JP2004002248A - Human-originated prostagrandin-synthesizing enzyme inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new human-originated prostagrandin D<SB>2</SB>-synthesizing enzyme inhibitor. <P>SOLUTION: This human-originated prostagrandin D<SB>2</SB>-synthesizing enzyme inhibitor contains 1-amino-4-(4-sulfamoylanilino)-anthraquinone-2-sulfonic acid (water-soluble red colorant) or 2-(2'-benzothiazolyl)-5-styryl-3-(4'-phthalhydradyl)tetrazonium chloride as an active ingredient. The inhibitor can control physiological actions such as sleep, body temperature, estrous cycle, analgesic or the sense of smell. <P>COPYRIGHT: (C)2004,JPO

Description

【化５】

ただし、式（Ｉ）中、Ａは、−Ｏ−、又は−ＣＯ−を、Ｒ^１は‐ＳＯ_２（ＯＨ）、−ＰＯ_３Ｈ若しくは−ＣＯＯＨ、またはそれらの塩（Ｎａ^＋，Ｋ^＋、ＮＨ_４ ^＋）を示し、Ｒ^２は−ＳＯ_２ＮＨ_２、−ＳＯ_２Ｎ（Ｒ^４）_２、ＣＯＮ（Ｒ^４）_２を示し、Ｒ^４は水素原子若しくは炭素数１〜６までのアルキル基を示す。Ｒ^１は２位または３位のいずれに存在してもよく、好ましくは２位に、Ｒ^２は、オルト、メタ、パラのいずれの位置に存在していてもよい。
また、式（ＩＩ）のＲ^３は
【化６】

を、また−ＮＨ−（ＣＨ_２）ｎ−ＮＨ−のｎは０、１又は２を示し、あるいはここで開環して−ＮＨ_２，ＮＨ_２−となっていてもよい。Ｒ^５，及びＲ^６は水素原子若しくは炭素数１から６までのアルキル基を示す。また、ＸはＩ⁻、Ｂｒ⁻、Ｃｌ⁻、Ｆ⁻、ＨＣｌＯ_４ ⁻、ＳＯ_４ ^２−、またはＰＯ_４ ^２−を示す。
また、本発明は、前記の化合物を含有するアレルギー予防乃至治療剤，性周期調節剤、睡眠調節剤、体温調節剤、鎮痛剤、臭覚調節剤に関する。さらに本発明はこれらの作用を有する保健乃至機能性飲食品に関する。
【０００７】
プロスタグランジンＰＧＤ_２は、末梢神経系において肥満細胞から炎症やアレルギーのメディエイターとして産出される。その生合成はＰＧＨ_２を基質として行われ、造血型のプロスタグランジンＰＧＤ合成酵素がＰＧＤ_２への異性化を担っている。近年、ＰＧＤ_２受容体を過剰発現させたマウスではアレルギー反応が促進されることが報告され（Ｆｕｊｉｔａｎｉ，Ｙ．，ｅｔ　ａｌ．　Ｊ．Ｉｍｍｕｎｏｌ，２００２）、また反対にＰＧＤ_２受容体のノックアウトマウスがアレルギー反応を示さないことも報告されている（Ｍａｔｓｕｏｋａ，　　Ｔ．ｅｔ　ａｌ．，　Ｓｃｉｅｎｃｅ，２０００）。このことからヒト由来のプロスタグランジンＤ_２合成酵素（Ｈ・ＰＧＤＳ）は、「抗アレルギー剤」または「鎮痛剤」を開発するターゲットタンパク質として注目され、次の化学式（ＩＩＩ）をもつ４−ベンズヒドリルオキシ−１−［３−（１Ｈ−テトラゾール−５−イル）−プロピル］ピペリジン（ＨＱＬ−７９）のラットＰＧＤＳ活性を阻害することが知られているが必ずしも十分な効果ではなかった。
【０００８】
【化７】

