JP5130201B2 - モジュール式生体吸収性又は生物医学用生物活性超分子材料 - Google Patents
モジュール式生体吸収性又は生物医学用生物活性超分子材料 Download PDFInfo
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- JP5130201B2 JP5130201B2 JP2008509958A JP2008509958A JP5130201B2 JP 5130201 B2 JP5130201 B2 JP 5130201B2 JP 2008509958 A JP2008509958 A JP 2008509958A JP 2008509958 A JP2008509958 A JP 2008509958A JP 5130201 B2 JP5130201 B2 JP 5130201B2
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Description
(a)少なくとも2個の4H単位を含むポリマー;及び
(b)生物活性化合物;
であって、
前記4H単位が、一般式(1)又は(2)
したがって、成分(a)は、ポリマー鎖に共有結合している少なくとも2個の4H単位、好ましくは2〜50個の、より好ましくは3〜50個の、さらに好ましくは3〜20個の、最も好ましくは4〜15個の4H単位を含むポリマーである。4H単位の結合位置は、ポリマー鎖の末端でもよく、ポリマー鎖の骨格でも、又はその両方でもよい。本発明の超分子生体吸収性又は生物医学用材料が、例えば、異なる化学的性質のポリマー、異なる分子量のポリマー、及び/又は異なる数の4H単位をもつポリマーなど、成分(a)を2個以上含んでいてもよいのは、明らかである。成分(a)が、異なる化学的性質及び/又は異なる分子量の成分から構成されていることも可能である。
(i)ポリオキシアルキレン構造及びOH末端基を有するポリエーテルジオール;
(ii)OH末端基を有するポリエステル及びコポリエステル;
(iii)OH末端基を有するポリカーボネート及びコポリカーボネート;
(iv)OH末端基を有するポリオルソエステル;
(v)(水素化)ポリオレフィンジオール;及び
(vi)これらの好ましいポリマー(i)〜(v)の組合せを主成分とするポリマー及びコポリマー。
4H単位が、X1...X4及びY1...Y4という配列で4個のドナー又はアクセプタを含むように、式(1)及び(2)においては、n=4であることが好ましい。4H単位は、自己相補的(すなわち、2個の水素結合単位が、ドナー及びアクセプタについて同等の配列を有する)であってもよく、非自己相補的(すなわち、2個の水素結合単位が、ドナー及びアクセプタについて2つの異なる配列を有する)であってもよい。4H単位は、2個の連続したドナーの後に2個の連続したアクセプタを含んでいることが好ましい。すなわち、X1及びX2がドナーで、X3及びX4がアクセプタであることが好ましい。かかるドナー及びアクセプタは、O、S、及びN原子であることが好ましい。4H単位は、参照により明示的に組み込まれる国際公開第98/14505号パンフレット及び米国特許第6320018号明細書にて、詳しく開示されている。
(a)水素;
(b)C1〜C20アルキル;
(c)C6〜C12アリール;
(d)C7〜C12アルカリル;
(e)C7〜C12アルキルアリール;
(f)式(5)を有するポリエステル基
(g)式(6)記載の1〜4個のウレイド基で置換されたC1〜C10アルキル基
R5−NH−C(O)−NH−
(6)
(式中、R5は、水素及びC1〜C6直鎖又は分岐アルキルからなる群から選択される。);
(h)式(7)を有するポリエーテル基
(i)1〜50個、好ましくは1〜10個のアミノ酸の配列からなるオリゴペプチド基。]、
前記4H単位は、R1、R2及び/又はR3を介して(R1、R2又はR3が直接結合を表すように)、(a)〜(h)に記載の側鎖を独立して表している他のR基と共にポリマー骨格に結合している。
さらに、本発明の超分子生体吸収性又は生物医学用材料は、生物活性化合物を成分(b)として含んでいる。成分(b)は、少なくとも1個から多くとも10個まで、好ましくは1〜4個、最も好ましくは2〜4個の4H単位を備えた生物活性化合物からなる群から選択されることが好ましい。これらの4H単位は、かかる生物活性化合物に共有結合している。
本発明の超分子生体吸収性又は生物医学用材料は、第三の成分(c)も含んでいることが好ましく、かかる第三の成分(c)とは、生体吸収性ポリマーである。
本発明は、超分子生体吸収性又は生物医学用材料の調製方法も提供する。この方法は、主に超分子生体吸収性又は生物医学用材料の機械的強度の成因となる成分(a)と、主に超分子生体吸収性又は生物医学用材料の生物活性の成因となる成分(b)とを混ぜ合わせるものである。本発明の好ましい実施形態によると、この方法は、成分(a)、成分(b)及び成分(c)を混ぜ合わせるものであって、後者は、主に超分子生体吸収性又は生物医学用材料の生体吸収を改変する及び/又は生体吸収の成因となる。成分(a)、(b)及び(c)を混ぜ合わせることにより、所望の材料特性を備えた超分子生体吸収性又は生物医学用材料がもたらされる。特に、全成分が4H単位を含む場合には、それらはすべて、混合物中の異なる成分間の強い物理的相互作用に強力に貢献することになる。それゆえに本発明によると、これら3つの成分(a)〜(c)のすべてが少なくとも1個の4H単位を有していることが特に好ましい。全成分の混合は、従来のプロセス、すなわち、溶液加工若しくは溶融加工、又は両者の組合せにより、行うことができる。
