JP2014062101A - 細胞増殖および血管新生を特徴とする疾患を治療する組成物および方法 - Google Patents
細胞増殖および血管新生を特徴とする疾患を治療する組成物および方法 Download PDFInfo
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Abstract
【解決手段】癌に限定されないがこれをはじめとする様々な疾患の治療のためヒト内皮細胞に向上した抗増殖性効果を示す、一連のベンゾ[c]クロメン−6−オン誘導体を用いて、異常な血管新生が関与する疾患を予防および/または治療する組成物および方法。
【選択図】図1
Description
R1=Hまたはアルキル;
R2=H、OH、O−アルキル、アミノ、O−ヘテロシクロ(heterocyc)、O−アリール、O−置換アルキル(ここで置換は例えばハロ、アリールまたはヘテロアリール)、O−Ac、O−PO3、O−SO3、またはOSO2NH2;
R3=H、OH、O−アルキル、O−CH2アリール、O−CH2ヘテロアリール、O−アルキルアリール、O−アシル、またはニトロ;
R4=H、アルキル、CH2アリール、置換アルキル、OH、O−アルキル、O−アリール、OCH2アリール、OCH2ヘテロアリール、O−アシル、OPO3、OSO3、またはOSO2NH2;
R5=H、オキソ、アリール、ヒドロキシル、アルキル、またはO−アルキル;
R6=H;
R7=H、アシル、置換アルキル(ここで置換は例えばヒドロキシルまたはスルファモイル)、アルキル、O−アルキル、またはO−置換アルキル(ここで置換はO−PO3またはOSO3);
R8=H;そして
X=O、N、またはSである)
を含む薬学的組成物が提供される。
R1=Hまたはアルキル;
R2=H、O−アルキル、OH、アミノ、O−ヘテロシクロ(heterocyc)、O−アリール、O−置換アルキル(ここで置換は例えばハロ、アリール、またはヘテロアリール)、O−Ac、O−PO3、O−SO3、またはOSO2NH2;
R3=H、O−アルキル、O−置換アルキル(ここで置換はアリールまたはヘテロアリール)、OH、O−アシル、またはニトロ;
R4=H、アルキル、CH2アリール、置換アルキル、O)、O−アルキル、O−アリール、OCH2アリール、OCH2へテロアリール、O−アシル、OPO3、OSO3、またはOSO2NH2;
R5=H、アリール、ヘテロアリール、または置換アルキル;そして
R6=H、アルキル、またはアリールである)
を含む薬学的組成物が提供される。
本発明によるベンゾ[c]クロメン−6−オン誘導体は、以下の反応スキーム、スキーム1および合成法スキーム2を用いて調製することができる。本発明はまた、スキーム1の出発点から調製されるベンゾ[c]クロメン−6−オン誘導体を含む。これらの類似体の合成は、スキーム3に示す合成法に記載され、スキーム3は表Iに示すとおりのベンゾ[c]クロメン−6−オン誘導体からの実施例を示す。
スキーム1
5−ベンジルオキシ−2−ブロモ−4−メトキシベンズアルデヒド(2)の合成
2−ブロモ−5−ヒドロキシ−4−メトキシベンズアルデヒド(25g、0.108mol)およびK2CO3(30g、0.216mol)をアセトニトリル(250mL)に加えて、Arフラッシュした。臭化ベンジル(20g、0.12mol)を加え、混合物をAr下、50℃で20時間加熱した。冷却してから、混合物を水(200ml)に注いでCH2Cl2(300mL)で抽出した。このCH2Cl2を水(3×100mL)で洗い、乾燥させ、そして濃縮した。イソプロパノール:水(3:1)で再結晶して、明褐色固体として2を28.8g(83%)得た。1H−NMR(400MHz、CDCl3)dH3.96(3H、s、OCH3)、5.16(2H、s、CH2Ph)、7.07−7.48(7H、m、ArH+CH2Ph)、10.16(1H、s、CHO)。
