JP5250876B2 - エトキシコンブレタスタチンとそのプロドラッグの製造方法及び用途 - Google Patents
エトキシコンブレタスタチンとそのプロドラッグの製造方法及び用途 Download PDFInfo
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- JP5250876B2 JP5250876B2 JP2009527000A JP2009527000A JP5250876B2 JP 5250876 B2 JP5250876 B2 JP 5250876B2 JP 2009527000 A JP2009527000 A JP 2009527000A JP 2009527000 A JP2009527000 A JP 2009527000A JP 5250876 B2 JP5250876 B2 JP 5250876B2
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- Prior art keywords
- combretastatin
- ethoxy
- reaction
- cancer
- group
- 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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- -1 ethoxy combretastatin Chemical compound 0.000 title claims description 60
- 238000004519 manufacturing process Methods 0.000 title claims description 24
- 239000000651 prodrug Substances 0.000 title description 11
- 229940002612 prodrug Drugs 0.000 title description 11
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 claims description 28
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- 239000003937 drug carrier Substances 0.000 claims description 4
- 229940122530 Tubulin polymerization inhibitor Drugs 0.000 claims description 2
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- 150000001875 compounds Chemical class 0.000 description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
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- BERFDQAMXIBOHM-UHFFFAOYSA-N 4-Ethoxy-3-methoxybenzaldehyde Chemical compound CCOC1=CC=C(C=O)C=C1OC BERFDQAMXIBOHM-UHFFFAOYSA-N 0.000 description 6
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
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- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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Description
本発明のもう一つの目的は、一般式Iの化合物の製造方法を提供することである。
本発明の四つ目の目的は、一般式Iの化合物の医薬用途を提供することである。
別の好ましい例において、前述のR はヒドロキシ基、アミノ基、リン酸、リン酸コリン、アミノ酸の側鎖、或はその薬学的に許容される塩である。
本発明の第二は、
(1)相間移動触媒作用で、p-ヒドロキシ-m-メトキシベンズアルデヒドIIブロムエタンでエチル化反応させ、4-エトキシ-3-メトキシベンズアルデヒドIIIを形成する工程と、
(5)アルカリ条件で、エトキシコンブレタスタチンリン酸エステル誘導体からエトキシコンブレタスタチンリン酸塩或はエトキシコンブレタスタチンリン酸コリン内塩を形成する工程と、を含む一般式Iで示される化合物の製造方法を提供する。
別の好ましい例において、工程(3)において、トリチルクロリドでm-ヒドロキシ基の保護反応を行う。
別の好ましい例において、一般式Iで示される化合物の製造方法は、
