V)を、上記モルモットの両眼に それぞれ 10 L/眼ずつ点眼投与した。なお、コントロールとして 0· 1 %ヒドロキシ プロピルメチルセルロース含有生理食塩液 (W/V)を、上記モルモットの両眼にそれ ぞれ 10 L/眼ずつ点眼投与した。 [0031] 感作後 15日目のォブアルブミン点眼 30分後に、化合物 A、化合物 Bおよびコント口 ールを点眼したモルモットの結膜炎症状を下記評価基準 (表 1)に従い、スコア化す ることにより評価した。 [0030] Compound suspended in 0.1% hydroxypropylmethylcellulose-containing physiological saline solution (W / V) 60 minutes and 30 minutes before ophthalmic ophthalmic administration on day 15 after sensitization (2 times in total) A1.0% suspension (W / V) or Compound B1.0% suspension (W / V) was instilled into both eyes of the guinea pig at 10 L / eye. As a control, 0.1% hydroxypropylmethylcellulose-containing physiological saline (W / V) was instilled at 10 L / eye into both eyes of the guinea pig. [0031] 30 minutes after ovalbumin instillation on day 15 after sensitization, conjunctivitis symptoms of guinea pigs instilled with compound A, compound B and control mouth were evaluated by scoring according to the following evaluation criteria (Table 1). .
[0032] 抑制率 = 100— ([被験化合物の結膜炎症状スコアの平均値] ÷ [コントロールの結膜 炎症状スコアの平均値]) X 100  [0032] Inhibition rate = 100— ([mean value of conjunctival inflammation score of test compound] ÷ [mean value of conjunctival inflammation score of control]) X 100
[表 1]  [table 1]
Figure imgf000007_0001
表 2に、化合物 Aに対する結膜炎症状スコア（平均値)および抑制率（％)を示し (例 数 16眼）、表 3に、化合物 Bに対する結膜炎症状スコア（平均値)および抑制率（％) を示す (例数 18眼)。
Figure imgf000007_0001
Table 2 shows the conjunctival inflammation score (average value) and inhibition rate (%) for compound A (16 subjects), and Table 3 shows the conjunctival inflammation score (average value) and inhibition rate (%) for compound B. Shown (18 eyes).
[表 2]  [Table 2]
Figure imgf000007_0002
Figure imgf000007_0002
[表 3] 被験化合物 結膜炎症状スコア （平均値） 抑制率 （％) コントロール 3 . 2 [Table 3] Test compound Conjunctival inflammation score (mean value) Inhibition rate (%) Control 3.2
化合物 B ( 1 . 0 %) 2 . 4 2 5 . 0  Compound B (1.0%) 2.4 2 5 .0
[0034] (実験結果） [0034] (Experimental result)
表 2および表 3から明らかなように、化合物 Aまたは化合物 Bを点眼投与したモルモ ットの結膜炎症状はコントロールよりも顕著に抑制するので、アレルギー性結膜炎症 状抑制効果を有することが確認された。  As is clear from Table 2 and Table 3, it was confirmed that the conjunctivitis symptoms of guinea pigs administered with eye drops of Compound A or Compound B were markedly suppressed as compared with the control, and therefore had an allergic conjunctival inflammation suppression effect. .
[0035] [製剤例] [0035] [Formulation example]
本発明に用いられる代表的な製剤例を以下に示す。  The typical formulation example used for this invention is shown below.
[0036] 1.点眼剤 [0036] 1. Eye drops
以下の処方の点眼剤を汎用される方法を用いて調製する。  An eye drop of the following prescription is prepared using a widely used method.
[0037] 処方例 1  [0037] Formulation Example 1
100ml中  In 100ml
化合物 A lOOmg  Compound A lOOmg
濃グリセリン 500mg  Concentrated glycerin 500mg
ポリソルベート 80 lOOOmg  Polysorbate 80 lOOOmg
リン酸二水素ナトリウム二水和物 適量  Sodium dihydrogen phosphate dihydrate
1N水酸化ナトリウム 適量  1N sodium hydroxide
塩酸 適量  Hydrochloric acid
滅菌精製水 適量  Sterilized purified water
処方例 1と同様にして、化合物 Aを 100ml中に 10mg、 50mg、 lOOOmg含有する 点眼剤を調製することができる。  In the same manner as in Formulation Example 1, an ophthalmic solution containing 10 mg, 50 mg, and lOOOO mg of Compound A in 100 ml can be prepared.
