JP2009184948A - ヒトアドレナリンβ3受容体アゴニスト剤、これを含む食品及び医薬品 - Google Patents
ヒトアドレナリンβ3受容体アゴニスト剤、これを含む食品及び医薬品 Download PDFInfo
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- JP2009184948A JP2009184948A JP2008025313A JP2008025313A JP2009184948A JP 2009184948 A JP2009184948 A JP 2009184948A JP 2008025313 A JP2008025313 A JP 2008025313A JP 2008025313 A JP2008025313 A JP 2008025313A JP 2009184948 A JP2009184948 A JP 2009184948A
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- receptor agonist
- human adrenergic
- adrenergic
- active ingredient
- alkyl
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Abstract
Description
本発明の他の目的は、上記ヒトアドレナリンβ3受容体アゴニスト剤を含む食品及び医薬品を提供することである。
本発明のさらに他の目的は、ヒトアドレナリンβ3受容体アゴニストを含有する、肥満、肥満症、糖尿病、高脂血症、高血圧症、痛風などの生活習慣病の予防及び/又は改善剤を提供することである。
本発明は以下の特定のインシステロール化合物を有効成分とするヒトアドレナリンβ3受容体アゴニスト剤、これを含有する食品及び医薬品を提供するものである。
2.下記の式(1’)又は(2’)で表される化合物、又はその薬学的に許容される塩を有効成分とするヒトアドレナリンβ3受容体アゴニスト剤。
3.下記の式(1”)で表される化合物、又はその薬学的に許容される塩を有効成分とするヒトアドレナリンβ3受容体アゴニスト剤。
4.茸の親水性溶媒抽出物を有効成分とするヒトアドレナリンβ3受容体アゴニスト剤。
5.親水性溶媒が、メチルアルコール、エチルアルコール、アセトン、又は非親水性溶媒が、酢酸エチル、クロロホルム及びこれらの2種以上の混合物からなる群から選ばれる上記4記載のヒトアドレナリンβ3受容体アゴニスト剤。
6.茸が、アガリクス、椎茸、エノキタケ、しめじ、舞茸、なめこ、ヒラタケ、クリタケからなる群から選ばれる少なくとも1種である上記4又は5記載のヒトアドレナリンβ3受容体アゴニスト剤。
7.上記1〜6のいずれか1項記載のヒトアドレナリンβ3受容体アゴニスト剤を含有する食品。
8.上記1〜6のいずれか1項記載のヒトアドレナリンβ3受容体アゴニスト剤を含有する医薬品。
植物キトサンは、担子菌類に濃厚なアルカリ溶液を加えるか、もしくは固形のアルカリと水を加えるかにより担子菌類を最終的に40%から60%のアルカリ溶液に浸し、液温が60℃〜120℃になるように1時間から24時間加熱する。加熱用の容器は、高温、高濃度のアルカリに耐えられるステンレス製のものが好ましい。
こうして最終的に精製された化合物は式(1’)においてXがOである化合物である。
なお式(1)においてXがOであり、R1がOHである化合物は下記式(1”)の構造異性体を有する。本発明の有効成分はこのような、構造異性体、その薬学的に許容される塩(例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、アルカリ土類金属塩、アミン塩、アンモニウム塩)、アミド、エステル(例えば、炭素数1〜10のアルキルエステル)も包含する。
例えば、本発明のアゴニスト剤を液剤の形態で使用するには、上記有効成分に、安息香酸ナトリウム、p−オキシ安息香酸メチル、デヒドロ酢酸ナトリウムなどの保存剤、リンゴ酸、アスコルビン酸、クエン酸、酢酸などの溶解補助剤、さらに着色剤、香料、風味剤、グルコース、マンニトールなどの甘味剤などを必要に応じて配合し、さらに蒸留水、生理食塩水などの希釈剤を必要に応じて加えて医薬品又は食品を調製する。