【０００９】
本発明者等はこのことに着目し、種々の化合物についてＨ・ＰＧＤＳ阻害活性を測定したところ阻害率が非常に高い化合物を見出し、本発明を完成するに至った。
【００１０】
すなわち、本発明は、前記一般式（Ｉ）または（ＩＩ）で表される化合物を有効成分とするプロスタグランジン合成酵素阻害剤に関する。
前記一般式で表される化合物のうち、次の化学式（ＩＶ）および（Ｖ）で表される化合物、すなわち１−アミノ−４−（４−スルファモイルアニリノ）−アントラキノン−２−スルホン酸（化合物式（ＩＶ）（水溶性の赤色色素））、２−（２’−ベンゾチアゾリル−５−スチリル−３−（４’−フタルヒドラジディル）テトラゾリウム塩化物（化合物式（Ｖ）（不溶性））がヒト由来プロスタグランジンＤ_２合成酵素を高い阻害率で阻害するので好ましく用いられる。
【００１１】
【化８】

【００１２】
【化９】

【００１３】
本発明において使用される化合物は、それ自体は、従来、色素等として知られていた公知化合物である。
本発明におけるこれらの化合物のヒト由来プロスタグランジンＤ_２合成酵素阻害活性を見出したものである。
【００１４】
【実施例】
次に本発明の実施例を示す。しかし、本発明は、実施例に限定して解釈されるべきではない。
【実施例１】
まず、本発明で使用する化合物のＰＧＤＳ活性を測定した。ＰＧＤＳ活性を測定するために表１に示すアッセイコポーネントを調製する。
【００１５】
【表１】