[0038] 2.眼軟膏 [0038] 2. Eye ointment
以下の処方の眼軟膏を汎用される方法を用いて調製する。  An eye ointment having the following formulation is prepared using a widely used method.
[0039] 処方例 2 [0039] Formulation Example 2
lOOg中 化合物 B 200mg in lOOg Compound B 200mg
流動パラフィン lOg  Liquid paraffin lOg
白色ワセリン 適量  White petrolatum
処方例 2と同様にして、化合物 Bの添加量を適宜変えることにより、種々の濃度の眼 軟膏を調製できる。  In the same manner as in Formulation Example 2, various concentrations of eye ointment can be prepared by appropriately changing the amount of Compound B added.

Claims

請求の範囲 The scope of the claims
[1] 9—シクロペンチノレ一 7—ェチル一3— (チォフェン一 2—ィル）一5, 6—ジヒドロ一  [1] 9-Cyclopentinole 1-Ethyl 1- (Thiophen 1-yl) 1,5,6-Dihydro 1
9H—ピラゾ口 [3， 4_c]_l, 2, 4_トリァゾロ [4, 3_a]ピリジン、 2_ (3—クロロフ エノキシ) _3_[3_ (3—ヒドロキシピリジン _4_ィル）プロポキシ]ピリジンまたはそ れらの塩類を有効成分として含有するアレルギー性結膜疾患の治療剤。  9H—Pyrazo mouth [3, 4_c] _l, 2, 4_triazolo [4, 3_a] pyridine, 2_ (3-chlorophenoxy) _3_ [3_ (3-hydroxypyridine _4_yl) propoxy] pyridine or them Therapeutic agent for allergic conjunctival diseases containing the above salts as active ingredients.
[2] アレルギー性結膜疾患が、アレルギー性結膜炎、春季カタルまたはアトピー性角結 膜炎である請求項 1記載の治療剤。  [2] The therapeutic agent according to claim 1, wherein the allergic conjunctivitis is allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis.
[3] アレルギー性結膜炎が、季節性アレルギー性結膜炎または通年性アレルギー性結 膜炎である請求項 2記載の治療剤。  [3] The therapeutic agent according to claim 2, wherein the allergic conjunctivitis is seasonal allergic conjunctivitis or perennial allergic conjunctivitis.
[4] 治療剤が、点眼剤または眼軟膏の形態である請求項 1〜3のいずれかに記載の治 療剤。  4. The therapeutic agent according to any one of claims 1 to 3, wherein the therapeutic agent is in the form of eye drops or eye ointment.
[5] 9 シクロペンチノレ一 7 ェチノレ一 3— (チォフェン一 2—ィノレ）一 5, 6 ジヒドロ一  [5] 9 Cyclopentinole 7 Ethenole 1— (Chiofene 2-Inole) 1, 5, 6 Dihydro 1
9H ピラゾ口 [3, 4— c]— 1, 2, 4 トリァゾロ [4, 3— a]ピリジン、 2— (3 クロロフ エノキシ) 3—[3—（3—ヒドロキシピリジンー4 ィル）プロポキシ]ピリジンまたはそ れらの塩類の有効量を患者に投与することからなるアレルギー性結膜疾患の治療方 法。  9H Pyrazo [3, 4— c] — 1, 2, 4 Triazolo [4, 3— a] pyridine, 2— (3 chlorophenoxy) 3— [3— (3-hydroxypyridine-4-yl) propoxy] A method for treating allergic conjunctival disease, comprising administering to a patient an effective amount of pyridine or a salt thereof.
[6] アレルギー性結膜疾患が、アレルギー性結膜炎、春季カタルまたはアトピー性角結 膜炎である請求項 5記載の治療方法。  6. The method according to claim 5, wherein the allergic conjunctival disease is allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis.
[7] アレルギー性結膜炎が、季節性アレルギー性結膜炎または通年性アレルギー性結 膜炎である請求項 6記載の治療方法。  7. The method according to claim 6, wherein the allergic conjunctivitis is seasonal allergic conjunctivitis or perennial allergic conjunctivitis.