錠剤の形態に形成するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えば乳糖、マンニトール、白糖、塩化ナトリウム、ブドウ糖、澱粉、炭酸カルシウム、カオリン、結晶セルロースなどの賦形剤、蒸留水、生理食塩水、単シロップ、ブドウ糖液、澱粉液、ゼラチン溶液、カルボキシメチルセルロース、リン酸カリウム、ポリビニルピロリドンなどの結合剤、乾燥澱粉、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、澱粉、乳糖などの崩壊剤、白糖、ステアリン、カカオバター、水素添加油などの崩壊抑制剤、酢酸、アスコルビン酸、リンゴ酸などの溶解吸収促進剤、グリセリン、澱粉、乳糖、カオリン、ベントナイト、コロイド状硅酸などの吸着剤、精製タルク、ステアリン酸塩、ポリエチレングリコールなどの滑沢剤などがあげられる。さらに錠剤は、必要に応じて糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。
有効成分の含有量は特に限定されず広範囲に選択されるが、式(1)又は(2)の化合物として通常製剤中に0.001〜30質量%、好ましくは0.01〜10質量%含有させるのがよい。
投与量は特に限定されないが、用法、患者の年齢、性別、疾患の程度などの条件に応じて適宜選択すればよい。例えば、体重1kgに対して式(1)又は(2)の化合物が0.01〜20mg、好ましくは0.02〜10mgとなる量を一日1〜4回に分けて経口投与する。
本発明の有効成分を含有する食品は特に限定されないが、例えば、スープ、味噌汁、ドリンク、ゼリー、グミ等が挙げられる。これら食品中の有効成分の含有量は、好ましくは0.001〜30質量%、さらに好ましくは0.01〜10質量%である。
実施例1
キノコキトサンからアドレナリンβ3受容体結合活性物質(CHG-EW-4-1-4-P)の分離・精製
特開2005−29770の実施例1に記載された方法により製造したキノコキトサン 308.7 g にエタノール 2L を加えて一昼夜放置した後、20分間超音波をかけ、濾過した。濾液を減圧下濃縮し、エタノールエキス 8.6 gを得た。次に、エタノール抽出残査のキノコキトサンを、 50% アセトン 2L にて4日間浸漬した後、20分間超音波をかけて濾渦した。濾液を減圧下濃縮し 50% アセトン抽出エキス 8.7 g を得た。これらエタノールエキスと 50% アセトンエキスについて、アドレナリンβ3受容体結合活性試験を行ったところ、10μg/mLの濃度において、41% および 45% と、ほぼ同程度の活性が認められた。
そこで、この分画をシリカゲルカラムクロマトグラフィーに付し、n-へキサン:酢酸エチル= 4 : 1 (3 L)、2 : 1 (3.9 L)、1 : 1 (3.8 L)、酢酸エチル (3 L)、MeOH (3 L)にて順次溶出し、CHG-EW-4-1 (2.3 g)、 CHG-EW-4-2 (1.0 g)、CHG-EW-4-3 (0.9 g)、CHG-EW-4-4 (0.4 g)、CHG-EW-4-5 (3.9 g) の5分画を得た。これら分画の β3受容体結合活性試験においては、CHG-EW-4-1に最も高い活性(71% at 10μg/mL) が認められた。
そこで、CHG-EW-4-1 (500 mg) を 逆相HPLC (カラム:Kaseisorb, ODS PH super、20 x 250 mm、溶離液:95% MeOH、流速 6.0 mL/min)にて分離・精製し、11の分画に分離した。[ CHG-EW-4-1-1 (5.3 mg)、2&3 (20.1 mg)、4 (6.0 mg)、5 (20.1 mg)、6 (191.2 mg)、7 (78.2 mg)、8 (99.5 mg)、9 (21.2 mg)、10 (12.2 mg)、11 (8.4 mg) ]
これらの分画について活性試験を行った結果、2&3、4、6、8、9 の分画に、50% 以上の活性(阻害率)が見られた。これらの中、CHG-EW-4-1-4 をさらにHPLC(カラム:Kaseisorb, ODS PH super、10 x 250 mm、溶離液:90% MeOH、流速 2.0 mL/min、Rt:23.7 min) にて精製し、活性物質 (CHG-EW-4-1-4-P) を単離した。活性試験の結果を表1に示す。
CHG-EW-4-1-4-P
HR-FAB-MS : m/z 333.2429 (M+1)+, 332.2430 (calcd for C21H32O3).
