JPWO2008016105A1 - 骨疾患の予防及び/又は治療用医薬組成物、その組成物を含有する機能性食品もしくは健康食品、並びにその組成物を有効成分とする医薬製剤 - Google Patents
骨疾患の予防及び/又は治療用医薬組成物、その組成物を含有する機能性食品もしくは健康食品、並びにその組成物を有効成分とする医薬製剤 Download PDFInfo
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- JPWO2008016105A1 JPWO2008016105A1 JP2008527787A JP2008527787A JPWO2008016105A1 JP WO2008016105 A1 JPWO2008016105 A1 JP WO2008016105A1 JP 2008527787 A JP2008527787 A JP 2008527787A JP 2008527787 A JP2008527787 A JP 2008527787A JP WO2008016105 A1 JPWO2008016105 A1 JP WO2008016105A1
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Abstract
Description
各種のスクリーニングの結果、生薬由来のジアリールヘプタノイド類化合物及びそれらの配糖体のうち、下記の一般式(I)で表されるものが、骨芽細胞の分化促進及び石灰化の促進という新たな活性を有することが明らかになった。
さらに、樹皮の部分には、葉にも含まれているα−アミリン、β−シトステロール及びその配糖体、スコポレチン、メチルヘマトメート(Methyl hematommate)、ロドデンドロール、アセロゲニン、カテキン、エピ−ロドデンドリン等が含まれる。
シラカンバ(Betula platyphylla)は、北海道(海抜0〜700m)及び岐阜県以東の本州(海抜700m〜1600m)に分布する落葉高木である。シラカンバからは、ロードデンドリン(rhododendrin、ベツロシド(betuloside)ともいうことがある)、アセロシドVII、アセロシドVIII、アセロゲニンE、(-)-ロードデンドロール、15-メトキシ-17-O-メチル-7-オキソアセロゲニンE、及びアセロゲニンK等が得られる。
ダケカンバ(Betula ermanii Cham.)は、国内では、北海道、中部以北の本州、四国に分布する、また、国外では、朝鮮半島、中国東北部、内蒙古、樺太、千島、カムチャツカに分布する。ダケカンバの材の内皮からは、アセロゲニンE((3R)-3,5'-ジヒドロキシ-4'-メトキシ-3',4”-オキソ-1,7-ジフェニル-1-ヘプテノン)等が得られる。また、ヤエガワカンバ(コオノオレ、Betula davurica Pall.)は、国内では、北海道、本州に、国外では、朝鮮、中国、ウスリー、アムール等に分布する。ヤエガワカンバの内皮からは、アセロゲニンE、17-O-メチル-7-オキソアセロゲニンE、15-メトキシ-17-O-メチル-7-オキソアセロゲニンE等が得られる。
特に、骨芽細胞の分化が促進されることにより骨形成が促進されるため、こうした骨疾患の発症を予防し、又は症状を緩和させる上で治療効果が高い。
本発明の第一の態様は、下記式(I)で表されるジアリールヘプタノイド化合物及びその類縁体からなる群から選ばれる少なくとも1種以上を有効成分として含有する、骨疾患の予防及び/又は治療用医薬組成物である。
アセロシドI、アセロシドB1、アセロゲニンA及び(R)−アセロゲニンBを、以下のようにして精製した。
(1−1)カラムクロマトグラフィー用抽出物の調製
メグスリノキの乾燥樹皮(450g)をn−ヘキサン 2.5Lにて3回抽出し、ろ過にて残渣を除去した。次いで、減圧下にてろ液の溶媒を留去し、n−ヘキサン抽出物(3.4g)を得た。n−ヘキサンで抽出し、ろ過した残渣をさらにメタノール 2.5Lにて3回抽出し、ろ過して残渣を除去した。ついで、減圧下にてろ液の溶媒を留去し、メタノール抽出物(63.6 g)を得た。
酢酸エチル相(25g)をシリカゲルカラムクロマトグラフィーに供し、グラジエント溶出用の溶離液を用いて、溶出を行った。溶離液としては、n−ヘキサン:酢酸エチルと酢酸エチル:メタノールとを用いた。最初に、n−ヘキサン:酢酸エチルを用いて、n−ヘキサン:酢酸エチル=1:0〜0:1まで、順次溶離液の極性を上げて溶出を行い、次いで、酢酸エチル:メタノールに代えて、酢酸エチル:メタノール=1:0〜0:1まで、順次溶媒の極性を上げて溶出を行った。
Fr.1〜9に分画し、Fr.9を、再度、シリカゲルカラムクロマトグラフィーに供した。溶離液として、酢酸エチル:メタノールを用い、酢酸エチル:メタノール=4:1〜0:1まで、順次、溶離液の極性を上げて溶出を行った。Fr.9-1〜9-5に分画した。
