JP7217245B2 - 高分子量双性イオン含有重合体 - Google Patents
高分子量双性イオン含有重合体 Download PDFInfo
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- JP7217245B2 JP7217245B2 JP2020077026A JP2020077026A JP7217245B2 JP 7217245 B2 JP7217245 B2 JP 7217245B2 JP 2020077026 A JP2020077026 A JP 2020077026A JP 2020077026 A JP2020077026 A JP 2020077026A JP 7217245 B2 JP7217245 B2 JP 7217245B2
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Description
該当せず。
各社が「医学的に差別化された製品」を届けようとしている大手製薬会社の間で、現在、或る種の激しい競争が起こっている。生物製剤(biopharmaceutical)はキーとなる媒体と見られている。差別化は必ずしも標的の新規性から生じて来るというわけでなく新規な薬剤フォーマットから生じて来ると考えられている。これらのフォーマットは、得られる薬剤がフォーマット中心というよりむしろ生物学中心であることができるように柔軟なものである。生物製剤のこの次の波は、モジュール型(modular)で、多機能性で、かつ標的化されたものである。これらの薬剤は、標的化される広範な疾病生物学を理解し多面的な薬剤にその知識を適用することを企図して設計される。抗体は素晴らしい薬剤であるが、有意量の抗体タンパク質工学にもかかわらず、それらの薬剤は硬直した融通の利かないフォーマットでありそしてあり続ける。
幾つかの実施形態において、本発明は、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル-ピリジン、ビニル-ピロリドン又はビニル-エステルからそれぞれ独立して選択される複数の単量体(各単量体は親水性基を含む)をそれぞれ有する重合体アーム少なくとも2つを有する重合体を提供する。前記重合体は重合体アームの基部末端(proximal end)に連結された開始剤フラグメントも含み、ここで開始剤成分はラジカル重合に好適である。前記重合体は重合体アームの遠位末端(distalend)に連結された末端基も含む。開始剤フラグメント及び重合体の末端基の少なくとも1つは機能性剤又は連結基を含む。
I.概論
本発明は、親水性基又は双性イオン、例えば、ホスホリルコリンなどと、及び少なくとも1の機能性剤(本明細書中に定義した通り)とを有する高分子量重合体を提供する。高い生体適合性の分子としてのホスホリルコリンは基本的な生体適合性をドライブする。それは、温度又は他のストレス下でタンパク質を保護することによって、シャペロンタイプの機能も有している。それは、可逆的な細胞取込み(reversible cellular uptake)などの他の機能を可能にすることもできる。機能性剤は、生体活性剤、例えば、薬剤、治療タンパク質又は標的化剤など、並びに検出剤、イメージング剤、標識化剤又は診断剤であることができる。高分子量重合体は、1又は2以上の適切な機能性剤を選択することによって、様々な症状及び疾患状態の治療に有効である。2以上の生体活性剤を高分子量重合体に連結することができ、このようにして単一の疾病の症状又はメカニズムだけでなく、むしろ疾病全体の治療を可能にする。さらに、本発明の高分子量重合体は、適当な標的化剤及びイメージング剤の結合によって診断及びイメージングの目的に対して有用である。本発明の高分子量重合体は治療剤及び診断剤の双方を単一の重合体中に含んでいることによって、疾病を治療し並びに検出及び診断をする治療診断剤を提供することができる。重合体は安定な又は不安定なリンケージを介して生体活性剤(1又は複数)に連結されることができる。
「重合体」とは一緒に連結された一連の単量体基をいう。高分子量重合体は、限定的でなく、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル-ピリジン、ビニル-ピロリドン及びビニルエステル、例えば、酢酸ビニルを含む単量体から製造される。さらなる単量体が本発明の高分子量重合体に有用である。2種の異なる単量体が用いられる場合、これら2つの単量体は「共単量体」と呼ばれるが、異なる単量体が共重合されて単一の重合体を形成することを意味する。重合体は直鎖又は分枝状であることができる。重合体が分枝状である場合、各重合体鎖は「重合体アーム」と呼ばれる。開始剤成分に連結された重合体アームの末端は基部末端であり、重合体アームの生長鎖末端は遠位末端である。重合体アームの生長鎖末端上の、重合体アーム末端基はラジカルスカベンジャー、又は別の基であることができる。
はもとのスルフヒドリルが保有している基の残部へのチオールの硫黄原子の結合点を表す]を有する-S-マレイミド基を形成する。
本発明は、親水性基及び官能基又は結合基を有する高分子量重合体を提供する。幾つかの実施形態において、本発明は、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル-ピリジン、ビニル-ピロリドン又はビニルエステル、例えば、酢酸ビニルからそれぞれ独立して選択される複数の単量体(各単量体は親水性基を含む)をそれぞれ有する少なくとも2つの重合体アームを有する重合体を提供する。重合体は、開始剤成分がラジカル重合に適当である、重合体アームの基部末端に連結された開始剤フラグメントも含む。重合体は重合体アームの遠位末端に連結された末端基も含む。重合体の開始剤フラグメント及び末端基の少なくとも1つは機能性剤又は連結基を含む。
本発明の高分子量重合体は任意の適当な開始剤を用いて重合される。本発明に有用な開始剤は次式:I-(I’)m[式中、下付き文字mは1~100の整数である]によって表わされることができる。開始剤フラグメントIは重合を開始する任意の基であることができる。ラジカルスカベンジャーI’は生長する重合体鎖を可逆的に停止する任意の基であることができる。ラジカルスカベンジャーI’は、重合後に重合体の末端が官能化されることを可能にする、ハロゲン、例えば、臭素などであることができる。幾つかの実施形態において、ラジカルスカベンジャーI’を末端基と呼ぶ。さらに、開始剤フラグメントIは場合により、種々の官能基を含んでいることができるR1基で官能化されて高分子量重合体の官能性を調整することができる。
