JP2012526151A - アリルプロピオン酸系ビタミンcステアレート、その調製方法及びそれらを含有する薬物 - Google Patents
アリルプロピオン酸系ビタミンcステアレート、その調製方法及びそれらを含有する薬物 Download PDFInfo
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- JP2012526151A JP2012526151A JP2012510092A JP2012510092A JP2012526151A JP 2012526151 A JP2012526151 A JP 2012526151A JP 2012510092 A JP2012510092 A JP 2012510092A JP 2012510092 A JP2012510092 A JP 2012510092A JP 2012526151 A JP2012526151 A JP 2012526151A
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- JP
- Japan
- Prior art keywords
- acid
- vitamin
- ibuprofen
- stearate
- ascorbic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 title claims abstract description 48
- 239000002253 acid Substances 0.000 title claims abstract description 23
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 229930003268 Vitamin C Natural products 0.000 title claims abstract description 14
- 239000011718 vitamin C Substances 0.000 title claims abstract description 14
- 235000019154 vitamin C Nutrition 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 17
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 title claims description 12
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- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 230000001754 anti-pyretic effect Effects 0.000 claims abstract description 8
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
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- 150000007513 acids Chemical class 0.000 abstract description 5
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- 230000008499 blood brain barrier function Effects 0.000 abstract description 4
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- 239000000730 antalgic agent Substances 0.000 abstract description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 abstract description 3
- 229960000991 ketoprofen Drugs 0.000 abstract description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 abstract description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 description 7
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Abstract
Description
元素微量分析:
計算値%:C: 62.64; H: 6.63
実測値%:C: 62.68; H: 6.69
構造確認の結果、得た生成物はL-アスコルビン酸-6-O-(S)-イブプロフェンエステルであった。その特徴の理化及び構造分析パラメータは:
m.p.145〜146℃
[α]D = +21.8°(c=0.00232g/ml,CH3OH)。0.1003g、50ml(c=0.00611g/ml,CH3OH)
IR(KBr,cm−1):3395.52,3222.26,3022.03,2954.93,2876.59,2954.93,2876.59,1761.60,1709.72,1665.92,1665.92,1510.01,1463.13,1382.85
1H NMR(400MHz,CD3OD):7.20(d,2H),7.11(d,2H),4.39(d,1H),4.12(t,2H),3.99(t,1H),3.75(t,1H),2.44(d,2H),1.82(t,1H),1.47(d,3H),0.88(t,6H)
