JP2004292416A - Agent for prevention and treatment of allergic disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new agent for the prevention and treatment of allergic diseases, effectively acting at a low dose without causing side actions and capable of improving the pathologic conditions of the allergic diseases. <P>SOLUTION: This agent for the prevention and treatment of allergic diseases contains a chromanol glycoside expressed by formula (1) (R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each independently H or a lower alkyl; R<SP>5</SP>is H, a lower alkyl or a lower acyl; X is a monosaccharide residue or an oligosaccharide residue wherein the hydrogen atoms of hydroxy groups in the saccharide residue may be substituted with a lower alkyl group or a lower acyl group; (n) is an integer of 0-6; and (m) is an integer of 1-6). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【００１０】
（ただし、式中、Ｒ^１ 、Ｒ^２ 、Ｒ^３ およびＲ^４ は同一または異なる水素原子または低級アルキル基を表し、Ｒ^５ は水素原子、低級アルキル基または低級アシル基を表し、Ｘは糖残基中の水酸基の水素原子が低級アルキル基または低級アシル基で置換されていてもよい単糖残基またはオリゴ糖残基を表し、ｎは０〜６の整数であり、およびｍは１〜６の整数である）で表されるクロマノール配糖体を含有してなるアレルギー性疾患予防および治療剤である。
【００１１】
本発明はまた、前記クロマノール配糖体は２−（α−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オールである前記アレルギー性疾患予防および治療剤である。
【００１２】
本発明はさらに、水性製剤である前記アレルギー性疾患予防および治療剤である。
【００１３】
本発明はさらに、前記アレルギー性疾患は、Ｉ型アレルギーにかかるものである前記アレルギー性疾患予防および治療剤。
【００１４】
本発明はさらに、脱顆粒を抑制するものである前記アレルギー性疾患予防および治療剤。
【００１５】
本発明はさらに、前記アレルギー性疾患は、アレルギー性鼻炎、アレルギー性結膜炎気管支喘息、蕁麻疹またはアトピー性皮膚炎である前記アレルギー性疾患予防および治療剤。
【００１６】
【発明の実施の形態】
本発明のアレルギー性疾患予防および治療剤は、前記一般式（１）で表されるクロマノール配糖体を有効成分とすることを特徴とするものである。
【００１７】
前記一般式（１）において、Ｒ^１ 、Ｒ^２ 、Ｒ^３ 、Ｒ^４ およびＲ^５ の低級アルキル基としては、炭素原子数が１〜８、好ましくは１〜６の低級アルキル基がよく、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ペンチル基、イソペンチル基、ヘキシル基、ヘプチル基、オクチル基等が挙げられる。これらの中では、メチル基またはエチル基が好ましい。また、Ｒ^５ の低級アシル基としては、炭素原子数が１〜８、好ましくは１〜６の低級アシル基がよく、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基、ヘキサノイル基、ヘプタノイル基、オクタノイル等が挙げられる。これらの中では、アセチル基、プロピオニル基またはブチリル基が好ましい。また、Ｘの単糖残基としては、グルコース、ガラクトース、フコース、キシロース、マンノース、ラムノース、フルクトース、アラビノース、リキソース、リボース、アロース、アルトロース、イドース、タロース、デオキシリボース、２−デオキシリボース、キノボース、アベクオース等の糖残基が挙げられる。Ｘのオリゴ糖残基としては、上記単糖が２〜４個結合したもの、例えばマルトース、ラクトース、セロビオース、ラフィノース、キシロビオース、スクロースの糖残基等が挙げられる。これらの中ではグルコース、ガラクトース、フコース、キシロース、ラムノース、マンノース、フルクトース等の単糖残基が好ましい。