(F)r-Sp1-C-Sp2-I’
[上記式中、開始剤フラグメントIはF-Sp1-C-Sp2に対応する]を有する。各F基は、本発明の機能性剤又は連結基との反応のための官能基である。ラジカルrは1~10である。Sp1基及びSp2基はスペーサーであり共有結合を形成する任意の適当な基、例えば、C1-6アルキル基、アリール基又はヘテロアリール基であることができる。C基は、1又は2以上のスペーサーSp2(同じであるか又は異なっていることができる)及び1又は2以上のラジカルスカベンジャーI’に連結するための1又は複数の点を提供し、かつ1又は2以上のスペーサーSp1(同じであるか又は異なっていることができる)及び1又は2以上の官能基F(同じであるか又は異なっていることができる)に連結するための1又は複数の点を提供する、任意のコアであることができる。コアCは任意の適当な構造、例えば、分枝状構造、ヘテロ原子を含む架橋構造、例えば、シルセスキロキサン(silsesquiloxane)など、及び複数のペンダント官能基を有する直鎖の短い重合体など、であることができる。さらに、コアCは、限定的でなく、エステル基、アミド基、エーテル基、及びケトン基を含む共有結合を形成するための任意の適当な基によって1又は2以上のSp1及びSp2スペーサーに結合されていることができる。ラジカルスカベンジャーI’はラジカル移動可能な(radically transferable)原子又は基、例えば、限定的でなく、ハロゲン原子、Cl原子、Br原子、I原子、OR10基、SR11基、SeR11基、OC(=O)R11基、OP(=O)R11基、OP(=O)(OR11)2基、O-(R11)2基、S-C(=S)N(R11)2基、CN基、NC基、SCN基、CNS基、OCN基、CNO基、N3基、OH基、O基、C1-C6-アルコキシ基、(SO4)基、PO4基、HPO4基、H2PO4基、トリフレート基、ヘキサフルオロホスフェート基、メタンスルホネート基、アリールスルホネート基、ハロゲン化カルボン酸基など、である。R10は、炭素原子1~20個のアルキル基又は各水素原子がハリド基で置換されていることができる炭素原子1~20個のアルキル基、炭素原子2~20個のアルケニル基、炭素原子2~10個のアルキニル基、フェニル基、ハロゲン原子1~5個又は炭素原子1~4個を有するアルキル基で置換されたフェニル基、アルアルキル基、アリール基、アリール置換されたアルキル基(アリール基はフェニル基又は置換されたフェニル基でありそしてアルキル基は炭素原子1~6個である)であり、そしてR11はアリール基又は直鎖若しくは分枝状のC1-C20アルキル基であるか又はN(R11)2基が存在する場合には、2つのR11基は結合されて5員、6員又は7員の複素環式環を形成することができる。スペーサーSp1は官能基F及びコアCと共有結合しているが、スペーサーSp2はコアC及びラジカルスカベンジャーI’と共有結合している。
本発明の高分子量重合体を製造するのに有用な単量体としてラジカル重合を行うことができる任意の単量体を挙げることができる。一般に、かかる単量体はビニル基を有する。好適な単量体として、限定的でなく、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル-ピリジン、ビニル-ピロリドン及びビニルエステル、例えば、酢酸ビニル単量体を挙げることができる。本発明に有用な単量体は親水性基を含む。本発明の親水性基は任意の適当な親水性基であることができる。例えば、親水性基は双性イオン基及び親水性重合体を含んでいることができる。幾つかの実施形態において、各親水性基は双性イオン基を含む。本発明の双性イオン基は陰電荷及び陽電荷の双方を有する任意の化合物を含む。本発明の双性イオンに用いるのに好適でかつ陰電荷を有する基として、限定的でなく、ホスフェート、スルフェート、他のオキソアニオン等を挙げることができる。本発明の双性イオンに用いるのに好適でかつ陽電荷を有する基として、限定的でなく、アンモニウムイオンを挙げることができる。幾つかの実施形態において、双性イオンはホスホリルコリンであることができる。本発明に有用な他の双性イオンとしてWO1994016748及びWO1994016749パンフレットに記載されたもの(引用として本明細書中に組み込まれる)を挙げることができる。本発明に有用な親水性重合体として、ポリエチレンオキシド、ポリオキサゾリン、セルロース、デキストラン、及び他の多糖重合体を挙げることができる。当業者であれば、他の親水性重合体が本発明に有用であることを理解されよう。
本発明の高分子量重合体は任意の適当なリンカーLを含んでいることもできる。リンカーL3は機能性剤の開始剤フラグメントIへの結合を提供しそしてリンカーL1及びL2は双性イオン基の共単量体M1及びM2への結合を提供する。リンカーは開裂性又は非開裂性の、ホモ二官能性又はヘテロ二官能性であることができる。他のリンカーはヘテロ二官能性でかつ開裂性、又はホモ二官能性でかつ開裂性であることができる。
本発明のリンカー及び機能性剤は開始剤フラグメントI上の連結基と反応して結合を形成することができる。本発明の連結基LGは、別の官能基への結合を形成し、それによって2つの基を一緒に連結することができる任意の適当な官能基であることができる。例えば、本発明に有用な連結基LGとして、とりわけ、クリックケミストリー、マレイミドケミストリー、及びNHS-エステルに用いられるものを挙げることができる。クリックケミストリーに関与する連結基として、限定的でなく、ヒュスゲン環化付加法によってトリアゾール環を形成するアジ化物及びアルキンを挙げることができる(例えば、その全体が本明細書中に組み込まれる、米国特許第7,375,234号参照)。マレイミドケミストリーは、安定な結合を形成する、マレイミドオレフィンと求核試薬、例えば、-OH、-SH又は-NH2など、との反応を包含する。他の連結基として、Bioconjugate Techniques, Greg T. Hermanson, Academic Press, 2d ed., 2008(その全体が本明細書中に組み込まれる)に記載されているものを挙げることができる。