13CNMR(400MHz,CD3OD):(ppm)18.8533(C8),22.8453,22.7906(C1+C1’),31.6083(C3),46.3302,46.1564(C9+C2),65.7436(C12),67.7221(C11),76.8915(C13),120.1202(C15),128.4167(C5+C5’),130.5936(C6+C6’),141.9723,139.4376(C7+C4),154.1888(C14),173.2871,176.1047(C10+C16)
MS(m/z):365.4(M+H+),363.3(M−1)。
融点:145〜146℃
元素微量分析:
計算値%:C: 62.64; H: 6.63
実測値%:C: 62.65; H: 6.70
[α]D = 0° (c =0.00611g/ml,CH3OH)
融点:165〜166℃
元素微量分析:
計算値%:C:64.07;H:4.88
実測値%:C:64.15;H:4.90
[α]D = +20.3° (c =0.00311g/ml,CH3OH)
融点:168〜169℃
元素微量分析:
計算値%:C: 62.36; H: 5.98
実測値%:C: 62.45; H: 6.13
[α]D = 0° (c =0.00231g/ml,CH3OH)
融点:198〜199℃
元素微量分析:
計算値%:C: 61.01; H: 4.63; N: 3.39
実測値%:C: 61.05; H: 4.73; N: 3.41
[α]D = 0° (c =0.00231g/ml,CH3OH)
融点:215〜216℃
元素微量分析:
計算値%:C: 61.85; H: 5.15
実測値%:C: 61.87; H: 5.18
[α]D = +18.5° (c =0.00511g/ml,CH3OH)
融点:218〜219℃
元素微量分析:
計算値%:C: 62.01; H: 6.06; N: 3.14
実測値%:C: 62.07; H: 6.10; N: 3.21
[α]D = 0° (c =0.00201g/ml,CH3OH)
連続撹拌する条件下で、0.05mol/LのL-アスコルビン酸-6-O-(S)-イブプロフェンエステル・メタノール溶液100mlを取って、等容積等モル濃度の水酸化ナトリウム・メタノール溶液と混合する。その後、回転蒸発装置において元の容積の1/3まで減圧濃縮を行い、4℃下で1夜放置し、ろ過を行い、標題の化合物を得る。測定結果、水におけるその溶解度が12.8gである。
正常ラット、メス・オスそれぞれ半分で、表1に基づいて群をランダムに分け、連続3日に胃管を用いてL-アスコルビン酸-6-O-(S)-イブプロフェンエステルナトリウム塩水溶液(pH7.4)及び空白対照群(等pH 生理食塩水)を強制投与する。最終回の投与後から1時間経過後に、8%抱水クロラール350mgkg−1を腹腔内注射して麻酔を行い、仰臥位に固定して、右側総頚動脈と左側外頚静脈とを分離する。
統計学処理:実験データはx±sで表示し、一元配置分散分析法で有意差があるか否かを判断する。tは空白対照群とL-アスコルビン酸-6-O-(S)-イブプロフェンエステルナトリウム塩との間のt検定結果を示す。
1000錠を調製するための処方:
L-アスコルビン酸-6-O-(S)-イブプロフェンエステル 300g
小麦澱粉 300g
ジャガイモ澱粉 300g
乳糖 1000g
ステアリン酸マグネシウム 50g
二酸化けい素 20g
ヒドロキシプロピルセルロース 30g
1000アンプルを調製するための処方:
L-アスコルビン酸-6-O-(S)-イブプロフェンエステルナトリウム 200g
乳糖 200g
Claims (10)
- L-アスコルビン酸-6-O-(S)-イブプロフェンエステル、L-アスコルビン酸-6-O-イブプロフェンエステルのラセミ混合物、またはそれと薬用可能な酸またはアルカリとの付加塩である、請求項1に記載の式(I)化合物。
- L-アスコルビン酸を基質として、リパーゼの触媒下で、特定の反応媒体において、他の基質である式(II)化合物を、以下の反応方程式に基づいてエステル化反応を行って、アリルプロピオン酸系ビタミンCステアレートを得る方法であって、
前記方法は、
(1)リパーゼを触媒として、特定の反応媒体において、L-アスコルビン酸の6−ヒドロキシル基を式(II)化合物とエステル化反応させて、L-アスコルビン酸の6-O-酸エステルを生成し、原料であるL-アスコルビン酸、式(II)化合物、及び反応生成物であるL−アスコルビン酸の6−O−酸エステル、並びに水によって構成される平衡混合物を得るステップと、
(2)該平衡混合物に対して分離抽出を行い、目的産物である式(I)化合物を得るステップと、
によって構成されることを特徴とする、請求項1に記載のアリルプロピオン酸系ビタミンCステアレートの調製方法。 - 前記リパーゼは、Novozym435、膵リパーゼなど市場から入手できる普通のリパーゼ品目であることを特徴とする、請求項3に記載の調製方法。
- 前記反応媒体は、アセトン、tert-ブタノール(2-メチル-2-プロパノール)、tert-アミルアルコール(2-メチル-2-ブタノール)、ヘキサン、カプリル、シクロヘキサン、ベンゼン、トルエン、キシレン、イオン液体、超臨界流体、またはリパーゼがそれにおいて該反応を触媒して行わせることができるその他のいずれかの液体もしくは流体であることを特徴とする、
請求項3に記載のアリルプロピオン酸系ビタミンCステアレートの調製方法。 - 前記エステル化反応は、反応システムが温度−30〜200℃、反応圧力0.0001〜0.5MPaの条件下で行われ、リパーゼ、触媒基質を利用して化学変化を発生して反応産物を生成するプロセスであることを特徴とする、