超分子モジュール式アプローチによると、異なる3つの方法により超分子生体吸収性又は生物医学用材料を入手することができる:方法(i)は、異なる成分(a)、(b)及び必要に応じ(c)を互いに混ぜ合わせ、その際に、これらの成分が溶解又は分散している、好ましくは溶解している、1以上の溶媒からなる培地を共に混ぜ合わせるものである。この第一の方法(i)に続いて、当該技術で周知の溶解ポリマー用のプロセスを行うことが好ましい。
本発明の超分子生体吸収性又は生物医学用材料に成分(c)が存在する場合、成分(a)〜(c)の好ましい重量比は以下の通りである:(a)が20〜59.99重量%、(b)が0.01〜40.00重量%、及び(c)が0.01〜40.00重量%。より好ましくは、成分(a)〜(c)の好ましい重量比は、(a)が40.00〜69.99重量%、(b)が0.01〜30.00重量%、及び(c)が0.01〜30.00重量%である。超分子生体吸収性又は生物医学用材料に関して本明細書に組み入れた重量パーセンテージはすべて、超分子生体吸収性又は生物医学用材料の総重量に対してのものである。
本発明の超分子生体吸収性又は生物医学用材料は、生物医学的応用に関連した応用に適していることが好ましい。特に超分子生体吸収性材料は、薬剤の放出制御又は医療用画像化技術(例えばMRI)に有用であるだけではなく、化粧品への応用、並びに除草剤及び害虫駆除などの農業への応用にも有用である。
以下の非限定的実施例により、本発明の好ましい実施形態についてさらに説明する。特に記載のない場合、化学品はAldrich社より入手している。
1,6−ヘキシルジイソシアネート(650g)及びメチルイソシトシン(又は2−アミノ−4−ヒドロキシ−6−メチル−ピリミジン、65.1g)を、容量2リットルのフラスコ内で懸濁した。混合液を、アルゴン雰囲気下、100℃にて一晩攪拌した。室温まで冷却した後、攪拌を続けながら、1リットルのペンタンを懸濁液に添加した。生成物を濾過し、ペンタンで数回洗浄して、真空乾燥を行った。白色粉末を得た。1H−NMR(400MHz、CDCl3):δ13.1(1H)、11.8(1H)、10.1(1H)、5.8(1H)、3.3(4H)、2.1(3H)、1.6(4H)、1.4(4H)。FT−IR(ニート):ν(cm−1)。2935、2281、1698、1668、1582、1524、1256。
2−アミノ−4−ヒドロキシ−5−(2−ヒドロキシエチル)−6−メチル−ピリミジン(12グラム)を、IPDI(150mL)中に懸濁し、アルゴン雰囲気下、90℃にて一晩攪拌した。透明な溶液となった。かかる溶液を冷却し、ヘキサン中で沈殿させた。固形物を濾過し、別のヘキサン中で攪拌した後、濾過、ヘキサンでの洗浄、及び残渣の乾燥により、生成物を単離した。収率:98%。1H−NMR(400MHz、CDCl3):δ13.1(1H)、11.9(1H)、10.2(1H)、4.8〜4.5(1H)、4.2(2H)、4.0〜3.2(3H)、3.1〜2.9(3H)、2.7(2H)、2.3(3H)、1.9〜1.6(4H)、1.4〜0.8(26H)。FT−IR(ニート):ν(cm−1)。2954、2254、1690、1664、1637、1590、1532、1461、1364、1307、1257、1034、791。MALDI−TOF−MS、[M+]=614、[M+Na+]=636。
メチルイソシトシン(10g)とカルボジイミダゾール(20.7g)との混合物を含む無水(dried)DMSO(50mL)を加熱し、アルゴン雰囲気下、100℃にて2時間攪拌した。結果として得られた固形物を濾過し、フィルター中に白色粉末が残るまで、無水(dry)アセトンで洗浄した。その後、かかる粉末に真空乾燥を行い、P2O5で保存した。FT−IR(ニート):ν(cm−1)3174、1701、1644、1600、1479、1375、1320、1276。
5mLのクロロホルムに、6−(2−エチルペンチル)イソシトシン(0.42g)を溶解させた。この透明な溶液に、1,1−カルボニルジイミダゾール(CDI)(0.71g)を添加した。反応混合液を室温で3時間攪拌した。混合液全体に対し、塩水での抽出を3回行った。水層を結合させ、クロロホルムで抽出した。結合させたクロロホルム層をNa2SO4で乾燥させ、濾過した。残った有機層を減圧下で乾燥させ、収率66%にて淡黄色の粉末を得た。1H−NMR(400MHz、CDCl3):δ8.8(1H)、7.6(1H)、7.1(1H)、5.8(1H)、2.5(1H)、1.7(4H)、1.3(4H)、1.0(3H)、0.9(3H)。