本発明の高分子量重合体に有用な機能性剤として、特定のリガンド、受容体、複合体、オルガネラ、細胞、組織、上皮シート、若しくは器官を標的化することができ、又は特定の症状又は疾患状態を治療することができる、任意の生物学的剤又は合成化合物を挙げることができる。幾つかの実施形態において、生体活性剤は、薬剤、治療タンパク質、小分子、ペプチド、ペプトイド、オリゴヌクレオチド(アプタマー、siRNA、microRNA)、ナノ粒子、炭水化物、脂質、糖脂質、リン脂質又は標的化剤である。本発明の高分子量重合体に有用な他の機能性剤として、限定的でなく、放射性ラベル、造影剤、フルオロフォア及び色素を挙げることができる。
1つのとりわけ有用な実施形態において、機能性剤は治療タンパク質である。多数の治療タンパク質、例えば、限定的でなく、エリトロポエチン、顆粒球コロニー刺激因子(G-CSF)、GM-CSF、インターフェロンα、インターフェロンβ、ヒト成長ホルモン、イミグルセラーゼ(imiglucerase)、及びRANKリガンドなど、が本願明細書中に開示される。
本明細書中に開示されたように生体活性剤として用いられるタンパク質及びペプチドは、インビトロ合成による製造及び生物学的系における製造を含む任意の有効な方法によって製造されることができる。当該技術分野で周知のインビトロ合成法の典型的な例として、固相合成(「SPPS」)及び固相フラグメント縮合(「SPFC」)を挙げることができる。タンパク質の製造に用いられる生物学的系も当該技術分野で周知である。細菌(例えば、大腸菌及びバチルス種(Bacillus sp.))及び酵母(例えば、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)及びピキア・パストリス(Pichia pastoris))が異種タンパク質の製造に広く用いられている。さらに、本明細書に開示されたように用いられる生体活性剤の製造のための異種遺伝子発現は、動物細胞系、例えば、哺乳動物細胞系(例えば、CHO細胞)など、を用いて達成されることができる。1つのとりわけ有用な実施形態において、生体活性剤はトランスジェニック又はクローン化動物、例えば、ウシ、ヒツジ、ヤギ及び鳥類(例えば、ニワトリ、ウズラ、アヒル及びシチメンチョウ)において産生され、そのそれぞれが当該技術分野で理解されている。例えば、引用としてその全体が本明細書中に組み込まれる、2004年8月24日に発行された米国特許第6,781,030号を参照されたい。
別の実施形態において、生体活性剤は、特異的に同定された薬剤又は治療剤から選択されることもでき、その例として、限定的でなく、以下を挙げることができる:タクリン、メマンチン、リバスチグミン、ガランタミン、ドネペジル、レベチラセタム、レパグリニド、アトルバスタチン、アレファセプト、タダラフィル、バルデナフィル、シルデナフィル、ホスアンプレナビル、オセルタミビル、バラシクロビル及びバルガンシクロビル、アバレリックス、アデホビル、アルフゾシン、アロセトロン、アミホスチン、アミオダロン、アミノカプロン酸、アミノ馬尿酸ナトリウム、アミノグルテチミド、アミノレブリン酸、アミノサリチル酸、アムロジピン、アムサクリン、アナグレリド、アナストロゾール、アプレピタント、アリピプラゾール、アスパラギナーゼ、アタザナビル、アトモキセチン、アントラサイクリン、ベキサロテン、ビカルタミド、ブレオマイシン、ボルテゾミブ、ブセレリン、ブスルファン、カベルゴリン、カペシタビン、カルボプラチン、カルムスチン、クロラムブシン(chlorambucin)、シラスタチンナトリウム、シスプラチン、クラドリビン、クロドロネート、シクロホスファミド、シプロテロン、シタラビン、カンプトテシン、13-シスレチノイン酸、すべてのトランスレチノイン酸;ダカルバジン、ダクチノマイシン、ダプトマイシン、ダウノルビシン、デフェロキサミン、デキサメタゾン、ジクロフェナク、ジエチルスチルベストロール、ドセタキセル、ドキソルビシン、デュタステリド、エレトリプタン、エムトリシタビン、エンフビルチド、エプレレノン、エピルビシン、エストラムスチン、エチニルエストラジオール、エトポシド、エキセメスタン、エゼチミブ、フェンタニル、フェキソフェナジン、フルダラビン、フルドロコルチゾン、フルオロウラシル、フルオキシメステロン、フルタルニド(flutarnide)、フルチカゾン、フォンダパリナックス、フルベストラント、γ-ヒドロキシブチレート、ゲフィチニブ、ゲムシタビン、エピネフリン、L-ドーパ、ヒドロキシウレア、イコデキストリン、イダルビシン、イホスファミド、イマチニブ、イリノテカン、イトラコナゾール、ゴセレリン、ラロニダーゼ、ランソプラゾール、レトロゾール、ロイコボリン、レバミゾール、リシノプリル、ロボチロキシンナトリウム(lovothyroxine sodium)、ロムスチン、メクロレタミン、メドロキシプロゲステロン、メゲストロール、メルファラン、メマンチン、メルカプトプリン、メキノール、酒石酸水素メタラミノール、メトトレキサート、メトクロプラミド、メキシレチン、ミグルスタット、マイトマイシン、ミトタン、ミトキサントロン、モダフィニル、ナロキソン、ナプロキセン、ネビラピン、ニコチン、ニルタミド、ニタゾキサニド、ニチシノン、ノルエチンドロン、オクトレオチド、オキサリプラチン、パロノセトロン、パミドロネート、ペメトレキセド、ペルゴリド、ペントスタチン、ピルカマイシン(pilcamycin)、ポルフィマー、プレドニゾン、プロカルバジン、プロクロルペラジン、オンダンセトロン、パロノセトロン、オキサリプラチン、ラルチトレキセド、ロスバスタチン、シロリムス、ストレプトゾシン、ピメクロリムス、セルタコナゾール、タクロリムス、タモキシフェン、テガセロッド、テモゾロミド、テニポシド、テストステロン、テトラヒドロカンナビノール、サリドマイド、チオグアニン、チオテパ、チオトロピウム、トピラメート、トポテカン、トレプロスチニル、トレチノイン、バルデコキシブ、セレコキシブ、ロフェコキシブ、バルルビシン、ビンブラスチン、ビンクリスチン、ビンデシン、ビノレルビン、ボリコナゾール、ドラセトロン、グラニセトロン、ホルモテロール、フルチカゾン、ロイプロリド、ミダゾラム、アルプラゾラム、アンホテリシンB、ポドフィロトキシン、ヌクレオシド抗ウイルス薬、アロイルヒドラゾン、スマトリプタン、エレトリプタン;マクロライド系薬剤、例えば、エリスロマイシン、オレアンドマイシン、トロレアンドマイシン、ロキシスロマイシン、クラリスロマイシン、ダベルシン(davercin)、アジスロマイシン、フルリスロマイシン、ジリスロマイシン、ジョサマイシン、スピロマイシン、ミデカマイシン、ロラタジン、デスロラタジン、ロイコマイシン、ミオカマイシン、ロキタマイシン、アンダジスロマイシン(