JP5694149B2 - ベンゾトロポロン環含有化合物を含む抗肥満剤 - Google Patents
ベンゾトロポロン環含有化合物を含む抗肥満剤 Download PDFInfo
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- JP5694149B2 JP5694149B2 JP2011514458A JP2011514458A JP5694149B2 JP 5694149 B2 JP5694149 B2 JP 5694149B2 JP 2011514458 A JP2011514458 A JP 2011514458A JP 2011514458 A JP2011514458 A JP 2011514458A JP 5694149 B2 JP5694149 B2 JP 5694149B2
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 239000001717 vitis vinifera seed extract Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 235000015041 whisky Nutrition 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
- 229940002552 xenical Drugs 0.000 description 1
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Description
で表される化合物(ただしエピテアフラガリン、エピテアフラガリン−3−O−ガレート、テアフラビン、テアフラビン−3−O−ガレート、テアフラビン−3’−O−ガレート、およびテアフラビン−3,3’−O−ジガレートを除く)を1種以上含む抗肥満剤。
本発明は、式(1)
本発明の抗肥満剤は、食事からの脂肪分の摂取に伴う血中中性脂肪の望ましくない上昇を抑制する飲食料の形態であることができる。飲食料の好ましい例は、日常的に摂取する飲食料、例えば、緑茶、麦茶、ウーロン茶、紅茶、コーヒー、スポーツドリンク、飲料水、調味料、ドレッシングである。しかし飲食料は通常食するものであればよく、清涼飲料、カクテル、ビール、ウイスキー、焼酎、ワイン、清酒、調味料、ドレッシング、味付け米、加工食品、インスタント食品、レトルト食品、チョコレート、生クリーム、洋菓子、乳製品、健康食品、サプリメント等であってもよい。
本発明の抗肥満剤は、リパーゼ阻害剤として、食事由来の脂肪の吸収を抑制し、血中中性脂肪の望ましくない上昇を防止および/または低下させるための医薬組成物としても使用できる。また本発明の抗肥満剤は、α−グルコシダーゼ阻害剤として、食事由来の脂肪の吸収を抑制し、血中中性脂肪の望ましくない上昇を防止および/または低下させるための医薬組成物としても使用できる。好ましい薬剤は、経口投与される薬剤であり、その例として、ドリンク剤、錠剤、カプセル剤、顆粒剤、散剤、キャンデー、ドロップ剤等があげられる。薬剤には、式(1)で表されるベンゾトロポロン環含有化合物ベンゾトロポロン環含有化合物を、1回服用量当たり0.1mg〜10g、好ましくは0.5mg〜5gの量で含む。
さらに本発明は、紅茶の中に存在する新規化合物として、下に示す化合物を提供する。
インド・アッサム種の紅茶葉を90℃の熱水で抽出し凍結乾燥した物に、10mg/mlとなるように蒸留水を加え、加温溶解させた。湯浴中で60−70℃に加温しながら、15mlをセファデックスLH−20(GEヘルスケア バイオサイエンス(株)製)60mlに負荷した。20%アセトン(アセトン:蒸留水=2:8、v/v)45ml、ついで60ml(1カラム体積)で洗浄し、その後、30%アセトン(アセトン:蒸留水=3:7、v/v)、50%アセトン(アセトン:蒸留水=1:1、v/v)、60%アセトン(アセトン:蒸留水=6:4、v/v)、それぞれ4カラム体積分の溶媒で溶出し1カラム体積ずつ分画した。合計14のフラクション各60mlから2mlを採取し、減圧濃縮処理によって0.1mlに調製した50%ジメチルスルホキシド水溶液(ジメチルスルホキシド:蒸留水=1:1、v/v)をリパーゼ阻害活性測定に供した。また、各フラクションを、減圧濃縮、凍結乾燥し、得た固形分から回収量を算出し、実施例5の成分分析に用いた。重量およびリパーゼ阻害活性の回収率は表1に示した。
1.プルプロガリン(purprogallin)
2.プルプロガリンカルボン酸(purprogallin carboxylic acid)