5−ベンジルオキシ−2−ブロモ−4−メトキシ−ベンズアルデヒド2(5g、16.0mmol)をCH2Cl2(40mL)に加え、Arフラッシュして氷浴で冷却した。mCPBA(5.2g)のCH2Cl2(50mL)溶液を滴下した。加え終わったら、反応混合物を、Ar下、14時間還流した。冷却してから、混合物を飽和NaHCO3(3×50mL)、ブラインで洗い、乾燥させ、そして濃縮した。残渣を酢酸エチル/ヘキサンから再結晶して、大きい褐色針状晶として3を4.1g(85%)得た。1H−NMR(400MHz、CDCl3)dH3.88(3H、s、OCH3)、5.10(2H、s、CH2Ph)、6.74(1H、s、ArH)、7.08(1H、s、ArH)、7.34−7.40(5H、m、CH2Ph)、8.25(1H、s、OH)。
5−ベンジルオキシ−2−ブロモ−4−メトキシ−フェノール3(2.76g、89.0mmol)とNaH(0.89g、13.0mmol、油中60%分散)をフラスコに入れてArフラッシュした。乾燥THF(50mL)を加えて、懸濁液を氷浴中20分間撹拌した。CH3I(1.7mL、27.0mmol、塩基性アルミナで濾過)を加えて、混合物をAr下、18時間室温で撹拌した。冷却してから、氷浴中、反応混合物に水をゆっくりと加えた。混合物を酢酸エチルで抽出し、乾燥させ、濃縮して黄色油状物を得た。この油状物は減圧下で固化した。シリカゲルと(10%酢酸エチル/ヘキサン)を用いてシリカゲルクロマトグラフィーで油状物を精製して、白色固体として4を2.5g(88%)得た。1H−NMR(400MHz、CDCl3)dH3.75(3H、s、OCH3)、3.84(3H、s、OCH3)、5.15(2H、s、CH2Ph)、6.57(1H、s、ArH)、7.07(1H、s、ArH)、7.32−7.42(5H、m、CH2Ph)。
1−ベンジルオキシ−4−ブロモ−2,5−ジメトキシベンゼン4(7.48g、23.0mmol)を乾燥したフラスコに入れてArフラッシュした。乾燥THF(75mL)を加え、溶液をドライアイス/アセトン浴で−78℃に冷却した。nBuLi(11mL、2.5Mヘキサン溶液)を加え、混合物を−78℃で20分間撹拌した。ホウ酸トリイソプロピル(10.7mL、0.463mol)を加え、反応物を−78℃で2時間撹拌してから室温まで昇温させた。このとき白色沈殿が形成されだした。さらに20時間撹拌した後、飽和NH4Cl(25mL)で反応物をクエンチした。有機層を分離した後、水層を酢酸エチル(2×50mL)で抽出した。有機層をまとめて、乾燥させ、濃縮した。残渣をヘキサンで粉末にして濾過し、明るいオフホワイトのクリーム状固体として5bを4.1g(62%)得た。1H−NMR(400MHz、DMSO−d6)dH3.70(3H、s、OCH3)、3.79(3H、s、OCH3)、5.16(2H、s、CH2Ph)、6.77(1H、s、ArH)、7.18(1H、s、ArH)、7.33−7.52(5H、m、CH2Ph)
Ar下、0℃で、5−アセチルサリチル酸メチル(25.0g、0.129mol)をCH2Cl2(250mL)とピリジン(60mL)に溶解した。次いでトリフルオロメタンスルホン酸無水物(37.9g、0.133mol)を20分かけて加えた。反応混合物を更に30分間撹拌してから、水(500mL)でクエンチした。有機層を分離して、5%のHCl(80mL)で3回洗った。溶媒を除去して得られた固体を減圧下乾燥して、6を40.3g(96%)得た。1H−NMR(400MHz、CDCl3)dH2.56(3H、s、COCH3)、3.89(3H、s、OCH3)、7.32(1H、d、ArH)、8.12(1H、d、ArH)、8.52(1H、s、ArH)。
4−ベンジルオキシ−2,5−ジメトキシフェニルボロン酸5b(4.15g、14.4mmol)、5−アセチル−2−トリフルオロメタンスルホニルオキシ安息香酸メチルエステル6(4.69g、14.4mmol)、およびK2CO3(3.98g、28.8mmol)をフラスコに入れて、Arフラッシュした。無水エタノール(83mL)およびDME(94mL)を加え、続いてPd(PPh3)4(0.87g、0.785mmol)を加えて、反応混合物を4時間還流させた。冷却してから、水(100mL)、酢酸エチル(100mL)、およびブライン(50mL)を加えた。有機層をブライン(2×50mL)で洗い、水性画分をまとめて酢酸エチルで逆抽出した。有機画分をまとめて乾燥させ、濃縮し、そして酢酸エチル/ヘキサンから再結晶して黄色固体として7bを6.5g(99%)得た。1H−NMR(400MHz、CDCl3)dH2.65(3H、s、COCH3)、3.58(3H、s、OCH3)、3.68(3H、s、OCH3)、3.88(3H、s、OCH3)、5.21(21H、s、CH2Ph)、6.55(1H、s、ArH)、6.86(1H、s、ArH)、7.30−7.48(6H、m、ArH+CH2Ph)、8.10(1H、d、ArH)、8.37(1H、s、ArH)、