(a)相間移動触媒の作用で、p-ヒドロキシ-m-ニトロベンズアルデヒドIXブロムエタンでエチル化反応させ、4-エトキシ-3-ニトロベンズアルデヒドXを形成する工程と、
(e)アルカリ条件で、前述アミノ酸アミド誘導体から3′-アミノエトキシコンブレタスタチンアミノ酸アミドを形成する工程と、を含む。
別の好ましい例において、前述の医薬品組成物の剤形は、冷凍乾燥粉剤、粉剤、顆粒剤、タブレット剤、カプセル剤、シロップ剤、坐剤、注射剤、乳剤、チンキ剤、懸濁液、溶液の形態による静脈内注射又は経口投与から選ばれる。
本発明の第五は、異常血管新生に起因する疾病の治療薬物を製造するための一般式Iの化合物の使用を提供する。
同時に、上述化合物の合成において、254nm の紫外線の触媒作用によるウィッティヒ反応を利用することにより、反応の立体選択性を向上させ、Z 型立体配置の産物の収率を大幅に増加させた。
(化合物)
本発明によって提供されるエトキシコンブレタスタチン誘導体は、コンブレタスタチンの芳香族環B の4'位にエトキシ基が導入され、3′位が主にヒドロキシ基及びそれから誘導されるリン酸塩又はリン酸コリン内塩、並びにアミノ基及びそれから誘導されるアミノ酸アミドである水溶性プロドラッグである。構造は一般式Iの通りである。
R としてリン酸塩、リン酸コリン内塩、アミノ酸の側鎖、或は薬学的に許容される塩が選ばれる場合、その水溶性プロドラッグが形成される。
R がアミノ基である場合、アミノ酸アミドのNH(COCHR′NH)n-H である水溶性プロドラッグが誘導される。ここで、R′は天然アミノ酸の側鎖である。
本発明において、相間移動触媒作用で、エチル化反応を行い、さらにリチウムジフェニルホスフィドを用いて選択的な脱メチル化反応を行うことにより、一連の新規なp-エトキシベンズアルデヒド誘導体が製造される。そして、これらの新規なp-エトキシベンズアルデヒド誘導体を原料として高立体選択性のウィッティヒ反応をおこなうことにより、一連のエトキシコンブレタスタチン誘導体が得られる。そして、リン酸塩化、或はアミノ酸化などの合成プロセスで最適化することにより、一連のエトキシコンブレタスタチン誘導体の水溶性プロドラッグが製造される。
無機塩基と相間移動触媒の作用下、ブロムエタンを用い、4-ヒドロキシ-3-メトキシベンズアルデヒド(バニリン)IIは4-ヒドロキシ-3-ニトロベンズアルデヒドIXら、4-エトキシ-3-メトキシベズアルデヒドIII又は4-エトキシ-3-ニトロベンズアルデヒドXが製造される。
有機塩基の触媒作用で、4-エトキシ-3-ヒドロキシベンズアルデヒドIVをトリチルクロリドと反応させ、3 位のヒドロキシ基が保護されたp-エトキシベンズアルデヒド誘導体Vが得られる。臭化3,4,5-トリメトキシベンジルトリフェニルホスホニウムをn-ブチルリチウムの作用で対応するリンイリドに変換し、上述の3 位のヒドロキシ基が保護されたエトキシベンズアルデヒド誘導体とウィッティヒ反応させ、シス型のジフェニルエチレン誘導体を高収率で形成し、濃塩酸とトリフルオロ酢酸の共同作用でトリチル基を脱離させ、エトキシコンブレタスタチンVIが得られる。
(三)3′-アミノエトキシコンブレタスタチンの製造
254nm の紫外線の触媒作用で、4-エトキシ-3-ニトロベンズアルデヒドXを上述リンイリドとウィッティヒ反応させ、シス型の3′-ニトロエトキシコンブレタスタチンXIが高選択性で形成される。そして、3′位のニトロ基を還元剤でアミノ基に還元し、3′-アミノエトキシコンブレタスタチンXIIが得られる。前述還元剤は、塩化第一スズ、亜鉛粉/酢酸、チオ硫酸ナトリウム、二塩化ニッケル/水素化ホウ素ナトリウムが好ましい。
図1 で示すように、上記エトキシコンブレタスタチンVIの3’位のヒドロキシ基を四塩化炭素、ジイソプロピルエチルアミン、亜リン酸ジベンジル、臭化トリメチルシラン、ナトリウムメトキシドの作用によってリン酸二ナトリウム塩に転化し、エトキシコンブレタスタチンのリン酸塩VIIが形成される。
或は、同図1 で示すように、リン酸化試薬の2-クロロ-1,3,2-ジオキサホスホラン-2-オキシドで上記エトキシコンブレタスタチンVIの3’位のヒドロキシ基と反応させ、エトキシコンブレタスタチンの環状リン酸エステル誘導体が得られる。トリメチルアミンの作用で、その環状リン酸エステル誘導体が開環し、エトキシコンブレタスタチンのリン酸コリン内塩VIIIが形成される。
図2 で示すように、上記3′-アミノエトキシコンブレタスタチンXIIは、N-α-9-フルオレニルメトキシカルボニルアミノ酸誘導体(FmocAA)とBOP 試薬、或はジシクロヘキシルカルボジイミド(DCC)と1-ヒドロキシベンゾトリアゾール(HOBt)の作用で、3′位アミノ基にアミノ酸の側鎖を導入し、構造が例えばXIIIとXIVになり、さらに水酸化ナトリウムの作用で、Fmoc 保護が脱離してアミノ酸アミドに転化し、構造が例えばXVとXVIのような一連の3′-アミノエトキシコンブレタスタチンアミノ酸アミド誘導体が得られる。