カラム:Pegasil ODS-II 10φ×250 mm
溶離液:MeCN:H2O=3:7
流 速:3.0mL/min
カラム:PEGASIL ODS-II 10φ×250 mm
溶離液:MeOH:H2O=65:35(AcOH 0.1%)
流速 3.0 mL/min
上記のようにして得られた各化合物及び配糖体は、各種スペクトルを文献値と比較することにより同定した。
HR-FAB-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(1)に記載のデータと対照し、同定した。
1H-NMR (400MHz, C5D5N) δ:1.00 (1H, m, 9-H), 1.12 (1H, m, 10-H), 1,26 (2H, m, 8,9-H), 1.39 (1H, m, 10-H), 1.50 (1H, m, 8-H), 1.71 (1H, m, 12-H), 2.13 (1H, m, 12-H), 2.42 (2H, m, 7-H2), 2.75 (1H, m, 13-H), 2.94 (1H, m, 13-H), 3.53 (1H, m, 11-H), 4.18 (1H, m, 5'-H), 4.43 (4H, m, 2',3',4',6'-H), 4.59 (1H, dd, J = 11.8, 1.7 Hz, 6'-H), 5.85 (1H, d, J = 6.6 Hz, 1'-H), 5.94 (1H, d, J = 1.0 Hz, 6-H), 6.69 (1H, dd, J = 8.0, 1.0 Hz, 4-H), 6.97 (1H, dd, J = 8.1, 2.2 Hz, 16-H or 18-H), 7.21 (1H, d, J = 3.7 Hz, 15-H or 19-H), 7.24 (1H, d, J = 2.2 Hz, 16-H or 18-H), 7.29 (1H, dd, J = 8.3, 1.7 Hz, 15-H or 19-H), 7.55 (1H, d, J = 8.3 Hz, 3-H).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(2)に記載のデータと対照し、同定した。
1H-NMR (400MHz, C5D5N) δ:0.86 (1H, m, 9-H), 1.08 (2H, m, 9,12-H), 1.22 (1H, m, 8-H), 1.43 (1H, m, 8-H), 1.54 (2H, m, 10,12-H), 2.36 (2H, m, 7,10-H), 2.50 (1H, m, 7-H), 2.87 (1H, m, 13-H), 3.14 (1H, m, 13-H), 3.57 (1H, m, 11-H), 4.02 (1H, m, 2'-H), 4.11 (2H, m, 4',5'-H), 4.14 (2H, s, 5''-H), 4.23 (2H, m, 3',6'-H), 4.35 (1H, d, J = 9.3 Hz, 4''-H), 4.60 (1H, d, J = 9.3 Hz, 4''-H), 4.77 (1H, d, J = 2.1 Hz, 2''-H), 4.80 (2H, m, 1',6'-H), 5.75 (1H, d, J = 2.4 Hz, 1''-H), 5.99 (1H, d, J = 2.1 Hz, 6-H), 6.72 (1H, dd, J = 7.9, 2.1 Hz, 4-H), 7.22 (3,16,18-H), 7.27 (1H, d, J = 7.9 Hz, 15-H or 19-H), 7.75 (1H, d, J = 8.2 Hz, 15-H or 19-H).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(3)に記載のデータと対照し、同定した。
1H-NMR (400 MHz, C5D5N) δ:0.96 (1H, m, H-10), 1.18 (1H, m, H-11), 1.48 (3H, m, H-10,11 and 12), 1.66 (1H, m, H-8), 1.68 (1H, m, H-12), 1.73 (1H, m, H-8), 2.48 (1H, m, H-13), 2.64 (1H, m, H-13), 2.69 (1H, m, H-7), 2.99 (1H, m, H-7), 5.82 (1H, d, J = 4.4 Hz, H-1'), 6.73 (1H, d, J = 8.1 Hz, H-4), 6.91 (1H, d, J = 8.3 Hz, H-16 or 18), 7.11 (1H, d, J = 8.3 Hz, H-15 or 18), 7.54 (1H, d, J = 8.3 Hz, H-3).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(1)に記載のデータと対照し、同定した。