また、Ｘの糖残基中の水酸基の水素原子は低級アルキル基、好ましくは炭素原子数が１〜８の低級アルキル基、または低級アシル基、好ましくは炭素原子数が１〜１０の低級アシル基で置換されていてもよい。さらに、ｎは０〜６、好ましくは１〜４の整数であり、ｍは１〜６、好ましくは１〜３の整数である。一般式（１）で表されるクロマノール配糖体の好ましい例としては、２−（α−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−ガラクトピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｌ−フコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（α−Ｌ−ラムノピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−キシロピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−フルクトフラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（α−Ｄ−マンノピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール等が挙げられる。
【００１８】
本発明に用いられるクロマノール配糖体は、例えば特開平７−１１８２８７号公報、特開平９−２４９６８８号公報、特開平１１−２１２９１号公報に記載の方法により、下記一般式（２）：
【００１９】
【化３】

【００２０】
（ただし、式中、Ｒ^１ ，Ｒ^２ ，Ｒ^３ 、Ｒ^４ 、Ｒ^５ およびｎは前記と同義である）で表される２−置換アルコールおよびオリゴ糖類を相当する糖転位作用を触媒する酵素の存在下に反応させ、２−置換アルコールの２位の水酸基に対して特異的に糖の特定の水酸基を結合させることからなる酵素反応によって製造される（酵素法）。
【００２１】
上記反応において原料として用いられる一般式（２）で表される２−置換アルコール（以下、単に「２−置換アルコール」という）は公知の物質であり、例えば、特公平１−４３７５５号公報や特公平１−４９１３５号公報等に開示された方法により得ることができる。また、例えば、一般式（２）中、Ｒ^１ 、Ｒ^２ 、Ｒ^３ およびＲ^４ がメチル基、Ｒ^５ が水素原子であり、ｎが１である２−置換アルコールは、α−トコフェロールのクロマン環の２位のフィチル基がカルボキシル基で置換された構造を有する６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸（商品名「トロロックス（Ｔｒｏｌｏｘ）」）を水素化リチウムアルミニウムの存在下においてジエチルエーテル中で加熱還流処理すること等により容易に得ることができる。
【００２２】
また、本発明に用いられるクロマノール配糖体は、特開平１１−２７９１９２号に記載の方法により、前記２−置換アルコールの６位の水酸基を保護基で保護したもの（以下「糖受容体」という）とアノマー位に脱離基を導入し他の水酸基を保護基で保護した糖の誘導体（以下、「糖供与体」という）とを縮合反応させることによっても製造できる（有機合成法）。
【００２３】
上記反応において使用される糖供与体糖供与体は、周知の方法により糖の全ての水酸基へ保護基を導入し、次いでアノマー位を脱離基に置換することにより容易に調製することができる。
【００２４】
上記酵素法または有機合成法により得られたクロマノール配糖体は、一般的に、極めて高い水溶性（約１００ｇ／１００ｍｌ）を有し、かつ油溶性にも富む（オクタノール／水系分配係数＞３）両親媒性分子である。いいかえると、本発明によるクロマノール配糖体は、高い脂質親和性を備えた水溶性ビタミンＥであるということができる。したがって、本発明によるクロマノール配糖体は、従来の水に不溶性あるいは貧溶性のビタミンＥ誘導体とは異なり、水に溶解して使用しても高い脂質親和性を保つので、細胞膜を透過しさらに細胞内にも入ることができ、アレルギー性疾患を飛躍的に改善する。また、上記反応により得られたクロマノール配糖体は、熱安定性およびｐＨ安定性に関してもトコフェロール、トロロックスまたは２−置換アルコールに比べて著しく向上するものである。
【００２５】
本発明のアレルギー性疾患予防および治療剤は、前記クロマノール配糖体を単体で、または錠剤、丸剤、散剤、粉剤、顆粒剤、シロップ剤、液剤、懸濁剤、乳剤、カプセル剤等として患者に経口投与できる。また、注射剤として静脈内、筋肉内、皮内、皮下、腹腔内、動脈内、脊髄腔内等に投与できる。さらに、点眼剤、点鼻剤、噴霧剤、吸入剤等として直接患部およびその周辺部位に局所的に投与することもできる。さらに、軟膏、クリーム、粉状もしくは液状塗布剤、貼付剤等の外用剤として経皮的に投与しても良い。上述したうち、好ましい製剤形態や投与形態等は、患者の年齢、性別、体質、症状、処置時期等に応じて、医師によって適宜選択される。
【００２６】
