WO2017104728A1 - Medicine for treating food allergy - Google Patents
Medicine for treating food allergy Download PDFInfo
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- WO2017104728A1 WO2017104728A1 PCT/JP2016/087326 JP2016087326W WO2017104728A1 WO 2017104728 A1 WO2017104728 A1 WO 2017104728A1 JP 2016087326 W JP2016087326 W JP 2016087326W WO 2017104728 A1 WO2017104728 A1 WO 2017104728A1
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
Definitions
- the present invention relates to a food allergy allergen-specific IgE production inhibitor useful for the treatment of food allergies.
- Food allergies are various allergic reactions that occur when allergens contained in food are taken into the body. Symptoms include diarrhea, vomiting, dermatitis, etc., and when severe, causes anaphylactic shock leading to death. The incidence of adults in Japan is as high as 2.6%, but it is a serious problem because it is 5.3% higher in newborns and there are many severe cases. In addition to eggs, milk and wheat that cause severe symptoms, there are many foods that can be allergens, and these are dangerous because even a very small amount can cause strong symptoms. The only way to prevent food allergies is to identify allergens and avoid eating, but this is difficult under the current food situation where processed foods are distributed globally, and the QOL of patients who cannot eat food with peace of mind is significantly impaired. It is. Changes in the living environment of modern people change the immune response balance in the body, further increasing the prevalence of allergic diseases and worsening symptoms, and the development of therapeutic drugs is urgently needed .
- Dendritic cells take in antigens that have entered the body and migrate to secondary lymphoid tissues such as the spleen to transmit antigen information to T cells.
- T cells transmit antigen information to B cells.
- B cells Promotes proliferation and IgE production
- IgE IgE production
- mast cells recognize it via IgE and release pro-inflammatory substances, causing strong inflammation.
- Prostaglandin D 2 (PGD 2 ) is a physiologically active substance that mast cells produce most.
- CRTH2 which is a receptor for PGD 2 exists in eosinophils and the like, and it is known that the CRTH2 antagonist is effective for allergic rhinitis and the like (Patent Documents 1 to 4).
- Non-patent Document 1 Non-patent Document 1
- food allergies are treated by removing foods that do not consume the causative allergen, and some desensitization treatments (oral immunotherapy) that ingest the causative allergen in small quantities are also dangerous.
- oral immunotherapy oral immunotherapy
- bronchodilators ⁇ 2 agonists
- an object of the present invention is to provide a drug capable of treating food allergy.
- ovalbumin ovalbumin
- a CRTH2 antagonist which is a representative food allergen
- symptom such as diarrhea
- inhibition of allergen-specific IgE production by a CRTH2 antagonist is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
- Allergic rhinitis also occurs in mast cell-deficient mice and is less dependent on mast cells.
- the present invention provides the following [1] to [20].
- a food allergy allergen-specific IgE production inhibitor comprising a CRTH2 antagonist as an active ingredient.
- Food allergy allergen-specific IgE production according to [1] wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist. Inhibitor.
- a food allergy remedy comprising the food allergy allergen-specific IgE production inhibitor of any one of [1] to [3].
- a CRTH2 antagonist for producing a food allergy allergen-specific IgE production inhibitor.
- a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist for the production of a food allergy therapeutic agent.
- a CRTH2 antagonist for producing an inhibitor of increased mast cell number and / or mast cell activity in food allergy.
- CRTH2 antagonist according to [11] or [12], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
- a method for inhibiting food allergy allergen-specific IgE production comprising administering an effective amount of a CRTH2 antagonist.
- a CRTH2 antagonist is used, food allergy can be treated as a result by suppressing the production of food allergen allergen-specific IgE and further suppressing the increase of mast cells and / or the activity of mast cells.
- the lipid dynamics of the secondary lymph nodes are shown. Serum OVA-specific IgE and IgA are shown. Showing food allergy symptoms. PGD 2 and IgE production are shown. Cell localization in the spleen is shown. FIG. 2 shows OVA-specific IgE of T cells, B cells, dendritic cell transplanted CRTH2 ⁇ / ⁇ mice. Cell localization in the spleen is shown. Shows food allergy treatment effect of ramatroban. Fig. 5 shows changes in mast cells by food allergy stimulation to CRHT2 knockout mice. The change of the mast cell of the food allergy mouse
- the active ingredient of the food allergy allergen-specific IgE production inhibitor, mast cell increase and / or mast cell activity inhibitor and food allergy therapeutic agent of the present invention is a CRTH2 antagonist.
- CRTH2 antagonists are effective for the treatment of allergic rhinitis and bronchial asthma as described in Patent Documents 1 to 3, but there are no examples of whether or not they are effective for the treatment of food allergies. There is no example of testing whether it is effective in suppressing specific IgE production. Allergic rhinitis also occurs in mast cell-deficient mice and is less dependent on mast cells.
- CRTH2 antagonists include ramatroban and CAY10471, as well as, for example, Japanese Patent No. 4313819, Japanese Patent No. 5629403, Japanese Translation of PCT International Publication No. 2009-511591, Japanese Patent Publication No. 2009-533473, Japanese Patent Publication No. And compounds described in JP-A No. 544721 and JP-A No. 2014-507449.
- ramatroban 4- (3- [3- [3- (diphenylmethyl) -6-oxopyridazin-1 (6H) -yl] propyl] phenoxy) butanoic acid, 1- ⁇ 6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methyl-pyrimidin-4-yl ⁇ -pyrrolidine-3-carboxylic acid, 2- (1- ⁇ 2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl ⁇ -piperidin-3-yl) -2-methyl-propionic acid, 2- [3- ⁇ 6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl ⁇ -5- (1-hydroxy-1-methyl-ethyl)- Phenyl] -propan-2-ol
- the CRTH2 antagonist has the effect of remarkably suppressing food allergy allergen-specific IgE production and improving food allergy symptoms.
- the IgE production inhibitory action is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
- CRTH2 antagonists suppress the increase in the number of mast cells and / or mast cell activity in food allergy.
- Foods containing food allergens include chicken eggs, dairy products, wheat, crustaceans, fruits, buckwheat, fish, peanuts, fish eggs, soybeans, and the like. Since IgE whose production is suppressed by the medicament of the present invention is specific to these allergens, it can effectively improve food allergy symptoms.
- Symptoms of food allergy improved by the medicament of the present invention include skin symptoms such as hives, itching and redness; respiratory symptoms such as cough and dyspnea; mucosal symptoms such as oral mucosa and throat mucosa; diarrhea, abdominal pain, Gastrointestinal symptoms such as nausea and vomiting; anaphylactic symptoms and the like.
- the IgE production inhibitor and food allergy therapeutic agent of the present invention can be a pharmaceutical composition containing CRTH2 as an active ingredient.
- the pharmaceutical composition can contain a pharmaceutically acceptable carrier.
- This pharmaceutical composition can be administered orally or parenterally in the form of tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments or poultices. May be.
- Tablets, powders, granules, etc. are used as solid compositions intended for oral administration.
- These types of solid compositions are one mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc. Or more active substances.
- the composition is in addition to the inert excipients described above, for example, a lubricant such as magnesium stearate, a disintegrant such as cellulose calcium glycolate, a stabilizer such as lactose, and glutamic acid or aspartic acid.
- tablets and pills may be coated with a sugar or gastric or enteric film, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or the like.
- Liquid compositions intended for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like containing conventional inert diluents such as pure water or ethyl alcohol.
- these compositions are further used for pharmaceuticals such as solubilizers, solubilizers, wetting promoters, suspension promoters, and sweeteners, flavoring agents, fragrances, and preservatives.
- An adjuvant may be contained.
- Injectables intended for parenteral administration include, for example, sterile, aqueous or non-aqueous solutions, suspensions, and emulsions.
- Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
- Diluents for non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, polysorbate 80 (registered trademark)).
- compositions may further contain additives such as isotonicity adjusting agents, preservatives, wetting accelerators, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizers, and dissolution accelerators. They are sterilized by filtration through a bacteria capture filter or by adding a bactericidal agent to them or by irradiating them with radiation. Sterile solid compositions may be prepared in advance and may be dissolved in sterile water or solvent for injection before use.
- additives such as isotonicity adjusting agents, preservatives, wetting accelerators, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizers, and dissolution accelerators. They are sterilized by filtration through a bacteria capture filter or by adding a bactericidal agent to them or by irradiating them with radiation. Sterile solid compositions may be prepared in advance and may be dissolved in sterile water or solvent for injection before use.
- the dose of the medicament of the present invention may be appropriately determined according to the disease state, body weight, age, and sex of the patient to be administered.
- the amount of the active ingredient is 0.1 to 500 mg /
- parenteral administration 0.01 to 100 mg / adult / day is preferred. This may be administered to the patient in full doses at once, or divided into several doses for multiple doses.
- Example 1 (Method) Using C57BL / 6 mice (wild; CRTH2 + / + ) and the same type of CRTH2 ⁇ / ⁇ (CRTH2 knockout mice), allergic symptoms, secondary lymph node lipid dynamics, dendritic cells in secondary lymphoid tissues, T cells and B cells: OVA-specific IgE was examined. Ovalbumin (OVA) was used as an antigen. Sensitization was performed by intraperitoneally administering 50 ⁇ g of OVA twice from Day 0 to Day 14. OVA 10 mg was orally administered once every two days from Day 28 to Day 46.
- OVA Ovalbumin
- FIG. 1 shows that arachidonic acid (AA), PGE 2, PGD 2 and the like in the spleen are significantly increased in food allergy.
- T cells, B cells, and dendritic cells were isolated from the spleen of wild-type mice, and each cell was transferred to CRTH2 knockout mice. Thereafter, sensitization with OVA was performed, and OVA-specific IgE of Day 28 was measured. As shown in FIG. 6, the production of OVA-specific IgE was suppressed in CRTH2 knockout mice compared to the wild type, whereas the production of OVA-specific IgE was increased in CRTH2 knockout mice transfected with wild type dendritic cells. . Transplantation of wild-type T cells and B cells did not change the production of OVA-specific IgE.
- H-PGDS prostaglandin D synthase
- Example 2 In the food allergy model mouse (wild type) by OVA administration used in Example 1, 30 mg / kg of ramatroban was orally administered once a day to Day 28 to Day 46. Allergic symptoms, diarrhea and serum OVA-specific IgE concentrations were measured. As a result, as shown in FIG. 8, administration of ramatroban, which is a CRTH2 antagonist, improved allergic symptoms and diarrhea symptoms, and significantly reduced the production of serum OVA-specific IgE.
- Example 3 Changes in the number of mast cells in food allergy and the effect of ramatroban administration on the number of mast cells were investigated.
- CRVA2-deficient mice were administered OVA in the same manner as in Example 1, and the number of mast cells in food allergy was measured.
- the change of the number of mast cells by ramatroban administration was also examined.
- the number of mast cells in the colon and ileum was increased by food allergy, but the number of mast cells in the colon and ileum was suppressed in CRTH2 knockout mice.
- the number of mast cells in the skin (ear) does not increase.
- Example 4 An antihistamine (diphenhydramine) used as a therapeutic agent for allergic rhinitis was administered to OVA-induced food allergies, and changes in the number of mast cells in the colon and ileum and changes in urinary PGDM were examined.
- the antihistamine H 1 -blocker
- FIG. 11A the antihistamine
- FIG. 11B the number of mast cells
- FIG. 11D the antihistamine (H 1 -blocker) does not suppress food allergy symptoms
- FIG. 11B the number of mast cells
- It does not affect urinary PGDM (FIG. 11C) and does not significantly change PGDM as an index of inflammation (FIG. 11D).
- Example 5 Bala / c mice (wild; CRTH2 + / + ) and the same kind of CRTH2 ⁇ / ⁇ (CRTH2 knockout mice) were used to examine OVA-specific IgE.
- Ovalbumin (OVA) was used as an antigen. Sensitization was performed by subcutaneously administering 300 ⁇ g of OVA twice every other week.
- OVA-specific IgE concentration of OVA-specific IgE in the serum was measured. As a result, as shown in FIG. 12, OVA-specific IgE increased in the wild type, whereas suppression of OVA-specific IgE production was observed in the CRTH2 knockout mouse.
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Abstract
Provided is a novel medicine for treating food allergy.
An inhibitor for the production of IgE specific for an allergen causing food allergy, said inhibitor comprising a CRTH2 antagonist as an active ingredient.
Description
本発明は、食物アレルギーの治療に有用な食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤に関する。
The present invention relates to a food allergy allergen-specific IgE production inhibitor useful for the treatment of food allergies.
食物アレルギーは食品中に含まれるアレルゲンを体内に取り込むことで起こる様々なアレルギー反応である。その症状には下痢や嘔吐、皮膚炎などが挙げられる他、重篤になるとアナフィラキシーショックを起こして死に至る。日本国内における成人の罹患率は２．６％と高いが、新生児では５．３％とさらに高く重症例が多いため大きな問題となっている。重篤な症状を引き起こす卵、牛乳、小麦以外にもアレルゲンとなり得る食品は多く、これらはごく少量の摂食でも強い症状を引き起こすため危険である。食物アレルギーの予防にはアレルゲンの特定と摂食回避しか方法は無いが、加工食品が世界的に流通する現在の食料事情の下でそれは難しく、安心して食物を口にできない患者のＱＯＬは著しく損なわれる。現代人の生活環境の変化は、体における免疫反応バランスを変化させ、アレルギー疾患の罹患率を、さらに増加させ、症状を悪化させる結果を招いており、その治療薬の開発が急務となっている。
Food allergies are various allergic reactions that occur when allergens contained in food are taken into the body. Symptoms include diarrhea, vomiting, dermatitis, etc., and when severe, causes anaphylactic shock leading to death. The incidence of adults in Japan is as high as 2.6%, but it is a serious problem because it is 5.3% higher in newborns and there are many severe cases. In addition to eggs, milk and wheat that cause severe symptoms, there are many foods that can be allergens, and these are dangerous because even a very small amount can cause strong symptoms. The only way to prevent food allergies is to identify allergens and avoid eating, but this is difficult under the current food situation where processed foods are distributed globally, and the QOL of patients who cannot eat food with peace of mind is significantly impaired. It is. Changes in the living environment of modern people change the immune response balance in the body, further increasing the prevalence of allergic diseases and worsening symptoms, and the development of therapeutic drugs is urgently needed .