治療有効量の一般式Iの化合物を薬学的に許容される担体と混合して、組成物の形態に調製する。ここで、治療有効量の一般式Iの化合物は組成物の0.1〜99%(w/w)である。本発明の組成物は多様な剤形とすることができる。前述の剤形は、冷凍乾燥粉剤、顆粒剤、粉剤、タブレット剤、カプセル剤、シロップ剤、坐剤、注射剤、乳剤、チンキ剤、懸濁液、溶液の形態による静脈内注射又は経口投与の剤形がある。
経口投与の場合、タブレット剤、錠剤、カプセル剤、丸剤、粉剤、顆粒剤、泥膏剤、懸濁剤、乳剤又は溶液剤を採用することができる。
以下、具体的な実施例によって、さらに本発明を説明する。これらの実施例は本発明を説明するために用いるもので、発明の範囲の制限にはならないと理解されるものである。以下の実施例に特に具体的な条件を説明しない実験方法は通常の条件、或いはメーカーの薦めの条件で行われる。特に説明しない限り、すべての%と部は重量基準である。
温度計、撹拌機、還流冷却管を装着した1000mL の四つ口フラスコに4-ヒドロキシ-3-メトキシベンズアルデヒド62g(0.41mol)、イソプロピルアルコール400mL を入れ、20 分間撹拌し、定圧滴下漏斗で18-クラウン-6 エーテル5g と水酸化ナトリウム106.3g(2.66mol)の120ml 水溶液をゆっくり滴下し、30 分間撹拌し、反応系を60℃に加熱し、同温度でブロムエタン67.3g(0.62mol)を5〜6 時間滴下し、TLC でモニターした。反応完成後、反応系を冷却し(15℃)、水400ml を加えて反応を停止させ、ジエチルエーテル(3×300ml)で産物を抽出し、中性になるまで有機層を水で洗浄し、無水MgSO4 で乾燥した。一部のジエチルエーテルを留去し、石油エーテルを大量に入れ、粗製品が沈殿した。ジエチルエーテル/石油エーテルで再結晶し、4-エトキシ-3-メトキシベンザアルデヒドが67g得られ、収率は91%であった。1H-NMR(ppm)δ:9.87(1H,s;-CHO);7.31(1H,m;2-ArH);7.26(1H,m;6-ArH);6.86(1H,m;5-ArH); 3.98(2H,q; -CH2); 3.73(3H,s; -OCH3); 1.42(3H,t; -CH3)。MS(m/Z): 180 (M+)。
実施例1に従って、4-ヒドロキシ-3-メトキシベンズアルデヒドの代わりに、4-ヒドロキシ-3-ニトロベンズアルデヒド68.5g(0.41mol)を用いて、4-エトキシ-3-ニトロベンズアルデヒドが68.7g得られ、収率は86%であった。1H-NMR(ppm)δ: 9.96(1H,s;-CHO);7.73(1H,m;2-ArH);7.58(1H,m;6-ArH);7.33(1H,m;5-ArH);4.15 (2H,q; -CH2); 3.82 (3H,s; -OCH3); 1.53 (3H,t; -CH3)。MS(m/Z):195 (M+)。
ステップ 1:アルゴンの保護下、4-エトキシ-3-メトキシベンズアルデヒド54g(0.3mol)を取って三つ口フラスコに入れ、さらにエチレングリコール130g(2.1mol)とオルトギ酸トリエチル133g(0.9mol)を加え、約100℃で還流し、触媒として三フッ化ホウ素のジエチルエーテル溶液1mlを添加した。24 時間反応させ、この反応をTLC でモニターした。室温まで冷却し、15%の水酸化ナトリウム水溶液200ml を加え、300ml のジエチルエーテルで抽出し、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧蒸留でエチレングリコールとオルトギ酸トリエチルを除去し、黄色油状物が得られた。
157.6(4-ArC),143.3(3-ArC),129.6(1-ArC),124.5(6-ArC),116.7(2-ArC),116.6(5-ArC),82.1(-OCH2), 23.5(-CH3)。MS(m/Z): 166 (M+)。
ステップ 1:アルゴン雰囲気下、4-エトキシ-3-ヒドロキシベンズアルデヒド11.0g(0.066mol)、トリチルクロリド21.1g(0.076mol)、乾燥テトラヒドロフラン42ml を500ml の四つ口フラスコに入れ、室温で均一に撹拌した。その後、トリエチルアミン1.3ml をゆっくり滴下した。滴下後、1 時間撹拌を継続し、この反応をTLC でモニターし、反応完成後、水50ml を加えて反応を中止させた。30 分間撹拌し、酢酸エチル100ml を添加して綿状の沈殿物を溶解させた。n-ヘプタン250ml を加えて、顆粒状の浅黄色の粗製品が沈殿した。ろ過し、得られた固体を水で二回洗浄し、さらに酢酸エチル/石油エーテル(10ml/20ml)で洗浄し、浅白色の結晶が得られた。この結晶を酢酸エチル/石油エーテルで再結晶し、白色の大粒の結晶が25g 得られ、収率は93%であった。1H-NMR(ppm)δ: 9.91(1H,s ; -CHO) ;7.33(1H,m ; 2-ArH) ; 7.26(1H,m ; 6-ArH) ;7.19(m,15H,Tr-H);6.89(1H,m;5-ArH);4.17 (2H,q; -CH2);1.53 (3H,t; -CH3)。