4−アセチル−4’−ベンジルオキシ−2’−メトキシビフェニル−2−カルボン酸メチルエステル7b(4.06g、9.7mmol)およびNaOH(0.773g、19.4mmol)に、メタノール(60mL)および水(60mL)を加えた。反応物をAr下で7時間還流させ、それから室温まで冷却した。氷浴に入れてから1MのHClを加えて黄色沈殿物を得、これを濾過し、水で洗って、THF/ヘキサンから再結晶して、黄色結晶として8bを2.7g(69%)得た。1H−NMR(400MHz、CDCl3)dH2.68(3H、s、COCH3)、3.62(3H、s、OCH3)、5.16(2H、s、CH2Ph)、6.77(1H、s、ArH)、7.18(1H.s、ArH)、7.33−7.52(5H、m、CH2Ph)、3.90(3H、s、OCH3)、5.22(2H、S、CH2Ph)、6.58(1H、s、ArH)、6.90(1H、s、ArH)、7.34−7.50(6H、m、ArH+Ch2Ph)、8.17(1H、d、ArH)、8.50(1H、s、ArH)、
4−アセチル−4’−ベンジルオキシ−2’−メトキシビフェニル−2−カルボン酸8b(1.0g、2.5mmol)を1,2−ジクロロエタン(30mL)に懸濁させた。SOCl2(200mL、2.7mmol)を加えて、反応混合物をAr下で2時間還流させた。室温まで冷却してから(いくらか沈殿が形成された)、AlCl3(0.262g、0.002mol)を加えると混合物は赤くなった。反応物を室温で17時間撹拌し、それから水(30mL)でクエンチしてCH2Cl2(100mL)で希釈した。有機層をブライン(2×50mL)で洗ってから乾燥させて濃縮した。残渣を熱CHCl2に溶解してから冷却した。ヘキサンを加えて、生成物が沈殿する助けとした。2回目の再結晶で、黄色固体として9bを0.3g(32%)得た。1H−NMR(400MHz、CDCl3)dH2.73(3H、s、COCH3)、4.05(3H、s、OCH3)、5.28(2H、s、CH2Ph)、6.94(1H、s、ArH)、7.35−7.50(6H、s、ArH+CH2Ph)、8.07(1H、d、ArH)、8.42(1H、d、ArH)、8.92(1H、s、ArH)
オーバーヘッド撹拌器および加熱マントルを備えた3リットルの三つ口フラスコ中、ギ酸ナトリウム(2.18g、32mmol)とギ酸(4.2mL、106.8mmol)を、9b(10.0g、26.71mmol)を乾燥THFと無水エタノール(1.5L)の1:1混合物に懸濁させたものに加えた。この混合物に、100mgの10%パラジウム炭素を加え、反応物をアルゴン下で7時間還流させた。このとき、出発物質の9bは全て溶解していた。溶液を熱いまま濾過して触媒を除去し、そして溶媒をロータリーエバポレーションで除去した。(溶液が冷えてしまった場合は、生成物が沈殿するが、6リットルの還流メタノールで固体を抽出することにより触媒から分離することができる)。得られる固体(7.8g)を以下に記載のようにシリカゲルクロマトグラフィーで精製した。
SG00393。SG00392(1.0g、2.67mmol)とNaBH4(0.1g、2.67mmol)を、THF(20mL)と無水エタノール(10mL)の2:1混合物に加えて、1.5時間撹拌放置した。反応混合物を氷浴で冷却して、色が黄色から無色に変わるまで0.5NのHClを加えた。水(20mL)を加えて、混合物をCH2Cl2で抽出し、乾燥させ、濃縮して、残渣をCH2Cl2:アセトン(8/1)を用いてシリカゲルフラッシュカラムクロマトグラフィーで精製して0.71gのSG00393を得た。
実験データ
以下の実施例は、表Iに示す化合物からの代表的な例示である。上記化合物は、抗増殖性、血管新生阻害性、および/または他の以下に記載されるべき重要な活性を有することが見出されている。