1H-NMR (400 MHz, C5D5N) δ:1.01 (1H, m, H-9), 1.13 (1H, m, H-10), 1.28 (2H, m, H-8 and 9), 1.40 (1H, m, H-10), 1.53 (1H, m, H-8), 1.72 (1H, m, H-12), 2.14 (1H, m, H-12), 2.47 (2H, m, H2-7), 2.76 (1H, m, H-13), 2.95 (1H, m, H-13), 3.54 (1H, m, H-11), 5.97 (1H, d, J = 2.0 Hz, H-6), 6.75 (1H, dd, J = 8.1, 2.0 Hz, H-4).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(3)に記載のデータと対照し、同定した。
1H-NMR (400 MHz, C5D5N) δ:0.79 (1H, m, H-10), 1.00 (1H, m, H-11), 1.23 (1H, m, H-10), 1.30 (1H, m, H-11), 1.50 (2H, m, H2-8), 1.53 (1H, m, H-12), 1.76 (1H, m, H-12), 2.57 (1H, m, H-7), 2.63 (2H, m, H-7 and 13), 2.80 (1H, m, H-13), 3.07 (1H, m, H-9), 5.57 (1H, d, J = 1.8 Hz, H-6), 6.63 (1H, dd, J = 8.2, 1.8 Hz, H-4), 6.84 (1H, d, J = 8.2 Hz, H-3), 6.93 (1H, dd, J = 2.5, 8.2 Hz, H-16 or 18), 7.13 (1H, dd, J = 2.5, 8.2 Hz, H-18 or 16), 7.23 (1H, dd, J = 2.1, 8.2 Hz, H-15 or 19), 7.30 (1H, dd, J = 2.1, 8.2 Hz, H-19 or 15).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(4)に記載のデータと対照し、同定した。
1H-NMR (400MHz, C5D5N) δ:1.45 (1H, m, 11-H), 1.74-1.83 (2H, m, 11, 12-H), 1.90 (1H, m, 10-H), 1.95-2.10 (3H, m, 8,10,12-H), 2.46 (1H, m, 8-H), 2.51 (1H, m, 13-H), 2.88 (1H, d, J = 16.8 Hz, 13-H), 3.00 (1H, d, J = 17.1 Hz), 3.34 (1H, m, 7-H), 4.49 (1H, t, J = 9.5 Hz, 9-H), 7.13-7.22 (4H, m, 4,5,15,16-H), 7.48 (1H, br.s, 18-H), 7.6 (br.s, 19-H: overlapped with solvent signal).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(5)に記載のデータと対照し、同定した。
1H-NMR (600 MHz, C5D5N) δ:1.58 (1H, m, 5-H), 1.68 (2H, m, 4 and 6-H), 1.72 (3H, m, 4, 5 and 6-H), 1.98 (2H, m, 2-H2), 2.61 (2H, m, 7-H2), 2.89 (1H, m, 1-H), 3.04 (1H, m, 1-H), 3.88 (1H, br.d, J = 3.8 Hz, 3-H), 7.16 (2H, d, J = 8.6 Hz, 3'' and 5''-H), 7.18 (2H, d, J = 8.6 Hz, 3' and 5'-H), 7.19 (2H, d, J = 8.9 Hz, 2'' and 3''-H), 7.29 (2H, d, J = 8.2 Hz, 2' and 6'-H), 13C-NMR (150MHz, C5D5N) δ26.0 (5-C), 31.9 (1-C), 32.5 (6-C), 35.5 (7-C), 38.4 (4-C), 40.8 (2-C), 70.3 (3-C), 116.2 (3' and 5'-C or 3'' and 5''-C), 116.3 (3'' and 5''-C or 3' and 5'-C), 129.9 (2' and 6'-C or 2'' and 6''-C), 130.3 (2'' and 6''-C or 2' and 6'-C), 133.5 (1''-C), 133.8 (1'-C), 157.0 (4' and 4''-C).