食物アレルギー反応の成立には複数種の免疫細胞のダイナミックな連携が必須である。ｉ）体内に侵入した抗原を樹状細胞が取り込み、脾臓などの二次リンパ組織へ遊走して抗原情報をＴ細胞へと伝達する、ii）Ｔ細胞はＢ細胞へ抗原情報を伝達してその増殖とＩｇＥ産生を促す、iii）抗原が再度体内に入ると、肥満細胞がＩｇＥを介してそれを認識し、炎症誘発物質を放出して強い炎症を引き起こす。食物アレルギーの克服を目指して、Ｔ細胞やＢ細胞の活性抑制に焦点を当てた研究が盛んに行なわれているが、現在も根本的な治療方法は開発されていない。
ダ イ ナ ミ ッ ク Dynamic coordination of multiple types of immune cells is essential for the establishment of food allergic reactions. i) Dendritic cells take in antigens that have entered the body and migrate to secondary lymphoid tissues such as the spleen to transmit antigen information to T cells. ii) T cells transmit antigen information to B cells. Promotes proliferation and IgE production iii) When the antigen enters the body again, mast cells recognize it via IgE and release pro-inflammatory substances, causing strong inflammation. A lot of research has been conducted with the aim of overcoming food allergies with a focus on suppressing the activity of T cells and B cells, but no fundamental treatment method has been developed.
プロスタグランジンＤ2（ＰＧＤ2）は肥満細胞が最も大量に産生する生理活性物質である。ＰＧＤ2の受容体であるＣＲＴＨ２は好酸球等に存在し、当該ＣＲＴＨ２拮抗薬がアレルギー性鼻炎等に有効であることが知られている（特許文献１～４）。
Prostaglandin D 2 (PGD 2 ) is a physiologically active substance that mast cells produce most. CRTH2 which is a receptor for PGD 2 exists in eosinophils and the like, and it is known that the CRTH2 antagonist is effective for allergic rhinitis and the like (Patent Documents 1 to 4).
しかしながら、花粉症に代表されるアレルギー性鼻炎の予防治療薬である抗ヒスタミン剤等の抗アレルギー薬は、食物アレルギーの治療には有効ではない（非特許文献１）。現在、食物アレルギーの治療は、原因となるアレルゲンを摂取しない食品除去が基本であり、原因となるアレルゲンを少量ずつ摂取させる減感作療法（経口免疫療法）も一部行なわれているが危険が伴う。これらの療法以外は、気管支拡張薬（β2刺激薬）、アドレナリン等の対症療法があるにすぎない。
従って、本発明の課題は、食物アレルギーを治療できる薬剤を提供することにある。 However, antiallergic drugs such as antihistamines, which are preventive and therapeutic drugs for allergic rhinitis represented by pollinosis, are not effective in the treatment of food allergies (Non-patent Document 1). Currently, food allergies are treated by removing foods that do not consume the causative allergen, and some desensitization treatments (oral immunotherapy) that ingest the causative allergen in small quantities are also dangerous. Accompany. Other than these therapy, bronchodilators (β 2 agonists), not only there is a symptomatic treatment of adrenaline and the like.
Accordingly, an object of the present invention is to provide a drug capable of treating food allergy.
従って、本発明の課題は、食物アレルギーを治療できる薬剤を提供することにある。 However, antiallergic drugs such as antihistamines, which are preventive and therapeutic drugs for allergic rhinitis represented by pollinosis, are not effective in the treatment of food allergies (Non-patent Document 1). Currently, food allergies are treated by removing foods that do not consume the causative allergen, and some desensitization treatments (oral immunotherapy) that ingest the causative allergen in small quantities are also dangerous. Accompany. Other than these therapy, bronchodilators (β 2 agonists), not only there is a symptomatic treatment of adrenaline and the like.
Accordingly, an object of the present invention is to provide a drug capable of treating food allergy.
そこで本発明者は、食物アレルギーのアレルゲンの代表であるオボアルブミン（ＯＶＡ：卵白アルブミン）を用いて食物アレルギーを発生させた後、ＣＲＴＨ２拮抗剤を投与すると血中のＯＶＡ特異的ＩｇＥ産生量が顕著に抑制され、食物アレルギーの症状である下痢等の症状を顕著に改善することを見出した。また、ＣＲＴＨ２拮抗剤によるアレルゲン特異的ＩｇＥ産生抑制は、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものであることも見出した。また、アレルギー性鼻炎は、肥満細胞欠損マウスでも症状が生じ、肥満細胞依存性が低い。一方、食物アレルギーは、肥満細胞欠損マウスではほとんど症状が出ず、肥満細胞数の増加が発症と進行に重要であり、脂肪細胞依存性が高いことから、ＣＲＴＨ２拮抗剤が肥満細胞を減らす作用を有し、肥満細胞数に依存的な食物アレルギーの治療に有効であることも判明した。
Therefore, the present inventor developed a food allergy using ovalbumin (OVA: ovalbumin), which is a representative food allergen, and then administered a CRTH2 antagonist, so that the amount of OVA-specific IgE production in blood was remarkable. It was found that symptom such as diarrhea, which is a symptom of food allergy, is markedly improved. It was also found that inhibition of allergen-specific IgE production by a CRTH2 antagonist is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist. Allergic rhinitis also occurs in mast cell-deficient mice and is less dependent on mast cells. On the other hand, food allergy has almost no symptoms in mast cell-deficient mice, and an increase in the number of mast cells is important for onset and progression, and since it is highly adipocyte-dependent, the action of CRTH2 antagonists reduces mast cells. It has also been found to be effective in treating food allergy depending on the number of mast cells.
すなわち、本発明は、次の〔１〕～〔２０〕を提供するものである。
That is, the present invention provides the following [1] to [20].
〔１〕ＣＲＴＨ２拮抗剤を有効成分とする、食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔２〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔１〕記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔３〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔１〕又は〔２〕記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔４〕〔１〕～〔３〕のいずれか１項記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤を含有する食物アレルギー治療薬。
〔５〕ＣＲＴＨ２拮抗剤を有効成分とする、食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制剤。
〔６〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤製造のための、ＣＲＴＨ２拮抗剤の使用。
〔７〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔６〕記載の使用。
〔８〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔６〕又は〔７〕記載の使用。
〔９〕ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤の、食物アレルギー治療薬製造のための使用。
〔10〕食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制剤製造のための、ＣＲＴＨ２拮抗剤の使用。
〔11〕食物アレルギーアレルゲン特異的ＩｇＥの産生を抑制するために用いる、ＣＲＴＨ２拮抗剤。
〔12〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔１１〕記載のＣＲＴＨ２拮抗剤。
〔13〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔１１〕又は〔１２〕記載のＣＲＴＨ２拮抗剤。
〔14〕食物アレルギーを治療するために用いる、ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔15〕食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性を抑制するために用いる、ＣＲＴＨ２拮抗剤。
〔16〕ＣＲＴＨ２拮抗剤の有効量を投与することを特徴とする、食物アレルギーアレルゲン特異的ＩｇＥ産生抑制方法。
〔17〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔１６〕記載の方法。
〔18〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔１６〕又は〔１７〕記載の方法。
〔19〕ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤の有効量を投与することを特徴とする、食物アレルギーの治療方法。
〔20〕ＣＲＴＨ２拮抗剤の有効量を投与することを特徴とする、食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制方法。 [1] A food allergy allergen-specific IgE production inhibitor comprising a CRTH2 antagonist as an active ingredient.
[2] Food allergy allergen-specific IgE production according to [1], wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist. Inhibitor.
[3] The food allergy allergen-specific IgE production inhibitor according to [1] or [2], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[4] A food allergy remedy comprising the food allergy allergen-specific IgE production inhibitor of any one of [1] to [3].
[5] An inhibitor of increased mast cell number and / or mast cell activity in food allergy, comprising a CRTH2 antagonist as an active ingredient.
[6] Use of a CRTH2 antagonist for producing a food allergy allergen-specific IgE production inhibitor.
[7] The use according to [6], wherein the suppression of food allergy allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
[8] Use of [6] or [7], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[9] Use of a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist for the production of a food allergy therapeutic agent.
[10] Use of a CRTH2 antagonist for producing an inhibitor of increased mast cell number and / or mast cell activity in food allergy.
[11] A CRTH2 antagonist used for suppressing the production of food allergen allergen-specific IgE.
[12] The CRTH2 antagonist according to [11], wherein the inhibition of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
[13] The CRTH2 antagonist according to [11] or [12], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[14] A food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist, used to treat food allergy.
[15] A CRTH2 antagonist used for suppressing an increase in the number of mast cells and / or mast cell activity in food allergy.
[16] A method for inhibiting food allergy allergen-specific IgE production, comprising administering an effective amount of a CRTH2 antagonist.
[17] The method according to [16], wherein the suppression of food allergen allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
[18] The method according to [16] or [17], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[19] A method for treating food allergy, comprising administering an effective amount of a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist.
[20] A method for suppressing an increase in mast cell number and / or mast cell activity in food allergy, which comprises administering an effective amount of a CRTH2 antagonist.
〔２〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔１〕記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔３〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔１〕又は〔２〕記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔４〕〔１〕～〔３〕のいずれか１項記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤を含有する食物アレルギー治療薬。
〔５〕ＣＲＴＨ２拮抗剤を有効成分とする、食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制剤。
〔６〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤製造のための、ＣＲＴＨ２拮抗剤の使用。
〔７〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔６〕記載の使用。
〔８〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔６〕又は〔７〕記載の使用。
〔９〕ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤の、食物アレルギー治療薬製造のための使用。
〔10〕食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制剤製造のための、ＣＲＴＨ２拮抗剤の使用。
〔11〕食物アレルギーアレルゲン特異的ＩｇＥの産生を抑制するために用いる、ＣＲＴＨ２拮抗剤。
〔12〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔１１〕記載のＣＲＴＨ２拮抗剤。
〔13〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔１１〕又は〔１２〕記載のＣＲＴＨ２拮抗剤。
〔14〕食物アレルギーを治療するために用いる、ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。
〔15〕食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性を抑制するために用いる、ＣＲＴＨ２拮抗剤。
〔16〕ＣＲＴＨ２拮抗剤の有効量を投与することを特徴とする、食物アレルギーアレルゲン特異的ＩｇＥ産生抑制方法。
〔17〕食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである〔１６〕記載の方法。
〔18〕ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である〔１６〕又は〔１７〕記載の方法。
〔19〕ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤の有効量を投与することを特徴とする、食物アレルギーの治療方法。
〔20〕ＣＲＴＨ２拮抗剤の有効量を投与することを特徴とする、食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制方法。 [1] A food allergy allergen-specific IgE production inhibitor comprising a CRTH2 antagonist as an active ingredient.
[2] Food allergy allergen-specific IgE production according to [1], wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist. Inhibitor.
[3] The food allergy allergen-specific IgE production inhibitor according to [1] or [2], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[4] A food allergy remedy comprising the food allergy allergen-specific IgE production inhibitor of any one of [1] to [3].
[5] An inhibitor of increased mast cell number and / or mast cell activity in food allergy, comprising a CRTH2 antagonist as an active ingredient.
[6] Use of a CRTH2 antagonist for producing a food allergy allergen-specific IgE production inhibitor.
[7] The use according to [6], wherein the suppression of food allergy allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
[8] Use of [6] or [7], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[9] Use of a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist for the production of a food allergy therapeutic agent.
[10] Use of a CRTH2 antagonist for producing an inhibitor of increased mast cell number and / or mast cell activity in food allergy.
[11] A CRTH2 antagonist used for suppressing the production of food allergen allergen-specific IgE.
[12] The CRTH2 antagonist according to [11], wherein the inhibition of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
[13] The CRTH2 antagonist according to [11] or [12], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[14] A food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist, used to treat food allergy.
[15] A CRTH2 antagonist used for suppressing an increase in the number of mast cells and / or mast cell activity in food allergy.
[16] A method for inhibiting food allergy allergen-specific IgE production, comprising administering an effective amount of a CRTH2 antagonist.
[17] The method according to [16], wherein the suppression of food allergen allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
[18] The method according to [16] or [17], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
[19] A method for treating food allergy, comprising administering an effective amount of a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist.
[20] A method for suppressing an increase in mast cell number and / or mast cell activity in food allergy, which comprises administering an effective amount of a CRTH2 antagonist.
ＣＲＴＨ２拮抗剤を用いれば、食物アレルギーアレルゲン特異的ＩｇＥの産生を抑制し、さらに肥満細胞の増加及び／又は肥満細胞の活性を抑制することで、その結果食物アレルギーを治療できる。
If a CRTH2 antagonist is used, food allergy can be treated as a result by suppressing the production of food allergen allergen-specific IgE and further suppressing the increase of mast cells and / or the activity of mast cells.