＊１）蒸留水で希釈
＊２）　　１ｍｇ／ｍｌのγＩｇＧで希釈
＊３）　　１０ｍＭの化合物式（Ｖ）、及び化合物式（ＩＶ）をそれぞれＤＭＳＯで調整、その後ｂｕｆｆｅｒで希釈（化合物式（Ｖ）はＳＩＧＭＡ・カタログコード：Ｂ８１３１、及び化合物式（ＩＶ）ＳＰＥＣＳ・カタログコード：ＡＨ―０３４／３２８５７０５９で市販品を購入して使用）
＊４）　　Ｄｉｅｔｈｙｌｅｎｅ　　ｇｌｙｃｏｌ　　ｄｉｅｔｈｙｌ　ｅｔｈｅｒで調整
【００１６】
測定方法は、次のとおりである。
［^１４Ｃ］ＰＧＨ_２以外を含んだ溶液を２５℃で５分間プレインキュベーションする。
１μｌの［^１４Ｃ］ＰＧＨ_２を加えてボルテックスし、反応を開始する。
２５℃、１分間反応させる。
２５０μｌのＳｔｏｐ　ｓｏｌｕｔｉｏｎ（エーテル：メタノール：１Ｍクエン酸＝３０：４：１）を加え、ボルテックスして、氷上に放置する。
硫酸ナトリウムをスパーテルで適量加えて水相部分を水和物にする。
上層（有機溶媒相）５０μｌをＴＬＣプレートにアプライし、展開（展開剤；エタノール：メタノール：酢酸＝９０：２：１）する。
プレートを乾燥後、イメージングプレートに露光する。
１時間〜ｏｖｅｒ　ｎｉｇｈｔ露光後、ＰＧＤ_２を定量する。この定量結果を図１に示す。
この図に基づいて、ＰＧＤ_２のバンドが１レーン中に占める％を算出した。この結果を表２に示す。
【００１７】
【表２】
──────────────────────────
ブランク　　　　　　　　　　９．４３
コントロール　　　　　　　　２９．６
化合物式（Ｖ）　　　　　　　　　　　　　　１５．６２
化合物式（ＩＶ）　　　　　　　　　　　　　１２．４５
──────────────────────────
このように、試料（薬物濃度）１０μＭにおいて、化合物式（Ｖ）は阻害率６９％、化合物式（ＩＶ）は阻害率８５％でプロスタグランジンＤ_２合成酵素を阻害する。
この結果を、ＨＱＬ−７９のＰＧＤ合成酵素阻害作用（蛋白質核酸酵素２０００年、ｖｏｌ．４５，Ｎｏ．６　３２０ｐ−３２４ｐ）と対比すると、ＨＱＬ−７９は薬物濃度１０μＭではＰＧＤ合成酵素阻害活性を全く示さず、１００μＭにおいて阻害率７５％を示したのに対し、化合物式（Ｖ）、及び化合物式（ＩＶ）ともに薬物濃度１０μＭでそれぞれ阻害率６９％、８５％という高い阻害活性を示した。
卵白アルブミンで能動感作したモルモットに抗原を反復吸入させて作製した喘息モデルを用いて好酸球浸潤作用を評価することもできる。
【００１８】
本発明における化合物をアレルギーの発症の予防あるいは治療に用いるときの投与量は、症状、年令、体重、性別等において異なるが、成人一人一日当り、１μｇ／ｋｇ〜１００ｍｇ／ｋｇを、好ましくは１０μｇ／ｋｇ〜１０ｍｇ／ｋｇを、さらに好ましくは５０μｇ／ｋｇ〜１ｍｇ／ｋｇを、経口あるいは非経口に投与するとよい。
このようにして投与すると、ヒトプロスタグランジンＤ_２合成酵素阻害作用を示し、アレルギーの発症防止あるいは発症した症状を低減することができる。さらに、睡眠調節、体温調節、性周期調節、鎮痛または臭覚調節等をすることができる。また、飲食品に添加する場合にも、成人一人当り一日に前記の量摂取できるように投与するとよい。その結果、アレルギーの発症を予防し発症したアレルギーを低減したり、前記の生理活性を奏することができる。
【００１９】
本発明における有効成分の化合物は、水などに溶解した形態、粉末化した形態、あるいはそのまま利用することが可能であり、製剤としてもよく、また飲食品、医薬などに適宜配合することができる。一般的には適当な液体担体に溶解するかもしくは分散させ、または、適当な粉末担体と混合するかもしくはこれに吸着させ、場合によっては、さらにこれらに乳化剤、分散剤、懸濁剤、展着剤、浸透剤、湿潤剤、安定剤などを添加し、乳剤、油剤、水和剤、散剤、錠剤、カプセル剤（ソフトカプセルを含む）、液剤などの製剤として使用する。化合物式（Ｖ）、及び化合物式（ＩＶ）は親水性が高く、このような場合には中長鎖脂肪酸トリグリセリド、若しくはごま油などの植物油のような油に超音波等で粉体のまま分散した状態でもしくは有機溶媒を用いて溶解させて服用させると良い。製剤として使用する場合における、化合物の使用量は製剤の形態によっても異なるが、０．０１重量％以上５０重量％以下が好ましく、この範囲において安全にヒト由来プロスタグランジンＤ_２合成酵素阻害作用を示し、アレルギーの発症を予防し、発症したアレルギーを治療することができる。さらに、睡眠調節、体温調節、性周期調節、鎮痛または臭覚調節等をすることができる。
【００２０】
本発明における有効成分をアレルギー症の予防乃至治療剤として用いる場合には、前記のように、製剤学的に許容することのできる担体を含有することができる。投与形態としては、特に限定がなく、例えば、散剤、細粒剤、顆粒剤、錠剤、カプセル剤、懸濁液、エマルジョン剤、シロップ剤、エキス剤、若しくは丸剤などの経口剤、又は注射剤、外用液剤、軟膏剤、坐剤、局所投与のクリーム、若しくは点眼薬などの非経口剤を挙げることができる。
これらのうち経口剤は、賦形剤、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、希釈剤、保存剤、着色剤、香料、安定化剤、保湿剤、防腐剤、又は酸化防止剤などを用いて、常法に従って製造することができる。非経口剤も同様に常法で製造することができ、その投与方法としては、筋肉注射、静脈注射、経皮投与、直腸投与などが例示される。
【００２１】
【実施例２】
化合物式（ＩＶ）３０ｇ及び大豆硬化油１００ｇをジャケット付き高速流動型混合機に仕込み、攪拌しながら７０℃に加温して大豆硬化油を溶融させた後、攪拌を続けた。これを攪拌下、５０℃に冷却して固化させ、整粒を行ってアレルギー発症予防（治療）剤を得た。これは花粉症の予防に１日３回１錠ずつ服用する。
【００２２】
【実施例３】
化合物式（Ｖ）２．５ｍｇ、デキストリン粉末１００ｍｇをゼラチンカプセルに充填してカプセル剤を得た。これは花粉症の予防に１日３回１カプセルずつ服用する。
【００２３】
【実施例４】
化合物ＩＶ　５０ｇをゴマ油２ｋｇに超音波で均一に分散し、ゴマ油懸濁液に高純度アルゴンガスをバブリングし、溶存酸素を除き、１カプセル中に５ｍｇの化合物ＩＶを含有するように　軟カプセル製造機を用いて常法により軟カプセル剤を製造した。
剤皮処方（最終形態における重量部）
ゼラチン　　　　　　　　　　　　　　１０重量部
グリセリン　　　　　　　　　　　　　　２
防腐剤（エチルパラベン）　０．０５
チタンホワイト　　　　　　　　０．２
水　　　　　　　　　　　　　　　０．２
【００２４】
【発明の効果】
本発明によると、ヒト由来プロスタグランジンＤ_２合成酵素を阻害することにより、ヒトで生ずるアレルギー反応を阻害し、アレルギーの発症を予防及び治療することができる。このような予防乃至治療できるアレルギー症として気管支喘息、アトピー性皮膚炎、アレルギー性鼻炎、結膜炎、花粉症などのＩ型アレルギーがある。また、本発明における化合物は、抗アレルギー剤開発のリード化合物として利用することもできる。さらに、本発明における化合物の摂取により、睡眠調節、体温調節、性周期調節，鎮痛、臭覚調節等を行うことができる。
【図面の簡単な説明】
【図１】本発明の実施例１のＴＬＣを示す。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel prostaglandin synthase inhibitors. The present invention also relates to an agent for preventing or treating allergies, a sleep regulator, a body temperature regulator, a sexual cycle regulator, an analgesic or an olfactory regulator utilizing the inhibitory action of the prostaglandin synthase. Further, the present invention relates to a health or functional food or drink capable of controlling allergy, controlling sleep, controlling body temperature, controlling estrous cycle, controlling pain or olfaction.