ESI-MS及び1H-NMR (400MHz, C5D5N)による分析で得られたスペクトルデータを、参考文献(6)に記載のデータと対照し、同定した。
(1) M. Nagai, M. Kubo, M. Fujita, T. Inoue and M. Matsuo, Studies on the Constituents of Aceraceae Plants. II. Structure of Aceroside I, a Glucoside of a Novel Cyclic Diarylheptanoid from Acer nikoense Maxim., Chem. Pharm. Bull., 26, 2805-2810 (1978).
(1)試薬等
アセロシドI、アセロシドB1、アセロゲニンA及び(R)−アセロゲニンBは、上記のようにして精製し、同定したものを使用した。MC3T3-E1細胞(マウス前骨芽細胞株)は、RIKEN Cell Bankより購入した。アスコルビン酸、β−グリセロリン酸、塩化マグネシウムは、SIGMA社より購入した。また、α−MEMは、INVITROGEN社(カタログ番号11900-024)より購入した。96ウェルマイクロプレート及び100mmφディッシュは、Nunc社(カタログ番号161093、同172958)より購入した。
マウス前骨芽細胞株であるMC3T3-E1細胞をα−MEMに縣濁して96ウェルマイクロプレートの各ウェルに、4×103cells/wellとなるようにまき、37℃、5%CO2インキュベータ中にて2日間前培養した。前培養開始3日目に、各濃度の試験サンプルと、50μg/mlアスコルビン酸及び10mMのβ−グリセロリン酸を含むα−MEMに培地を交換して7日間から21日間、本培養した。また、本培養中も、3〜4日ごとに培地を交換した。
骨芽細胞の石灰化は、アリザリンレッドS染色にて確認した。
細胞毒性は上記(2)と同じ条件でMC3T3-E1細胞を培養した後、セルカウンティングキット−8又はMTTを用いて定法により測定した。結果を図2A〜Dに示す。
図2A及びCに示すように、アセロシドI及びアセロゲニンAを添加しても、細胞数にはほとんど影響は見られなかったが、高濃度になるとわずかに細胞数が減少する傾向が見られた。これは、骨芽細胞の分化が促進された結果、細胞の増殖が抑制されたものであり、細胞毒性によるものではないと考えられた。
骨芽細胞によるカルシウムの石灰化に対する上記4種類の化合物及び配糖体の効果を、図5に示す。図5に示されるように、コントロールではアリザリンレッドSによっても、ほとんど染色されなかった。一方、上記の化合物及び配糖体で処理を行うと、顕著な染色が認められ、これらは骨芽細胞分化を促進してカルシウムの石灰化も亢進させることが示された。
なお、染色を行ったときの染色の濃さにより、これらによるこのカルシウムの石灰化の亢進は、濃度依存的な傾向があることが示された。
(1)試薬等
ダルベッコ変法リン酸緩衝生理食塩水(Dulbecco's phosphate buffered saline, 以下「D-PBS」ということがある。)は、大日本製薬(株)より購入した。Affi-Gelアガロースビーズ(アフィゲルヘパリン カタログ番号:15306173)は、BioRad社より購入した。
生後5日齢のC57BL/6マウスは、三協ラボサービス(株)より購入した。また、ホストマウスとしては、成体マウスの器官において、腎臓及び前眼房は免疫応答の非常に少ない組織であることが知られており、前記移植培養実験においては特にヌードマウスを用いる必要はないため、三協ラボサービス(株)より購入した生後10〜15週齢のC57BL/6マウス(雌)を2匹一群として使用した。
アセロゲニンAを含浸させたアガロースビーズ(以下、「アセロゲニンA含浸ビーズ」という。)を、以下のようにして調製した。
アセロゲニンAを100μM(終濃度)となるように、D-PBSを用いて希釈した。Affi-Gelアガロースビーズを、PBSを用いて洗浄した。洗浄後のアガロースビーズを1.5ml角底エッペンドルフ型チューブに入れ、上記のように希釈した前記アセロゲニンA溶液を100μlの量で添加した。室温で45分間、インキュベートすることにより、アセロゲニンAをアガロースビーズに含浸させた。得られたアセロゲニンA含浸アガロースビーズを下記の歯髄への埋入に供した。
また、陰性対照として、アセロゲニンAを含まないD-PBSに含浸した以外は、アセロゲニンA含浸ビーズと同様にして調整したアガロースビーズ(以下、「D-PBS含浸ビーズ」という。)を使用した。