本剤を錠剤、丸剤、散剤、粉剤、顆粒剤等の固形製剤とする場合には、前記クロマノール配糖体を、常法に従って適当な添加剤、例えば、乳糖、ショ糖、マンニット、トウモロコシデンプン、合成もしくは天然ガム、結晶セルロース等の賦形剤、デンプン、セルロース誘導体、アラビアゴム、ゼラチン、ポリビニルピロリドン等の結合剤、カルボシキメチルセルーロースカルシウム、カルボシキメチルセルーロースナトリウム、デンプン、コーンスターチ、アルギン酸ナトリウム等の崩壊剤、タルク、ステアリン酸マグネシウム、ステアリン酸ナトリウム等の滑沢剤、炭酸カルシウム、炭酸ナトリウム、リン酸カルシウム、リン酸ナトリウム等の充填剤または希釈剤等と適宜混合して製造することができる。錠剤等は、必要に応じて適当な被覆用基剤を用いて、糖衣、ゼラチン、腸溶被覆、フイルムコーティング等を施しても良い。
【００２７】
本剤を注射剤、点眼剤、点鼻剤、吸入剤、噴霧剤、ローション剤、シロップ剤、液剤、懸濁剤、乳剤等の液状製剤とする場合には、前記クロマノール配糖体を、精製水、リン酸緩衝液等の適当な緩衝液、生理的食塩水、リンゲル溶液、ロック溶液等の生理的塩類溶液、カカオバター、ゴマ油、オリーブ油等の植物油、鉱油、高級アルコール、高級脂肪酸、エタノール等の有機溶媒等に溶解して、必要に応じてコレステロール等の乳化剤、アラビアゴム等の懸濁剤、分散助剤、浸潤剤、ポリオキシエチレン硬化ヒマシ油系、ポリエチレングリコール系等の界面活性剤、リン酸ナトリウム等の溶解補助剤、糖、糖アルコール、アルブミン等の安定化剤、パラベン等の保存剤、塩化ナトリウム、ブドウ糖、グリセリン等の等張化剤、緩衝剤、無痛化剤、吸着防止剤、保湿剤、酸化防止剤、着色剤、甘味料、フレーバー、芳香物質等を適宜添加することにより、滅菌された水溶液、非水溶液、懸濁液、リポソームまたはエマルジョン等として調整できる。この際、液状製剤は、生理学的なｐＨ、好ましくは６〜８の範囲内のｐＨを有することが好ましい。
【００２８】
本剤を、ローション剤、クリーム剤、軟膏等の半固形製剤とするには、前記クロマノール配糖体を脂肪、脂肪油、ラノリン、ワセリン、パラフィン、蝋、硬膏剤、樹脂、プラスチック、グリコール類、高級アルコール、グリセリン、水、乳化剤、懸濁化剤等と適宜混和することにより製造することができる。
【００２９】
本発明のアレルギー性疾患予防および治療剤に含まれるクロマノール配糖体の濃度は、投与形態、疾病の種類や重篤度や目的とする投与量などによって様々であるが、一般的には、原料の全質量に対して０．１〜１００質量％、好ましくは１〜９０質量％である。特に、本発明の製剤が経口投与される場合には、原料の全質量に対して１〜１００質量％、好ましくは５〜９０質量％であり、非経口投与される場合には、原料の全体積に対して０．１〜９０体積％、好ましくは１〜８０体積％であることが好ましい。この際、クロマノール配糖体の濃度が前記上限値を超えると過剰な投与量に見合った改善効果が得られず、前記下限値未満であると改善効果が十分に期待できずいずれも好ましくない。
【００３０】
本発明のアレルギー性疾患予防および治療剤の上記投与量は、患者の年齢、体重及び症状、目的とする投与形態や方法、治療効果、および処置期間等によって異なり、正確な量は医師により決定されるものであるが、通常、本剤が経口投与される場合には、クロマノール配糖体の投与量換算で、０．１〜１００００ｍｇ／ｋｇ体重／日の投与量の範囲であり、１日１〜３回に分けて投与される。この際、１日当たりの経口投与量が多い場合には、１回に複数個の錠剤等の製剤を投与してもよい。また、本発明のアレルギー性疾患予防および治療剤を非経口投与する場合には、クロマノール配糖体の投与量換算で、０．０１〜１０００ｍｇ／ｋｇ体重／日の投与量になるように１日１〜３回に分けて投与される。
【００３１】
本発明の抗アレルギー剤は、優れた脱顆粒抑制作用を有し、Ｉ型アレルギー反応による血管透過性亢進、平滑筋収縮、腺分泌亢進、血管拡張等の諸症状の発現を抑制し、および諸症状を改善する。従って、本発明の抗アレルギー剤は、Ｉ型アレルギー反応が関与する各疾患、例えば、アナフィラキシーショック、アレルギー性鼻炎、アレルギー性結膜炎、気管支喘息、蕁麻疹、アトピー性皮膚炎等の予防および治療に用いることができる。
【００３２】
【実施例】
本発明のアレルギー性疾患予防および治療剤の抗アレルギー作用を、以下に述べる薬理試験により確認した。
【００３３】
クロマノール配糖体として、特開平７−１１８２８７号公報の実施例１に記載の方法で製造した下記式（３）で示される２−（α−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール（ＴＭＧ）を用いた。
【００３４】
【化４】

【００３５】
試験結果は、平均値±標準誤差で示した。統計解析は、浜田らの方法（Ｈａｍａｄａ Ｃ． ｅｔ ａｌ， ”Ｔｒｅｅ−ｔｙｐｅ ａｌｇｏｒｉｔｈｍ ｆｏｒ ｓｔａｔｉｓｔｉｃａｌ ａｎａｌｙｓｉｓ ｉｎ ｃｈｒｏｎｉｃ ｔｏｘｉｃｉｔｙ ｓｔｕｄｉｅｓ．” Ｊ． Ｔｏｘｉｃｏｌ． Ｓｃｉ．，（１９９８） ２３： １７３−１８１）に従い、Ｂａｒｔｌｅｔｔの分散検定を行った後、Ｄｕｎｎｅｔｔの多重比較検定を用いた（図中、＊は危険率０．００１％以下で有意であることを示す）。