1H-NMR (500 MHz, CDCl3, δ) : 0.61 (3H, s), 0.83 (3H, d, J=6.9 Hz), 0.84 (3H, d, J=6.9 Hz), 0.92 (3H, d, J=6.9 Hz), 1.04 (3H, d, J=6.6 Hz), 1.45-1.56 (4H, m), 1.62 (1H, ddd, J=13.4, 13.4, 4.3 Hz), 1.70-1.75 (1H, m), 1.84-1.92 (3H, m), 1.98 (1H, ddd, J=13.4, 4.6, 2.3Hz), 2.06 (1H, bdt, J=15.4, 6.6 Hz), 2.28 (1H, ddd, J=14.3, 4.0, 2.3Hz), 2.63-2.67 (1H, m), 5.17 (1H, dd, J=15.2, 7.7 Hz), 5.26 (1H, dd, J=15.2, 8.3 Hz), 5.62 (1H, d, J=1.8 Hz)、
13C-NMR (125 MHz, CDCl3, δ) : 11.8 (CH3), 17.6 (CH3), 19.7 (CH3), 20.0 (CH3), 21.0 (CH3), 21.4 (CH2), 28.8 (CH2), 33.1 (CH2), 35.1 (CH2), 35.3 (CH2), 40.1 (CH), 42.9 (CH), 48.9 (C), 50.4 (CH), 55.4 (CH), 104.8 (C), 112.3 (CH), 132.9 (CH), 134.7 (CH), 170.6 (C), 170.9 (C).
上記データから、上記物質は式(1’)においてXがOである4−ヒドロキシ−17−メチルインシステロール(9α‐ハイドロキシ‐1,2,3,4,5,10,19‐ヘプタノルエルゴスタ‐7,22‐ジエン‐6,9‐ラクトン:9α‐hydroxy‐1,2,3,4,5,10,19‐heptanor‐ergosta‐7,22‐diene‐6,9‐lactone)であることを確認した。
実施例1で製造した活性物質 (CHG-EW-4-1-4-P)10gに、リンゴ酸10g、アスコルビン酸10gを加えて1000mlの水に溶解し、凍結乾燥して水溶性キトサンを製造した。このものは純水に瞬時に溶解する特性を有する。この凍結乾燥物10gにマンニトール20g、乳糖50g、ポリデキストロース20gを加えて良く混合し、結着剤としてショ糖脂肪酸エステル2gを加えて錠剤を作った。
実施例1で製造した活性物質 (CHG-EW-4-1-4-P)1gをデキストリン100gに十分に分散させた後、これをデキストリン900gと混ぜ、流動層造粒により顆粒剤を作った。
実施例1で製造した活性物質 (CHG-EW-4-1-4-P)1gにアスコルビン酸10gを加えて500gの液糖に分散・溶解し、ゲル化剤0.1g、レモン香料0.1gと水500mlを加えて、プラスチック容器に充填し、冷却してゼリーを作った。
Claims (8)
- 茸の親水性溶媒又は非親水性溶媒抽出物を有効成分とするヒトアドレナリンβ3受容体アゴニスト剤。
- 親水性溶媒が、メチルアルコール、エチルアルコール、アセトン、非親水性溶媒が、酢酸エチル、クロロホルム及びこれらの2種以上の混合物からなる群から選ばれる請求項4記載のヒトアドレナリンβ3受容体アゴニスト剤。
- 茸が、アガリクス、椎茸、エノキタケ、しめじ、舞茸、なめこ、ヒラタケ、クリタケからなる群から選ばれる少なくとも1種である請求項4又は5記載のヒトアドレナリンβ3受容体アゴニスト剤。
- 請求項1〜6のいずれか1項記載のヒトアドレナリンβ3受容体アゴニスト剤を含有する食品。
- 請求項1〜6のいずれか1項記載のヒトアドレナリンβ3受容体アゴニスト剤を含有する医薬品。
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