本発明の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤、肥満細胞増加及び／又は肥満細胞活性の抑制剤及び食物アレルギー治療薬の有効成分は、ＣＲＴＨ２拮抗剤である。ＣＲＴＨ２拮抗剤は、特許文献１～３に記載のようにアレルギー性鼻炎や気管支喘息の治療に有効とされているが、食物アレルギーの治療に有効か否かを試験した例はなく、食物アレルギーアレルゲン特異的ＩｇＥ産生抑制に有効か否かを試験した例もない。また、アレルギー性鼻炎は、肥満細胞欠損マウスでも症状が生じ、肥満細胞依存性が低い。一方、食物アレルギーは、肥満細胞欠損マウスではほとんど症状が出ず、肥満細胞数の増加が発症と進行に重要であり、脂肪細胞依存性が高いことから、ＣＲＴＨ２拮抗剤がアレルギー性鼻炎に有効であることが知られていたとしても、食物アレルギーの治療に有効か否かは不明である。
The active ingredient of the food allergy allergen-specific IgE production inhibitor, mast cell increase and / or mast cell activity inhibitor and food allergy therapeutic agent of the present invention is a CRTH2 antagonist. CRTH2 antagonists are effective for the treatment of allergic rhinitis and bronchial asthma as described in Patent Documents 1 to 3, but there are no examples of whether or not they are effective for the treatment of food allergies. There is no example of testing whether it is effective in suppressing specific IgE production. Allergic rhinitis also occurs in mast cell-deficient mice and is less dependent on mast cells. On the other hand, food allergy has almost no symptoms in mast cell-deficient mice, and an increase in the number of mast cells is important for onset and progression, and since it is highly adipocyte-dependent, CRTH2 antagonists are effective for allergic rhinitis. Even if it is known, it is unclear whether it is effective in treating food allergies.
ＣＲＴＨ２拮抗剤としては、ラマトロバン、ＣＡＹ１０４７１の他、例えば特許第４３１３８１９号公報、特許第５６２９４０３号公報、特表２００９－５１１５９１号公報、特表２００９－５３３４７３号公報、特許第５２７８３１８号公報、特表２００９－５４４７２１号公報、特表２０１４－５０７４４９号公報に記載の化合物が挙げられる。より具体的には、ラマトロバン、４－（３－[３－〔３－（ジフェニルメチル）－６－オキソピリダジン－１（６Ｈ）－イル〕プロピル]フェノキシ）ブタン酸、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メチル－ピリミジン－４－イル｝－ピロリジン－３－カルボン酸、
２－（１－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－ピペリジン－３－イル）－２－メチル－プロピオン酸、
２－［３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－５－（１－ヒドロキシ－１－メチル－エチル）－フェニル］－プロパン－２－オール、
［６－（３－アミノ－ピペリジン－１－イル）－２－メトキシ－ピリミジン－４－イル］－［２－（２，４－ジクロロ－フェニル）－エチル］－アミン、
［６－（４－アミノ－ピペリジン－１－イル）－２－メトキシ－ピリミジン－４－イル］－［２－（２，４－ジクロロ－フェニル）－エチル］－アミン、
Ｎ－（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－４－イル）－アセトアミド、
５－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－１－メチル－２，３－ジヒドロ－１Ｈ－インドール－２－カルボン酸、
２－メチル－プロパン－２－スルホン酸［２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－プロピオニル］－アミド、
Ｎ，Ｎ－ジメチルアミド－２－スルホン酸［２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－プロピオニル］－アミド、
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－１－チオモルホリン－４－イル－プロパン－１－オン、
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－イソブチルアミド、
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－Ｎ，Ｎ－ジメチル－イソブチルアミド、
（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－イル）－酢酸、
１－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸、
Ｎ－（１－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－メタンスルホンアミド、
５－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－１－メチル－２，３－ジヒドロ－１Ｈ－インドール－２－カルボン酸エチルエステル、
（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－イル）－酢酸エチルエステル、
Ｎ－（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－メタンスルホンアミド、
エタンスルホン酸（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－アミド、
２－メチル－プロパン－２－スルホン酸（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－アミド、
Ｎ－（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－Ｃ，Ｃ，Ｃ－トリフルオロ－メタンスルホンアミド、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸（１Ｈ－テトラゾール－５－イル）－アミド、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸アミド、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸ジメチルアミド、
Ｎ，Ｎ－ジメチルアミド－２－スルホン酸 １－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボキシアミド、
５－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－チオフェン－２－カルボン酸、
５－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－２，３－ジヒドロ－ベンゾフラン－２－カルボン酸、 Examples of CRTH2 antagonists include ramatroban and CAY10471, as well as, for example, Japanese Patent No. 4313819, Japanese Patent No. 5629403, Japanese Translation of PCT International Publication No. 2009-511591, Japanese Patent Publication No. 2009-533473, Japanese Patent Publication No. And compounds described in JP-A No. 544721 and JP-A No. 2014-507449. More specifically, ramatroban, 4- (3- [3- [3- (diphenylmethyl) -6-oxopyridazin-1 (6H) -yl] propyl] phenoxy) butanoic acid,
1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methyl-pyrimidin-4-yl} -pyrrolidine-3-carboxylic acid,
2- (1- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -piperidin-3-yl) -2-methyl-propionic acid,
2- [3- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -5- (1-hydroxy-1-methyl-ethyl)- Phenyl] -propan-2-ol,
[6- (3-amino-piperidin-1-yl) -2-methoxy-pyrimidin-4-yl]-[2- (2,4-dichloro-phenyl) -ethyl] -amine,
[6- (4-amino-piperidin-1-yl) -2-methoxy-pyrimidin-4-yl]-[2- (2,4-dichloro-phenyl) -ethyl] -amine,
N- (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-4-yl) -acetamide,
5- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -1-methyl-2,3-dihydro-1H-indole-2-carvone acid,
2-Methyl-propane-2-sulfonic acid [2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl)- 2-methyl-propionyl] -amide,
N, N-dimethylamido-2-sulfonic acid [2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -2-methyl-propionyl] -amide,
2- (3- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -2-methyl-1-thiomorpholine-4- Yl-propan-1-one,
2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -isobutyramide,
2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -N, N-dimethyl-isobutyramide,
(1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-yl) -acetic acid,
1- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -piperidine-3-carboxylic acid,
N- (1- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -piperidin-3-carbonyl) -methanesulfonamide,
5- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -1-methyl-2,3-dihydro-1H-indole-2-carvone Acid ethyl ester,
(1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-yl) -acetic acid ethyl ester,
N- (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-carbonyl) -methanesulfonamide,
Ethanesulfonic acid (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-carbonyl) -amide,
2-Methyl-propane-2-sulfonic acid (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carbonyl) -Amide,
N- (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-carbonyl) -C, C, C-tri Fluoro-methanesulfonamide,
1- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxylic acid (1H-tetrazol-5-yl) -amide ,
1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxylic acid amide,
1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxylic acid dimethylamide,
N, N-dimethylamido-2-sulfonic acid 1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxamide ,
5- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -thiophene-2-carboxylic acid,
5- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -2,3-dihydro-benzofuran-2-carboxylic acid,
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メチル－ピリミジン－４－イル｝－ピロリジン－３－カルボン酸、
２－（１－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－ピペリジン－３－イル）－２－メチル－プロピオン酸、
２－［３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－５－（１－ヒドロキシ－１－メチル－エチル）－フェニル］－プロパン－２－オール、
［６－（３－アミノ－ピペリジン－１－イル）－２－メトキシ－ピリミジン－４－イル］－［２－（２，４－ジクロロ－フェニル）－エチル］－アミン、
［６－（４－アミノ－ピペリジン－１－イル）－２－メトキシ－ピリミジン－４－イル］－［２－（２，４－ジクロロ－フェニル）－エチル］－アミン、
Ｎ－（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－４－イル）－アセトアミド、
５－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－１－メチル－２，３－ジヒドロ－１Ｈ－インドール－２－カルボン酸、
２－メチル－プロパン－２－スルホン酸［２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－プロピオニル］－アミド、
Ｎ，Ｎ－ジメチルアミド－２－スルホン酸［２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－プロピオニル］－アミド、
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－１－チオモルホリン－４－イル－プロパン－１－オン、
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－イソブチルアミド、
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－Ｎ，Ｎ－ジメチル－イソブチルアミド、
（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－イル）－酢酸、
１－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸、
Ｎ－（１－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－メタンスルホンアミド、
５－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－１－メチル－２，３－ジヒドロ－１Ｈ－インドール－２－カルボン酸エチルエステル、
（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－イル）－酢酸エチルエステル、
Ｎ－（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－メタンスルホンアミド、
エタンスルホン酸（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－アミド、
２－メチル－プロパン－２－スルホン酸（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－アミド、
Ｎ－（１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボニル）－Ｃ，Ｃ，Ｃ－トリフルオロ－メタンスルホンアミド、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸（１Ｈ－テトラゾール－５－イル）－アミド、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸アミド、
１－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボン酸ジメチルアミド、
Ｎ，Ｎ－ジメチルアミド－２－スルホン酸 １－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－ピペリジン－３－カルボキシアミド、
５－｛２－メトキシ－６－［２－（４－トリフルオロメトキシ－フェニル）－エチルアミノ］－ピリミジン－４－イル｝－チオフェン－２－カルボン酸、
５－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－２，３－ジヒドロ－ベンゾフラン－２－カルボン酸、 Examples of CRTH2 antagonists include ramatroban and CAY10471, as well as, for example, Japanese Patent No. 4313819, Japanese Patent No. 5629403, Japanese Translation of PCT International Publication No. 2009-511591, Japanese Patent Publication No. 2009-533473, Japanese Patent Publication No. And compounds described in JP-A No. 544721 and JP-A No. 2014-507449. More specifically, ramatroban, 4- (3- [3- [3- (diphenylmethyl) -6-oxopyridazin-1 (6H) -yl] propyl] phenoxy) butanoic acid,
1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methyl-pyrimidin-4-yl} -pyrrolidine-3-carboxylic acid,
2- (1- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -piperidin-3-yl) -2-methyl-propionic acid,
2- [3- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -5- (1-hydroxy-1-methyl-ethyl)- Phenyl] -propan-2-ol,
[6- (3-amino-piperidin-1-yl) -2-methoxy-pyrimidin-4-yl]-[2- (2,4-dichloro-phenyl) -ethyl] -amine,
[6- (4-amino-piperidin-1-yl) -2-methoxy-pyrimidin-4-yl]-[2- (2,4-dichloro-phenyl) -ethyl] -amine,
N- (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-4-yl) -acetamide,
5- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -1-methyl-2,3-dihydro-1H-indole-2-carvone acid,
2-Methyl-propane-2-sulfonic acid [2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl)- 2-methyl-propionyl] -amide,
N, N-dimethylamido-2-sulfonic acid [2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -2-methyl-propionyl] -amide,