15mLのTHF中で、UPy3(0.9g)と1,6−ジアミノヘキサン(0.54g;1.1等量)を室温で72時間攪拌した。かかる混合液を、アルゴン下に置いておいた。エタノール(25mL)を添加し、懸濁液を30分間攪拌した。固形物を濾過し、10mLのエタノールで数回洗浄し、乾燥させた。結果として0.86gの2(6−アミノヘキシルアミノカルボニルアミノ)−6−メチル−4[1H]ピリミジノンを得た。1H−NMR(400MHz、1滴のCH3COOHを含むD2O):δ=5.9(1H)、3.2(2H)、2.9(2H)、2.2(3H)、1.7−1.2(8H)。
メチルイソシトシン(5.2グラム)をイソホロンジイソシアネート(IPDI、50mL)に添加した後、アルゴン雰囲気下、90℃にて3日間攪拌した。結果として得られた透明な溶液を、ヘプタン中で沈殿させた。白色の粘性物質を回収し、150mLのヘプタン中で加熱して、氷上で冷却し、濾過した。白色の残渣について同じ手順をもう1回繰り返し、1単位のIPDIを有するウレイドピリミジノンからなる白色粉末を得た。この生成物(10.22g)をクロロホルム(20mL)に溶解させ、その後、ヒドロキシエチルアクリレート(HEA、3.6mL)及び1滴のジブチル錫ジラウレート(DBTDL)を添加した。混合液を、オイルバス温度65℃にて4時間攪拌し、その後、冷却して濾過した。濾過物を濃縮して過剰のジエチルエーテル中に滴下した。沈殿物を濾過により回収し、ジエチルエーテルで洗浄した。真空乾燥を行い、固形生成物を得た。1H−NMR(400MHz、CDCl3):δ13.1(1H)、11.7〜12.0(1H)、9.8−10.0(1H)、6.4(1H)、6.2(1H)、5.8(2H)、5.2(1H)、4.3(4H)、4.1〜3.6(1H)、3.1〜2.9(2H)、2.1(3H)、2.0(3H)、1.8〜1.5(2H)、1.4〜0.8(13H)1.9(3H)、1.7〜1.2(8H)。FT−IR(ニート):ν3212、2954、1697、1660、1572、1520、1242、1165。
テレケリックヒドロキシ末端PEO−6000(10.20g)を、三つ口フラスコ内において真空中で120分間、120℃に加熱し、その後、80℃に冷却した。UPy2(1.25g)及び2滴のジブチル錫ジラウレートを溶解させたトルエン(40mL)をポリマー融液に添加し、アルゴン下、80℃にて、溶液を一晩攪拌した。反応混合液を40mLのTHFで希釈し、ジエチルエーテル中に沈殿させた。物質は白色(半結晶状)で、弾性及び頑強性がある。1H−NMR(300MHz、CDCl3/CD3OD):δ4.1、3.6、2.8、2.2、1.8〜1.4、1.2〜0.8。
分子量が1250Dのテレケリックヒドロキシ末端ポリカプロラクトン(25.9g、真空乾燥)、UPy2(10.9g)及び2滴のジブチル錫ジラウレートを無水酢酸エチル(130mL)に溶解させ、オイルバス温度70℃にて一晩攪拌した。翌日、酢酸エチル(70mL)及びエタノール(50mL)を反応混合液に添加し、その後、エタノール中で沈殿させた。沈殿物の乾燥後、ポリマーを単離し、弾性物質を得た。1H−NMR(300MHz、CDCl3):δ13.1、12.0、10.1、4.5〜3.8、3.0、2.6〜2.2、2.0〜0.8。SEC(THF、PS標準):Mn=8.8kD、D=2。
テレケリックヒドロキシ末端PEO−3000(12.78g)を、三つ口フラスコ内において真空中で30分間、120℃に加熱し、続いて、5滴のジブチル錫ジラウレート及びUPy1(2.51g)を添加した。その後、この不均一反応混合液をアルゴン雰囲気下において機械式攪拌装置で攪拌し、140℃に加熱した。140℃で10分間攪拌した後、透明で均一な粘液を得た。冷却後、この液体を単離して、硬質で脆弱な白色物質を得た。1H−NMR(400MHz、CDCl3):δ13.1、11.9、10.1、5.8、5.0、4.2、3.8〜3.3、3.2、3.1、2.1、1.6〜1.2。FT−IR(ニート):ν(cm−1)2882、1698、1663、1588、1527、1466、1342、1100、962、841。SEC(THF、PS標準):Mn=2.9kD、D=1.2。
粘度が100〜120cStであって、ビス(アミノプロピル)で末端が封鎖されたポリシロキサンDMS−A21を、Gelest社より入手した。DMS−A21(14.7g)を含むテトラヒドロフラン(200mL)の溶液に、UPy3(1.5g)を添加した。その後、この混合液をオイルバス温度80℃に加熱し、この温度にて、アルゴン雰囲気下で16時間攪拌した。反応混合液にクロロホルム(200mL)を添加し、その後、反応混合液をシリカで濾過した。透明な濾過液を塩化ナトリウム飽和水溶液で2回洗浄した。有機画分をNa2SO4で乾燥させ、濾過し、真空乾燥を行い、オフホワイトで透明感のある弾性物質を得た。分子量(Mn)は5.0kg/モル;ゲル浸透クロマトグラフィー(ポリスチレン標準)で確認した分子量分布は1.8である。1H−NMR(400MHz、CDCl3):δ13.1、11.9、10.2、5.9、3.3、2.3、1.6、0.6、0.4〜−0.1。FT−IR(ニート):ν(cm−1)2961、1698、1659、1587、1527、1258、1010、780。SEC(THF、PS標準):Mw=8.1kD。