アポトーシスアッセイ。アポトーシスアッセイを行って、誘導体がプログラム細胞死を誘導することにより細胞増殖を阻害しているかどうかを求めた。ケラチン生成細胞などの他の増殖細胞に暗示される活性を有する内皮細胞について、代表的なアポトーシス活性を示す。内皮細胞のアポトーシスは、血管新生阻害活性を示す更に別の手段である。細胞死は、細胞に蓄積する細胞質ヒストン付随DNAフラグメントの量を定量することにより、モニタリングした。アポトーシスアッセイキットは、ELISA検出およびモノクローナル抗ヒストン抗体とともにRoche(cat#1544675)から入手した。簡単には、HUVECまたはケラチン生成細胞をトリプシン処理し、希釈して、50,000個/チューブの濃度でマイクロチューブに分取した。化合物での処理は、37℃で6時間で、続いて細胞を溶解して検出キットを用いて製造者に従って分析した。
皮膚疾患は、少なくとも部分的には、ケラチン生成細胞の異常な存在と増殖によるものである。こうした疾患で、このケラチン生成細胞の増殖を阻害および/またはケラチン生成細胞のアポトーシスを誘導する能力のいずれかの手段は、異常皮膚病理の寛解の助けとなることが期待される。以下に、例示のデータを示してこの仮定を支持する。
細胞に基づくアッセイは細胞中の化合物の安定性または半減期を求めるのに役立つ。こうした専門化した肝細胞は、薬に作用し得る必要な第I相および第II相酵素を全て含有する。こうした細胞でまったく、またはほとんど代謝されない化合物は、代謝的に安定と考えられ、肝細胞で代謝されるものよりも長い半減期をin vivoで有することが期待できる。図6に結果を示す。誘導体をヒト初代肝細胞とともに120分間または240分間インキュベートした。化合物の残存%を左に示す。第I相および/または第II相酵素で代謝され得る対照誘導体を誘導体292として示す。
Claims (26)
- 式I:
R1は、Hまたはアルキルであり;
R2は、H、OH、O−アルキル、アミノ、O−ヘテロシクロ(heterocyc)、O−アリール、O−Ac、O−PO3、O−SO3、OSO2NH2、またはO−置換アルキル、ここで前記置換はハロ、アリールまたはヘテロアリールであり;
R3は、H、OH、O−アルキル、O−CH2アリール、O−CH2ヘテロアリール、O−アルキルアリール、O−アシル、またはニトロであり;
R4は、H、アルキル、CH2アリール、置換アルキル、OH、O−アルキル、O−アリール、OCH2アリール、OCH2ヘテロアリール、O−アシル、OPO3、OSO3、またはOSO2NH2であり;
R5は、H、オキソ、アリール、ヒドロキシル、アルキル、またはO−アルキルであり;
R6は、Hであり;
R7は、H、アシル、アルキル、O−アルキル、置換アルキル、ここで前記置換はヒドロキシルまたはスルファモイルであり、またはO−置換アルキル、ここで前記置換はO−PO3またはOSO3であり;
R8は、Hであり;
Xは、O、N、またはSである)
の化合物を含む組成物。 - 式II:
R1は、Hまたはアルキルであり;
R2は、H、O−アルキル、OH、アミノ、O−ヘテロシクロ(heterocyc)、O−アリール、O−Ac、O−PO3、O−SO3、OSO2NH2、またはO−置換アルキル、ここで前記置換はハロ、アリール、またはヘテロアリールであり;
R3は、H、O−アルキル、OH、O−アシル、ニトロ、またはO−置換アルキル、ここで置換はアリールまたはヘテロアリールであり;
R4は、H、アルキル、CH2アリール、置換アルキル、OH、O−アルキル、O−アリール、OCH2アリール、OCH2へテロアリール、O−アシル、OPO3、OSO3、またはOSO2NH2であり;
R5は、H、アリール、ヘテロアリール、または置換アルキルであり;
R6は、H、アルキル、またはアリールである)
の化合物を含む組成物。 - 前記組成物が、表Iからなる群から選択される組成物の1種または複数である、請求項1から4のいずれか一項に記載の組成物。