【００３６】
ｐＬＴ遊離抑制作用確認試験
松下らの方法（Ｎｏｂｕｔｏｓｈｉ Ｍａｔｓｕｓｈｉｔａ ｅｔ ａｌ．，”Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ ｓｔｕｄｉｅｓ ｏｎ ｔｈｅ ｎｏｖｅｌ ａｎｔｉａｌｌｅｒｇｉｃ ｄｒｕｇ ＨＱＬ−７９： ”． Ｅｌｕｃｉｄａｔｉｏｎ ｏｆ ｍｅｃｈａｎｉｓｍｓ ｆｏｒ ａｎｔｉａｌｌｅｒｇｉｃ ａｎｄ ａｎｔｉａｓｔｈｍａｔｉｃ ｅｆｆｅｃｔｓ．”， Ｊｐｎ．Ｊ． Ｐｈａｒｍａｃｏｌ． （１９９８） ７８： １１−２２）を応用してｐＬＴ（ｐｅｐｔｉｄｅ ｌｅｕｋｏｔｒｉｅｎｅ）の遊離抑制作用を確認した。
【００３７】
すなわち、Ｗｉｓｔｅｒ系雄性ラットより腹腔滲出肥満細胞を採取し、２×１０５ ／ｍｌに懸濁した。懸濁細胞を１μＭのＡ−２３１８７で刺激することにより、ｐＬＴ（ＬＴＣ_４ 、ＬＴＤ_４ 、ＬＴＥ_４ を含む）の遊離を促した。細胞懸濁液に被験薬を添加し、１０分間、３７℃でインキュベートした。次いでＡ−２３１８７を添加し、１０分後に反応液を氷上にとり急冷することにより反応を停止した。４℃で遠心し細胞上清を回収し、上清に含まれるｐＬＴ量測定した。結果を図１に示す。
【００３８】
ＴＭＧは、１００〜１０００μＭで肥満細胞からのｐＬＴの遊離を有意に抑制した（図１参照）。このことから、ＴＭＧは、Ｉ型アレルギー反応における肥満細胞からの脱顆粒抑制作用を有していることがわかった。
【００３９】
急性毒性試験
本発明のアレルギー性疾患予防および治療剤について急性毒性試験を行い、その安全性を確認した。４〜５週令のＩＣＲ系マウスを１群３匹として用い、クロマノール配糖体として上記と同じＴＭＧを５％アラビアゴム液に懸濁した後、ＴＭＧ換算で５００ｍｇ／ｋｇを経口投与して１週間観察した。この際、対照群として５％アラビアゴム液を０．３ｍｌ経口投与した。その結果、いずれの投与群においてもマウスの死亡例は認められなかった。
【００４０】
製剤例１
ＴＭＧ１００ｇ、乳糖８００ｇおよびトウモロコシデンプン１００ｇをブレンダーで混合して散剤を得た。
【００４１】
製剤例２
ＴＭＧ１００ｇ、乳糖４５０ｇおよび低置換度ヒドロキシプロピルセルロース１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液３５０ｇを加えて混練した。これを押出し造粒機を用いて造粒、乾燥して顆粒剤を得た。
【００４２】
製剤例３
ＴＭＧ１００ｇ、乳糖５５０ｇ、トウモロコシデンプン２１５ｇ、結晶セルロース１３０ｇおよびステアリン酸マグネシウム５ｇをブレンダーで混合した後、錠剤機で打錠して錠剤を得た。
【００４３】
製剤例４
ＴＭＧ１０ｇ、乳糖１１０ｇ、トウモロコシデンプン５８ｇおよびステアリン酸マグネシウム２ｇをＶ型混合機を用いて混合した後、３号カプセルに１８０ｍｇずつ充填してカプセル剤を得た。
【００４４】
製剤例５
ＴＭＧ２００ｍｇおよびグルコース１００ｍｇを精製水２ｍｌに溶解した後濾過し、濾液を２ｍｌアンプルに分注、封入した後滅菌して注射剤を得た。
【００４５】
製剤例６
ＴＭＧ１ｇ、エタノール３ｇ、ヒドロキシエチルセルロース０．２ｇおよびパラオキシ安息香酸メチル０．１ｇを精製水１００ｍｌに混合溶解してローション剤を得た。
【００４６】
【発明の効果】
上述したように、本発明のアレルギー性疾患予防および治療剤は、水溶性のクロマノール配糖体を有効成分とするので、アレルギー性疾患の病態を飛躍的に改善することができるとともに、副作用を伴わないので極めて安全に使用することができる。
【００４７】
また、本発明の本発明のアレルギー性疾患予防および治療剤は、高い水溶性を有するクロマノール配糖体を有効成分とするので、有効成分を高濃度で含有する水性製剤とすることができ、患部に局所的に投与したり、外用剤として患部に経皮的に投与することも可能であり、保存安定性が高いうえ、少用量で効果的に作用してアレルギー性疾患を予防および治療することができる。
【００４８】
本発明のアレルギー性疾患予防および治療剤は、優れたＩ型アレルギー抑制作用を有するので、Ｉ型アレルギーが関与する疾患、例えば、アナフィラキシーショック、アレルギー性鼻炎、アレルギー性結膜炎、気管支喘息、蕁麻疹、アトピー性皮膚炎等の予防および治療に用いた場合有用である。
【図面の簡単な説明】
【図１】ＴＭＧのｐＬＴ遊離抑制作用確認試験の結果を示すグラフである。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel agent for preventing and treating allergic diseases. More specifically, the present invention relates to a prophylactic and therapeutic agent for allergic diseases comprising a water-soluble chromanol glycoside as an active ingredient.