請求項3に記載のアリルプロピオン酸系ビタミンCステアレートの調製方法。 - 前記分離抽出は、リーチング、結晶化、カラムクロマトグラフィー、溶剤回収及び反応混合物から純物質を得るその他のいずれかの必要の操作プロセスであることを特徴とする、
請求項3に記載のアリルプロピオン酸系ビタミンCステアレートの調製方法。 - 前記分離抽出は、温度−30〜200℃、圧力0.0001〜3.5MPaの条件下で行われることを特徴とする、
請求項7に記載のアリルプロピオン酸系ビタミンCステアレートの調製方法。 - 活性成分としての、請求項1または2に記載の化合物の1種そのもの、または
前記化合物の1種そのものと、一または複数種の不活性かつ無毒の薬用可能な賦形剤または担体との組み合わせ
を含む、薬物組成物。 - 請求項1または2に記載の非ステロイド性抗炎症薬の少なくとも1種の活性成分を含み、
消炎、解熱、鎮痛、関節炎・月経痛・多発性硬化症・嚢胞性肺線維症・早産児動脈管開存症の治療、脳卒中・虚血性脳障害・アルツハイマー型認知症及び一部のガンの予防及び治療をするために用いられる、請求項9に記載の薬物組成物。
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JP2006510603A (ja) * | 2002-10-07 | 2006-03-30 | アンコール ファーマスーティカルズ インコーポレイテッド | R−非ステロイド性抗炎症薬エステル及びそれらの使用 |
WO2008017346A2 (de) * | 2006-08-11 | 2008-02-14 | Merck Patent Gmbh | Verwendung von ascorbinsäurederivaten zur funktionalisierung von matrices |
JP2009035509A (ja) * | 2007-08-01 | 2009-02-19 | Green Products Laboratory Ltd | アスコルビン酸エステル及びその合成方法 |
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US6924129B2 (en) * | 2002-10-23 | 2005-08-02 | Polytechnic University | Enzyme-catalyzed esterification of pendant carboxylic acid groups |
CN1629303A (zh) * | 2004-08-24 | 2005-06-22 | 魏嘉士 | L-抗坏血酸不饱和脂肪酸酯酶催合成方法 |
CN101080436B (zh) * | 2004-12-16 | 2010-09-22 | 陶氏康宁公司 | 抗坏血酸和2-酮酸糖的酯衍生物 |
CN101220119A (zh) * | 2008-01-23 | 2008-07-16 | 中国科学院化学研究所 | 一种超支化共聚物及其制备方法 |
CN101550119B (zh) | 2009-05-11 | 2012-05-30 | 无锡宏瑞生物医药科技有限公司 | 芳基(乙)丙酸抗坏血酸酯,其制备方法及含有它们的药物 |
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JP2006510603A (ja) * | 2002-10-07 | 2006-03-30 | アンコール ファーマスーティカルズ インコーポレイテッド | R−非ステロイド性抗炎症薬エステル及びそれらの使用 |
WO2008017346A2 (de) * | 2006-08-11 | 2008-02-14 | Merck Patent Gmbh | Verwendung von ascorbinsäurederivaten zur funktionalisierung von matrices |
JP2010505749A (ja) * | 2006-08-11 | 2010-02-25 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | マトリックスの官能化のためのアスコルビン酸誘導体の使用 |
JP2009035509A (ja) * | 2007-08-01 | 2009-02-19 | Green Products Laboratory Ltd | アスコルビン酸エステル及びその合成方法 |
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JPN6013040933; European Journal of Pharmaceutical Sciences 24, 2005, pp259-269 * |
JPN6013040936; Journal of Pharmaceutical Sciences 93(1), 2004, pp78-85 * |
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US20120115897A1 (en) | 2012-05-10 |
EP2431361A4 (en) | 2012-11-07 |
EP2431361A1 (en) | 2012-03-21 |
CN101550119B (zh) | 2012-05-30 |
US8703975B2 (en) | 2014-04-22 |
WO2010130139A1 (zh) | 2010-11-18 |
CN101550119A (zh) | 2009-10-07 |
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