andazithromycin)、及びスウィノリド(swinolide)A;フルオロキノロン、例えば、シプロフロキサシン、オフロキサシン、レボフロキサシン、トロバフロキサシン、アラトロフロキサシン(alatrofloxacin)、モキシフロキシシン(moxifloxicin)、ノルフロキサシン、エノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、ロメフロキサシン、スパルフロキサシン、テマフロキサシン、ペフロキサシン、アミフロキサシン、フレロキサシン、トスフロキサシン、プルリフロキサシン、イルロキサシン(irloxacin)、パズフロキサシン、クリナフロキサシン、及びシタフロキサシン;アミノグリコシド、例えば、ゲンタマイシン、ネチルマイシン、パラメシン、トブラマイシン、アミカシン、カナマイシン、ネオマイシン、及びストレプトマイシン、バンコマイシン、テイコプラニン、ラムポラニン(rampolanin)、ミデプラニン(mideplanin)、コリスチン、ダプトマイシン、グラミシジン、コリスチメタート;ポリミキシン、例えば、ポリミキシンB、カプレオマイシン、バシトラシン、ペネム;ペニクリナーゼ感受性(penicllinase-sensitive)薬剤を含むペニシリン、例えば、ペニシリンG、ペニシリンV;ペニシリナーゼ耐性薬剤、例えば、メチシリン、オキサシリン、クロキサシリン、ジクロキサシリン、フロキサシリン、ナフシリン;グラム陰性微生物活性剤、例えば、アンピシリン、アモキシシリン、及びヘタシリン、シリン(cillin)、及びガランピシリン(galampicillin);抗緑膿菌性(antipseudomonal)ペニシリン、例えば、カルベニシリン、チカルシリン、アズロシリン、メズロシリン、及びピペラシリン;セファロスポリン、例えば、セフポドキシム、セフプロジル、セフトブテン(ceftbuten)、セフチゾキシム、セフトリアキソン、セファロチン、セファピリン、セファレキシン、セフラドリン(cephradrine)、セフォキシチン、セファマンドール、セファゾリン、セファロリジン、セファクロル、セファドロキシル、セファログリシン、セフロキシム、セフォラニド、セフォタキシム、セファトリジン、セファセトリル、セフェピム、セフィキシム、セフォニシド、セフォペラゾン、セフォテタン、セフメタゾール、セフタジジム、ロラカルベフ、及びモキサラクタム、モノバクタム、例えば、アズトレオナム;及びカルバペネム、例えば、イミペネム、メロペネム、及びエルタペネム、ペンタミジンイセチオネート、硫酸アルブテロール、リドカイン、硫酸メタプロテレノール、ベクロメタゾンジプレピオネート(beclomethasone diprepionate)、トリアムシノロンアセトアミド(triamcinolone acetamide)、ブデソニドアセトニド(budesonide acetonide)、サルメテロール、臭化イプラトロピウム、フルニソリド、クロモリンナトリウム、及び酒石酸エルゴタミン;タキサン、例えば、パクリタキセル;SN-38、及びチルホスチン。生体活性剤は、別の実施形態において、アミノ馬尿酸ナトリウム、アンホテリシンB、ドキソルビシン、アミノカプロン酸、アミノレブリン酸、アミノサリチル酸(arninosalicylic acid)、酒石酸水素メタラミノール、パミドロネート二ナトリウム、ダウノルビシン、レボチロキシンナトリウム、リシノプリル、シラスタチンナトリウム、メキシレチン、セファレキシン、デフェロキサミン、及びアミホスチンからなる群から選択されることもできる。
本発明の高分子量重合体に有用な診断剤として、イメージング剤及び検出剤、例えば、放射性ラベル、フルオロフォア、色素及び造影剤などを挙げることができる。
機能性剤はナノ粒子を含んでいることもできる。本発明に有用なナノ粒子は1~1000nm範囲の大きさを有する粒子を含む。ナノ粒子はビーズ、金属粒子であることができるか又は或る場合にミセルであることができそして或る他の場合にリポソームであることができる。他のナノ粒子として、カーボンナノチューブ、量子ドット及びコロイド金を挙げることができる。ナノ粒子に診断剤及び/又は治療剤を詰める(pack)ことができる。
本発明の重合体は上記の様々な機能性剤に連結されてコンジュゲートを形成することができる。幾つかの実施形態において、本発明は、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル-ピリジン、ビニル-ピロリドン及びビニルエステル、例えば、酢酸ビニルからなる群からそれぞれ独立して選択される複数の単量体(各単量体は親水性基を含む)を有する重合体アームと、該重合体アームの基部末端に連結された開始剤フラグメント(開始剤成分はラジカル重合に好適である)と、及び重合体アームの遠位末端に連結された末端基と、を有する重合体少なくとも1種を含むコンジュゲートを提供する。本発明のコンジュゲートは、開始剤フラグメント又は末端基に連結された、生体活性剤又は診断剤を有する機能性剤少なくとも1種も含む。
本発明の高分子量重合体は当該技術分野で公知の任意の手段によって製造されることができる。幾つかの実施形態において、本発明は、本発明の高分子量重合体の製造方法であって、フリーラジカル重合によって高分子量重合体を製造するのに充分な条件下に、第一の単量体と第二の単量体との混合物を開始剤I’と接触させ、ここで前記第一の単量体がホスホリルコリンを含み、そして第二の単量体及び開始剤がそれぞれ独立して少なくとも1の機能性剤又は機能性剤に連結するための連結基を含んでいる工程を含む方法を提供する。
本発明の高分子量重合体の製造に有用な開始剤として、ラジカル重合による重合に適した任意の開始剤を挙げることができる。幾つかの実施形態において、開始剤は原子移動ラジカル重合(ATRP)に適しており、例えば、上記したものなどである。他の有用な開始剤として、ニトロキシド媒介ラジカル重合(NMP)、又は可逆的付加-開裂-停止(reversible addition-fragmentation-termination)(RAFT又はMADIX)重合用のものを挙げることができる。フリーラジカル重合法を制御するさらに他の技術を用いることができ、例えば、イニファーター、縮退的移動法又はテロメリゼーション法を用いることができる。さらに、本発明に有用な開始剤として、少なくとも1の分枝点を有するもの、例えば、上記したものなど、を挙げることができる。他の実施形態において、開始剤は制御されたラジカル重合に有用である。