[0002]
[Prior art]
In recent years, allergic diseases have rapidly increased due to changes in living environment and dietary habits, and have become a social problem. In particular, hay fever in early spring and atopic dermatitis, which spreads from young people to adults, are sometimes accompanied by severe symptoms that hinder daily life. Asthma disease with an increasing prevalence is a fatal disease if it worsens.
[0003]
Allergies are classified into four types from type I to type IV according to their onset mechanism. Among them, type I allergy is caused by activation of IgE-sensitized mast cells due to reaction with an antigen to cause degranulation and release of chemical mediators such as histamine and leukotriene. Anaphylactic shock, topical allergic rhinitis, allergic conjunctivitis, bronchial asthma, urticaria, atopic dermatitis, etc. correspond to this. In order to prevent and treat such allergic diseases, it is necessary to suppress any of the steps of the above reaction, and various antiallergic agents have been developed and marketed from this point of view. None were satisfactory in terms of efficacy and side effects.
[0004]
On the other hand, the chromanol glycoside used in the present invention is a known compound (see Patent Document 1, Patent Document 2, and Patent Document 3). The chromanol glycoside is obtained by substituting the phytyl group at the 2-position of the chroman ring of α-tocopherol, which is a typical vitamin E, with an alcohol and further binding a sugar, and has high water solubility and excellent water solubility. Has antioxidant action. However, it is not known that the chromanol glycoside has an antiallergic effect and that it is used as an agent for preventing and treating allergic diseases.
[0005]
[Patent Document 1]
JP-A-7-118287 [Patent Document 2]
JP-A-9-249688 [Patent Document 3]
JP-A-11-21291
[Problems to be solved by the invention]
The present invention has been made in view of the above-mentioned problems of the related art, and an object of the present invention is to provide a prophylactic and therapeutic agent for allergic diseases having excellent antiallergic activity without side effects.
[0007]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on allergic diseases and found that the chromanol glycoside has an excellent antiallergic effect and is useful as an agent for preventing and treating allergic diseases. completed.
[0008]
That is, the present invention provides the following general formula (1)
[0009]
Embedded image

[0010]
(Wherein, R ¹ , R ² , R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups, R ⁵ represents a hydrogen atom, a lower alkyl group or a lower acyl group, and X represents a sugar residue. A hydrogen atom of a hydroxyl group in the group represents a monosaccharide residue or an oligosaccharide residue which may be substituted with a lower alkyl group or a lower acyl group, n is an integer of 0 to 6, and m is 1 to 6 Which is an integer of 2) which is a chromanol glycoside represented by the formula (1):
[0011]
The present invention is also the agent for preventing and treating allergic diseases, wherein the chromanol glycoside is 2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol.
[0012]
The present invention is further the above agent for preventing and treating allergic diseases, which is an aqueous preparation.
[0013]
The present invention further provides the preventive and therapeutic agent for an allergic disease, wherein the allergic disease involves type I allergy.
[0014]
The present invention further provides the preventive and therapeutic agent for an allergic disease, which suppresses degranulation.
[0015]
The present invention further provides the preventive and therapeutic agent for allergic disease, wherein the allergic disease is allergic rhinitis, allergic conjunctivitis, bronchial asthma, urticaria or atopic dermatitis.
[0016]
BEST MODE FOR CARRYING OUT THE INVENTION
The agent for preventing and treating allergic diseases according to the present invention is characterized by comprising a chromanol glycoside represented by the general formula (1) as an active ingredient.
[0017]
In the general formula (1), the lower alkyl group of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is preferably a lower alkyl group having 1 to 8, preferably 1 to 6 carbon atoms. , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, octyl and the like. Among them, a methyl group or an ethyl group is preferred. As the lower acyl group for R ^5, a lower acyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms is preferred, and examples thereof include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like. Among these, an acetyl group, a propionyl group or a butyryl group is preferred. Examples of the monosaccharide residue of X include glucose, galactose, fucose, xylose, mannose, rhamnose, fructose, arabinose, lyxose, ribose, allose, altrose, idose, talose, deoxyribose, 2-deoxyribose, quinobiose, Sugar residues such as avequose; Examples of the oligosaccharide residue of X include those in which 2 to 4 of the above-mentioned monosaccharides are bonded, for example, sugar residues of maltose, lactose, cellobiose, raffinose, xylobiose, and sucrose. Among them, monosaccharide residues such as glucose, galactose, fucose, xylose, rhamnose, mannose and fructose are preferred. Further, the hydrogen atom of the hydroxyl group in the sugar residue of X is a lower alkyl group, preferably a lower alkyl group having 1 to 8 carbon atoms, or a lower acyl group, preferably a lower acyl group having 1 to 10 carbon atoms. May be substituted. Further, n is an integer of 0 to 6, preferably 1 to 4, and m is an integer of 1 to 6, preferably 1 to 3. Preferred examples of the chromanol glycoside represented by the general formula (1) include 2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol and 2- (β -D-galactopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-L-fucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6 -Ol, 2- (α-L-rhamnopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-D-xylopyranosyl) methyl-2,5,7,8-tetra Methylchroman-6-ol, 2- (β-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-D-fructofuranosyl) methyl-2, 5,7,8-tetramethi Chroman-6-ol, 2- (α-D- mannopyranosyl) methyl-2,5,7,8-tetramethyl-chroman-6-ol, and the like.