[0002]
[Prior art]
In recent years, allergic diseases have been rapidly increasing. For example, according to Miyamoto, “Clinical and Research; February 20, 2002 (Vol. 925)”, p. 189, the incidence of bronchial asthma in Japan was said to be around 1% of the total population for both children and adults. Is 4.5% for infants, 4-7% for children, and 3-4% for adults. In addition, hay fever, which was considered to be none or very rare even before the war, is considerably more than 10% of the population in some areas even if cedar hay fever alone is taken, and the incidence of allergic rhinitis including hay fever is included. Are 7.5% for infants, 24.6% for children, and 22.0% for adults, and it is said that the onset age tends to shift to younger people.
Genetic factors and environmental factors are involved in the onset of these allergic diseases, and specific various factors are mentioned.
[0003]
Allergic reactions have been classified by Coombs and Gel into types I, II, III and IV. Of these, it is said that the onset of bronchial asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, and the like involves a type I allergic reaction. Anti-allergic agents are used for the purpose of preventing this type I allergic reaction and preventing or treating allergy. Such anti-allergic agents, antihistamines, chemical mediator release inhibitors, leukotriene receptor antagonists, TXA ₂ synthesis inhibitors and receptor antagonists, Th ₂ cytokine inhibitors, and are used like immunosuppressants (“Clinical Studies”, Vol. 79, No. 2, pp. 30-33 (February 2002)).
However, many of these antiallergic agents have insufficient drug efficacy or have side effects, and there has been a demand for the development of an antiallergic agent having high drug efficacy and low side effects.
[0004]
[Problems to be solved by the invention]
The present invention was made under such circumstances, that inhibits human prostaglandin D ₂ synthase in low doses, providing little side effects human prostaglandin synthesis inhibitors Make it an issue.
It is also known that prostaglandin D ₂ induces sleep, lowers body temperature, suppresses progestin secretion, and regulates pain and odor responses in the central nervous system (Urade Y. et al., Vitamin Horm, 58, 89-120 (2000), Urade Y. et al., J. Biol. Chem., 260, 2140-2415 (1985), Urade Y. et al., Biochimica Biophysica Acta, 1482, 259-271 (2000)), prostaglandin substances which inhibit D ₂ synthase becomes physiopathology modifier from those surfaces.
Also, the present invention provides an antiallergic preventive or therapeutic agent containing such an inhibitor, a sexual cycle regulator, a sleep regulator, a body temperature regulator, an analgesic or an olfactory regulator or a health food or drink for those uses, It is intended to provide functional food and drink, fortified food and drink, and the like.
The present invention provides an antiallergic prophylactic or therapeutic agent or a sexual cycle regulator, a sleep regulator, a body temperature regulator, an analgesic, an olfactory regulator or the above-mentioned food or drink for use thereof, whereby allergy is obtained. An object of the present invention is to prevent the onset of sexual cycle abnormalities, sleep abnormalities, abnormal body temperature, pain, and abnormal olfaction, or to treat allergies, abnormal sexual cycle, abnormal sleep, abnormal body temperature, pain, and abnormal olfactory sensation.
[0005]
[Means for Solving the Problems]
That is, the present invention relates to a prostaglandin synthase inhibitor comprising a compound represented by the following general formula (I) or (II) as an active ingredient.
[0006]
Embedded image