3.エピテアフラガリン(epitheaflagallin)
4.エピテアフラガリン−3−O−ガレート(epitheaflagallin-3-O-gallate)
5.テアフラベートA(theaflavate A)
6.テアジベンゾトロポロンA(theadibenzotropolone A)
7.テアフラビンジガレート−トリマー1(TFdiGA-tri1)
8.テアフラビンジガレート−トリマー2(TFdiGA-tri2)
9.エピテアフラビン酸(epitheaflavic acid)
10.テアフラバニン(theaflavanin)
11.エピテアフラビン酸−3−O−ガレート(epitheaflavic acid-3-O-gallate)
12.(2R,3R)−2−(3,4−ジヒドロキシフェニル)−5,7−ジヒドロキシクロマン−3−イル2,3,4,6−テトラヒドロキシ−5−オキソ−5H−ベンゾ[7]アヌレン−8−カルボキシレート
エピガロカテキン(EGC;和光純薬株式会社製)または、エピガロカテキン−3−O-ガレート(EGCG;和光純薬株式会社製)0.2mmolにフェリシアン化カリウム、0.8mmolおよびNaHCO3、0.8mmolを加えた水溶液150mlを氷冷し、0.2mmolのピロガロールの水溶液50mlを滴下し、1時間撹拌を続けた。反応液を20ml容のSep-pak C18(ウォーターズ株式会社製)に負荷し、60mlの水洗いの後、5%アセトニトリル/水で洗浄し、0.1%ギ酸を含む50%アセトニトリル/水で反応生成物を溶出した。溶出物を凍結乾燥し、以下の分取HPLCで精製した。
実施例2で得られた化合物について、MSおよびNMR測定を行った。マススペクトルはQ−TOF Premier(Micromass社製、UK)により、イオン源にZスプレーイオンソースをつけたESIを用い、ネガティブ、Vモードで測定した。Cone voltage:45V Capillary voltage:3KV、Source Temp.:80℃、Desolvation Temp:180℃、ロックスプレーによる質量補正を行い、リファレンスにはロイシンエンケファリン(m/z554.2615[M−H]−)を用いた。
LC−MS/MSの測定は、4000 Q TRAP(アプライド社製)で、ターボイオンスプレーを用い、ネガティブモードで、以下の条件で測定した;Collision energy:46eV(nega.)、Ionspray voltage:4500V、温度:450℃。
流速:0.2mL/分
カラム温度:40℃
移動相A:0.1V/V%HCOOH/H2O
移動相B:0.1V/V%HCOOH/CH3CN
グラジエントプログラム:A/B=91/9(0分)→A/B=40/60(17分)→A/B=15/85(17.1分)→A/B=15/85(17.1分〜19分)
LC−MS/MSの測定は、Q−TOF Premier(Micromass社製、英国)で、イオン源にZスプレーイオンソースをつけたESIを用い、ネガティブ、Vモードで測定した。Cone voltage:33V、Capillary voltage:3KV、Source Temp:150℃、Desolvation Temp:250℃、ロックスプレーによる質量補正を行い、リファレンスにはロイシンエンケファリン(m/z554.2615[M−H]−)を用いた。
カラム:YMC-Polymer C18、S-6μm(株式会社ワイエムシー、2mmφ×150mm)
流速:0.2mL/分
カラム温度:40℃
移動相A:0.1V/V% HCOOH/H2O
移動相B:0.1V/V% HCOOH/CH3CN
グラジエントプログラム:A/B=70/30→A/B=50/50(20分)→A/B=50/50(25分)
測定サンプルは実施例2の方法に従い合成、精製した。
1.プルプロガリン(purprogallin)
2.プルプロガリンカルボン酸(purprogallin carboxylic acid)
5.テアフラベートA(theaflavate A)
6.テアジベンゾトロポロンA(theadibenzotropolone A)
7.テアフラビンジガレート−トリマー1(TFdiGA-tri1)
8.テアフラビンジガレート−トリマー2(TFdiGA-tri2)
9.エピテアフラビン酸(epitheaflavic acid)
10.テアフラバニン(theaflavanin)
11.エピテアフラビン酸−3−O−ガレート(epitheaflavic acid-3-O-gallate)
12.(2R,3R)−2−(3,4−ジヒドロキシフェニル)−5,7−ジヒドロキシクロマン−3−イル2,3,4,6−テトラヒドロキシ−5−オキソ−5H−ベンゾ[7]アヌレン−8−カルボキシレート