ATRP又は基ラジカル移動重合(group radical transfer polymerization)に用い
られる触媒として、Cu1+、Cu2+、Fe2+、Fe3+、Ru2+、Ru3+、Cr2+、Cr3+、Mo2+、Mo3+、W2+、W3+、Mn2+、Mn2+、Mn4+、Rh3+、Rh4+、Re2+、Re3+、Co1+、Co2+、Co3+、V2+、V3+、Zn1+、Zn2+、Ni2+、Ni3+、Au1+、Au2+、Ag1+及びAg2+の適当な塩を挙げることができる。適当な塩として、限定的でなく、以下:ハロゲン、C1-C6-アルコシキ、硫酸塩、リン酸塩、トリフラート、ヘキサフルオロリン酸塩、メタンスルホン酸塩、アリールスルホン酸塩を挙げることができる。幾つかの実施形態において、触媒は上記した金属イオンの塩素塩、臭素塩である。他の実施形態において、触媒はCuBr、CuCl又はRuCl2である。
幾つかの実施形態において、好ましくは、本発明のリビングラジカル重合法を実施し、3~約2000の範囲の重合度を、そして他の実施形態において約5~約500を達成する。他の実施形態における重合度は10~100の範囲にあり、又は代わりに約10~約50の範囲にある。基又は原子移動ラジカル重合法における重合度は、開始剤と単量体との初期比に直接関連する。従って、幾つかの実施形態において、開始剤と単量体との初期比は、1:(3~約2,000)又は約1:(5~500)、又は約1:(10~100)、又は約1:(10~50)の範囲にある。
幾つかの実施形態において、ハロゲン又は他の開始剤フラグメントI’を別の官能基で置換することが望ましいことがある。脂肪族ハロゲンの変換には様々な反応を用いることができる。幾つかの実施形態において、脂肪族ハロゲンの変換は、アルキル基、アルコキシ基、シクロアルキル基、アリール基、ヘテロアリール基又はヒドロキシ基を生成する反応を含んでいることができる。ハロゲン原子はアルケン(二重結合)を生じる脱離反応を起こしやすいこともある。ハロゲン化末端を修飾する他の方法は、その全体が引用として本明細書中に組み込まれる、Matyjaszewski et al. Prog. Polym. Sci. 2001, 26, 337に記載されている。
本発明の高分子量重合体への機能性剤の結合は、行われる反応に適用可能な化学的条件及び試薬を用いて行われることができる。典型的な方法は、Bioconjugate Techniques, Greg T. Hermanson, Academic Press, 2d ed., 2008(その全体が本明細書中に組み込まれる)に記載されている。他のバイオコンジュゲーション法は、それぞれ全体が引用として本明細書中に組み込まれる、Bertozzi et al. Angewandte Chemie 2009, 48, 6974、及びGauthier et al. Chem. Commun. 2008, 2591に記載されている。
1.非常にスケーラブルであること;
2.樹脂は商業的に入手可能でありかつ必要な機器はすでに工業規格であるので現行の商業的製造プロセスに従うことができること;
3.インプロセス解析(In Process Analytics)(IPA)並びにスケールアップ生産の双方にサンプル技術を用いることができること;
4.一般的プロセスの開発が実施可能であること;
5.その単一工程的特徴及び直交設計(orthogonal design)によって費用効果的であること;
6.優れた回収率(現在のプロセスの収率は80%を超える)であること、
を有する。
本発明は、本発明の化合物1種又は2種以上及び薬剤学的に許容することのできる賦形剤1種又は2種以上を含む医薬組成物を含みかつそれを提供する。本発明の化合物は、薬剤学的に許容することのできる塩、プロドラッグ、代謝物、それらの類似体又は誘導体として本発明の医薬組成物中に存在することができる。「薬剤学的に許容することのできる賦形剤」又は「薬剤学的に許容することのできる担体」とは、本明細書中で用いる場合、医薬品投与と適合性のある、任意かつあらゆる溶媒、分散媒、被覆剤、抗菌剤及び抗真菌剤、等張性剤及び吸収遅延剤などを含むことを意図する。
本発明の高分子量重合体は任意の疾患状態又は症状を治療するのに有効である。疾患状態又は症状は急性又は慢性であることができる。
性を変化させる技術を有するサウスサンフランシスコのCatalyst Biosciences社参照)のセリンプロテアーゼ、の修飾を説明する。米国特許第7,632,921号はその全体が本明細書中に包含される。官能化された重合体の部位特異的コンジュゲーションを可能にする酵素の修飾が開示されている。タンパク質が適当な環境(proper setting)においてインビボ放出されることができ、例えば、ゼロオーダー放出プロファイルへの接近を可能にする(enable close to)ような、重合体と酵素との間の柔軟な
ケミストリーの使用が開示されている。次世代第VIII因子の目標製品プロファイルは、50kDaを超える分子量の拡張された形態の、マルチアーム双性イオン含有重合体が部位特異的アミノ酸、例えば、システインに結合された組換え第VIII因子又は組換えBドメイン欠失第VIII因子の共有結合コンジュゲートを含んでいることができるであろう。コンジュゲートの臨床薬理学はクリアランス及び免疫系からコンジュゲートを遮蔽する比類のない水構造化(water structuring)を証明するであろう。コンジュゲートは
ヒトにおいて50時間を超える(好ましくは、80時間を超える)排出半減期を示すであろう。コンジュゲートは同じ生体活性を有する60kDaのPEG-BDD第VIII因子に対して2倍(好ましくは、4倍)の半減期の増加を示すであろう。コンジュゲートは患者に用いられたときに臨床的に取るに足りない抗体形成を示すであろう。生物製剤のコンジュゲートは予防的(週に1回又はそれより少ない頻度)及び血友病の患者のオンデマンド治療の双方に用いられるであろう。それは、例えば、前の第VIII因子生物製剤治療からの、第VIII因子中和抗体が存在する患者に対するレスキュー治療としても用いられるであろう。薬剤は、高い安定性、高濃度、及び低粘性を有し静脈内(IV)及び/又は皮下投与のための液体製剤を可能にするであろう。活性成分は、理想的に名目容積(nominal volume)0.4mL中の重合体薬剤コンジュゲート30~250マイクログラムからなる250~2,000IUの範囲であることができるであろう。