Kraton Polymers社製のクラトンL−2203(平均分子量Mn=3400、10g)を、無水トルエン(100mL)中に溶解させた。この混合液に、UPy1(1.75g)及び2滴のジブチル錫ジラウレートを添加し、その後、混濁混合液を、アルゴン雰囲気下にて80℃で12時間攪拌した。試料を採取して、1H−NMR(3.6ppmにて多重線消失(disappearance multiplet))で反応の完全性について調べてみた。粘性反応混合液を、攪拌しながら70℃に冷却し、0.3mLの水を添加した。反応混合液をさらに1時間攪拌し、続いてメタノール中に沈殿させた(エタノールをより多く添加することにより、反応混合液の粘度を下げることができる)。白色の粘性物質を回収し、真空乾燥を行い、やや黄色味を帯びた透明なゴムを得た。収率:94%;1H−NMR(CDCl3):d13.1、11.9、10.1、5.8、4.9、4.6、4.1、3.8、3.3、3.2、2.2、1.6〜1.1、0.8。
テレケリックポリ(2−メチル−1,3−アジピン酸プロピレン)(平均分子量Mn=2.0kD、ヒドロキシ末端基、5.55g)に対し、トルエンで3回ストリッピングを行い、UPy2(1.31g)及び数滴のジブチル錫ジラウレートと共にトルエン(25mL)に溶解させた。混合液を80℃に加熱し、アルゴン雰囲気下で16時間攪拌した。その後、イソシアネート機能が消失したかどうかについてFT−IRで確認し、クロロホルム/メタノール溶液からエーテル中への沈殿、及び固形物の乾燥によりポリマーを単離した。1H−NMR(300MHz、CDCl3):δ13.1、12.0〜11.8、10.1〜9.8、5.0〜4.6、4.3〜3.8、3.4〜2.8、2.5〜2.0、1.9〜1.6、1.4〜0.8。SEC(THF、PS標準):Mn=15.5kD、D=1.7。
平均分子量が2.0kDのテレケリックヒドロキシ末端ポリ(2−メチル−1,3−アジピン酸プロピレン)(2.39g)と平均分子量が2.0kDのテレケリックヒドロキシ末端ポリカプロラクトン(2.39g)との混合物に対し、トルエンで3回ストリッピングを行い、モノマーUPy2(1.18g)及び数滴のジブチル錫ジラウレートと共にクロロホルム(25mL)に溶解させた。混合液を60℃で一晩攪拌し、続いて、イソシアネート機能が存在しないことをFT−IR分光法で確認し、UPy3(0.35g)を添加して、溶液を20mLのクロロホルムで希釈し、もう一晩還流した。再度、イソシアネート機能が消失したかどうかについてFT−IRで確認し、クロロホルム/メタノール溶液からヘキサン中への沈殿、及び固形物の乾燥によりポリマーを単離した。1H−NMR(300MHz、CDCl3):δ13.2〜12.8、12.1〜11.8、10.2〜9.8、5.8、5.2〜4.5、4.4〜3.6、3.4〜2.6、2.6〜2.0、2.0〜0.6。SEC(THF、PS標準):Mn=12.2kD、D=2.0。
ヒドロキシ末端ポリカプロラクトンジオール(Mn=2.1kg/モル;ジエチレングリコールで開始した開環重合により入手;Acros社より購入)をトルエンに溶解させた後、トルエンを減圧下で除去して水を同時蒸発させた。この手順を2回繰り返した。このプレポリマー(25.0g;12.5mmol)を無水クロロホルム(750mL)に溶解させ、その後、UPy1(8.8g)を添加した。ジブチル錫ジラウレートを2滴添加した後、溶液を16時間還流した。OH末端基の有無について1H−NMR及び13C−NMRを行い、反応の完全性を確認した。その後、5グラムのシリカキーゼルゲル60及び2滴のジブチル錫ジラウレートを添加し、混合液を16時間還流した。溶液中にUPy1が存在しないことを、IRで確認した。クロロホルムで混合液を希釈した後、ハイフローを用いた濾過により、シリカを除去した。溶液を減圧下で濃縮した。クロロホルム(500mL)を含むヘキサン(4.0L)中で物質を沈殿させ、濾過した。結果として得られた物質に24時間の真空乾燥を行い、白色綿毛状の物質として、24.4gの4H単位含有テレケリックポリカプロラクトンを得た。1H−NMR(CDCl3):δ13.1、11.9、10.1、5.9、4.9、4.2、4.1、3.7、3.2、2.3、2.2、1.6、1.5、1.4。FT−IR:ν=2941、2865、1729、1699、1669、1587、1527、1461、1418、1359、1251、1162、1105cm−1。
平均分子量が1250ダルトンのテレケリックヒドロキシ末端ポリカプロラクトン(10.94g)を、三つ口フラスコ内において真空中で30分間、120℃に加熱し、続いて、8滴のジブチル錫ジラウレート及びUPy1(5.13g)を添加した。その後、この不均一反応混合液を、アルゴン雰囲気下にて機械式攪拌装置で攪拌し、145℃に加熱した。145℃で50分間攪拌した後、均一な粘性ペーストを得た。冷却後、ペーストを単離して硬質白色物質を得た。IR分光法により、かかる生成物がもはやイソシアネートを含有していないことを確認した。1H−NMR(400MHz、CDCl3):δ13.2、11.9、10.2、5.8、4.9、4.3、4.1、3.7、3.4〜3.1、2.4〜2.2、3.1、1.8〜1.2。FT−IR(ニート):ν(cm−1)2882、1698、1663、1588、1527、1466、1342、1100、962、841。SEC(THF、PS標準):Mn=2.1kD、D=1.4。