ステップ 1:光化学合成器内において、アルゴンの保護で、臭化トリメトキシフェニルメチレントリフェニルホスホニウム15g(28.7mmol)をTHF 300ml に懸濁させ、-15℃程度に冷却した。1.6mol/L のn-ブチルリチウムのシクロヘキサン溶液22ml を滴下し、1 時間反応させた。その後、254nm の紫外線ランプをつけ、UV 放射下、4-エトキシ-3-ニトロベンズアルデヒド5.7g(29mmol)のTHF 溶液24ml をゆっくり反応系に滴下した。この反応をTLC でモニターし、一夜撹拌し、反応温度が室温まで上がった。次の日、紫外線ランプを消し、溶液の温度を-5 ℃に冷却し、飽和食塩水を加えて反応を中止させた。有機層を分取し、溶媒を除いた。常圧カラムクロマトグラフィー(シリカゲルカラム、n-へキサン/酢酸エチル=4:1)によって、浅黄色の結晶6.5gを分離し、収率は63 %であった。1H-NMR(ppm)δ : 7.32(d,1H,2'-H) ; 7.16(dd,1H,6'-H) ;6.90(d,1H,5'-H) ;6.64(s,2H,2,6-H );6.49(d,1H, J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a'-H);4.18(2H,q; -CH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3 );1.55 (3H,t; -CH3)。MS(m/Z): 359(M+)。高分解能質量分析、計算値:359.14、実測値:359.13。
ステップ 1:アルゴン雰囲気下、1000ml の四つ口フラスコにエトキシコンブレタスタチン41.6g(126mmol)を入れて400mL の無水アセトニトリルで溶解させ、-25℃に冷却した後、四塩化炭素61ml を入れ、撹拌を5 分間継続した後、ジイソプロピルエチルアミン47ml と4-ジメチルアミノピリジン(DMAP)1.5g を入れ、1 分間後に亜リン酸ジベンジル(80%)41ml をゆっくり加えた。温度を-10℃以下に保持し、3.5 時間反応を継続し、TLC でモニターし、反応完成後、0.5M のKH2PO4を100ml 入れ、室温に自然昇温した。酢酸エチルで抽出し、有機層を合併し、蒸留水、飽和食塩水の順で洗浄し、無水硫酸マグネシウムで乾燥し、減圧蒸留で溶媒を除去し、混濁の油状物が得られた。快速カラムクロマトグラフィー(シリカゲルカラム、石油エーテル/酢酸エチル=3:2)によって、浅黄色の油状物を75g分離した。酢酸エチル-n-ヘキサンで再結晶することにより、無色の針状の結晶が68.4g 得られた。収率は92%であった。
ステップ 1:乾燥した500ml の三つ口フラスコに乾燥した三塩化リン68g(0.5mol)の100ml塩化メチレン溶液を注入した。体系を冷却し、0℃に保持し、乾燥したエチレングリコール31g(0.5mol)の100ml 塩化メチレン溶液を滴下した。滴下後室温に昇温し、3 時間反応を継続した。蒸留で溶媒を除去し、残液を減圧蒸留で60℃/20mmHg の留分を収集し、2-クロロ-1,3,2-ジオキサホスホランが41g 得られ、収率は65%であった。1H-NMR(CDCl3, 500M) δ: 4.46 (m, 2H, a-CHCH-),4.24 (m, 2H, e-CHCH-)。
ステップ 1: 3′-アミノエトキシコンブレタスタチン4.28g(13mmol)とFmoc-グリシン4.75g(16mmol)及びBOP 試薬22.7g(51.6mmol)を取ってDMF 100ml に溶解させた。撹拌しながら、反応混合物を60℃に加熱し、2 時間反応させ、TLC でモニターした。反応完成後、冷却し、飽和重炭酸ナトリウム溶液100ml を入れ、均一に混合した。塩化メチレン120ml×3 で抽出し、有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。その後、快速カラムクロマトグラフィー(シリカゲル、n-へキサン/酢酸エチル=2:1)によって、白色の泡沫状物質を3.3g 分離し、収率は42%であった。1H-NMR(CDCl3, 500M) δ:9.61(brs.1H, -NH); 7.74(m, 2H, Fmoc); 7.59(d, 2H, J=6.2Hz,Fmoc); 7.37(m, 2H, Fmoc); 7.29(m, 2H, Fmoc); 7.08(d, 1H, 2'-H); 6.92(dd, 1H, 6'-H);6.76(d,1H, 5'-H); 6.62(s, 2H, 2,6-H); 6.49(d, 1H, J=12.2Hz, 1a-H);6.43(d, 1H, J=12.2Hz, 1a'-H);5.79(brs.1H, Gly-NH); 4.38(d, 2H, J=7.0Hz, Fmoc); 4.22(t, 1H, J=7.0Hz, Fmoc); 4.18(2H,q; -CH2);4.04(m, 2H, Gly-CH2); 3.86(s, 3H, 4-OCH3); 3.70(s, 6H, 3,5-OCH3 );1.55(3H, t;-CH3)。MS(m/Z):608(M+)。高分解能質量分析、計算値:608.25、実測値:608.27。