[0018]
The chromanol glycoside used in the present invention can be prepared, for example, by the method described in JP-A-7-118287, JP-A-9-249688, or JP-A-11-21291, by the following general formula (2):
[0019]
Embedded image

[0020]
(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined above) and an enzyme that catalyzes a sugar translocation effect corresponding to a 2-substituted alcohol and an oligosaccharide. In the presence of a saccharide, and specifically produced by an enzymatic reaction comprising binding a specific hydroxyl group of a sugar to a hydroxyl group at the 2-position of a 2-substituted alcohol (enzymatic method).
[0021]
The 2-substituted alcohol represented by the general formula (2) (hereinafter, simply referred to as “2-substituted alcohol”) used as a raw material in the above reaction is a known substance. It can be obtained by a method disclosed in, for example, Japanese Patent Publication No. 1-49135. Further, for example, in the general formula (2), a 2-substituted alcohol in which R ¹ , R ² , R ³ and R ⁴ are a methyl group, R ⁵ is a hydrogen atom, and n is 1 is α-tocopherol chroman. 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid having a structure in which the phytyl group at the 2-position of the ring is substituted by a carboxyl group (trade name “Trolox”) is converted to hydrogen. It can be easily obtained by heating and refluxing in diethyl ether in the presence of lithium aluminum chloride.
[0022]
The chromanol glycoside used in the present invention is obtained by protecting the hydroxyl group at the 6-position of the 2-substituted alcohol with a protecting group by the method described in JP-A-11-279192 (hereinafter referred to as “sugar acceptor”). ) And a derivative of a saccharide in which a leaving group is introduced at the anomeric position and another hydroxyl group is protected with a protecting group (hereinafter, referred to as “sugar donor”).
[0023]
The sugar donor used in the above reaction can be easily prepared by introducing a protecting group into all the hydroxyl groups of the sugar by a well-known method, and then replacing the anomeric position with a leaving group.
[0024]
Chromanol glycosides obtained by the above-mentioned enzymatic method or organic synthesis method generally have extremely high water solubility (about 100 g / 100 ml) and are also highly oil-soluble (octanol / water-based partition coefficient> 3). It is an amphiphilic molecule. In other words, it can be said that the chromanol glycoside according to the present invention is a water-soluble vitamin E with high lipophilicity. Therefore, unlike conventional water-insoluble or poorly soluble vitamin E derivatives, the chromanol glycosides of the present invention maintain high lipophilicity even when used in water, so that they can penetrate cell membranes and It can get inside and dramatically improve allergic diseases. In addition, the chromanol glycoside obtained by the above-mentioned reaction has significantly improved thermal stability and pH stability as compared with tocopherol, trolox or 2-substituted alcohol.
[0025]
The agent for preventing and treating allergic diseases of the present invention comprises the above chromanol glycoside alone or as a tablet, pill, powder, powder, granule, syrup, solution, suspension, emulsion, capsule, etc. Can be administered orally. It can also be administered as an injection intravenously, intramuscularly, intradermally, subcutaneously, intraperitoneally, intraarterially, intrathecally, etc. Furthermore, it can also be locally administered directly to the affected area and surrounding areas as eye drops, nasal drops, sprays, inhalants and the like. Further, it may be transdermally administered as an external preparation such as an ointment, cream, powder or liquid application, patch or the like. Among the above, the preferred preparation form, administration form and the like are appropriately selected by a doctor according to the patient's age, gender, constitution, symptom, treatment time and the like.
[0026]
When the present preparation is made into a solid preparation such as tablets, pills, powders, powders, granules, etc., the chromanol glycoside is added to a suitable additive according to a conventional method, for example, lactose, sucrose, mannitol, corn. Excipients such as starch, synthetic or natural gum, crystalline cellulose, starch, cellulose derivatives, gum arabic, gelatin, binders such as polyvinylpyrrolidone, carboxymethyl cellulose cellulose, carboxymethyl cellulose sodium, starch, corn starch, It can be manufactured by appropriately mixing with a disintegrating agent such as sodium alginate, a lubricant such as talc, magnesium stearate, sodium stearate, a filler or a diluent such as calcium carbonate, sodium carbonate, calcium phosphate, and sodium phosphate. it can. Tablets and the like may be sugar-coated, gelatin, enteric-coated, film-coated or the like using an appropriate coating base as necessary.