2- (3- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -2-methyl-1-thiomorpholine-4- Yl-propan-1-one,
2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -isobutyramide,
2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -N, N-dimethyl-isobutyramide,
(1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-yl) -acetic acid,
1- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -piperidine-3-carboxylic acid,
N- (1- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -piperidin-3-carbonyl) -methanesulfonamide,
5- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -1-methyl-2,3-dihydro-1H-indole-2-carvone Acid ethyl ester,
(1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-yl) -acetic acid ethyl ester,
N- (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-carbonyl) -methanesulfonamide,
Ethanesulfonic acid (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-carbonyl) -amide,
2-Methyl-propane-2-sulfonic acid (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carbonyl) -Amide,
N- (1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidin-3-carbonyl) -C, C, C-tri Fluoro-methanesulfonamide,
1- {6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxylic acid (1H-tetrazol-5-yl) -amide ,
1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxylic acid amide,
1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxylic acid dimethylamide,
N, N-dimethylamido-2-sulfonic acid 1- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -piperidine-3-carboxamide ,
5- {2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -thiophene-2-carboxylic acid,
5- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -2,3-dihydro-benzofuran-2-carboxylic acid,
２－（３－｛６－［２－（２，４－ジクロロ－フェニル）－エチルアミノ］－２－メトキシ－ピリミジン－４－イル｝－フェニル）－２－メチル－プロピオン酸、
2- (3- {6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl} -phenyl) -2-methyl-propionic acid,
４－｛シクロプロピル［ｃｉｓ，ｃｉｓ－４－｛［４－（トリフルオロメトキシ）フェニル］カルボニル｝－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ｝－４－オキソブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－７－フルオロ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－（トリフルオロメトキシ）ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ］－４－オキソブタン酸、
４－［［ｃｉｓ，ｃｉｓ－６－クロロ－７－フルオロ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－（トリフルオロメトキシ）ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］シクロプロピルアミノ］－４－オキソブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－５－フルオロ－１，２，２ａ，３，８，８ａ－ヘキサヒドロ－３－［４－（トリフルオロメトキシ）ベンゾイル］シクロブタ［ｂ］キノリン－８－イル］アミノ］－４－オキソブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－６－フルオロ－１，２，２ａ，３，８，８ａ－ヘキサヒドロ－３－［４－（トリフルオロメトキシ）ベンゾイル］シクロブタ［ｂ］キノリン－８－イル］アミノ］－４－オキソブタン酸、
（ｃｉｓ，ｃｉｓ）－８－［（３－カルボキシ－１－オキソプロピル）シクロプロピルアミノ］－５－クロロ－２，２ａ，８，８ａ－テトラヒドロシクロブタ［ｂ］キノリン－３（１Ｈ）－カルボン酸３－（フェニルメチル）、
（ｃｉｓ，ｃｉｓ）－８－［（３－カルボキシ－１－オキソプロピル）シクロプロピルアミノ］－２，２ａ，８，８ａ－テトラヒドロシクロブタ［ｂ］キノリン－３（１Ｈ）－カルボン酸３－（フェニルメチル）、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－１，２，２ａ，３，８，８ａ－ヘキサヒドロ－３－［４－（トリフルオロメトキシ）ベンゾイル］シクロブタ［ｂ］キノリン－８－イル］アミノ］－４－オキソブタン酸、
［［［シクロプロピル［ｃｉｓ，ｃｉｓ－３－（３，４－ジフルオロベンゾイル）－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル］アミノ］カルボニル］オキシ］酢酸、
ｃｉｓ，ｃｉｓ－８－［（３－カルボキシプロピル）シクロプロピルアミノ］－５－フルオロ－２，２ａ，８，８ａ－テトラヒドロシクロブタ［ｂ］キノリン－３（１Ｈ）－カルボン酸３－（フェニルメチル）、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－（トリフルオロメトキシ）ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ］ブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－［（トリフルオロメチル）チオ］ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ］－４－オキソブタン酸、
（Ｒ）－１－（（ｃｉｓ，ｃｉｓ－３－（ベンジルオキシカルボニル）－５，６－ジフルオロ－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル）（シクロプロピル）カルバモイル）アゼチジン－２－カルボン酸、
４－（シクロプロピル（ｃｉｓ，ｃｉｓ－３－（４－（（トリフルオロメチル）チオ）ベンゾイル）－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル）アミノ）－４－オキソブタン酸、
４－（エチル（ｃｉｓ，ｃｉｓ－６－フルオロ－３－（４－（（トリフルオロメチル）チオ）ベンゾイル）－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル）アミノ）－４－オキソブタン酸、
４－（エチル（ｃｉｓ，ｃｉｓ－７－フルオロ－４－（４－（（トリフルオロメチル）チオ）ベンゾイル）－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル）アミノ）－４－オキソブタン酸、
４－（シクロプロピル（ｃｉｓ，ｃｉｓ－７－フルオロ－４－（４－（（トリフルオロメチル）チオ）ベンゾイル）－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル）アミノ）－４－オキソブタン酸、
４－（シクロプロピル（ｃｉｓ，ｃｉｓ－７－フルオロ－４－（４－（トリフルオロメトキシ）ベンゾイル）－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル）アミノ）ブタン酸、 4- {cyclopropyl [cis, cis-4-{[4- (trifluoromethoxy) phenyl] carbonyl} -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] quinoline-9- Yl] amino} -4-oxobutanoic acid,
4- [cyclopropyl [cis, cis-7-fluoro-2,3,3a, 4,9,9a-hexahydro-4- [4- (trifluoromethoxy) benzoyl] -1H-cyclopenta [b] quinoline-9 -Yl] amino] -4-oxobutanoic acid,
4-[[cis, cis-6-chloro-7-fluoro-2,3,3a, 4,9,9a-hexahydro-4- [4- (trifluoromethoxy) benzoyl] -1H-cyclopenta [b] quinoline -9-yl] cyclopropylamino] -4-oxobutanoic acid,
4- [cyclopropyl [cis, cis-5-fluoro-1,2,2a, 3,8,8a-hexahydro-3- [4- (trifluoromethoxy) benzoyl] cyclobuta [b] quinolin-8-yl] Amino] -4-oxobutanoic acid,
4- [cyclopropyl [cis, cis-6-fluoro-1,2,2a, 3,8,8a-hexahydro-3- [4- (trifluoromethoxy) benzoyl] cyclobuta [b] quinolin-8-yl] Amino] -4-oxobutanoic acid,
(Cis, cis) -8-[(3-carboxy-1-oxopropyl) cyclopropylamino] -5-chloro-2,2a, 8,8a-tetrahydrocyclobuta [b] quinoline-3 (1H) -carvone Acid 3- (phenylmethyl),
(Cis, cis) -8-[(3-carboxy-1-oxopropyl) cyclopropylamino] -2,2a, 8,8a-tetrahydrocyclobuta [b] quinoline-3 (1H) -carboxylic acid 3- ( Phenylmethyl),
4- [cyclopropyl [cis, cis-1,2,2a, 3,8,8a-hexahydro-3- [4- (trifluoromethoxy) benzoyl] cyclobuta [b] quinolin-8-yl] amino] -4 -Oxobutanoic acid,
[[[Cyclopropyl [cis, cis-3- (3,4-difluorobenzoyl) -1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinolin-8-yl] amino] carbonyl] Oxy] acetic acid,
cis, cis-8-[(3-Carboxypropyl) cyclopropylamino] -5-fluoro-2,2a, 8,8a-tetrahydrocyclobuta [b] quinoline-3 (1H) -carboxylic acid 3- (phenylmethyl) ),
4- [cyclopropyl [cis, cis-2,3,3a, 4,9,9a-hexahydro-4- [4- (trifluoromethoxy) benzoyl] -1H-cyclopenta [b] quinolin-9-yl] amino ] Butanoic acid,
4- [cyclopropyl [cis, cis-2,3,3a, 4,9,9a-hexahydro-4- [4-[(trifluoromethyl) thio] benzoyl] -1H-cyclopenta [b] quinoline-9- Yl] amino] -4-oxobutanoic acid,
(R) -1-((cis, cis-3- (benzyloxycarbonyl) -5,6-difluoro-1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinolin-8-yl ) (Cyclopropyl) carbamoyl) azetidine-2-carboxylic acid,
4- (Cyclopropyl (cis, cis-3- (4-((trifluoromethyl) thio) benzoyl) -1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinolin-8-yl ) Amino) -4-oxobutanoic acid,
4- (Ethyl (cis, cis-6-fluoro-3- (4-((trifluoromethyl) thio) benzoyl) -1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinoline- 8-yl) amino) -4-oxobutanoic acid,
4- (Ethyl (cis, cis-7-fluoro-4- (4-((trifluoromethyl) thio) benzoyl) -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] quinoline) -9-yl) amino) -4-oxobutanoic acid,
4- (cyclopropyl (cis, cis-7-fluoro-4- (4-((trifluoromethyl) thio) benzoyl) -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] Quinolin-9-yl) amino) -4-oxobutanoic acid,
4- (Cyclopropyl (cis, cis-7-fluoro-4- (4- (trifluoromethoxy) benzoyl) -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] quinoline-9 -Yl) amino) butanoic acid,
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－７－フルオロ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－（トリフルオロメトキシ）ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ］－４－オキソブタン酸、
４－［［ｃｉｓ，ｃｉｓ－６－クロロ－７－フルオロ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－（トリフルオロメトキシ）ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］シクロプロピルアミノ］－４－オキソブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－５－フルオロ－１，２，２ａ，３，８，８ａ－ヘキサヒドロ－３－［４－（トリフルオロメトキシ）ベンゾイル］シクロブタ［ｂ］キノリン－８－イル］アミノ］－４－オキソブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－６－フルオロ－１，２，２ａ，３，８，８ａ－ヘキサヒドロ－３－［４－（トリフルオロメトキシ）ベンゾイル］シクロブタ［ｂ］キノリン－８－イル］アミノ］－４－オキソブタン酸、
（ｃｉｓ，ｃｉｓ）－８－［（３－カルボキシ－１－オキソプロピル）シクロプロピルアミノ］－５－クロロ－２，２ａ，８，８ａ－テトラヒドロシクロブタ［ｂ］キノリン－３（１Ｈ）－カルボン酸３－（フェニルメチル）、
（ｃｉｓ，ｃｉｓ）－８－［（３－カルボキシ－１－オキソプロピル）シクロプロピルアミノ］－２，２ａ，８，８ａ－テトラヒドロシクロブタ［ｂ］キノリン－３（１Ｈ）－カルボン酸３－（フェニルメチル）、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－１，２，２ａ，３，８，８ａ－ヘキサヒドロ－３－［４－（トリフルオロメトキシ）ベンゾイル］シクロブタ［ｂ］キノリン－８－イル］アミノ］－４－オキソブタン酸、
［［［シクロプロピル［ｃｉｓ，ｃｉｓ－３－（３，４－ジフルオロベンゾイル）－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル］アミノ］カルボニル］オキシ］酢酸、
ｃｉｓ，ｃｉｓ－８－［（３－カルボキシプロピル）シクロプロピルアミノ］－５－フルオロ－２，２ａ，８，８ａ－テトラヒドロシクロブタ［ｂ］キノリン－３（１Ｈ）－カルボン酸３－（フェニルメチル）、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－（トリフルオロメトキシ）ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ］ブタン酸、
４－［シクロプロピル［ｃｉｓ，ｃｉｓ－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－４－［４－［（トリフルオロメチル）チオ］ベンゾイル］－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル］アミノ］－４－オキソブタン酸、
（Ｒ）－１－（（ｃｉｓ，ｃｉｓ－３－（ベンジルオキシカルボニル）－５，６－ジフルオロ－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル）（シクロプロピル）カルバモイル）アゼチジン－２－カルボン酸、
４－（シクロプロピル（ｃｉｓ，ｃｉｓ－３－（４－（（トリフルオロメチル）チオ）ベンゾイル）－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル）アミノ）－４－オキソブタン酸、
４－（エチル（ｃｉｓ，ｃｉｓ－６－フルオロ－３－（４－（（トリフルオロメチル）チオ）ベンゾイル）－１，２，２ａ，３，８，８ａ－ヘキサヒドロシクロブタ［ｂ］キノリン－８－イル）アミノ）－４－オキソブタン酸、
４－（エチル（ｃｉｓ，ｃｉｓ－７－フルオロ－４－（４－（（トリフルオロメチル）チオ）ベンゾイル）－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル）アミノ）－４－オキソブタン酸、
４－（シクロプロピル（ｃｉｓ，ｃｉｓ－７－フルオロ－４－（４－（（トリフルオロメチル）チオ）ベンゾイル）－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル）アミノ）－４－オキソブタン酸、
４－（シクロプロピル（ｃｉｓ，ｃｉｓ－７－フルオロ－４－（４－（トリフルオロメトキシ）ベンゾイル）－２，３，３ａ，４，９，９ａ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］キノリン－９－イル）アミノ）ブタン酸、 4- {cyclopropyl [cis, cis-4-{[4- (trifluoromethoxy) phenyl] carbonyl} -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] quinoline-9- Yl] amino} -4-oxobutanoic acid,
4- [cyclopropyl [cis, cis-7-fluoro-2,3,3a, 4,9,9a-hexahydro-4- [4- (trifluoromethoxy) benzoyl] -1H-cyclopenta [b] quinoline-9 -Yl] amino] -4-oxobutanoic acid,
4-[[cis, cis-6-chloro-7-fluoro-2,3,3a, 4,9,9a-hexahydro-4- [4- (trifluoromethoxy) benzoyl] -1H-cyclopenta [b] quinoline -9-yl] cyclopropylamino] -4-oxobutanoic acid,
4- [cyclopropyl [cis, cis-5-fluoro-1,2,2a, 3,8,8a-hexahydro-3- [4- (trifluoromethoxy) benzoyl] cyclobuta [b] quinolin-8-yl] Amino] -4-oxobutanoic acid,
4- [cyclopropyl [cis, cis-6-fluoro-1,2,2a, 3,8,8a-hexahydro-3- [4- (trifluoromethoxy) benzoyl] cyclobuta [b] quinolin-8-yl] Amino] -4-oxobutanoic acid,
(Cis, cis) -8-[(3-carboxy-1-oxopropyl) cyclopropylamino] -5-chloro-2,2a, 8,8a-tetrahydrocyclobuta [b] quinoline-3 (1H) -carvone Acid 3- (phenylmethyl),