重合体のコストは低いであろうし、第VIII因子又はBDD第VIII因子タンパク質に対する重合体のコンジュゲーション効率は非常に高く、例えば、75%を超えるであろう。かかる製品及び製品プロファイルは重合体の極度の生体適合性をタンパク質に移されたときに利用するであろう。具体的には、極度の生体適合性は非常に堅固な水結合、極度の溶解性、非常に高い濃度、非常に低い粘性、及び極度の安定性に現れる。技術的には、これはPEG化又はその等価技術に対して>2倍(又は理想的には、>4倍)増の排出半減期、極度に低い免疫原性又は無免疫原性、高濃度、及び室温で安定の液体製剤になる。製品プロファイル利益として、より少ない頻度の投薬、曲線下面積に対するより低い投与量、未投与(naive)患者に対する効果的な安全治療、中和抗体を有する患者に対するレスキュー治療、在宅での皮下投与、室温保存のプレフィルドシリンジ/オートインジェクタ、より高ゲージ(より低直径)の注射針、より少ない注射量、及びより長い有効期間を挙げることができる。製造面では、シングルポット合成、非常に高い重合体分子量、複合体アーキテクチャ、及び低い製造コストが達成可能である。さらに、薬剤に対する重合体の高効率のコンジュゲーションが可能である。これらの製造利益は、より安価でより入手しやすい医薬及びより高い粗利益に変わることができる。
ができるであろう。かかるペプチドに本発明の重合体を加えたものは将来の新規かつ強力な薬剤フォーマットを表している。
二重特異性抗体、他のマルチドメインをベースとするタンパク質、例えば、修飾されたフィブロネクチンドメインの多量体、抗体フラグメント(アゴニスト又はアンタゴニストとしてのscFv単量体、scFv二量体)、Fab’、Fab’-2’、可溶性細胞外ドメイン(例えば、sTNFR1、又は可溶性cMet受容体フラグメント)、オープンリーディングフレームの一部として形成されたアミノ酸1,500までの親水性アミノ酸ストリングを含むAmunix XTENとの組み合わせ、オリゴヌクレオチド、例えば、アプタマー、microRNA、siRNA、全体抗体(Fc領域にコンジュゲート;非Fc領域にコンジュゲート)、Fc融合体(Fc-fusions)(Fc領域にコンジュゲート;融合タンパク質にコンジュゲート)、かかる重合体のCovX抗体骨格に対する置換としての利用(高分子量重合体はペプチド自体に直接コンジュゲートされる)、より広範には本発明の重合体の全長天然又はムテイン抗体さえへの結合(CovXボディ、ペプチボディ、ヒト化抗体又は他の抗体、ペプチドが抗体上の様々な位置にコンジュゲートされて抗体骨格の上にモジュラー多機能薬を形成するCarlos Barbasからの新たなZyngeniaプラットフォーム)。また、米国特許出願第60/514,391号に概説された多くのドメイン構造はその全体が本明細書中に含まれる。とりわけ興味深いのは細胞表面の標的に結合して該標的を阻害するためのコンジュゲートであり、その環境において本発明で述べられた重合体コンジュゲートの大きなサイズ、拡張された形態のアーキテクチャ、及び遅いオフ速度はとりわけ有利な生物学的効果を及ぼすことができる。
当業者であれば、ペプチドへ炭化水素成分を付加して細胞透過を促進するステープルペプチド(stapled peptide)技術と組み合わせる可能性も認識するであろう。
し100%ローディングに相当するゼロオーダー動態と同様であるか又はそれと同等であるように操作される。
実施例1:N-(2-ヒドロキシエチル)-エキソ-3,6-エポキシ-1,2,3,6-テトラヒドロフタリミドの調製
1HNMR(400MHz,CDCl3):δ=2.90(s,2H,CH),3.71(m,2H,OCH2),3.77(t,J=5.0Hz,NCH2),5.29(t,J=1.0Hz,2H,OCH),6.53(t,J=1.0Hz,2H,CH=CH)。
1HNMR(400MHz,CDCl3):δ=1.20(s,3H,CH3CC=O),1.43(s,3H,CH3),1.46(s,3H,CH3),3.70(d,J=12.4Hz,2H,OCH2),4.17(d,J=12.4Hz,2H,OCH2)。
1HNMR(400MHz,CDCl3):δ=1.89(s,6H,CH3),2.87(s,2H,CH),3.82(t,J=5.4Hz,2H,NCH2),4.33
(t,J=5.4Hz,2H,OCH2),5.27(t,J=1.0Hz,2H,OCH),6.51(t,J=1.0Hz,2H,CHビニル)。
1HNMR(400MHz,CDCl3):δ=1.19(s,3H,CH3CC=OO),1.37(s,3H,CH3),1.41(s,3H,CH3),1.55(s,6H,(CH3)2C),2.86(s,2H,C=OCHCHC=O),3.58(d,J=12Hz,CH2O),3.78(t,J=5.4Hz,CH2CH2O),4.14(d,J=12H,CH2O),4.30(t,J=5.4Hz,CH2CH2O),5.27(t,2H,CHOCH),6.51(s,2H,CH=CH)。
1HNMR(400MHz,CDCl3):δ=1.32(s,3H,CH 3CC=O),1.91[s,12H,(CH3)2CBr],2.90(s,2H,CHC=O),3.78(t,2H,NCH2CH 2O),4.28(t,2H,NCH 2CH2O),4.31(app q,4H,CH2OC=O),5.30(s,2H,CHOCH),6.52(s,2H,CH=CH)。
1HNMR(400MHz,CDCl3):δ=2.90(s,2H,CH),3.49(m,2H,OCH2),3.59(m,4H,OCH2),3.65(m,2H,NCH2),5.15(t,J=0.8Hz,2H,OCH),6.55(t,J=0.8Hz,2H,CH=CH)。
1HNMR(400MHz,CD3OD):δ=1.33(s,3H,CCH3),1.90(s,12H,(CH 3)2CBr),4.30(d,J=5.4Hz,2H,NCH2),4.39(d,J=5.4Hz,2H,OCH2)。
1HNMR(400MHz,CD3OD):δ=1.34(s,3H,CH3),1.90(s,6H,CH3),2.94(s,2H,CH),3.64(m,6H,OCH2),4.22(t,J=5.4Hz,2H,NCH2),4.35(app q,4H,OCH2),5.15(t,J=1.0Hz,2H,OCH),6.54(t,J=1.0Hz,2H,CH=CH)