[0027]
When the preparation is used as a liquid preparation such as an injection, an eye drop, a nasal drop, an inhalant, a spray, a lotion, a syrup, a liquid, a suspension, an emulsion, etc., the chromanol glycoside is purified. Water, suitable buffers such as phosphate buffer, physiological saline, Ringer's solution, physiological saline such as Rock's solution, cocoa butter, vegetable oil such as sesame oil, olive oil, mineral oil, higher alcohol, higher fatty acid, ethanol, etc. Dissolved in an organic solvent or the like, an emulsifier such as cholesterol as necessary, a suspending agent such as gum arabic, a dispersing aid, a wetting agent, a polyoxyethylene hydrogenated castor oil type, a surfactant such as a polyethylene glycol type, Solubilizing agents such as sodium phosphate, stabilizers such as sugar, sugar alcohol and albumin, preservatives such as paraben, isotonic agents such as sodium chloride, glucose, glycerin, buffers, soothing , Adsorption preventing agents, humectants, antioxidants, colorants, sweeteners, flavors, by appropriately adding aromatic substances and the like, can be adjusted sterile aqueous solution, non-aqueous solutions, suspensions, liposomes or emulsions, and the like. At this time, the liquid preparation preferably has a physiological pH, preferably a pH in the range of 6 to 8.
[0028]
In order to make the present agent into a semi-solid preparation such as a lotion, a cream and an ointment, the chromanol glycoside is prepared by converting the chromanol glycoside into fat, fatty oil, lanolin, petrolatum, paraffin, wax, plaster, resin, plastic, glycols, It can be produced by appropriately mixing with a higher alcohol, glycerin, water, an emulsifier, a suspending agent and the like.
[0029]
The concentration of the chromanol glycoside contained in the agent for preventing and treating allergic diseases of the present invention varies depending on the administration form, the type and severity of the disease, the intended dose, and the like. Is from 0.1 to 100% by mass, and preferably from 1 to 90% by mass, based on the total mass of the polymer. In particular, when the formulation of the present invention is administered orally, it is 1 to 100% by mass, preferably 5 to 90% by mass relative to the total mass of the raw material, and when administered parenterally, the total amount of the raw material is It is preferably from 0.1 to 90% by volume, preferably from 1 to 80% by volume, based on the product. At this time, if the concentration of the chromanol glycoside exceeds the upper limit, an improvement effect commensurate with the excessive dose cannot be obtained, and if the concentration is less than the lower limit, the improvement effect cannot be sufficiently expected, and neither is preferable.
[0030]
The above dosage of the agent for preventing and treating allergic diseases of the present invention varies depending on the age, weight and condition of the patient, the intended dosage form and method, the therapeutic effect, the treatment period, etc., and the exact amount is determined by a doctor. Usually, when the drug is orally administered, the dose is 0.1 to 10000 mg / kg body weight / day in terms of the dose of chromanol glycoside, and is 1 day / day.投 与 3 divided doses. At this time, when the daily oral dose is large, a plurality of preparations such as tablets may be administered at one time. When the prophylactic and therapeutic agent for an allergic disease of the present invention is administered parenterally, the amount of chromanol glycoside per day is adjusted to 0.01 to 1000 mg / kg body weight / day. It is administered in 1 to 3 divided doses.
[0031]
The antiallergic agent of the present invention has an excellent degranulation-inhibiting effect, suppresses the manifestation of various symptoms such as vascular hyperpermeability, smooth muscle contraction, increased gland secretion, and vasodilation due to type I allergic reaction, and Improve symptoms. Therefore, the antiallergic agent of the present invention is used for the prevention and treatment of various diseases associated with type I allergic reaction, for example, anaphylactic shock, allergic rhinitis, allergic conjunctivitis, bronchial asthma, urticaria, atopic dermatitis and the like. be able to.
[0032]
【Example】
The antiallergic activity of the preventive and therapeutic agents for allergic diseases of the present invention was confirmed by the following pharmacological tests.
[0033]
As a chromanol glycoside, 2- (α-D-glucopyranosyl) methyl-2,5,7,8 represented by the following formula (3) produced by the method described in Example 1 of JP-A-7-118287. -Tetramethylchroman-6-ol (TMG) was used.
[0034]
Embedded image

[0035]
The test results are shown as mean ± standard error. Statistical analysis was performed according to the method of Hamada et al. (Hamada C. et al., "Tree-type algorithm for statistical analysis in chronic toxicity studies." After performing the test, Dunnett's multiple comparison test was used (in the figure, * indicates that the significance is 0.001% or less).
[0036]
pLT release inhibiting effect confirmation test <br/> Matsushita et al's method (Nobutoshi Matsushita et al, "Pharmacological studies on the novel antiallergic drug HQL-79:"... Elucidation of mechanisms for antiallergic and antiasthmatic effects ", Jpn.J. Pharmacol. (1998) 78: 11-22) was applied to confirm the inhibitory action of pLT (peptide leukotriene) on release.