386(M+)。高分解能質量分析、計算値:386.18、実測値:386.20。
ステップ 1: 3′-アミノエトキシコンブレタスタチン4.28g(13mmol)とFmoc-セリン
5.89g(16mmol)及びDCC 3.37g(16mmol)とHOBt 2.44g を取ってDMF 80ml に溶解させた。撹拌しながら、反応混合物を室温で5 時間反応させ、TLC でモニターした。反応完成後、冷却し、酢酸エチル50ml を入れて希釈し、均一に混合した。ろ過し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。その後、快速カラムクロマトグラフィー(シリカゲル、n-へキサン/酢酸エチル=2:1)によって、白色の泡沫状物質を5.1g 分離し、収率は61%であった。1H-NMR(CDCl3 ,500M) δ:9.73( brs.1H,-NH ); 7.73(m,2H,Fmoc); 7.56 (d,2H,J=6.2Hz,Fmoc); 7.35(m,2H,Fmoc);7.22(m,2H,Fmoc); 7.05 (d,1H,2'-H);6.91(dd,1H, 6'-H );6.74(d,1H,5'-H);6.60(s,2H, 2,6-H );6.51(d,1H,J=12.2Hz,1a-H) ; 6.43(d,1H,J=12.2Hz,1a'-H) ; 5.82 (brs.1H,Ser-NH);4.63(brs.1H,Ser-OH) 4.38 (d, 2H,J=7.0 Hz ,Fmoc); 4.22(t,1H,J=7.0 Hz ,Fmoc); 4.18(2H,q; -CH2);3.91(m,1H, Ser-CH); 3.85(s,3H,4-OCH3);3.71(s,6H, 3,5-OCH3 );2.66(m,2H,Ser-CH2) 1.56 (3H,t; -CH3)。MS(m/Z): 638(M+)。高分解能質量分析、計算値:638.26、実測値:638.27。
プロポキシコンブレタスタチンの製造
実施例1に従って、ブロムエタンの代わりに、n-ブロムプロパンを用いて、4-プロポキシ-3-メトキシベンズアルデヒドが製造された。その後、実施例3 と4 に従って、プロポキシコンブレタスタチンが製造された。1H-NMR(ppm)δ:7.02(d,1H,2'-H);6.94(dd,1H,6'-H );6.80(d,1H,5'-H);6.62(s,2H,2,6-H );6.46(d,1H, J=12Hz,1a-H );6.40(d,1H, J=12Hz,1a'-H);5.51(broad,1H;OH);4.16 (q, 2H; -CH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);2.27(m,2H; -CH2);1.18 (3H,t; -CH3)。MS(m/Z): 344(M+)。高分解能質量分析、計算値:344.18、実測値:344.16。
生体外で培養された腫瘍細胞にエトキシコンブレタスタチン誘導体で72 時間処理した後、MTT或はSRB 方法で、腫瘍増殖に対する抑制効果を評価し、CA-4 と比較した。
(実験設計):細胞は異なる濃度の化合物(それぞれ100、10、1、0.1、0.01、0.001 μM)と72 時間インキュベートし、SRB 方法で、化合物の細胞増殖に対するの抑制効果を評価し、抑制率を算出して、IC50 を抑制率によってLogit 法を用いて算出し、化合物の生体外抗腫瘍活性を比較した。
抑制率(%) =(対照群のOD 値−投与群のOD 値)/対照群のOD 値×100%
実施例10 の方法に従って、ヒト臍静脈内皮細胞(HUVEC)を作用対象として、エトキシコンブレタスタチン誘導体の抗新生血管の性能を調べた。
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US (1) | US7838706B2 (ja) |
EP (1) | EP2065358B1 (ja) |
JP (1) | JP5250876B2 (ja) |
KR (1) | KR101349925B1 (ja) |
CN (1) | CN101139358B (ja) |
AU (1) | AU2007295835B2 (ja) |
CA (1) | CA2662737C (ja) |
RU (1) | RU2451664C2 (ja) |
WO (1) | WO2008031333A1 (ja) |
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CN101723813A (zh) * | 2008-10-15 | 2010-06-09 | 上海华理生物医药有限公司 | 一种乙氧基二苯乙烷衍生物及其制备方法和用途 |