[8] 9—シクロペンチノレ一 7—ェチル一3— (チォフェン一 2—ィル）一5, 6—ジヒドロ一  [8] 9-Cyclopentinole 1-Ethyl 1- (Thiophene 1-yl) 1,5,6-Dihydro
9H—ピラゾ口 [3， 4_c]_l, 2, 4_トリァゾロ [4, 3_a]ピリジン、 2_ (3—クロロフ エノキシ) _3_[3_ (3—ヒドロキシピリジン _4_ィル）プロポキシ]ピリジンまたはそ れらの塩類の有効量を点眼剤または眼軟膏の形態で患者に投与することからなるァ レルギ一性結膜疾患の治療方法。  9H—Pyrazo mouth [3, 4_c] _l, 2, 4_triazolo [4, 3_a] pyridine, 2_ (3-chlorophenoxy) _3_ [3_ (3-hydroxypyridine _4_yl) propoxy] pyridine or them A method for treating allergic conjunctival disease, comprising administering an effective amount of the above salt to a patient in the form of eye drops or eye ointment.
[9] アレルギー性結膜疾患の治療剤を製造するための、 9ーシクロペンチルー 7—ェチ ノレ 3 （チォフェン 2 ィル） 5, 6 ジヒドロー 9H ピラゾ口 [3, 4— c] 1, 2 , 4 トリァゾロ [4, 3— a]ピリジン、 2— (3 クロロフエノキシ） 3— [3— (3 ヒドロキ シピリジンー4 ィル）プロボキシ]ピリジンまたはそれらの塩類の使用。 [9] 9-Cyclopentyl- 7-etenole 3 (thiophene 2 yl) 5, 6 dihydro-9H pyrazo mouth [3, 4-c] 1, 2, for the manufacture of therapeutic agents for allergic conjunctival diseases 4 Triazolo [4, 3— a] pyridine, 2- (3 chlorophenoxy) 3 — [3— (3 Hydroxyl Cypyridine-4-yl) propoxy] pyridine or their salts.
[10] アレルギー性結膜疾患が、アレルギー性結膜炎、春季カタルまたはアトピー性角結 膜炎である請求項 9記載の使用。 [10] The use according to claim 9, wherein the allergic conjunctivitis is allergic conjunctivitis, spring catarrh or atopic keratoconjunctivitis.
[11] アレルギー性結膜炎が、季節性アレルギー性結膜炎または通年性アレルギー性結 膜炎である請求項 10記載の使用。 [11] The use according to claim 10, wherein the allergic conjunctivitis is seasonal allergic conjunctivitis or perennial allergic conjunctivitis.
[12] 治療剤が、点眼剤または眼軟膏の形態である請求項 9〜： 11のいずれかに記載の 使用。 [12] The use according to any one of [9] to [11], wherein the therapeutic agent is in the form of eye drops or eye ointment.
PCT/JP2006/300464 2005-01-17 2006-01-17 Therapeutic agent for allergic conjunctival disease WO2006075748A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996039408A1 (en) * 1995-06-06 1996-12-12 Pfizer Inc. TRICYCLIC 5,6-DIHYDRO-9H-PYRAZOLO[3,4-c]-1,2,4-TRIAZOLO[4,3-α]PYRIDINES
JPH09291032A (en) * 1995-10-27 1997-11-11 Pfizer Inc Therapeutic agent for acute and chronic inflammatory disease
WO2000020391A1 (en) * 1998-10-06 2000-04-13 Dainippon Pharmaceutical Co., Ltd. 2,3-disubstituted pyridine derivatives, process for the preparation thereof, drug compositions containing the same and intermediates for the preparation
JP2002532411A (en) * 1998-12-17 2002-10-02 ベーリンガー インゲルハイム ファルマ コマンディトゲゼルシャフト Tricyclic nitrogen heterocyclic compounds as PDEIV inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996039408A1 (en) * 1995-06-06 1996-12-12 Pfizer Inc. TRICYCLIC 5,6-DIHYDRO-9H-PYRAZOLO[3,4-c]-1,2,4-TRIAZOLO[4,3-α]PYRIDINES
JPH09291032A (en) * 1995-10-27 1997-11-11 Pfizer Inc Therapeutic agent for acute and chronic inflammatory disease
WO2000020391A1 (en) * 1998-10-06 2000-04-13 Dainippon Pharmaceutical Co., Ltd. 2,3-disubstituted pyridine derivatives, process for the preparation thereof, drug compositions containing the same and intermediates for the preparation
JP2002532411A (en) * 1998-12-17 2002-10-02 ベーリンガー インゲルハイム ファルマ コマンディトゲゼルシャフト Tricyclic nitrogen heterocyclic compounds as PDEIV inhibitors

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