歯根-歯周組織形成直前の、生後5日齢のC57BL/6マウスを、エーテル麻酔後に断頭屠殺した。下顎を摘出後、下顎第1臼歯を、歯小嚢ごと摘出した。試料投与群には、アセロゲニンA含浸アガロースビーズを3粒、摘出歯(下顎第1臼歯)の歯髄に埋入した。また、対照群には、D-PBS含浸ビーズを3粒、摘出歯(下顎第1臼歯)の歯髄に埋入した。
アセロゲニンA含浸ビーズを埋入した摘出歯、及び、陰性対照としてD-PBS含浸ビーズを埋入した摘出歯を、ホストマウスの腎臓皮膜下に移植して培養した。ホストマウスは、12時間点灯、室温25℃の条件下におき、水と飼料は自由に摂取させて3週間飼育した。
上記の摘出歯の移植3週間後、ホストマウスを頸骨脱臼にて屠殺し、腎臓を摘出して、各群の培養後の摘出歯(移植歯)を回収した。
回収された培養後の移植歯における歯根-歯周組織形成(伸長)、歯根膜、及び骨を、実体顕微鏡下にて観察し、CCDカメラにて撮影した。前記移植培養後の各群における移植歯の観察結果を、図4に示す。
なお、骨形成部分とは逆向きの斜線で示された部分は、歯根膜領域を示し、白色の部分は歯を示す。
次に、本発明の組成物を含有する製剤例を示すが、本発明はこれらに限定されるものではない。
Claims (13)
- 下記式(I)で表されるジアリールヘプタノイド化合物及びその類縁体化合物を有効成分として含有する、骨疾患の予防及び/又は治療用医薬組成物。
- 上記式(I)で表されるジアリールヘプタノイド化合物は、下記式(Ia)で表されるものであることを特徴とする、請求項1に記載の骨疾患の予防及び/又は治療用医薬組成物。
- 前記式(I)で表されるジアリールヘプタノイド化合物及びその類縁体は、下記式(II)又は(III)で表される化合物であることを特徴とする、請求項1に記載の骨疾患の予防及び/又は治療用医薬組成物。
- 前記式(II)で表されるジアリールヘプタノイド化合物及びその類縁体は、下記式(IIa)〜(IIg)及び(IIh)からなる群から選ばれるものであることを特徴とする、請求項1又は3に記載の骨疾患の予防及び/又は治療用医薬組成物。
- 下記式(IV)で表されるジアリールヘプタノイドの半量体化合物及びその類縁体化合物を有効成分として含有する、骨疾患の予防及び/又は治療用医薬組成物。
- メグスリノキ(Acer nikoense Maximowicz)、三花槭(サンファチ、和名:オニメグスリ)(Acer triflorum)、血皮槭(シュエピチ、Acer griseum)、ダケカンバ(Betula ermanii Cham.)、シラカンバ(Betula platyphylla)、ウダイカンバ(Betula maximowicziana)、ヤエガワカンバ(コオノオレ、Betula davurica Pall.)、ハンノキ(Alnus japonica Steud.)、及びボスウェリア・オバリフォリオラータ(Boswellia ovalifoliolata)からなる群から選ばれるいずれかの樹木の乾燥樹皮から抽出され、請求項1〜5のいずれかに記載のジアリールヘプタノイド化合物又はこれらの類縁体を含有する抽出物を含む、骨疾患の予防及び/又は治療用医薬組成物。
- 歯槽骨の増加作用を有する、請求項1〜6のいずれかに記載の骨疾患の予防及び/又は治療用医薬組成物。
- 請求項1〜7のいずれかに記載の医薬組成物を含有する骨疾患の予防及び/又は治療用医薬製剤。
- 請求項1〜7のいずれかに記載の医薬組成物を少なくとも1種以上含有する、骨疾患の予防及び/又は治療を補助するための機能性食品。
- メグスリノキ(Acer nikoense Maximowicz)、三花槭(サンファチ、和名:オニメグスリ)(Acer triflorum)、血皮槭(シュエピチ、Acer griseum)、ダケカンバ(Betula ermanii Cham.)、シラカンバ(Betula platyphylla)、ウダイカンバ(Betula maximowicziana)、ヤエガワカンバ(コオノオレ、Betula davurica Pall.)、ハンノキ(Alnus japonica Steud.)、及びボスウェリア・オバリフォリオラータ(Boswellia ovalifoliolata)からなる群から選ばれるいずれかの樹木の乾燥樹皮から抽出され、請求項1〜5のいずれかに記載のジアリールヘプタノイド化合物又はこれらの類縁体を含有する抽出物を含む、機能性食品。
- 請求項1〜7のいずれかに記載の医薬組成物を少なくとも1種以上含有する、健康食品。