13.エピガロカテキンガレート(EGCG)(和光純薬株式会社製)
リパーゼ活性の測定は、基質に蛍光性の4−メチルウンベリフェロンのオレイン酸エステル(4−MUO;シグマ社製)を使用し、反応によって生成した4−メチルウンベリフェロンの蛍光を測定することにより実施した。測定にあたり、緩衝液は150mM NaCl、1.36mM CaCl2を含む13mM Tris−HCl(pH8.0)を用いた。基質である4−MUOは0.1MのDMSO溶液とした後に上記緩衝液で4000倍希釈したものを、また、リパーゼはブタ膵リパーゼ(シグマ社製)を同様に上記緩衝液を用いて400U/ml溶液として調製したものを酵素測定に供した。
化合物1〜2、および5〜14のリパーゼ阻害活性を表5に示した。
ペルオキシダーゼを用いた化合物12および 化合物14(テアフラバニン 3−O−ガレート)の合成
ペルオキシダーゼはZymed Laboratories製Horseradish Peroxidaseを用い、epicatechin 3-O-gallate(ECG)は茶抽出物より逆相HPLCで精製した純度90 % 以上のもの、ピロガロールはナカライテスク(株)製(純度99.0%)を使用した。
4.3 mgのHorseradish Peroxidaseを10 ml の0.058 M 酢酸バッファーに溶解し、アセトン500 μlに溶解したECG 250 mg(0.566 mmol)と、アセトン500 μlに溶解したPyrogallol 192.8 mg (1.53 mmol)を加え、攪拌し、30℃の条件下で、3%(w/v) 過酸化水素水を450 μl加え反応を開始した。反応の効率を上げる為、反応開始より10分後、20分後に二度にわたり3% 過酸化水素水を450 μl 追加した。反応開始より30分後に 192.8 mg (1.53 mmol)のPyrogallol と3% 過酸化水素水、450 μlを追加して、さらに30分間反応した。
実施例7で得られた化合物12および14について、MSおよびNMR測定を行った。
epigallocatechin−3−O-gallate(EGCG;和光純薬株式会社製)229.2mg(0.5mmol)にフェリシアン化カリウム(ナカライテスク製)、3.293g(10mmol)およびNaHCO3、0.84g(10mmol)を加えた水溶液400mlを氷冷し、275.3mg(2.5mmol)のcatecholの水溶液100mlを1時間かけて滴下し、撹拌を続けた。反応液を300mLのSephadex LH-20(GEヘルスケア バイオサイエンス(株)製)に負荷し、40%アセトン/水 1L、45%アセトン/水 1.2L、50%アセトン/水900mLで順次溶出し、凍結乾燥し、45%画分に77mgのEGCG−catecholを含む画分が得られた。以下の分取HPLCで精製した。
リパーゼ活性の測定は、基質に蛍光性の4−メチルウンベリフェロンのオレイン酸エステル(4−MUO;シグマ社製)を使用し、反応によって生成した4−メチルウンベリフェロンの蛍光を測定することにより実施した。測定にあたり、緩衝液は150mM NaCl、1.36mM CaCl2を含む13mM Tris−HCl(pH8.0)を用いた。基質である4−MUOは0.01MのDMSO溶液とした後に上記緩衝液で667倍希釈したものを、また、リパーゼはブタ膵リパーゼ(シグマ社製:Type VI-S )を同様に上記緩衝液を用いて400U/ml溶液として調製したものを酵素測定に供した。
1Mリン酸ナトリウム緩衝液は、0.1M NaH2PO4・2H2Oと0.1M Na2HPO4・12H2Oを混合しpH7.0に調整し、2g/Lの牛血清アルブミン(ナカライテスク株式会社製、F−V、pH5.2、純度96%)および0.2g/LのNaN3(ナカライテスク株式会社製、試薬特級)を添加した。酵素溶液は上記、緩衝液にα−グルコシダーゼ(和光純薬工業株式会社製、酵母由来、100units/mg)を0.5units/mgタンパク/ml(100μg/20ml)となるように溶解した。基質溶液は、上記、緩衝液にp−ニトロフェニル−α−D−グルコピラノシド(ナカライテスク株式会社製、試薬特級)を5mM(7.525mg/5ml)となるように溶解した。
Claims (7)
- リパーゼ阻害剤および/またはα−グルコシダーゼ阻害剤である、請求項1記載の抗肥満剤。
- 食事由来の脂肪および糖の吸収を抑制するための、請求項1または2記載の抗肥満剤。
- リパーゼ阻害剤および/またはα−グルコシダーゼ阻害剤である、請求項5記載の抗肥満剤。