分子量が2.0kDのテレケリックヒドロキシ末端ポリカプロラクトン(9.73g)、UPy2(2.5g)及び数滴のジブチル錫ジラウレートをクロロホルム(100mL)に溶解させ、オイルバス温度60℃にて一晩攪拌した。翌日、クロロホルムを蒸発させ、2回目のUPy2(0.5g)と共にトルエン(100mL)及びピリジン(20mL)を添加した。かかる混合液を、オイルバス温度120℃にてさらに一晩加熱し、ピリジン蒸発、クロロホルム/メタノール(10:1)からメタノール中への沈殿、及び固形物の乾燥によりポリマー生成物を単離した。その物質を置いておくと、白色(半結晶状)の弾性ポリマーとなる。1H−NMR(300MHz、CDCl3):δ13.1、12.0、10.1、4.5〜3.8、3.0、2.6〜2.2、2.0〜0.8。SEC(THF、PS標準):Mn=38.5kD、D=2.0。
テレケリックPEO−1500(5.83g)に対し、トルエンで3回ストリッピングを行った後、トルエン(30mL)に溶解させた。UPy2(2.39g)を含むトルエン(14mL)を数滴のジブチル錫ジラウレートと共に添加し、溶液をアルゴン下で一晩加熱した(オイルバス温度は120℃)。ジエチルエーテル中への沈殿によってポリマーを単離した。物質は白色(半結晶状)で、弾性及び強度がある。1H−NMR(300MHz、CDCl3/CD3OD):δ4.1、3.6、2.8、2.2、1.8〜1.4、1.2〜0.8。SEC(THF、PS標準):Mw=7.0kD。
標準的なFmocカップリング化学反応を利用した従来の固相ペプチド合成(SPPS)法により、Wang樹脂上でGRGDSペプチドを合成した(Wang樹脂へのFmoc−Ser(tBu)−OHの負荷量は、0.63mmol/gであった;Bachem社製)。いずれの場合も、20%のピペリジンを含むDMFでFmoc保護基を脱保護した。(必要に応じて)保護したアミノ酸(3等量;(Fmoc−Asp(OtBu)−OH、Fmoc−Gly−OH、Fmoc−Arg(Pmc)−OH及びFmoc−Gly−OH;Bachem社製))をDMFに溶解させた。カップリング試薬として、DMF中の1−ヒドロキシベンゾトリアゾール(3.6等量)及びジイソプロピルカルボジイミド(3.3等量)を使用した。4H単位と、保護されたGRGDSペプチドの最後のアミノ酸(Gly)の遊離アミンとのカップリングを、UPy3(5等量)を含む無水DMF(分子ふるい上で無水化)を使用し、固相支持体上で、アルゴン雰囲気下、50℃にて16時間行った。これにより、保護されたUPy−GRGDSを樹脂上に得た。過剰のUPy3を酸性水により洗い流した。ペプチドを脱保護し、95%のトリフルオロ酢酸(TFA)及び5%の水で、固相支持体から切り出した。これを(冷)ジエチルエーテル中に沈殿させ、遠沈を行い、ジエチルエーテルで3回洗浄した。その後、10〜20%のアセトニトリルを含む水からペプチドを3回凍結乾燥し、白色綿毛状の粉末を得た。必要に応じて、分取逆相液体クロマトグラフィー(RPLC)を利用してUPy−GRGDSを精製した。NMR技術、IR、RPLC、及び質量分析法により、化合物の特徴付けを行った。1H−NMR(D2O/ACN−d3):δ5.98(1H)、4.78(1H)、4.48(1H)、4.32(1H)、3.98〜3.84(2H)、3.15(2H)、2.90〜2.78(2H)、2.23(3H)、1.85〜1.61(4H)。1H−NMRのスペクトルのアサインメントを、二次元1H,1H−COSY分光法により確認した。内部標準としてヘキサフルオロリン酸カリウムを用いた19F−NMR(D2O/ACN−d3)により、試料には0.1重量%未満のTFAが含まれることがわかった。FT−IR(ニート):ν(cm−1)3280、3182、3073、2948、2542、1701、1642、1528、1413、1224、1180、1135、1076、1046。RPLC−MS:クロマトグラム中に1本のピーク、m/z:計算値、641.3g/モル。測定値、[M+H]+=642.2g/モル及び[M+H]2+=321.7g/モル。
標準的なFmocカップリング化学反応を利用した従来の固相ペプチド合成(SPPS)法により、Wang樹脂上でPHSRNペプチドを合成した(Wang樹脂へのFmoc−Asn(Trt)−OHの負荷量は、0.43mmol/gであった;Bachem社製)。いずれの場合も、20%のピペリジンを含むDMFでFmoc保護基を脱保護した。(必要に応じて)保護したアミノ酸(3等量;(PHSRN用の、Fmoc−Arg(Pmc)−OH、Fmoc−Ser(tBu)−OH、Fmoc−His(Trt)−OH及びFmoc−Pro−OH;Bachem社製))をDMFに溶解させた。カップリング試薬として、DMF中の1−ヒドロキシベンゾトリアゾール(3.6等量)及びジイソプロピルカルボジイミド(3.3等量)を使用した。4H単位と、保護されたPHSRNペプチドの最後のアミノ酸(Pro)の遊離アミンとのカップリングを、UPy1(8等量)を含む無水クロロホルム(分子ふるい)を使用し、固相支持体上で、21℃にて16時間行った。これにより、保護されたUPy−PHSRNを樹脂上に得た。過剰のUPy1を酸性水により洗い流した。