- 前記表Iが、ベンゾ[c]クロメン−6−オン誘導体SG00272、SG00273、SG00373、SG00477、SG00519、SG00526、SG00527、SG00528、SG00529、SG00530、SG00531、SG00532、SG00533、SG00535、SG00536、SG00537、SG00538、SG00539、SG00540、SG00541、SG00542、SG00543、SG00544、SG00545、SG00546、SG00547、SG00548、SG00549、SG00550、SG00551、SG00552、SG00553、SG00554、SG00555、SG00556、SG00557、SG00558、SG00559、SG00560、SG00561、SG00562、SG00563、SG00564、SG00565、SG00566、SG00567、SG00568、SG00569、SG00570、SG00571、SG00572、SG00573、SG00574、SGG0575、SG00576、SG00577、SG00579、SG00580、SG00581、SG00582、SG00583、SG00584、SG00585、SG00586、SG00587、SG00588、SG00589、SG00590、SG00591、SG00592、SG00593、SG00594、SG00595、SG00596、SG00597、SG00598、SG00599、SG00600、SG00601、SG00602、SG00603、SG00604、SG00605、SG00606、SG00607、SG00608、SG00609、SG00610、SG00611、SG00612、SG00613、SG00614、SG00615、SG00616、SG00617、SG00618、SG00619、SG00620、およびSG00629を含む、請求項5に記載の組成物。
- 式I、式II、式III、および式IVからなる群より選択される化合物を含む、望ましくない血管新生を特徴とする疾患を予防または治療するための組成物。
- 前記疾患がさらに望ましくない細胞増殖を特徴とする、請求項7に記載の組成物。
- 前記組成物が、血管新生阻害活性または抗増殖活性を示す、請求項8に記載の組成物。
- 前記組成物が、血管新生阻害活性および抗増殖活性を示す、請求項8に記載の組成物。
- 前記組成物が、アポトーシス活性を示す、請求項8に記載の組成物。
- 前記組成物が、徐放のため生分解性または非生分解性フォーマットで配合されている、請求項1から11のいずれか一項に記載の組成物。
- 前記組成物が、プロドラッグと複合している、請求項1から11のいずれか一項に記載の組成物。
- 前記プロドラッグが、ペプチド、抗体、抗体フラグメント、加水分解性エステルアミド、およびカルバメートからなる群より選択される、請求項13に記載の組成物。
- 前記プロドラッグが、グリコール酸、乳酸、2−ヒドロキシオクタン酸、ヒドロキシラウリングリコール酸(hydroxylauric glycolic acid)、およびそれらの組合せからなる群より選択される、請求項13に記載の組成物。
- 患者に、式I、式II、式III、および式IVからなる群より選択される組成物の1種または複数を治療量で投与することを含む、望ましくない血管新生を特徴とする疾患を予防または治療するための方法。
- 前記組成物がさらに、許容可能な送達ビヒクルを含む、請求項16に記載の方法。
- 前記患者が癌であるか癌になる可能性が高い、請求項16に記載の方法。
- 前記癌が、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、内皮肉腫(endotheliosarcoma)、リンパ管肉腫、リンパ管内皮肉腫(lymphangioendotheliosarcoma)、滑膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、結腸癌、膵癌、乳癌、卵巣癌、前立腺癌、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、脂腺癌、乳頭癌、乳頭状腺癌、嚢胞腺癌、血管腫、髄様癌、気管支原性肺癌、腎細胞癌、肝細胞腫、胆管癌、絨毛癌、精上皮腫、胚性癌腫、ウィルムス腫瘍、子宮頸癌、精巣腫瘍、肺癌、小細胞肺癌、膀胱癌、上皮癌、神経膠腫、星状膠細胞腫、髄芽細胞腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽細胞腫、聴神経腫瘍、乏突起膠腫、骨肉腫、髄膜腫、黒色腫、神経芽細胞腫、網膜芽細胞腫、聴神経腫瘍(acousticneuroma)、神経線維腫、トラコーマおよび化膿性肉芽腫、急性リンパ性白血病および急性骨髄性白血病、慢性白血病、真性赤血球増加症、リンパ腫、多発性骨髄腫、ワルデンシュトレームマクログロブリン血症、ならびに重鎖病からなる群より選択される、請求項18に記載の方法。