- 食事由来の脂肪および糖の吸収を抑制するための、請求項5または6記載の抗肥満剤。
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JP5744507B2 (ja) * | 2010-12-24 | 2015-07-08 | 三井農林株式会社 | α−アミラーゼ阻害剤 |
JP2012184208A (ja) * | 2011-03-08 | 2012-09-27 | Mitsui Norin Co Ltd | シュクラーゼ阻害剤 |
CN105712997A (zh) * | 2014-12-02 | 2016-06-29 | 重庆宁牧生态农业有限公司 | 一种用作抗肥胖剂的化合物 |
CN105713000A (zh) * | 2014-12-02 | 2016-06-29 | 重庆宁牧生态农业有限公司 | 一种用作抗肥胖剂的化合物 |
CN105646510A (zh) * | 2014-12-02 | 2016-06-08 | 重庆宁牧生态农业有限公司 | 一种用作抗肥胖剂的化合物 |
JP6628970B2 (ja) * | 2015-03-09 | 2020-01-15 | サントリーホールディングス株式会社 | ベンゾトロポロン環含有化合物を定量する方法 |
WO2017079564A1 (en) | 2015-11-04 | 2017-05-11 | The Penn State Research Foundation | Compounds, compositions and methods for coloring edible materials |
CN109422785A (zh) * | 2017-08-22 | 2019-03-05 | 苏州凯祥生物科技有限公司 | 苯并卓酚酮类及其制备方法与用途 |
CN109422786A (zh) * | 2017-08-22 | 2019-03-05 | 苏州凯祥生物科技有限公司 | 苯并卓酚酮衍生物及其制备方法与用途 |
CN109422787A (zh) * | 2017-08-22 | 2019-03-05 | 苏州凯祥生物科技有限公司 | 苯并卓酚酮类似物及其制备方法与用途 |
CN109422714A (zh) * | 2017-08-22 | 2019-03-05 | 苏州禾研生物技术有限公司 | 苯并卓酚酮类化合物及其制备方法与用途 |
MX2021000635A (es) | 2018-07-16 | 2021-06-23 | Gregory Ray Ziegler | Compuestos, composiciones y metodos para dar color a materiales comestibles. |
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EP2433625B1 (en) | 2017-09-27 |
US20120065410A1 (en) | 2012-03-15 |
US9169231B2 (en) | 2015-10-27 |
ES2643463T3 (es) | 2017-11-23 |
TW201109018A (en) | 2011-03-16 |
KR101624006B1 (ko) | 2016-05-24 |
AU2010250330B2 (en) | 2014-03-06 |
JPWO2010134595A1 (ja) | 2012-11-12 |
JP2014237649A (ja) | 2014-12-18 |
US20150038573A1 (en) | 2015-02-05 |
CN102427807B (zh) | 2013-12-04 |
WO2010134595A1 (ja) | 2010-11-25 |
US8658237B2 (en) | 2014-02-25 |
EP2433625A1 (en) | 2012-03-28 |
JP5881780B2 (ja) | 2016-03-09 |
AU2010250330A1 (en) | 2011-12-22 |
US20140121388A1 (en) | 2014-05-01 |
EP2433625A4 (en) | 2012-10-31 |
CN102427807A (zh) | 2012-04-25 |
KR20120023814A (ko) | 2012-03-13 |
NZ596387A (en) | 2013-07-26 |
TWI483722B (zh) | 2015-05-11 |
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