1HNMR(400MHz,CDCl3):δ=1.20(t,6H,CH 3CH2O),1.34(s,3H,CH 3CC=O),1.92[s,12H,(CH3)2CBr],1.98(app q,2H,CHCH 2CH2),3.50(m,2H,OCH 2CH3),3.66(m,2H,OCH 2CH3),4.24(t,2H,CH2CH 2OC=O),4.37(app q,4H,CH2OC=OCBr),4.60(t,1H,O-CH-O)。
1HNMR(400MHz,CD3OD):δ=1.34(s,3H,CH3),1.77(m,2H,CH2CH 2CH2),1.90(s,12H,CH3),2.15(q,J=7.2Hz,2H,CHCH 2CH2),4.16(t,J=6.4Hz,2H,OCH2),4.36(app q,4H,CCH2O),5.02(m,2H,CH 2=CH),5.82(m,1H,CH2=CH)。
1HNMR(400MHz,CDCl3):δ=1.36(s,3H,CH3),1.92(s,12H,CH3),3.90(app q,J=5.4Hz,2H,NCH 2CH2O),4.05(dd,1H,J=2.4,6.8Hz,=CH),4.19(dd,J=2.4,14.4Hz,1H,=CH),4.39(m,2H,NCH2CH 2O),4.40(app q,4H,OCH2),6.45(dd,1H,J=6.8,14.4Hz,=CHO)。
1HNMR(400MHz,CDCl3):δ=4.8(br s,1H,NH),4.37(app q,4H,CH2OC=OCBr),4.22(t,2H,CH2CH 2OC=O),3.20(app q,2H,NHCH2),1.92[s,12H,(CH3)2CBr],1.85(t,2H,CH2CH 2CH2),1.43(s,9H,(CH3)3O),1.35(s,CH 3CC=O)。
1HNMR(400MHz,CDCl3):δ=1.13(s,6H,CH3),1.25(s,3H,CH3),2.96(s,2H,CHC=ON),3.57-3.65(m,8H,CH2OH),3.64(t,J=2.8Hz,2H,CH2CH 2OC=O),4.22(app q,4H,C(CH3)CH 2OC=Ol),4.22(t,J=2.8Hz,CH 2CH2OC=O),5.21(t,J=0.8Hz,CHOCH),6.55(t,J=0.8Hz,CH=CH)。
1HNMR(400MHz,CDCl3):δ=1.26(s,3H,CH 3CC=O),1.34(s,6H,CH 3CC=O),1.90(s,24H,(CH3)2CBr),2.95(s,2H,CH),3.78(t,J=5Hz,2H,NCH2),4.25(m,6H,OCH2C(4H) and CH 2CH2N(2H)),4.35(app q,8H,OCH2),5.23(tJ=1Hz,2H,CHOCH),6.55(t,J=1Hz,2H,CH=CH)。
「リビング」制御フリーラジカル法[原子移動ラジカル重合(ATRP)]を用いて、双性イオン単量体のテーラーメイド親水性重合体[2-メタクリロイルオキシエチルホスホリルコリン(HEMA-PC)]の高分子量を製造する代表的プロトコルは、以下の通りである。
実施例15からの共重合体を、丸底フラスコでエタノール(20から50%w/w)中で分解した。エタノールを回転留去によってゆっくりと除去し、フラスコの壁に薄い膜を作った。反応容器を真空下で90分間、少なくとも110℃の温度の油状浴に置き、そして室温で冷却した。
脱保護後:δ(ppm):6.95(2H,-CO-CH=CH-CO-)。
実施例15の官能化共重合体へのコンジュゲーション(conjugation)のためのF(a
b’)2抗体フラグメントのでの使用のために、Rockland・Laboratories、Innovative・Research及び/又はJackson・Immunochemから全ヒトIgGを購入した。透析又はPD-10脱塩カラム(GE・Healthcare)いずれか1つの使用による酢酸ナトリウムバッファーでの4.5へのpH調整後にIgGを、固定化ペプシンを用いて消化した(Thermo・Scientific)。pH調整に続いて、固定化ペプシンの0.5mL量を、酢酸ナトリウムバッファー(pH4)を用いて3回洗浄し、0.5mLの最終量に再懸濁した。IgG1mLを10mg/mLの濃度で固定化ペプシンに加え、37℃下でロッカー(rocker)/攪拌器に置いた。消化を4時間進行下においた。4時間後、サンプル40μLを除去し、PBS移動相を有するShodex・Protein・KW-802.5カラムを使いHPLCにより分析した。IgGピークをF(ab’)2ピークから分解し、消化の進行を、消化率を基に決定した。固定化ペプシンは、ヒンジ領域を超えてFcドメインのみを除去することによるF(ab’)2抗体フラグメントを製造するために使用されるタンパク質分解酵素である。これによってヒンジ領域中の共有ジスルフィド結合によって結合した2抗体-結合Fab’フラグメントからなるF(ab’)2フラグメントが得られる。
最終濃度15mM(溶液中)で水素化ホウ素ナトリウムを用いるジスルフィド結合の還元によって、実施例17のF(ab’)2調製物からFab’フラグメントを製造した。F(ab’)2調製物を、4mM-EDTA含有PBSを用いて希釈し、同バッファー中の水素化ホウ素ナトリウムの等溶量を加え、混合物を室温で攪拌プレート上に置いた。反応物を放置して1~1.5時間室温で進行させ、還元の進行を移動相としてShodex・Protein・KW-802.5カラム及びPBSを用いたHPLCによりモニタリングした。F(ab’)2が90%を超える消費された時点で還元は完了したと思われた。ジスルフィド還元に続いてすぐに、サンプルpHを、0.1N-HClを用いて約4~5に下げて調整した。溶液のpHの調整後、サンプルをさらに10分間混合し、それからpHを0.1N-NaOHを用いて6.5~7.5まで調整した。攪拌しながら、実施例16からのマレイミド官能化重合体の10モル過剰量を混合物に加え、室温でインキュベートした。反応の進展をモニタリングするためにHPLCによる分析でタイム0にてサンプルを除去し、1時間、2時間の時点で再び除去した。Waters・Alliance・2695・HPLC・system・2695は、PBS移動相を有するShodex・Protein・KW-803カラムとWaters・2996・Photodiode・Detectorを備えた。コンジュゲート効率を220nm及び280nmでモニタリングした。2時間後、サンプルをAKTA・Prime・Plus(GE・Healthcare)及びSuperdex・200・HR・10/30・preparative・size・exclusionカラムを用いて精製した。使用した溶出バッファーはPBSであった。重合体は、遊離重合体および未反応Fab’に続いて最初に溶出したFab’をコンジュゲートした。収集したフラクションはPBS移動相を用いたShodex・Protein・KW-803カラムを用いて分析した。精製したFab’コンジュゲートを含有するフラクションを一緒にし、ビバスピン(Vivaspin)2(3000MWCO)フィルター(Sartorius社より)を用いて濃縮した。