- メグスリノキ(Acer nikoense Maximowicz)、三花槭(サンファチ、和名:オニメグスリ)(Acer triflorum)、血皮槭(シュエピチ、Acer griseum)、ダケカンバ(Betula ermanii Cham.)、シラカンバ(Betula platyphylla)、ウダイカンバ(Betula maximowicziana)、ヤエガワカンバ(コオノオレ、Betula davurica Pall.)、ハンノキ(Alnus japonica Steud.)、及びボスウェリア・オバリフォリオラータ(Boswellia ovalifoliolata)からなる群から選ばれるいずれかの樹木の乾燥樹皮から抽出され、請求項1〜5のいずれかに記載のジアリールヘプタノイド化合物又はこれらの類縁体を含有する抽出物を含む、健康食品。
- 骨疾患の予防及び/又は治療を補助するために使用されるものであることを特徴とする、請求項10〜12のいずれかに記載の健康食品。
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JP (1) | JP5038310B2 (ja) |
KR (1) | KR101509554B1 (ja) |
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KR20110051876A (ko) * | 2009-11-11 | 2011-05-18 | 남종현 | 흡연 독성 해독용 조성물 |
WO2013011513A1 (en) * | 2011-07-21 | 2013-01-24 | Ramot at Tel- Aviv University Ltd. | Methods of determinig enzyme activity in preserved cell samples |
CN102327301A (zh) * | 2011-09-26 | 2012-01-25 | 暨南大学 | 赤杨在制备防治骨质疏松药物中的应用 |
CN105412181A (zh) * | 2015-11-23 | 2016-03-23 | 吉林农业大学 | 拧筋槭的制备糖尿病治疗产品用途 |
CN105412180A (zh) * | 2015-11-23 | 2016-03-23 | 吉林农业大学 | 拧筋槭的制备降血脂产品用途 |
CN111084780A (zh) * | 2020-01-09 | 2020-05-01 | 昆明医科大学 | 老鹳草素在制备治疗骨质疏松合并骨折的药物中的用途 |
CN111067915A (zh) * | 2020-01-09 | 2020-04-28 | 昆明医科大学 | 老鹳草素在制备用于治疗维生素d不足和/或缺乏疾病的药物中的用途 |
KR102697084B1 (ko) * | 2022-07-07 | 2024-08-21 | 재단법인 경기도경제과학진흥원 | 물박달나무 추출물을 이용한 항비만용 조성물 |
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US20050215635A1 (en) * | 2004-03-08 | 2005-09-29 | Rafi M Mohamed | Diarylheptanoid compounds and uses thereof |
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EP2407160A1 (en) | 2012-01-18 |
EP2050442A1 (en) | 2009-04-22 |
EP2407160B1 (en) | 2016-07-27 |
KR101509554B1 (ko) | 2015-04-06 |
CN101522183A (zh) | 2009-09-02 |
WO2008016105A1 (fr) | 2008-02-07 |
KR20090045221A (ko) | 2009-05-07 |
JP5038310B2 (ja) | 2012-10-03 |
US20090227527A1 (en) | 2009-09-10 |
US8822705B2 (en) | 2014-09-02 |
EP2050442A4 (en) | 2010-04-14 |
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