(Cis, cis) -8-[(3-carboxy-1-oxopropyl) cyclopropylamino] -2,2a, 8,8a-tetrahydrocyclobuta [b] quinoline-3 (1H) -carboxylic acid 3- ( Phenylmethyl),
4- [cyclopropyl [cis, cis-1,2,2a, 3,8,8a-hexahydro-3- [4- (trifluoromethoxy) benzoyl] cyclobuta [b] quinolin-8-yl] amino] -4 -Oxobutanoic acid,
[[[Cyclopropyl [cis, cis-3- (3,4-difluorobenzoyl) -1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinolin-8-yl] amino] carbonyl] Oxy] acetic acid,
cis, cis-8-[(3-Carboxypropyl) cyclopropylamino] -5-fluoro-2,2a, 8,8a-tetrahydrocyclobuta [b] quinoline-3 (1H) -carboxylic acid 3- (phenylmethyl) ),
4- [cyclopropyl [cis, cis-2,3,3a, 4,9,9a-hexahydro-4- [4- (trifluoromethoxy) benzoyl] -1H-cyclopenta [b] quinolin-9-yl] amino ] Butanoic acid,
4- [cyclopropyl [cis, cis-2,3,3a, 4,9,9a-hexahydro-4- [4-[(trifluoromethyl) thio] benzoyl] -1H-cyclopenta [b] quinoline-9- Yl] amino] -4-oxobutanoic acid,
(R) -1-((cis, cis-3- (benzyloxycarbonyl) -5,6-difluoro-1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinolin-8-yl ) (Cyclopropyl) carbamoyl) azetidine-2-carboxylic acid,
4- (Cyclopropyl (cis, cis-3- (4-((trifluoromethyl) thio) benzoyl) -1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinolin-8-yl ) Amino) -4-oxobutanoic acid,
4- (Ethyl (cis, cis-6-fluoro-3- (4-((trifluoromethyl) thio) benzoyl) -1,2,2a, 3,8,8a-hexahydrocyclobuta [b] quinoline- 8-yl) amino) -4-oxobutanoic acid,
4- (Ethyl (cis, cis-7-fluoro-4- (4-((trifluoromethyl) thio) benzoyl) -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] quinoline) -9-yl) amino) -4-oxobutanoic acid,
4- (cyclopropyl (cis, cis-7-fluoro-4- (4-((trifluoromethyl) thio) benzoyl) -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] Quinolin-9-yl) amino) -4-oxobutanoic acid,
4- (Cyclopropyl (cis, cis-7-fluoro-4- (4- (trifluoromethoxy) benzoyl) -2,3,3a, 4,9,9a-hexahydro-1H-cyclopenta [b] quinoline-9 -Yl) amino) butanoic acid,
｛３－［１－（４－クロロ－フェニル）－エチル］－５－フルオロ－２－メチル－インドール－１－イル｝－酢酸、
｛５－フルオロ－２－メチル－３－［１－（４－トリフロロメチル－フェニル）－エチル］－インドール－１－イル｝－酢酸、
｛３－［１－（４－ｔｅｒｔ－ブチル－フェニル）－エチル］－５－フルオロ－２－メチル－インドール－１－イル｝－酢酸、
｛５－フルオロ－３－［１－（４－メタンスルフォニル－フェニル）－エチル］－２－メチル－インドール－１－イル｝－酢酸、
［５－フルオロ－２－メチル－３－（１－ナフタレン－２－イル－エチル）－インドール－１－イル］－酢酸、
（５－フルオロ－２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸、
（５－フルオロ－２－メチル－３－ナフタレン－２－イルメチル－インドール－１－イル）－酢酸、
［５－フルオロ－３－（８－ヒドロキシ－キノリン－２－イルメチル）－２－メチル－インドール－１－イル］－酢酸、
（５－フルオロ－２－メチル－３－キノキサリン－２－イルメチル－インドール－１－イル）－酢酸、
［５－フルオロ－３－（４－メトキシ－ベンジル）－２－メチル－インドール－１－イル］－酢酸、
（５－フルオロ－２－メチル－３－チアゾール－２－イルメチル－インドール－１－イル）－酢酸エチルエステル、
［３－（４－クロロ－ベンジル）－５－フルオロ－２－メチル－インドール－１－イル］－酢酸、
［５－フルオロ－２－メチル－３－（４－トリフロロメチル－ベンジル）－インドール－１－イル］－酢酸、
［５－フルオロ－２－メチル－３－（４－ｔｅｒｔ－ブチル－ベンジル）－インドール－１－イル］－酢酸、
（３－ビフェニル－４－イルメチル－５－フルオロ－２－メチル－インドール－１－イル）－酢酸、
［５－フルオロ－３－（４－メタンスルフォニル－ベンジル）－２－メチル－インドール－１－イル］－酢酸、
［５－フルオロ－３－（６－フルオロ－キノリン－２－イルメチル）－２－メチル－インドール－１－イル］－酢酸、
（２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸、
（５－クロロ－２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸、 {3- [1- (4-chloro-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid,
{5-fluoro-2-methyl-3- [1- (4-trifluoromethyl-phenyl) -ethyl] -indol-1-yl} -acetic acid,
{3- [1- (4-tert-butyl-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid,
{5-fluoro-3- [1- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-indol-1-yl} -acetic acid,
[5-fluoro-2-methyl-3- (1-naphthalen-2-yl-ethyl) -indol-1-yl] -acetic acid,
(5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid,
(5-fluoro-2-methyl-3-naphthalen-2-ylmethyl-indol-1-yl) -acetic acid,
[5-fluoro-3- (8-hydroxy-quinolin-2-ylmethyl) -2-methyl-indol-1-yl] -acetic acid,
(5-fluoro-2-methyl-3-quinoxalin-2-ylmethyl-indol-1-yl) -acetic acid,
[5-fluoro-3- (4-methoxy-benzyl) -2-methyl-indol-1-yl] -acetic acid,
(5-fluoro-2-methyl-3-thiazol-2-ylmethyl-indol-1-yl) -acetic acid ethyl ester,
[3- (4-chloro-benzyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid,
[5-fluoro-2-methyl-3- (4-trifluoromethyl-benzyl) -indol-1-yl] -acetic acid,
[5-fluoro-2-methyl-3- (4-tert-butyl-benzyl) -indol-1-yl] -acetic acid,
(3-biphenyl-4-ylmethyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid,
[5-fluoro-3- (4-methanesulfonyl-benzyl) -2-methyl-indol-1-yl] -acetic acid,
[5-fluoro-3- (6-fluoro-quinolin-2-ylmethyl) -2-methyl-indol-1-yl] -acetic acid,
(2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid,
(5-chloro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid,
｛５－フルオロ－２－メチル－３－［１－（４－トリフロロメチル－フェニル）－エチル］－インドール－１－イル｝－酢酸、
｛３－［１－（４－ｔｅｒｔ－ブチル－フェニル）－エチル］－５－フルオロ－２－メチル－インドール－１－イル｝－酢酸、
｛５－フルオロ－３－［１－（４－メタンスルフォニル－フェニル）－エチル］－２－メチル－インドール－１－イル｝－酢酸、
［５－フルオロ－２－メチル－３－（１－ナフタレン－２－イル－エチル）－インドール－１－イル］－酢酸、
（５－フルオロ－２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸、
（５－フルオロ－２－メチル－３－ナフタレン－２－イルメチル－インドール－１－イル）－酢酸、
［５－フルオロ－３－（８－ヒドロキシ－キノリン－２－イルメチル）－２－メチル－インドール－１－イル］－酢酸、
（５－フルオロ－２－メチル－３－キノキサリン－２－イルメチル－インドール－１－イル）－酢酸、
［５－フルオロ－３－（４－メトキシ－ベンジル）－２－メチル－インドール－１－イル］－酢酸、
（５－フルオロ－２－メチル－３－チアゾール－２－イルメチル－インドール－１－イル）－酢酸エチルエステル、
［３－（４－クロロ－ベンジル）－５－フルオロ－２－メチル－インドール－１－イル］－酢酸、
［５－フルオロ－２－メチル－３－（４－トリフロロメチル－ベンジル）－インドール－１－イル］－酢酸、
［５－フルオロ－２－メチル－３－（４－ｔｅｒｔ－ブチル－ベンジル）－インドール－１－イル］－酢酸、
（３－ビフェニル－４－イルメチル－５－フルオロ－２－メチル－インドール－１－イル）－酢酸、
［５－フルオロ－３－（４－メタンスルフォニル－ベンジル）－２－メチル－インドール－１－イル］－酢酸、
［５－フルオロ－３－（６－フルオロ－キノリン－２－イルメチル）－２－メチル－インドール－１－イル］－酢酸、
（２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸、
（５－クロロ－２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸、 {3- [1- (4-chloro-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid,
{5-fluoro-2-methyl-3- [1- (4-trifluoromethyl-phenyl) -ethyl] -indol-1-yl} -acetic acid,
{3- [1- (4-tert-butyl-phenyl) -ethyl] -5-fluoro-2-methyl-indol-1-yl} -acetic acid,
{5-fluoro-3- [1- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-indol-1-yl} -acetic acid,
[5-fluoro-2-methyl-3- (1-naphthalen-2-yl-ethyl) -indol-1-yl] -acetic acid,
(5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid,
(5-fluoro-2-methyl-3-naphthalen-2-ylmethyl-indol-1-yl) -acetic acid,
[5-fluoro-3- (8-hydroxy-quinolin-2-ylmethyl) -2-methyl-indol-1-yl] -acetic acid,
(5-fluoro-2-methyl-3-quinoxalin-2-ylmethyl-indol-1-yl) -acetic acid,
[5-fluoro-3- (4-methoxy-benzyl) -2-methyl-indol-1-yl] -acetic acid,
(5-fluoro-2-methyl-3-thiazol-2-ylmethyl-indol-1-yl) -acetic acid ethyl ester,
[3- (4-chloro-benzyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid,
[5-fluoro-2-methyl-3- (4-trifluoromethyl-benzyl) -indol-1-yl] -acetic acid,
[5-fluoro-2-methyl-3- (4-tert-butyl-benzyl) -indol-1-yl] -acetic acid,
(3-biphenyl-4-ylmethyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid,
[5-fluoro-3- (4-methanesulfonyl-benzyl) -2-methyl-indol-1-yl] -acetic acid,
[5-fluoro-3- (6-fluoro-quinolin-2-ylmethyl) -2-methyl-indol-1-yl] -acetic acid,
(2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid,
(5-chloro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl) -acetic acid,
｛２－［４－クロロ－３－（２，６－ジクロロ－ベンジルスルファモイル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
｛２－［４－クロロ－３－（３，５－ジクロロ－ベンジルスルファモイル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
（２－｛４－クロロ－３－［２－（２，４－ジクロロ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（２－メトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（３－メトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（４－メトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（２－トリフルオロメトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
［２－（４－クロロ－３－フェネチルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
｛２－［４－クロロ－３－（３－フェニル－プロピルスルファモイル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
２－［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－Ｎ－メチル－アセトアミド、
［４－クロロ－２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
［４－クロロ－２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸カリウム、
［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－４－フルオロ－１Ｈ－インドール－３－イル］－酢酸、
［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－４－メチル－１Ｈ－インドール－３－イル］－酢酸、
［７－クロロ－２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
２－クロロ－Ｎ－シクロヘキシル－５－［３－（２－メタンスルホニルアミノ－２－オキソ－エチル）－１Ｈ－インドール－２－イル］－ベンゼンスルホンアミド、
２－クロロ－Ｎ－シクロヘキシル－５－［３－（２－エタンスルホニルアミノ－２－オキソ－エチル）－１Ｈ－インドール－２－イル］－ベンゼンスルホンアミド、
２－クロロ－Ｎ－シクロヘキシル－５－［３－（２－オキソ－２－トリフルオロメタンスルホニルアミノ－エチル）－１Ｈ－インドール－２－イル］－ベンゼンスルホンアミド、
２－［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－Ｎ－（１Ｈ－テトラゾール－５－イル）－アセトアミド、
［２－（３－シクロヘキシルスルファモイル－４－エチル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
２－［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－プロピオン酸、
｛２－［４－クロロ－３－（３－クロロ－フェニルメタンスルホニル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
｛２－［４－クロロ－３－（３－クロロ－フェニルメタンスルホニルアミノ）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、及び（５－フルオロ－２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸から選ばれる化合物又はその薬学的に許容される塩が挙げられる。 {2- [4-Chloro-3- (2,6-dichloro-benzylsulfamoyl) -phenyl] -1H-indol-3-yl} -acetic acid,
{2- [4-chloro-3- (3,5-dichloro-benzylsulfamoyl) -phenyl] -1H-indol-3-yl} -acetic acid,
(2- {4-chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
[2- (4-Chloro-3-phenethylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid,
{2- [4-Chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -1H-indol-3-yl} -acetic acid,
2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N-methyl-acetamide,
[4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid,
[4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -potassium acetate,
[2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-fluoro-1H-indol-3-yl] -acetic acid,
[2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indol-3-yl] -acetic acid,
[7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid,
2-chloro-N-cyclohexyl-5- [3- (2-methanesulfonylamino-2-oxo-ethyl) -1H-indol-2-yl] -benzenesulfonamide,
2-chloro-N-cyclohexyl-5- [3- (2-ethanesulfonylamino-2-oxo-ethyl) -1H-indol-2-yl] -benzenesulfonamide,
2-chloro-N-cyclohexyl-5- [3- (2-oxo-2-trifluoromethanesulfonylamino-ethyl) -1H-indol-2-yl] -benzenesulfonamide,
2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N- (1H-tetrazol-5-yl) -acetamide,
[2- (3-cyclohexylsulfamoyl-4-ethyl-phenyl) -1H-indol-3-yl] -acetic acid,
2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -propionic acid,
{2- [4-Chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -1H-indol-3-yl} -acetic acid,
{2- [4-Chloro-3- (3-chloro-phenylmethanesulfonylamino) -phenyl] -1H-indol-3-yl} -acetic acid, and (5-fluoro-2-methyl-3-quinoline-2 A compound selected from -ylmethyl-indol-1-yl) -acetic acid or a pharmaceutically acceptable salt thereof.