ペプチドを脱保護し、95%のトリフルオロ酢酸(TFA)及び5%の水で、固相支持体から切り出した。これを(冷)ジエチルエーテル中に沈殿させ、遠沈を行い、ジエチルエーテルで3回洗浄した。その後、10〜20%のアセトニトリルを含む水からペプチドを3回凍結乾燥し、白色綿毛状の粉末を得た。必要に応じて、分取逆相液体クロマトグラフィー(RPLC)を利用してUPy−PHSRNを精製した。1H−NMR(D2O/ACN−d3):δ8.58(1H)、7.27(1H)、5.92(1H)、4.73(1H)、4.66(1H)、4.36(1H)、4.15(1H)、3.86(2H)、3.40〜3.05(2H)、2.82〜2.73(2H)、2.21(3H)、2.15(1H)、2.03〜2.00(3H)、1.94〜1.62(4H)、1.54〜1.46(4H)、1.34〜1.27(8H)。1H−NMRのスペクトルのアサインメントを、二次元1H,1H−COSY分光法により確認した。内部標準としてヘキサフルオロリン酸カリウムを用いた19F−NMR(D2O/ACN−d3)により、試料には1重量%未満のTFAが含まれることがわかった。FT−IR(ニート):ν(cm−1)3263、2943、1657、1542、1441、1361、1317、1252、1201、1133、1078。RPLC−MS:クロマトグラム中に1本のピーク、m/z:計算値、902.4g/モル。測定値、[M+H]+=903.3g/モル、[M+H]2+=452.3g/モル及び[M+H]3+=301.9g/モル。
室温にて、ヘキサンジアミン(2.03g)を含むクロロホルム溶液に、UPy4(0.51g)を添加した。混合液を一晩攪拌した。この混合液に、塩基性水(5gのNaOHを含む20mLの水)を添加し、遠心分離(4300rpmで5分間)後、透明な水層が分離し、その後、それを単離した。3MのHClを含む水で、塩基性水層のpHを6にした。アミノ官能性4H単位が単離されて白色沈殿物が形成され、それをクロロホルムで抽出した。クロロホルム層をNa2SO4で乾燥させ、蒸発させた。1H−NMR(CDCl3):δ13.25(1H)、11.91(1H)、10.21(1H)、5.82(1H)、3.27(2H)、2.66(2H)、2.31(1H)、1.69〜1.28(16H)、0.90(6H)。FT−IR(ニート):ν(cm−1)3064;2956;2856;2927;2856;1939;1664;1594;1558;1520;1428;1265;1178;1117;1073;950;840;814;773;756;728;697。元素分析:C61.34、H9.64;N19.82、計算値(C61.51、H9.46、N19.92)。RPLC−MS:[M+H]+=352.2(計算値:351.41)g/モル;[イソシトシン+H]+=210.2(計算値:209.29)g/モル;[UPy−C6−UPy+H]+=587.3(計算値:586.78)g/モル。
N−(+)−ビオチニル−3−アミノプロピルアンモニウムトリフルオロ酢酸(165mg、Sigma-Aldrich社より入手)を含むDMF(1.0mL)の溶液に、UPy4(124mg)及びジイソプロピルエチルアミン(DIPEA;133mg)を添加した。混合液を60℃にて7時間攪拌した。減圧下でDMFを除去し、すべてをクロロホルムに溶解させた。以下の抽出を行った;塩水で3回、1MのHClで3回。結合した有機層をNa2SO4で乾燥させ、1.5mLに濃縮した。これを冷アセトン中で沈殿させ、遠心分離にかけた。アセトンを取り除き、生成物を減圧下で40℃にて2時間乾燥させた。これにより、収率65%で白色粉末を得た。1H−NMR(400MHz、CDCl3):δ13.32(1H)、11.82(1H)、10.07(1H)、5.92(1H)、4.51(1H)、4.36(1H)、3.37(4H)、3.13(1H)、2.90(1H)、2.73(1H)、2.39(1H)、2.23(2H)、1.81〜1.19(16H)、0.89(6H)。FT−IR(ニート):ν(cm−1)3217;3038;2929;2860;1699;1641;1583;1526;1460;1439;1381;1306;1251;1145;1075;1009;951;850;796;763;739;686。MALDI−TOF:536.14g/モル(計算値535.71g/モル)、301.07g/モル、334.23g/モル。
UPy4(0.376g、1.24mmol)を含むジクロロメタン(5mL)の無色の溶液に、t−ブチル−6−アミノ−2−{{ビス{2−[ビス−(t−ブトキシカルボニルメチル)アミノ]−エチル}−アミノ}}ヘキサノエート(0.713g、Anelli, P.L. et al. Bioconjugate Chem. 1999, 10, p. 137, compound 7に記載の通りに得られる化合物)の溶液を、ゆっくりと添加した。かかる溶液を、20℃で12時間、激しく攪拌した。黄色味を帯びた溶液を、1MのKHSO3(水溶液)pH1.95(2×10mL)で洗浄した。その後、有機層を1MのK2CO3(水溶液)pH10(3×10mL)及び塩水(3×10mL)で洗浄した。結合した水層をDCM(2×10mL)で乾燥させ、有機層をMgSO4で乾燥させた。