CN102399137B (zh) * | 2011-07-29 | 2014-07-16 | 北京中融阳光投资管理有限公司 | 1-取代芳基-3-(3,4,5-三甲氧基苯基)-1,2-丙二酮类化合物及衍生物 |
CN104447598B (zh) * | 2013-09-18 | 2017-09-22 | 浙江大德药业集团有限公司 | Ca‑4的大环多胺衍生物及其抗肿瘤特性 |
CN109310686B (zh) * | 2016-04-04 | 2022-06-21 | 凯莫森特里克斯股份有限公司 | 可溶性C5aR拮抗剂 |
CN108727222B (zh) * | 2017-04-24 | 2020-12-08 | 延边大学 | 一种选择性抗癌活性的tyd1608及其制备及用途 |
CN111362837A (zh) * | 2020-03-23 | 2020-07-03 | 新乡医学院 | 一种NQO1激活型Combretastatin A4前药及其合成方法和应用 |
CN112125805B (zh) | 2020-09-11 | 2022-10-18 | 北京红惠新医药科技有限公司 | 水溶性厚朴酚衍生物及和厚朴酚衍生物和其中间体的制备方法、和相关的单羟基保护中间体 |
CN112225673B (zh) * | 2020-11-13 | 2022-08-02 | 义乌市华耀医药科技有限公司 | 氨基康普立停衍生物及其应用 |
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AU4385293A (en) * | 1992-05-21 | 1993-12-13 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
TW325458B (en) * | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
TW334418B (en) | 1995-03-07 | 1998-06-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions |
RU2001106631A (ru) * | 1998-09-11 | 2004-03-20 | Адзиномото Ко., Инк. (Jp) | Производные бензола и их фармацевтическое применение |
US6919324B2 (en) * | 2001-10-26 | 2005-07-19 | Oxigene, Inc. | Functionalized stilbene derivatives as improved vascular targeting agents |
WO2004078126A2 (en) * | 2003-02-28 | 2004-09-16 | Oxigene, Inc. | Compositions and methods with enhanced therapeutic activity |
GB0306908D0 (en) * | 2003-03-26 | 2003-04-30 | Angiogene Pharm Ltd | Bioreductively activated stilbene prodrugs |
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Also Published As
Publication number | Publication date |
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AU2007295835B2 (en) | 2012-07-12 |
KR20090048504A (ko) | 2009-05-13 |
CN101139358B (zh) | 2011-10-12 |
RU2451664C2 (ru) | 2012-05-27 |
EP2065358A1 (en) | 2009-06-03 |
RU2009117488A (ru) | 2010-11-10 |
CA2662737A1 (en) | 2008-03-20 |
US20090170956A1 (en) | 2009-07-02 |
EP2065358A4 (en) | 2009-11-25 |
EP2065358B1 (en) | 2015-07-08 |
AU2007295835A1 (en) | 2008-03-20 |
JP2010502656A (ja) | 2010-01-28 |
US7838706B2 (en) | 2010-11-23 |
CN101139358A (zh) | 2008-03-12 |
WO2008031333A1 (fr) | 2008-03-20 |
KR101349925B1 (ko) | 2014-01-14 |
CA2662737C (en) | 2013-06-11 |
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