[0037]
That is, peritoneal exudate mast cells were collected from male Wister rats and suspended at 2 × 10 5 / ml. Stimulation of the suspended cells with 1 μM A-23187 stimulated the release of pLT (including LTC ₄ , LTD ₄ , LTE ₄ ). The test drug was added to the cell suspension and incubated at 37 ° C. for 10 minutes. Next, A-23187 was added, and after 10 minutes, the reaction solution was put on ice and rapidly cooled to stop the reaction. After centrifugation at 4 ° C., the cell supernatant was collected, and the amount of pLT contained in the supernatant was measured. The results are shown in FIG.
[0038]
TMG significantly suppressed the release of pLT from mast cells at 100-1000 μM (see FIG. 1). This indicates that TMG has an inhibitory effect on degranulation from mast cells in a type I allergic reaction.
[0039]
Acute toxicity test An acute toxicity test was performed for the preventive and therapeutic agents for allergic diseases of the present invention to confirm their safety. Using 4 to 5 week old ICR mice as a group, 3 mice were suspended in 5% gum arabic solution of the same TMG as a chromanol glycoside, and then 500 mg / kg in terms of TMG was orally administered. Observed for a week. At this time, 0.3 ml of a 5% gum arabic solution was orally administered as a control group. As a result, no death cases were observed in any of the administration groups.
[0040]
Formulation Example 1
A powder was obtained by mixing 100 g of TMG, 800 g of lactose and 100 g of corn starch with a blender.
[0041]
Formulation Example 2
After mixing 100 g of TMG, 450 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 350 g of a 10% aqueous solution of hydroxypropylcellulose was added and kneaded. This was granulated using an extruder and dried to obtain granules.
[0042]
Formulation Example 3
After 100 g of TMG, 550 g of lactose, 215 g of corn starch, 130 g of crystalline cellulose and 5 g of magnesium stearate were mixed with a blender, the mixture was tabletted with a tablet machine to obtain tablets.
[0043]
Formulation Example 4
TMG (10 g), lactose (110 g), corn starch (58 g), and magnesium stearate (2 g) were mixed using a V-type mixer, and the mixture was filled in No. 3 capsules by 180 mg to obtain capsules.
[0044]
Formulation Example 5
200 mg of TMG and 100 mg of glucose were dissolved in 2 ml of purified water and filtered, and the filtrate was dispensed into 2 ml ampules, sealed, and sterilized to obtain an injection.
[0045]
Formulation Example 6
A lotion was obtained by mixing and dissolving 1 g of TMG, 3 g of ethanol, 0.2 g of hydroxyethylcellulose, and 0.1 g of methyl paraoxybenzoate in 100 ml of purified water.
[0046]
【The invention's effect】
As described above, since the allergic disease preventive and therapeutic agent of the present invention contains a water-soluble chromanol glycoside as an active ingredient, it can dramatically improve the pathology of allergic disease and has side effects. It can be used very safely because there is no.
[0047]
In addition, since the allergic disease preventive and therapeutic agent of the present invention contains a highly water-soluble chromanol glycoside as an active ingredient, an aqueous preparation containing the active ingredient at a high concentration can be obtained. It can be administered topically to the skin, or it can be applied transdermally to the affected area as an external preparation, has high storage stability, and works effectively in small doses to prevent and treat allergic diseases. Can be.
[0048]
The preventive and therapeutic agent for allergic diseases of the present invention has an excellent type I allergy suppressing action, and therefore, diseases associated with type I allergy, such as anaphylactic shock, allergic rhinitis, allergic conjunctivitis, bronchial asthma, urticaria, It is useful when used for prevention and treatment of atopic dermatitis and the like.
[Brief description of the drawings]
FIG. 1 is a graph showing the results of a test for confirming the action of TMG to inhibit pLT release.

Claims (6)

The following general formula (1)

(Wherein, R ¹ , R ² , R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups, R ⁵ represents a hydrogen atom, a lower alkyl group or a lower acyl group, and X represents a sugar residue. A hydrogen atom of a hydroxyl group in the group represents a monosaccharide residue or an oligosaccharide residue which may be substituted with a lower alkyl group or a lower acyl group, n is an integer of 0 to 6, and m is 1 to 6 For preventing and treating allergic diseases, comprising a chromanol glycoside represented by the formula: The preventive and therapeutic agent for allergic diseases according to claim 1, wherein the chromanol glycoside is 2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol. The agent for preventing and treating allergic diseases according to claim 1 or 2, which is an aqueous preparation. The preventive and therapeutic agent for an allergic disease according to any one of claims 1 to 3, wherein the allergic disease involves type I allergy. The agent for preventing and treating allergic diseases according to any one of claims 1 to 4, which suppresses degranulation. The preventive and therapeutic agent for allergic disease according to any one of claims 1 to 5, wherein the allergic disease is allergic rhinitis, allergic conjunctivitis bronchial asthma, urticaria or atopic dermatitis.

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