Embedded image

In the formula (I), A represents —O— or —CO—, R ¹ represents —SO ₂ (OH), —PO ₃ H or —COOH, or a salt thereof (Na ⁺ , K ⁺ , NH ₄ ⁺ ), R ² represents —SO ₂ NH ₂ , —SO ₂ N (R ⁴ ) ₂ , CON (R ⁴ ) ₂ , and R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms Is shown. R ¹ may be in either the 2- or 3-position, preferably in the 2-position, R ² may be in any of the ortho, meta and para positions.
Further, R ³ in the formula (II) is

And n in —NH— (CH ₂ ) n —NH— represents 0, 1 or 2, or the ring may be opened to form —NH ₂ , NH ₂ —. R ⁵ and R ⁶ represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. X represents I ⁻ , Br ⁻ , Cl ⁻ , F ⁻ , HClO ₄ ⁻ , SO ₄ ²⁻ , or PO ₄ ²⁻ .
Further, the present invention relates to an agent for preventing or treating allergy, a sexual cycle regulator, a sleep regulator, a body temperature regulator, an analgesic, and an olfactory regulator containing the above compound. Furthermore, the present invention relates to health or functional food and drink having these effects.
[0007]
Prostaglandin PGD ₂ is produced from mast cells in the peripheral nervous system as a mediator of inflammation and allergy. Its biosynthesis is performed using PGH ₂ as a substrate, and hematopoietic prostaglandin PGD synthase is responsible for isomerization to PGD ₂ . In recent years, in mice overexpressing PGD ₂ receptor is reported that allergic reaction is accelerated (Fujitani, Y., et al. J.Immunol, 2002), also knockout mice of PGD ₂ receptors in the opposite It has also been reported that it does not show an allergic reaction (Matsuoka, T. et al., Science, 2000). Prostaglandin D ₂ synthase from human Therefore (H · PGDS) is attracting attention as a target protein for developing "anti-allergic agents" or "analgesic", with the following chemical formula (III) 4-benz It is known that hydryloxy-1- [3- (1H-tetrazol-5-yl) -propyl] piperidine (HQL-79) inhibits rat PGDS activity, but it was not always sufficient.
[0008]
Embedded image

[0009]
The present inventors have paid attention to this fact, and have measured H.PGDS inhibitory activity of various compounds. As a result, they have found compounds having a very high inhibition rate, and have completed the present invention.
[0010]
That is, the present invention relates to a prostaglandin synthase inhibitor comprising a compound represented by the above general formula (I) or (II) as an active ingredient.
Among the compounds represented by the general formula, compounds represented by the following chemical formulas (IV) and (V), namely, 1-amino-4- (4-sulfamoylanilino) -anthraquinone-2-sulfonic acid (Compound formula (IV) (water-soluble red dye)), 2- (2′-benzothiazolyl-5-styryl-3- (4′-phthalhydrazyl) tetrazolium chloride (compound formula (V) (insoluble) ) is preferably used because it inhibits a high inhibition rate of human-derived prostaglandin D ₂ synthase.
[0011]
Embedded image

[0012]
Embedded image

[0013]
The compound used in the present invention is a known compound which has been known as a dye or the like.
It has been found for the human prostaglandin D ₂ synthase inhibitory activity of these compounds in the present invention.
[0014]
【Example】
Next, examples of the present invention will be described. However, the present invention should not be construed as limited to the examples.
Embodiment 1
First, the PGDS activity of the compound used in the present invention was measured. Prepare the assay components shown in Table 1 for measuring PGDS activity.
[0015]
[Table 1]