｛２－［４－クロロ－３－（３，５－ジクロロ－ベンジルスルファモイル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
（２－｛４－クロロ－３－［２－（２，４－ジクロロ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（２－メトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（３－メトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（４－メトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
（２－｛４－クロロ－３－［２－（２－トリフルオロメトキシ－フェニル）－エチルスルファモイル］－フェニル｝－１Ｈ－インドール－３－イル）－酢酸、
［２－（４－クロロ－３－フェネチルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
｛２－［４－クロロ－３－（３－フェニル－プロピルスルファモイル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
２－［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－Ｎ－メチル－アセトアミド、
［４－クロロ－２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
［４－クロロ－２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸カリウム、
［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－４－フルオロ－１Ｈ－インドール－３－イル］－酢酸、
［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－４－メチル－１Ｈ－インドール－３－イル］－酢酸、
［７－クロロ－２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
２－クロロ－Ｎ－シクロヘキシル－５－［３－（２－メタンスルホニルアミノ－２－オキソ－エチル）－１Ｈ－インドール－２－イル］－ベンゼンスルホンアミド、
２－クロロ－Ｎ－シクロヘキシル－５－［３－（２－エタンスルホニルアミノ－２－オキソ－エチル）－１Ｈ－インドール－２－イル］－ベンゼンスルホンアミド、
２－クロロ－Ｎ－シクロヘキシル－５－［３－（２－オキソ－２－トリフルオロメタンスルホニルアミノ－エチル）－１Ｈ－インドール－２－イル］－ベンゼンスルホンアミド、
２－［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－Ｎ－（１Ｈ－テトラゾール－５－イル）－アセトアミド、
［２－（３－シクロヘキシルスルファモイル－４－エチル－フェニル）－１Ｈ－インドール－３－イル］－酢酸、
２－［２－（４－クロロ－３－シクロヘキシルスルファモイル－フェニル）－１Ｈ－インドール－３－イル］－プロピオン酸、
｛２－［４－クロロ－３－（３－クロロ－フェニルメタンスルホニル）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、
｛２－［４－クロロ－３－（３－クロロ－フェニルメタンスルホニルアミノ）－フェニル］－１Ｈ－インドール－３－イル｝－酢酸、及び（５－フルオロ－２－メチル－３－キノリン－２－イルメチル－インドール－１－イル）－酢酸から選ばれる化合物又はその薬学的に許容される塩が挙げられる。 {2- [4-Chloro-3- (2,6-dichloro-benzylsulfamoyl) -phenyl] -1H-indol-3-yl} -acetic acid,
{2- [4-chloro-3- (3,5-dichloro-benzylsulfamoyl) -phenyl] -1H-indol-3-yl} -acetic acid,
(2- {4-chloro-3- [2- (2,4-dichloro-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (2-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (3-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (4-methoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
(2- {4-chloro-3- [2- (2-trifluoromethoxy-phenyl) -ethylsulfamoyl] -phenyl} -1H-indol-3-yl) -acetic acid,
[2- (4-Chloro-3-phenethylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid,
{2- [4-Chloro-3- (3-phenyl-propylsulfamoyl) -phenyl] -1H-indol-3-yl} -acetic acid,
2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N-methyl-acetamide,
[4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid,
[4-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -potassium acetate,
[2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-fluoro-1H-indol-3-yl] -acetic acid,
[2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -4-methyl-1H-indol-3-yl] -acetic acid,
[7-chloro-2- (4-chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -acetic acid,
2-chloro-N-cyclohexyl-5- [3- (2-methanesulfonylamino-2-oxo-ethyl) -1H-indol-2-yl] -benzenesulfonamide,
2-chloro-N-cyclohexyl-5- [3- (2-ethanesulfonylamino-2-oxo-ethyl) -1H-indol-2-yl] -benzenesulfonamide,
2-chloro-N-cyclohexyl-5- [3- (2-oxo-2-trifluoromethanesulfonylamino-ethyl) -1H-indol-2-yl] -benzenesulfonamide,
2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -N- (1H-tetrazol-5-yl) -acetamide,
[2- (3-cyclohexylsulfamoyl-4-ethyl-phenyl) -1H-indol-3-yl] -acetic acid,
2- [2- (4-Chloro-3-cyclohexylsulfamoyl-phenyl) -1H-indol-3-yl] -propionic acid,
{2- [4-Chloro-3- (3-chloro-phenylmethanesulfonyl) -phenyl] -1H-indol-3-yl} -acetic acid,
{2- [4-Chloro-3- (3-chloro-phenylmethanesulfonylamino) -phenyl] -1H-indol-3-yl} -acetic acid, and (5-fluoro-2-methyl-3-quinoline-2 A compound selected from -ylmethyl-indol-1-yl) -acetic acid or a pharmaceutically acceptable salt thereof.
さらに、以下に示す化合物もＣＲＴＨ２拮抗剤の例として好ましい。
Furthermore, the following compounds are also preferred as examples of CRTH2 antagonists.
ＣＲＴＨ２拮抗剤は、食物アレルギーアレルゲン特異的なＩｇＥ産生を顕著に抑制し、食物アレルギーの症状を改善する作用を有する。また、当該ＩｇＥ産生抑制作用は、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである。また、ＣＲＴＨ２拮抗剤は、食物アレルギーにおける肥満細胞数の増加及び／又は肥満細胞活性を抑制する。
The CRTH2 antagonist has the effect of remarkably suppressing food allergy allergen-specific IgE production and improving food allergy symptoms. In addition, the IgE production inhibitory action is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist. In addition, CRTH2 antagonists suppress the increase in the number of mast cells and / or mast cell activity in food allergy.
食物アレルギーアレルゲンを含む食品としては、鶏卵、乳製品、小麦、甲殻類、果物類、ソバ、魚類、ピーナッツ、魚卵、大豆等が挙げられる。本発明の医薬により産生が抑制されるＩｇＥは、これらのアレルゲン特異的であるから、食物アレルギーの症状を有効に改善できる。
Foods containing food allergens include chicken eggs, dairy products, wheat, crustaceans, fruits, buckwheat, fish, peanuts, fish eggs, soybeans, and the like. Since IgE whose production is suppressed by the medicament of the present invention is specific to these allergens, it can effectively improve food allergy symptoms.
本発明の医薬により改善される食物アレルギーの症状としては、じんましん、かゆみ、赤みなどの皮膚症状；せき、呼吸困難などの呼吸器症状；口腔粘膜、のどの粘膜等の粘膜症状；下痢、腹痛、吐き気、嘔吐などの消化器症状；アナフィラキシー症状等が挙げられる。
Symptoms of food allergy improved by the medicament of the present invention include skin symptoms such as hives, itching and redness; respiratory symptoms such as cough and dyspnea; mucosal symptoms such as oral mucosa and throat mucosa; diarrhea, abdominal pain, Gastrointestinal symptoms such as nausea and vomiting; anaphylactic symptoms and the like.
本発明のＩｇＥ産生抑制剤及び食物アレルギー治療薬は、ＣＲＴＨ２を有効成分として含有する医薬組成物とすることができる。当該医薬組成物には、薬学的に許容される担体を含有することができる。この医薬組成物は、錠剤、散剤、細粒剤、顆粒剤、カプセル剤、丸剤、液剤、注射剤、坐剤、軟膏剤または湿布剤のいずれかの形態で経口投与しても非経口投与してもよい。
The IgE production inhibitor and food allergy therapeutic agent of the present invention can be a pharmaceutical composition containing CRTH2 as an active ingredient. The pharmaceutical composition can contain a pharmaceutically acceptable carrier. This pharmaceutical composition can be administered orally or parenterally in the form of tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments or poultices. May be.
経口投与を目的とした固形組成物として、錠剤、散剤、顆粒剤などが用いられる。それらの種類の固形組成物は、乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶性セルロース、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウムなどの少なくとも１つの不活性賦形剤と混合された１つまたはそれ以上の有効物質を含む。通常の方法では、組成物は上記の不活性賦形剤以外の、例えばステアリン酸マグネシウムなどの潤滑剤、グリコール酸セルロースカルシウムなどの崩壊剤、乳糖などの安定化剤、およびグルタミン酸またはアスパラギン酸などの可溶化剤または溶解促進剤などの他の何らかの添加剤を含んでもよい。所望であれば、錠剤および丸剤はショ糖、ゼラチン、ヒドロキシプロピルセルロース、フタル酸ヒドロキシプロピルメチルセルロースなどの糖または胃溶または腸溶物質のフィルムで被覆してもよい。
Tablets, powders, granules, etc. are used as solid compositions intended for oral administration. These types of solid compositions are one mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc. Or more active substances. In a conventional manner, the composition is in addition to the inert excipients described above, for example, a lubricant such as magnesium stearate, a disintegrant such as cellulose calcium glycolate, a stabilizer such as lactose, and glutamic acid or aspartic acid. Any other additive such as a solubilizer or dissolution enhancer may be included. If desired, tablets and pills may be coated with a sugar or gastric or enteric film, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or the like.
経口投与を目的とした液状組成物は、例えば、純水またはエチルアルコールなどの通常の不活性希釈剤を含有する医薬品として許容できる乳剤、溶液、懸濁剤、シロップ剤、エリキシル剤などを含む。それらの組成物は、不活性希釈剤に加えてさらに可溶化剤、溶解補助剤、湿潤促進剤、懸濁促進剤、またさらに甘味料、矯味矯臭剤、芳香剤、および保存料などの医薬品用補助剤を含有してもよい。
非経口投与を目的とした注射剤は、例えば無菌、水性または非水性溶液、懸濁剤および乳剤を含む。水性溶液および懸濁剤用の希釈剤は、例えば注射用蒸留水および生理食塩水を含む。非水性溶液および懸濁液用の希釈剤は、例えばプロピレングリコール、ポリエチレングリコール、オリーブ油などの植物油、エチルアルコールなどのアルコール、ポリソルベート８０（登録商標））を含む。 Liquid compositions intended for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like containing conventional inert diluents such as pure water or ethyl alcohol. In addition to inert diluents, these compositions are further used for pharmaceuticals such as solubilizers, solubilizers, wetting promoters, suspension promoters, and sweeteners, flavoring agents, fragrances, and preservatives. An adjuvant may be contained.
Injectables intended for parenteral administration include, for example, sterile, aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Diluents for non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, polysorbate 80 (registered trademark)).
非経口投与を目的とした注射剤は、例えば無菌、水性または非水性溶液、懸濁剤および乳剤を含む。水性溶液および懸濁剤用の希釈剤は、例えば注射用蒸留水および生理食塩水を含む。非水性溶液および懸濁液用の希釈剤は、例えばプロピレングリコール、ポリエチレングリコール、オリーブ油などの植物油、エチルアルコールなどのアルコール、ポリソルベート８０（登録商標））を含む。 Liquid compositions intended for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like containing conventional inert diluents such as pure water or ethyl alcohol. In addition to inert diluents, these compositions are further used for pharmaceuticals such as solubilizers, solubilizers, wetting promoters, suspension promoters, and sweeteners, flavoring agents, fragrances, and preservatives. An adjuvant may be contained.
Injectables intended for parenteral administration include, for example, sterile, aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Diluents for non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, polysorbate 80 (registered trademark)).
それらの組成物はさらに等張性調整剤、保存料、湿潤促進剤、乳化剤、分散剤、安定化剤（例：乳糖）、可溶化剤、溶解促進剤などの添加剤をさらに含んでもよい。これらは細菌捕捉フィルターで濾過することによって、またはこれらに殺菌剤を加えることによって、または放射線を照射することによって滅菌される。無菌固形組成物をあらかじめ調製してもよく、さらにそれらを使用する前に注射用の無菌水または無菌溶媒に溶解してもよい。
These compositions may further contain additives such as isotonicity adjusting agents, preservatives, wetting accelerators, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizers, and dissolution accelerators. They are sterilized by filtration through a bacteria capture filter or by adding a bactericidal agent to them or by irradiating them with radiation. Sterile solid compositions may be prepared in advance and may be dissolved in sterile water or solvent for injection before use.
本発明の医薬の投与量は、投与する患者の病状、体重、年齢および性別に応じて適切に決定してもよいが、一般的には経口投与については有効成分量として０．１から５００ｍｇ／成人／日、非経口投与については０．０１から１００ｍｇ／成人／日が好ましい。これは患者に対して一度に全量を投与しても、または数回投与するために数回分に分割してもよい。
The dose of the medicament of the present invention may be appropriately determined according to the disease state, body weight, age, and sex of the patient to be administered. Generally, for oral administration, the amount of the active ingredient is 0.1 to 500 mg / For adult / day, parenteral administration, 0.01 to 100 mg / adult / day is preferred. This may be administered to the patient in full doses at once, or divided into several doses for multiple doses.
次に実施例を挙げて本発明をさらに詳細に説明する。
Next, the present invention will be described in more detail with reference to examples.
実施例１
（方法）
Ｃ５７ＢＬ／６系マウス（野生；ＣＲＴＨ２+/+）及び同種のＣＲＴＨ２-/-（ＣＲＴＨ２ノックアウトマウス）を用いて、アレルギー症状、二次リンパ節の脂質動態、二次リンパ組織中の樹状細胞、Ｔ細胞、Ｂ細胞：ＯＶＡ特異的ＩｇＥの検討を行った。
抗原としてオボアルブミン（ＯＶＡ）を用いた。ＯＶＡ５０μgをＤａｙ０からＤａｙ１４まで２回腹腔内投与し、感作を行った。Ｄａｙ２８からＤａｙ４６まで２日に１回ＯＶＡ１０mgを経口投与した。 Example 1
(Method)
Using C57BL / 6 mice (wild; CRTH2 + / + ) and the same type of CRTH2 − / − (CRTH2 knockout mice), allergic symptoms, secondary lymph node lipid dynamics, dendritic cells in secondary lymphoid tissues, T cells and B cells: OVA-specific IgE was examined.
Ovalbumin (OVA) was used as an antigen. Sensitization was performed by intraperitoneally administering 50 μg of OVA twice fromDay 0 to Day 14. OVA 10 mg was orally administered once every two days from Day 28 to Day 46.
（方法）
Ｃ５７ＢＬ／６系マウス（野生；ＣＲＴＨ２+/+）及び同種のＣＲＴＨ２-/-（ＣＲＴＨ２ノックアウトマウス）を用いて、アレルギー症状、二次リンパ節の脂質動態、二次リンパ組織中の樹状細胞、Ｔ細胞、Ｂ細胞：ＯＶＡ特異的ＩｇＥの検討を行った。
抗原としてオボアルブミン（ＯＶＡ）を用いた。ＯＶＡ５０μgをＤａｙ０からＤａｙ１４まで２回腹腔内投与し、感作を行った。Ｄａｙ２８からＤａｙ４６まで２日に１回ＯＶＡ１０mgを経口投与した。 Example 1
(Method)
Using C57BL / 6 mice (wild; CRTH2 + / + ) and the same type of CRTH2 − / − (CRTH2 knockout mice), allergic symptoms, secondary lymph node lipid dynamics, dendritic cells in secondary lymphoid tissues, T cells and B cells: OVA-specific IgE was examined.