- 前記患者が、遺伝性出血性毛細血管拡張症、固形または血液腫瘍、後天性免疫不全症候群、閉経後の症候、骨粗鬆症、循環器疾患、アルツハイマー病、発作、血管奇形、異常創傷治癒、炎症性および免疫性の障害、痛風、黄斑変性症、糖尿病性網膜症、早産児の網膜症、角膜移植片拒絶反応、多巣性脈絡膜炎、ベスト病、シュタルガルト病、cblC型コバラミン欠乏症、過粘稠度症候群、ソースビー眼底変性症、弾力線維性仮性黄色腫、虹彩ルベオーシス、オスラー・ウェーバー症候群、オスラー・ウェーバー・ランデュ病、角結膜炎、ビタミンA欠乏症、フリクテン症(phylectenulosis)、細菌感染、ウイルス感染、寄生虫感染、真菌感染、アトピー性および上肢皮膚炎、慢性ブドウ膜炎、慢性硝子体炎、イールズ病、放射状角膜切開、血管結合組織または線維組織の特質のない増殖、増殖性硝子体網膜症、慢性網膜剥離、外傷(擦過傷、角膜同種移植拒絶など合併症を伴う過去の手術、アルカリ火傷、酸火傷、または炭化水素火傷、ブルッフ膜の機械的または熱的損傷が挙げられるがこれらに限定されない)、翼状片、関節炎(リウマチ性および変形性関節炎)、乾癬、アトピー性皮膚炎、皮膚の光損傷、シェーグレン症候群、全身性狼瘡、多発性動脈炎、類天疱瘡、鎌状赤血球貧血、パジェット病、静脈または動脈閉塞、頚動脈閉塞性疾患、ライム病、ベーチェット病、バルトネラ症(bartonelosis)、動脈硬化症、排卵をブロックまたは着床を予防するための胞胚による無月経の誘導、手術の癒着、慢性炎、潰瘍性大腸炎、およびクローン病からなる群より選択される疾患であるか疾患になる可能性が高い、請求項16に記載の方法。
- 前記患者に、式I、式II、式III、および式IVからなる群より選択される前記組成物の1種または複数と、前記疾患の治療または予防のための治療薬剤を同時投与することをさらに含む、請求項16に記載の方法。
- 前記治療薬剤が、腫瘍退縮剤、抗癌剤、抗悪心剤、および鎮吐剤からなる群より選択される、請求項21に記載の方法。
- 前記投与が、前記1種または複数の組成物の局所的、経口、経鼻、直腸、非経口投与を含む、請求項16に記載の方法。
- 前記1種または複数の組成物はインプラントに伴うものである、請求項16に記載の方法。
- 前記1種または複数の組成物はデバイスに伴うものである、請求項16に記載の方法。
- 前記デバイスが血管ステントである、請求項25に記載の方法。
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MX2008011013A (es) | 2008-10-23 |
CA2643579A1 (en) | 2007-09-07 |
AU2007219981B2 (en) | 2013-11-07 |
EP1996021B1 (en) | 2017-12-13 |
US20140105920A1 (en) | 2014-04-17 |
EP1996021A2 (en) | 2008-12-03 |
EP1996021A4 (en) | 2010-03-31 |
BRPI0708318A2 (pt) | 2011-05-24 |
US8475776B2 (en) | 2013-07-02 |
JP5877425B2 (ja) | 2016-03-08 |
US20070197567A1 (en) | 2007-08-23 |
WO2007101247A2 (en) | 2007-09-07 |
JP2009528381A (ja) | 2009-08-06 |
CA2643579C (en) | 2018-05-15 |
AU2007219981A1 (en) | 2007-09-07 |
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JP2015221801A (ja) | 2015-12-10 |
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