* 1) Diluted with distilled water * 2) Diluted with 1 mg / ml γIgG * 3) Prepare 10 mM of compound formula (V) and compound formula (IV) with DMSO, and then dilute with buffer (compound formula (V) Is a SIGMA catalog code: B8131 and a compound of the formula (IV) SPECS catalog code: AH-034 / 32857059, which is purchased and used.)
* 4) Adjusted by Diethylene glycol diethyl ether
The measuring method is as follows.
^[14 C] PGH a solution containing ₂ except preincubated for 5 minutes at 25 ° C..
Add 1 μl [ ¹⁴ C] PGH ₂ and vortex to start the reaction.
Incubate at 25 ° C for 1 minute.
Add 250 μl of Stop solution (ether: methanol: 1M citric acid = 30: 4: 1), vortex and leave on ice.
The aqueous phase is hydrated by adding an appropriate amount of sodium sulfate with a spatula.
50 μl of the upper layer (organic solvent phase) is applied to a TLC plate and developed (developing agent; ethanol: methanol: acetic acid = 90: 2: 1).
After drying the plate, the imaging plate is exposed.
After 1 hour ～Over night exposure to quantify the PGD _2. FIG. 1 shows the results of the quantification.
Based on this figure, the band of PGD ₂ was calculated% occupied in one lane. Table 2 shows the results.
[0017]
[Table 2]
──────────────────────────
Blank 9.43
Control 29.6
Compound formula (V) 15.62
Compound formula (IV) 12.45
──────────────────────────
Thus, in the sample (drug concentration) 10 [mu] M, compound formula (V) inhibition rate of 69%, the compound formula (IV) inhibits prostaglandin _{D 2} synthase at 85% inhibition.
When this result is compared with the PGD synthase inhibitory activity of HQL-79 (Protein Nucleic Acid Enzyme 2000, vol. 45, No. 6 320p-324p), HQL-79 has no PGD synthase inhibitory activity at a drug concentration of 10 μM. Although not shown, the inhibitory rate was 75% at 100 μM, whereas the compound formulas (V) and (IV) both showed high inhibitory activities of 69% and 85% at the drug concentration of 10 μM, respectively.
Eosinophil infiltration can also be evaluated using an asthma model prepared by repeatedly inhaling antigens in guinea pigs actively sensitized with ovalbumin.
[0018]
The dose of the compound of the present invention for preventing or treating the onset of allergy varies depending on symptoms, age, body weight, sex, etc., but is preferably 1 μg / kg to 100 mg / kg, more preferably 10 μg, per adult per day. / Kg to 10 mg / kg, more preferably 50 μg / kg to 1 mg / kg, may be administered orally or parenterally.
When administered in this way to show the human prostaglandin D ₂ synthase inhibitory action, it is possible to reduce the onset prevent or onset symptoms of allergy. Furthermore, it can control sleep, regulate body temperature, regulate estrous cycle, regulate pain or smell. Also, when added to food or drink, it may be administered so that the above-mentioned amount can be ingested per adult per day. As a result, it is possible to prevent the onset of allergy and reduce the allergy that has developed or to exhibit the above-mentioned physiological activity.
[0019]
The compound of the active ingredient in the present invention can be used in a form dissolved in water or the like, a powdered form, or as it is, and may be used as a preparation, and may be appropriately compounded in foods and drinks, medicines and the like. It is generally dissolved or dispersed in a suitable liquid carrier, or mixed with or adsorbed on a suitable powdered carrier, optionally further containing an emulsifier, dispersant, suspending agent, spreading agent or the like. Agents, penetrants, wetting agents, stabilizers, etc., and used as formulations such as emulsions, oils, wettable powders, powders, tablets, capsules (including soft capsules), and liquids. The compound formula (V) and the compound formula (IV) have high hydrophilicity. In such a case, the compound is dispersed as a powder in an oil such as a vegetable oil such as medium- to long-chain fatty acid triglyceride or sesame oil by ultrasonic waves or the like. It is good to take in a state or by dissolving with an organic solvent. When used as the formulation, also differ depending on the form of usage formulations of compounds is preferably 50 wt% or less than 0.01 wt%, the safe human prostaglandin D ₂ synthase inhibitory activity in this range To prevent the onset of allergies and treat the onset allergies. Furthermore, it can control sleep, regulate body temperature, regulate estrous cycle, regulate pain or smell.
[0020]
When the active ingredient of the present invention is used as a preventive or therapeutic agent for allergy, it may contain a pharmaceutically acceptable carrier as described above. The administration form is not particularly limited. For example, oral preparations such as powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, or pills, or injections And parenteral preparations such as topical solutions, ointments, suppositories, creams for topical administration, and eye drops.
Of these, oral preparations include excipients, binders, disintegrants, surfactants, lubricants, fluidity enhancers, diluents, preservatives, coloring agents, fragrances, stabilizers, humectants, preservatives Or using an antioxidant or the like according to a conventional method. Parenteral preparations can also be produced in a conventional manner, and examples of the administration method include intramuscular injection, intravenous injection, transdermal administration, and rectal administration.
[0021]
Embodiment 2
30 g of the compound of formula (IV) and 100 g of hardened soybean oil were charged into a high-speed fluidized mixer equipped with a jacket, heated to 70 ° C. while stirring to melt the hardened soybean oil, and then stirring was continued. This was cooled to 50 ° C. under stirring and solidified, and sized to obtain an allergy prevention (treatment) agent. It is taken 1 tablet 3 times a day to prevent hay fever.
[0022]
Embodiment 3
Gelatin capsules were filled with 2.5 mg of the compound of formula (V) and 100 mg of dextrin powder to obtain capsules. It is taken 1 capsule 3 times a day to prevent hay fever.
[0023]
Embodiment 4
50 g of compound IV is uniformly dispersed in 2 kg of sesame oil by ultrasonic wave, high-purity argon gas is bubbled into the sesame oil suspension, and dissolved oxygen is removed so that 5 mg of compound IV is contained in one capsule. Was used to produce a soft capsule in a conventional manner.
Skin formulation (parts by weight in final form)
Gelatin 10 parts by weight glycerin 2
Preservative (ethyl paraben) 0.05
Titanium white 0.2
Water 0.2
[0024]
【The invention's effect】
According to the present invention, by inhibiting the human prostaglandin D ₂ synthase, it can inhibit allergic reactions occurring in humans to prevent and treat the development of allergy. Such allergic diseases that can be prevented or treated include type I allergy such as bronchial asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, and hay fever. Further, the compound of the present invention can also be used as a lead compound for the development of antiallergic agents. Furthermore, by taking the compound of the present invention, sleep regulation, body temperature regulation, estrous cycle regulation, analgesia, olfactory regulation and the like can be performed.
[Brief description of the drawings]
FIG. 1 shows a TLC of Example 1 of the present invention.