Ovalbumin (OVA) was used as an antigen. Sensitization was performed by intraperitoneally administering 50 μg of OVA twice from
（結果）
（１）Ｄａｙ４６に、脾臓中の脂質動態を測定した。各脂質は、液体クロマトグラフィー質量分析装置により測定した。
結果を図１に示す。図１より、食物アレルギーにおいては、脾臓中のアラキドン酸（ＡＡ）、ＰＧＥ2及びＰＧＤ2等が有意に上昇していることがわかる。 (result)
(1) At Day 46, lipid dynamics in the spleen were measured. Each lipid was measured by a liquid chromatography mass spectrometer.
The results are shown in FIG. FIG. 1 shows that arachidonic acid (AA), PGE 2, PGD 2 and the like in the spleen are significantly increased in food allergy.
（１）Ｄａｙ４６に、脾臓中の脂質動態を測定した。各脂質は、液体クロマトグラフィー質量分析装置により測定した。
結果を図１に示す。図１より、食物アレルギーにおいては、脾臓中のアラキドン酸（ＡＡ）、ＰＧＥ2及びＰＧＤ2等が有意に上昇していることがわかる。 (result)
(1) At Day 46, lipid dynamics in the spleen were measured. Each lipid was measured by a liquid chromatography mass spectrometer.
The results are shown in FIG. FIG. 1 shows that arachidonic acid (AA), PGE 2, PGD 2 and the like in the spleen are significantly increased in food allergy.
（２）Ｄａｙ４６に、血清中のＯＶＡ特異的ＩｇＥ、ＩｇＡ、ＩｇＭ、ＩｇＧ１及びＩｇＧ２ａ濃度を測定した。
その結果、ＩｇＭ、ＩｇＧ１及びＩｇＧ２には変化がなかったが、図２に示すように、野生種ではＯＶＡ特異的ＩｇＥ及びＩｇＡの産生が増加するのに対し、ＣＲＴＨ２ノックアウトマウスでＯＶＡ特異的ＩｇＥ及びＩｇＡの産生抑制が観察された。 (2) The concentration of OVA-specific IgE, IgA, IgM, IgG1, and IgG2a in serum was measured at Day 46.
As a result, although there was no change in IgM, IgG1, and IgG2, as shown in FIG. 2, the production of OVA-specific IgE and IgA increased in the wild type, whereas the OVA-specific IgE and the CRVA2 knockout mice increased. Inhibition of IgA production was observed.
その結果、ＩｇＭ、ＩｇＧ１及びＩｇＧ２には変化がなかったが、図２に示すように、野生種ではＯＶＡ特異的ＩｇＥ及びＩｇＡの産生が増加するのに対し、ＣＲＴＨ２ノックアウトマウスでＯＶＡ特異的ＩｇＥ及びＩｇＡの産生抑制が観察された。 (2) The concentration of OVA-specific IgE, IgA, IgM, IgG1, and IgG2a in serum was measured at Day 46.
As a result, although there was no change in IgM, IgG1, and IgG2, as shown in FIG. 2, the production of OVA-specific IgE and IgA increased in the wild type, whereas the OVA-specific IgE and the CRVA2 knockout mice increased. Inhibition of IgA production was observed.
（３）ＯＶＡによるアレルギー症状（痒み、不動化、目の腫脹／立毛／努加呼吸をスコア化したもの）及び下痢（発生率）を検討した。その結果を図３に示す。
図３より、野生種がアレルギー症状及び下痢を発症するのに対し、ＣＲＴＨ２ノックアウトマウスは、これらの症状が明らかに抑制された。 (3) Allergic symptoms caused by OVA (scoring, immobilization, swelling of eyes / napped / stressed breathing) and diarrhea (incidence) were examined. The result is shown in FIG.
From FIG. 3, wild species developed allergic symptoms and diarrhea, whereas CRTH2 knockout mice clearly suppressed these symptoms.
図３より、野生種がアレルギー症状及び下痢を発症するのに対し、ＣＲＴＨ２ノックアウトマウスは、これらの症状が明らかに抑制された。 (3) Allergic symptoms caused by OVA (scoring, immobilization, swelling of eyes / napped / stressed breathing) and diarrhea (incidence) were examined. The result is shown in FIG.
From FIG. 3, wild species developed allergic symptoms and diarrhea, whereas CRTH2 knockout mice clearly suppressed these symptoms.
（４）Ｃ５７ＢＬ／６系マウス（野生型）及び同系統種のプロスタグランジンＤ合成酵素欠損マウス（Ｌ－ＰＧＤＳ-/-及びＨ－ＰＧＤＳ-/-）、プロスタグランジンＤ合成酵素トランスジェニックマウス（Ｈ－ＰＧＤＳTG/+）を用いて、感作後（Ｄａｙ２８）のＯＶＡ特異的ＩｇＥの検討を行った。
その結果を図４に示す。図４より、プロスタグランジンＤ合成酵素遺伝子を有するマウスではＯＶＡ特異的ＩｇＥの産生が強いのに対し、プロスタグランジンＤ合成酵素遺伝子欠損マウスではＯＶＡ特異的ＩｇＥの産生が抑制されることが判明した。プロスタグランジンＤ合成酵素トランスジェニックマウスではＯＶＡ特異的ＩｇＥの産生が野生種よりも増強した。 (4) C57BL / 6 mouse (wild type), prostaglandin D synthase deficient mouse (L-PGDS − / − and H-PGDS − / − ), prostaglandin D synthase transgenic mouse of the same strain (VA-PGDS TG / + ) was used to examine OVA-specific IgE after sensitization (Day 28).
The result is shown in FIG. FIG. 4 reveals that mice with prostaglandin D synthase gene produce strong OVA-specific IgE, whereas mice lacking prostaglandin D synthase gene suppress the production of OVA-specific IgE. did. In the prostaglandin D synthase transgenic mouse, the production of OVA-specific IgE was enhanced as compared to the wild type.
その結果を図４に示す。図４より、プロスタグランジンＤ合成酵素遺伝子を有するマウスではＯＶＡ特異的ＩｇＥの産生が強いのに対し、プロスタグランジンＤ合成酵素遺伝子欠損マウスではＯＶＡ特異的ＩｇＥの産生が抑制されることが判明した。プロスタグランジンＤ合成酵素トランスジェニックマウスではＯＶＡ特異的ＩｇＥの産生が野生種よりも増強した。 (4) C57BL / 6 mouse (wild type), prostaglandin D synthase deficient mouse (L-PGDS − / − and H-PGDS − / − ), prostaglandin D synthase transgenic mouse of the same strain (VA-PGDS TG / + ) was used to examine OVA-specific IgE after sensitization (Day 28).
The result is shown in FIG. FIG. 4 reveals that mice with prostaglandin D synthase gene produce strong OVA-specific IgE, whereas mice lacking prostaglandin D synthase gene suppress the production of OVA-specific IgE. did. In the prostaglandin D synthase transgenic mouse, the production of OVA-specific IgE was enhanced as compared to the wild type.
（５）Ｄａｙ２８に脾臓中の樹状細胞、Ｔ細胞、Ｂ細胞等の局在を検討した。
その結果、図５に示すように、食物アレルギー反応により、樹状細胞、Ｔ細胞及びＢ細胞の会合が生じているのに対し、ＣＲＴＨ２ノックアウトマウスではそれらの細胞の会合が抑制されていた。 (5) The localization of dendritic cells, T cells, B cells, etc. in the spleen was examined on Day 28.
As a result, as shown in FIG. 5, the association of dendritic cells, T cells and B cells was caused by food allergic reaction, whereas the association of those cells was suppressed in CRTH2 knockout mice.
その結果、図５に示すように、食物アレルギー反応により、樹状細胞、Ｔ細胞及びＢ細胞の会合が生じているのに対し、ＣＲＴＨ２ノックアウトマウスではそれらの細胞の会合が抑制されていた。 (5) The localization of dendritic cells, T cells, B cells, etc. in the spleen was examined on Day 28.
As a result, as shown in FIG. 5, the association of dendritic cells, T cells and B cells was caused by food allergic reaction, whereas the association of those cells was suppressed in CRTH2 knockout mice.
（６）野生種マウスの脾臓からＴ細胞、Ｂ細胞、樹状細胞を分離し、ＣＲＴＨ２ノックアウトマウスに各細胞を移入した。その後ＯＶＡで感作し、Ｄａｙ２８のＯＶＡ特異的ＩｇＥを測定した。
図６に示すように、野生種と比べてＣＲＴＨ２ノックアウトマウスではＯＶＡ特異的ＩｇＥの産生が抑制されたが、野生種の樹状細胞を移入したＣＲＴＨ２ノックアウトマウスではＯＶＡ特異的ＩｇＥの産生が増加した。野生種のＴ細胞やＢ細胞を移入してもＯＶＡ特異的ＩｇＥの産生は変わらなかった。 (6) T cells, B cells, and dendritic cells were isolated from the spleen of wild-type mice, and each cell was transferred to CRTH2 knockout mice. Thereafter, sensitization with OVA was performed, and OVA-specific IgE of Day 28 was measured.
As shown in FIG. 6, the production of OVA-specific IgE was suppressed in CRTH2 knockout mice compared to the wild type, whereas the production of OVA-specific IgE was increased in CRTH2 knockout mice transfected with wild type dendritic cells. . Transplantation of wild-type T cells and B cells did not change the production of OVA-specific IgE.
図６に示すように、野生種と比べてＣＲＴＨ２ノックアウトマウスではＯＶＡ特異的ＩｇＥの産生が抑制されたが、野生種の樹状細胞を移入したＣＲＴＨ２ノックアウトマウスではＯＶＡ特異的ＩｇＥの産生が増加した。野生種のＴ細胞やＢ細胞を移入してもＯＶＡ特異的ＩｇＥの産生は変わらなかった。 (6) T cells, B cells, and dendritic cells were isolated from the spleen of wild-type mice, and each cell was transferred to CRTH2 knockout mice. Thereafter, sensitization with OVA was performed, and OVA-specific IgE of Day 28 was measured.
As shown in FIG. 6, the production of OVA-specific IgE was suppressed in CRTH2 knockout mice compared to the wild type, whereas the production of OVA-specific IgE was increased in CRTH2 knockout mice transfected with wild type dendritic cells. . Transplantation of wild-type T cells and B cells did not change the production of OVA-specific IgE.
（７）ＯＶＡで感作した（Ｄａｙ１５）野生種マウスの脾臓中のプロスタグランジンＤ合成酵素（Ｈ－ＰＧＤＳ）発現の局在を検討した。
図７に示すように、プロスタグランジンＤ合成酵素は脾臓中心動脈の内皮細胞で発現していた。プロスタグランジンＤ合成酵素を発現している中心動脈の周囲には樹状細胞が局在していた。 (7) The localization of prostaglandin D synthase (H-PGDS) expression in the spleen of wild-type mice sensitized with OVA (Day 15) was examined.
As shown in FIG. 7, prostaglandin D synthase was expressed in endothelial cells of the splenic central artery. Dendritic cells were localized around the central artery expressing prostaglandin D synthase.
図７に示すように、プロスタグランジンＤ合成酵素は脾臓中心動脈の内皮細胞で発現していた。プロスタグランジンＤ合成酵素を発現している中心動脈の周囲には樹状細胞が局在していた。 (7) The localization of prostaglandin D synthase (H-PGDS) expression in the spleen of wild-type mice sensitized with OVA (Day 15) was examined.
As shown in FIG. 7, prostaglandin D synthase was expressed in endothelial cells of the splenic central artery. Dendritic cells were localized around the central artery expressing prostaglandin D synthase.
実施例２
実施例１で用いたＯＶＡ投与による食物アレルギーモデルマウス（野生種）において、Ｄａｙ２８～Ｄａｙ４６に１日に１回ラマトロバン３０ｍｇ／ｋｇを経口投与した。アレルギー症状、下痢及び血清中ＯＶＡ特異的ＩｇＥ濃度を測定した。
その結果、図８に示すように、ＣＲＴＨ２拮抗剤であるラマトロバン投与により、アレルギー症状及び下痢症状が改善し、かつ血清中ＯＶＡ特異的ＩｇＥの産生が有意に抑制された。 Example 2
In the food allergy model mouse (wild type) by OVA administration used in Example 1, 30 mg / kg of ramatroban was orally administered once a day to Day 28 to Day 46. Allergic symptoms, diarrhea and serum OVA-specific IgE concentrations were measured.
As a result, as shown in FIG. 8, administration of ramatroban, which is a CRTH2 antagonist, improved allergic symptoms and diarrhea symptoms, and significantly reduced the production of serum OVA-specific IgE.
実施例１で用いたＯＶＡ投与による食物アレルギーモデルマウス（野生種）において、Ｄａｙ２８～Ｄａｙ４６に１日に１回ラマトロバン３０ｍｇ／ｋｇを経口投与した。アレルギー症状、下痢及び血清中ＯＶＡ特異的ＩｇＥ濃度を測定した。
その結果、図８に示すように、ＣＲＴＨ２拮抗剤であるラマトロバン投与により、アレルギー症状及び下痢症状が改善し、かつ血清中ＯＶＡ特異的ＩｇＥの産生が有意に抑制された。 Example 2
In the food allergy model mouse (wild type) by OVA administration used in Example 1, 30 mg / kg of ramatroban was orally administered once a day to Day 28 to Day 46. Allergic symptoms, diarrhea and serum OVA-specific IgE concentrations were measured.