反応混合液を減圧下で濃縮し、黄色味を帯びた液体(0.84g)を得た。EtOAcを用いたカラムクロマトグラフィーで粗生成物(0.730g)を精製し、保護されたSupraB含有DTPA類似体を0.51g得た(Rf=0.5(EtOAc))。1H−NMR(CDCl3):δ13.3(1H)、11.9(1H)、10.2(1H)、5.8(1H)、3.5(8H)、3.3−3.2(3H)、3.0−2.6(8H)、2.3(1H)、2.0−1.2(14H)、0.94(6H)。1H−NMRのスペクトルのアサインメントを、1H,1H−COSYにより確認した。FT−IR(ニート):ν(cm−1)2975、2932、1724、1698、1658、1646、1586、1526、1367、1253、1219、1148。ESI−QTOF−MS:m/z[C50H89N7O12+H]+、計算値980.67Da、測定値980.71Da;[C50H89N7O12+Na]+、計算値1002.65Da、測定値1002.65Da。
標準的なFmocカップリング化学反応を利用した従来の固相ペプチド合成(SPPS)法により、Wang樹脂上でCGGKGペプチドを合成した(Wang樹脂へのFmoc−Gly−OHの負荷量は、0.75mmol/gであった;Bachem社製)。いずれの場合も、20%のピペリジンを含むDMFでFmoc保護基を脱保護した。(必要に応じて)保護したアミノ酸(3等量;(Fmoc−Lys(Mtt)−OH、Fmoc−Gly−OH、Fmoc−Gly−OH及びFmoc−Cys(Trt)−OH;Bachem社製))をDMFに溶解させた。カップリング試薬として、DMF中の1−ヒドロキシベンゾトリアゾール(3.6等量)及びジイソプロピルカルボジイミド(3.3等量)を使用した。
ヘパリンナトリウム塩(1.0g、Mn=12000、活性=195IU/mg、ブタ腸粘膜、ドイツ国、Merck Biosciences社より入手)を水に溶解させ、ダウエックス50X8(H+)カラムに通し、続いて水での透析(分画分子量=12000〜14000)及び凍結乾燥を行って、ヘパリン(0.95g)を得た。2重量%の凍結ヘパリンの溶液を含む、0.05Mの2−モルホリノエタン硫酸緩衝液(MES緩衝液、pH=5.60)に、N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド(EDC)及びN−ヒドロキシスクシンイミド(NHS)を、NHS:EDC:ヘパリン−CO2H=0.24:0.40:1.0というモル比で添加することにより、ヘパリンのカルボン酸基を活性化した。10分間の前活性化の後、UPy5(64mg)をMES緩衝液(3mL、pH=5.60)に溶解させ、NHS/EDC活性化ヘパリン溶液(25mL)に添加し、結果として6:1(UPy5:ヘパリン)というモル比になった。3時間後、反応混合液をMES緩衝液(pH=5.60)で1回透析し、続いて水で大規模な透析を行った後に凍結乾燥を行って、約6個の4H単位で官能基化したヘパリンを得た。
ヘパリンナトリウム塩(1.0g、Mn=12000、活性=195IU/mg、ブタ腸粘膜、ドイツ国、Merck Biosciences社より入手)を水に溶解させ、ダウエックス50X8(H+)カラムに通し、続いて水での透析(分画分子量=12000〜14000)及び凍結乾燥を行って、ヘパリン(0.95g)を得た。ヨウ化物(0.2g)を含む20%のメタノール水溶液(25mL)で、ヘパリンの還元末端を室温で6時間酸化した。4重量%の水酸化カリウムを含むメタノール(50mL)に、反応液を添加した。結果として生じた白色沈殿物を濾過し、水に溶解させて透析(分画分子量=12000〜14000)した。凍結乾燥後、酸化ヘパリンを得た。その後酸化ヘパリンを水に溶解させ、ダウエックス50X8(H+)カラムに通し、続いて凍結乾燥を行ってラクトン−ヘパリン(0.74g)を得た。10倍モル過剰のUPy5(45mg)をDMF(2mL)に溶解させた後、DMF(10mL)に溶解させたラクトン−ヘパリン(200mg)に添加した。反応物を80℃にて16時間攪拌した。反応混合液を真空中で濃縮し、続いて水に溶解させた。その後、希釈した反応混合液をダウエックス50X8(H+)カラムに通した。溶出液を水で大々的に透析し、続いて凍結乾燥を行った。その結果、末端が4H単位で官能基化されたヘパリンを得た。
アクリルアミド水溶液(1.3mL;水に対して40%w/v)とビスアクリルアミド水溶液(0.6mL;水に対して2%w/v)とを混合した。この混合液を、トリス(ヒドロキシメチル)アミノメタン緩衝液(トリス、1.2mL;0.4Mのトリス−HCl、pH8.8)及び水(1.5mL)で希釈し、続いて、実施例25の4H単位官能基化ヘパリン(123mg)を添加した。この混合液を80℃に加熱し、その後、アクリルアミド(0.20mL)に溶解させたUPy6(48mg)を添加した。過硫酸アンモニウム(50μL;最終濃度0.1%)及びN,N,N’,N’−テトラメチルエチレンジアミン(TEMED、2.5μL;最終濃度0.1%)を添加した後、混合液を重合した。その結果、4H単位で官能基化された部分を含み、実施例24の生物活性成分を2重量%含む、12%のアクリルアミドゲルを得た。