Claims (3)

Human prostaglandin D ₂ synthase inhibitor comprising as an active ingredient a compound represented by the following general formula (I) or (II).

In the formula (I), A represents —O— or —CO—, R ¹ represents —SO ₂ (OH), —PO ₃ H or —COOH, or a salt thereof (Na ⁺ , K ⁺ , NH ₄ ⁺ ), R ² represents —SO ₂ NH ₂ , —SO ₂ N (R ⁴ ) ₂ , CON (R ⁴ ) ₂ , CONH (R ⁴ ), and R ⁴ is a hydrogen atom or a carbon atom having 1 to 1 Shows up to 6 alkyl groups.
R ¹ may be in either the 2- or 3-position, preferably in the 2-position, R ² may be in any of the ortho, meta and para positions.
R ³ in the formula (II) is

Is shown. The _{-NH- (CH 2) n-NH-} n of represents 0, 1 or 2, or where ring opening _-NH 2, NH ₂ - indicates that may become. R ⁵ and R ^{6 each} represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. X represents I ⁻ , Br ⁻ , Cl ⁻ , F ⁻ , HClO ₄ ⁻ , SO ₄ ²⁻ , or PO ₄ ²⁻ . An agent for preventing or treating allergies, an agent for controlling estrous cycle, an agent for controlling sleep, an agent for controlling temperature, an agent for controlling pain, or an agent for controlling olfaction, comprising the compound of claim 1. A health food or drink, a functional food or drink, or an enriched food or drink having the compound of claim 1 and having an allergy preventive or therapeutic action, a sexual cycle control action, a sleep control action, a body temperature control action, an analgesic action or an odor control action.

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