As a result, as shown in FIG. 8, administration of ramatroban, which is a CRTH2 antagonist, improved allergic symptoms and diarrhea symptoms, and significantly reduced the production of serum OVA-specific IgE.
実施例３
食物アレルギーにおける肥満細胞数の変化及びラマトロバン投与による肥満細胞数に及ぼす作用を検討した。
ＣＲＴＨ２欠損マウスに実施例１と同様にＯＶＡ投与を行い、食物アレルギーにおける肥満細胞数を測定した。また、ラマトロバン投与（実施例２と同じ）による肥満細胞数の変化も検討した。
その結果、図９に示すように、食物アレルギーにより結腸及び回腸の肥満細胞数は増加するが、ＣＲＴＨ２ノックアウトマウスでは結腸（ｃｏｌｏｎ）と回腸（ｉｌｅｕｍ）の肥満細胞数は抑制された。また、皮膚（ｅａｒ）の肥満細胞数は増加しない。これらの結果、アレルギー性鼻炎は肥満細胞依存性ではないが、食物アレルギーは肥満細胞依存性であることがわかる。
また、ラマトロバン投与により、結腸の肥満細胞数は顕著に抑制された（図１０）。 Example 3
Changes in the number of mast cells in food allergy and the effect of ramatroban administration on the number of mast cells were investigated.
CRVA2-deficient mice were administered OVA in the same manner as in Example 1, and the number of mast cells in food allergy was measured. Moreover, the change of the number of mast cells by ramatroban administration (same as Example 2) was also examined.
As a result, as shown in FIG. 9, the number of mast cells in the colon and ileum was increased by food allergy, but the number of mast cells in the colon and ileum was suppressed in CRTH2 knockout mice. Also, the number of mast cells in the skin (ear) does not increase. These results show that allergic rhinitis is not mast cell-dependent, but food allergy is mast cell-dependent.
In addition, administration of ramatroban significantly suppressed the number of mast cells in the colon (FIG. 10).
食物アレルギーにおける肥満細胞数の変化及びラマトロバン投与による肥満細胞数に及ぼす作用を検討した。
ＣＲＴＨ２欠損マウスに実施例１と同様にＯＶＡ投与を行い、食物アレルギーにおける肥満細胞数を測定した。また、ラマトロバン投与（実施例２と同じ）による肥満細胞数の変化も検討した。
その結果、図９に示すように、食物アレルギーにより結腸及び回腸の肥満細胞数は増加するが、ＣＲＴＨ２ノックアウトマウスでは結腸（ｃｏｌｏｎ）と回腸（ｉｌｅｕｍ）の肥満細胞数は抑制された。また、皮膚（ｅａｒ）の肥満細胞数は増加しない。これらの結果、アレルギー性鼻炎は肥満細胞依存性ではないが、食物アレルギーは肥満細胞依存性であることがわかる。
また、ラマトロバン投与により、結腸の肥満細胞数は顕著に抑制された（図１０）。 Example 3
Changes in the number of mast cells in food allergy and the effect of ramatroban administration on the number of mast cells were investigated.
CRVA2-deficient mice were administered OVA in the same manner as in Example 1, and the number of mast cells in food allergy was measured. Moreover, the change of the number of mast cells by ramatroban administration (same as Example 2) was also examined.
As a result, as shown in FIG. 9, the number of mast cells in the colon and ileum was increased by food allergy, but the number of mast cells in the colon and ileum was suppressed in CRTH2 knockout mice. Also, the number of mast cells in the skin (ear) does not increase. These results show that allergic rhinitis is not mast cell-dependent, but food allergy is mast cell-dependent.
In addition, administration of ramatroban significantly suppressed the number of mast cells in the colon (FIG. 10).
実施例４
ＯＶＡ誘発性の食物アレルギーに対して、アレルギー性鼻炎治療薬として用いられている抗ヒスタミン剤（ジフェンヒドラミン）を投与し、結腸、回腸の肥満細胞数の変化、尿中ＰＧＤＭの変化を検討した。
その結果、図１１に示すように、抗ヒスタミン剤（H1-blocker）では、食物アレルギー症状を抑制せず（図１１Ａ）、肥満細胞数も減少せず（図１１Ｂ）、肥満細胞数の指標となる尿中ＰＧＤＭにも影響せず（図１１Ｃ）、炎症の指標となるＰＧＤＭに大きな変化を与えない（図１１Ｄ）。 Example 4
An antihistamine (diphenhydramine) used as a therapeutic agent for allergic rhinitis was administered to OVA-induced food allergies, and changes in the number of mast cells in the colon and ileum and changes in urinary PGDM were examined.
As a result, as shown in FIG. 11, the antihistamine (H 1 -blocker) does not suppress food allergy symptoms (FIG. 11A), does not decrease the number of mast cells (FIG. 11B), and is an index of the number of mast cells. It does not affect urinary PGDM (FIG. 11C) and does not significantly change PGDM as an index of inflammation (FIG. 11D).
ＯＶＡ誘発性の食物アレルギーに対して、アレルギー性鼻炎治療薬として用いられている抗ヒスタミン剤（ジフェンヒドラミン）を投与し、結腸、回腸の肥満細胞数の変化、尿中ＰＧＤＭの変化を検討した。
その結果、図１１に示すように、抗ヒスタミン剤（H1-blocker）では、食物アレルギー症状を抑制せず（図１１Ａ）、肥満細胞数も減少せず（図１１Ｂ）、肥満細胞数の指標となる尿中ＰＧＤＭにも影響せず（図１１Ｃ）、炎症の指標となるＰＧＤＭに大きな変化を与えない（図１１Ｄ）。 Example 4
An antihistamine (diphenhydramine) used as a therapeutic agent for allergic rhinitis was administered to OVA-induced food allergies, and changes in the number of mast cells in the colon and ileum and changes in urinary PGDM were examined.
As a result, as shown in FIG. 11, the antihistamine (H 1 -blocker) does not suppress food allergy symptoms (FIG. 11A), does not decrease the number of mast cells (FIG. 11B), and is an index of the number of mast cells. It does not affect urinary PGDM (FIG. 11C) and does not significantly change PGDM as an index of inflammation (FIG. 11D).
実施例５
（方法）
Ｂａｌｂ／ｃ系マウス（野生；ＣＲＴＨ２+/+）及び同種のＣＲＴＨ２-/-（ＣＲＴＨ２ノックアウトマウス）を用いて、ＯＶＡ特異的ＩｇＥの検討を行った。
抗原としてオボアルブミン（ＯＶＡ）を用いた。ＯＶＡ３００μgを１週間おきに２回皮下投与し、感作を行った。 Example 5
(Method)
Bala / c mice (wild; CRTH2 + / + ) and the same kind of CRTH2 − / − (CRTH2 knockout mice) were used to examine OVA-specific IgE.
Ovalbumin (OVA) was used as an antigen. Sensitization was performed by subcutaneously administering 300 μg of OVA twice every other week.
（方法）
Ｂａｌｂ／ｃ系マウス（野生；ＣＲＴＨ２+/+）及び同種のＣＲＴＨ２-/-（ＣＲＴＨ２ノックアウトマウス）を用いて、ＯＶＡ特異的ＩｇＥの検討を行った。
抗原としてオボアルブミン（ＯＶＡ）を用いた。ＯＶＡ３００μgを１週間おきに２回皮下投与し、感作を行った。 Example 5
(Method)
Bala / c mice (wild; CRTH2 + / + ) and the same kind of CRTH2 − / − (CRTH2 knockout mice) were used to examine OVA-specific IgE.
Ovalbumin (OVA) was used as an antigen. Sensitization was performed by subcutaneously administering 300 μg of OVA twice every other week.
ＯＶＡ最終皮下投与後の１週間後に、血清中のＯＶＡ特異的ＩｇＥ濃度を測定した。
その結果、図１２に示すように、野生種ではＯＶＡ特異的ＩｇＥが増加するのに対し、ＣＲＴＨ２ノックアウトマウスでＯＶＡ特異的ＩｇＥの産生抑制が観察された。 One week after the final subcutaneous administration of OVA, the concentration of OVA-specific IgE in the serum was measured.
As a result, as shown in FIG. 12, OVA-specific IgE increased in the wild type, whereas suppression of OVA-specific IgE production was observed in the CRTH2 knockout mouse.
その結果、図１２に示すように、野生種ではＯＶＡ特異的ＩｇＥが増加するのに対し、ＣＲＴＨ２ノックアウトマウスでＯＶＡ特異的ＩｇＥの産生抑制が観察された。 One week after the final subcutaneous administration of OVA, the concentration of OVA-specific IgE in the serum was measured.
As a result, as shown in FIG. 12, OVA-specific IgE increased in the wild type, whereas suppression of OVA-specific IgE production was observed in the CRTH2 knockout mouse.
Claims (20)
- ＣＲＴＨ２拮抗剤を有効成分とする、食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。 A food allergy allergen-specific IgE production inhibitor comprising a CRTH2 antagonist as an active ingredient.
- 食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである請求項１記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。 The food allergy allergen-specific IgE production inhibitor according to claim 1, wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
- ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である請求項１又は２記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。 The food allergen allergen-specific IgE production inhibitor according to claim 1 or 2, wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
- 請求項１～３のいずれか１項記載の食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤を含有する食物アレルギー治療薬。 A food allergy remedy comprising the food allergy allergen-specific IgE production inhibitor according to any one of claims 1 to 3.
- ＣＲＴＨ２拮抗剤を有効成分とする、食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制剤。 An inhibitor of an increase in the number of mast cells and / or mast cell activity in food allergy, comprising a CRTH2 antagonist as an active ingredient.
- 食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤製造のための、ＣＲＴＨ２拮抗剤の使用。 Use of a CRTH2 antagonist for the production of a food allergy allergen-specific IgE production inhibitor.
- 食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである請求項６記載の使用。 The use according to claim 6, wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
- ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である請求項６又は７記載の使用。 The use according to claim 6 or 7, wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
- ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤の、食物アレルギー治療薬製造のための使用。 Use of a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist for the production of a food allergy treatment.
- 食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制剤製造のための、ＣＲＴＨ２拮抗剤の使用。 Use of a CRTH2 antagonist for the production of an inhibitor of increased mast cell number and / or mast cell activity in food allergy.
- 食物アレルギーアレルゲン特異的ＩｇＥの産生を抑制するために用いる、ＣＲＴＨ２拮抗剤。 CRTH2 antagonist used to suppress the production of food allergen allergen-specific IgE.
- 食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである請求項１１記載のＣＲＴＨ２拮抗剤。 12. The CRTH2 antagonist according to claim 11, wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells, and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
- ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である請求項１１又は１２記載のＣＲＴＨ２拮抗剤。 The CRTH2 antagonist according to claim 11 or 12, wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
- 食物アレルギーを治療するために用いる、ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤。 A food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist, used to treat food allergies.
- 食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性を抑制するために用いる、ＣＲＴＨ２拮抗剤。 CRTH2 antagonist used for suppressing mast cell number increase and / or mast cell activity in food allergy.
- ＣＲＴＨ２拮抗剤の有効量を投与することを特徴とする、食物アレルギーアレルゲン特異的ＩｇＥ産生抑制方法。 A method for suppressing food allergy allergen-specific IgE production, comprising administering an effective amount of a CRTH2 antagonist.
- 食物アレルギーアレルゲン特異的ＩｇＥ産生抑制が、ＣＲＴＨ２拮抗剤による二次リンパ組織における樹状細胞、Ｔ細胞及びＢ細胞の会合抑制によるものである請求項１６記載の方法。 The method according to claim 16, wherein the suppression of food allergen allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist.
- ＣＲＴＨ２拮抗剤が、ラマトロバン及びＣＡＹ１０４７１から選ばれる成分である請求項１６又は１７記載の方法。 The method according to claim 16 or 17, wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
- ＣＲＴＨ２拮抗剤を含有する食物アレルギーアレルゲン特異的ＩｇＥ産生抑制剤の有効量を投与することを特徴とする、食物アレルギーの治療方法。 A method for treating food allergy, comprising administering an effective amount of a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist.
- ＣＲＴＨ２拮抗剤の有効量を投与することを特徴とする、食物アレルギーにおける肥満細胞数増加及び／又は肥満細胞活性の抑制方法。 A method for suppressing an increase in the number of mast cells and / or mast cell activity in food allergy, comprising administering an effective amount of a CRTH2 antagonist.
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| JP2010513224A (en) * | 2006-12-14 | 2010-04-30 | アステラス製薬株式会社 | Polycyclic acid compounds useful as CRTH2 antagonists and antiallergic agents |
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| US20110311483A1 (en) * | 2010-03-30 | 2011-12-22 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
| WO2012137885A1 (en) * | 2011-04-05 | 2012-10-11 | 学校法人 慶應義塾 | Agent for inhibiting or preventing renal interstitial fibrosis |
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| JP2010513224A (en) * | 2006-12-14 | 2010-04-30 | アステラス製薬株式会社 | Polycyclic acid compounds useful as CRTH2 antagonists and antiallergic agents |
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| JP2011503045A (en) * | 2007-11-13 | 2011-01-27 | オキサジェン リミテッド | Use of CRTH2 antagonistic compounds |
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