ポリマーXI(2.5g)及びUPy6(1.5g)を、テトラエチレングリコールジアクリレート(TEGDA、1.0g)、Irgacure 907TM(150mg、スイス国、Ciba社より入手)と共に、ヒドロキシエチルアクリレート(HEA、10g)に80℃で溶解させた。その後、ガラス製の基質上に100μmのフィルムを機械的に引き延ばし、照射時間0.3秒に相当するベルト速度10.4m/分にてFusion F600 D-bulb(I0=5W/cm2)を用いて、窒素雰囲気下でUV硬化させた。すぐれた機械的特性を備えた透明なコーティングを得た。
Claims (12)
- 以下の成分を含む超分子生体吸収性材料又は超分子生物医学用材料:
(a)少なくとも2個の4H単位に共有結合しているポリマーであり、前記超分子材料が生体吸収性の場合は生体吸収性であるポリマー;及び
(b)1〜4個の4H単位に共有結合している生物活性化合物;
であって、
前記(a)及び(b)の4H単位が、同一又は異なって、一般式(1)又は(2)
前記生物活性化合物が、抗菌剤、抗ウィルス剤、抗腫瘍剤、抗血栓剤、ホルモン、免疫原性薬剤、成長因子、(蛍光)染色剤、造影剤、核酸、脂質、リポ多糖類、(多)糖類、ビタミン、ペプチド、オリゴペプチド及びタンパク質からなる群から選択されることを特徴とする超分子生体吸収性材料又は超分子生物医学用材料。 - 成分(a)が、3〜50個の4H単位に共有結合しているポリマーであることを特徴とする請求項1記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 成分(a)のMnが、100〜100,000であることを特徴とする請求項1又は2記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 成分(a)が、2個の末端ヒドロキシ基又は2個の末端第一級アミノ基を有するポリマーに由来することを特徴とする請求項1〜3のいずれか記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 2個の末端ヒドロキシ基又は2個の末端第一級アミノ基を有するポリマーのMnが、500〜10000であることを特徴とする請求項4記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 超分子生体吸収性材料又は超分子生物医学用材料が、第三の成分(c)を含み、該第三の成分(c)が、生体吸収性ポリマー又は生物医学用ポリマーであることを特徴とする請求項1〜5のいずれか記載の超分子生体吸収性材料又は超分子生物医学用材料。
- (c)が、1〜50個の4H単位に共有結合している生体吸収性ポリマー又は生物医学用ポリマーであることを特徴とする請求項6記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 超分子生体吸収性材料又は超分子生物医学用材料が、該超分子生体吸収性材料又は超分子生物医学用材料の総重量に対して50.00〜99.99重量%の成分(a)及び0.01〜50.00重量%の成分(b)を含むことを特徴とする請求項1〜7のいずれか記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 超分子生体吸収性材料又は超分子生物医学用材料が、該超分子生体吸収性材料又は超分子生物医学用材料の総重量に対して20.00〜59.99重量%の成分(a)、0.01〜40.0重量%の成分(b)及び0.01〜40.00重量%の成分(c)を含むことを特徴とする請求項1〜7のいずれか記載の超分子生体吸収性材料又は超分子生物医学用材料。
- 請求項1〜9のいずれか記載の超分子生物医学用材料の、組織工学用材料、インプラント又は生物医学用コーティング組成物における使用。
- 請求項1〜9のいずれか記載の超分子生物医学用材料の、薬剤の放出制御を目的とした使用。
- 請求項1〜9のいずれか記載の超分子生物医学用材料を含む、生物医学用コーティング組成物。
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US60/679,671 | 2005-05-11 | ||
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PCT/NL2006/050107 WO2006118461A2 (en) | 2005-05-04 | 2006-05-03 | Modular bioresorbable or biomedical, biologically active supramolecular materials |
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ES2376888T3 (es) | 2012-03-20 |
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EP1877113B1 (en) | 2011-11-09 |
US20160228229A1 (en) | 2016-08-11 |
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