末端アミン基を含有する抗-VEGFアプタマー(Agilent,Boulder,CO)を、実施例15のマレイミド官能化重合体(サンプル5)にコンジュゲートし、続いて実施例16により脱保護した。Traut試薬を使用して以下のように末端アミノをチオールに変換した。アプタマー(5.4mg)を0.1M重炭酸ナトリウムバッファー(pH=8.0)500μL中で溶解した。分離バイアル(separate viral)において、2-イミノチオラン(Iminothiolane)・HCl(Traut試薬、Sigma)7.2
mgを精製した水3.6mL中で溶解し、溶液2mg/mLを得た。2-イミノチオラン・HCl100μL量を、アプタマー混合物に加えて、1時間室温で攪拌した。Traut試薬を含有するアプタマーサンプルをPD-10脱塩カラムに通過させ、いずれの未反応の2-イミノチオランを除去し、最終的なバッファーは、4mM-EDTAを含有したPBSに交換された。末端チオール基のごく一部を含有したアプタマーサンプルを、攪拌棒を用いて混ぜ、マレイミド官能化重合体14.0mgを常に攪拌させながら反応物に加えた。サンプル60μLを、KW-803カラム、PBS移動相及び1mL/分の流速を有するHPLCにより分析のために、タイム0で除去した。220及び280nmの波長及び屈折率検出により、サンプルをモニタリングした。アリコートを除去し、2時間後に試験し、再び1晩4℃で攪拌した後再び試験した。
実施例19による重合体-アプタマーコンジュゲートを、ポリ(ラクティック-コ-グリコリック)酸(PLGA)マイクロスフェアを用いたオイル・イン・オイル溶媒混合物に処方した。重合体-アプタマーコンジュゲート(20mg)をジクロロメタン中のクロロホルム0.1%におけるPLGA100mg/mLの溶液中に室温で懸濁した。懸濁したコンジュゲートをポリ(ジメチル)シロキサンを用いて混合し、マイクロスフェアの均質分散体を生産した。混合物を、ヘプタンを含有するフラスコに移し、室温で3時間攪拌させた。得られたマイクロスフェアを、0.2マイクロンフィルターを用いて分離し、収集し、1晩真空化で乾燥させた。
システインミューテイン(米国特許第7,632,921号)を用いたBDD第VIII因子の部位特異的コンジュゲートを固定化トリス(2-カルボキシエチル)ホスフィン(TCEP)又はジチオスチエトール(DTT)のいずれかを用いて希釈し“cap”を除去した。還元に続いて、還元剤(固定化TCEP)を、遠心分離で除去し、又は、DTTを使用する場合PD-10脱塩カラム(GE・Healthcare)を用いて除去を遂行した。BDD第VIII因子での還元システインを、50-200kDa(2-アーム)又は100-200kDa(4-アーム)の分子量sを用いた実施例16によるマレイミド官能化重合体1及び10-倍モル過剰(量)の間で室温にて2時間以下又は4℃下で1晩処理した。最終コンジュゲートBDD第VIII因子サンプルを、塩化ナトリウムグラディエントを用いたアニオン交換クロマトグラフィーで精製した。コンジュゲートしたミューテインを無反応した第VIII因子及び遊離マレイミド官能化重合体から分離した。確認のために、分画したサンプルをSEC・HPLC及びSDS-PAGEにより分析をした。第VIII因子のコンジュゲート化ミューテインを含有する全てのフラクションを一緒にし、バッファーを、リン酸ナトリウムバッファー中で最終製剤へとPD-10脱塩カラムを用いて交換した。ある場合には、未反応の種から分離したコンジュゲート化第VIII因子を分離するためにSECを使用する精製が更に必要であった。
c-末端保護システインで変性されたscFvフラグメントを4mM-EDTA含有PBSを用いて希釈し、同バッファー中水素化ホウ素ナトリウムの等容量を加えた。混合物を室温で攪拌プレート上に置いた。6~7のpH範囲にて固定化TCEPを用いて交互に還元を実施した。反応物を室温で0.5~2時間進行下に置き、還元の進展を、移動相としてPBS及びShodex・Protein・KW-802.5カラムを用いたHPLCによりモニタリングした。ジスルフィド還元に続いてすぐに、室温で、実施例16からのマレイミド官能化重合体の10-モル過剰量で攪拌しながら、サンプルを反応した。HPLCによる分析のためにサンプルをタイム0にて除去し、反応の進展をモニタリングするために再び1時間、2時間の時点に除去した。Waters・Alliance・2695・HPLC・system・2695にはWaters・2996・Photodiode・Detector及び、PBS移動相を用いたShodex・Protein・KW-803・カラムが備えられていた。コンジュゲーション効率を220nm及び280nmでモニタリングした。2時間後、サンプルをAKTA・Prime・Plus(GE・Healthcare)及びSuperdex・200・HR・10/30・preparative・size・exclusionカラムを用いて精製した。使用した溶出バッファーはPBSであった。遊離重合体及び未反応Fab’に続いて最初に重合体コンジュゲートしたscFvを溶出した。収集したフラクションを、PBS移動相を有するShodex・Protein・KW-803カラムを用いて分析した。精製したscFvコンジュゲートを含有するフラクションを一緒にし、ビバスピン2(3000MWCO)フィルター(Sartorius社より)を用いて濃縮した。
1HNMR(400MHz,CDCl3):δ=1.35(s,3H,CCH3),1.92(s及び重複(overlapping)m,14H,(CH 3)2CBr及びCH2CH 2CH2),3.71(app q,J=6Hz,2H,HOCH 2),4.31(t,J=6Hz,2H,CH2OC=O),4.37(app q,4H,CH 2OC=OCBr)。
1HNMR(400MHz,CDCl3):δ=1.33(s,3H,CCH3),1.92(s,12H,(CH 3)2CBr),2.83(t,J=6.4Hz,2H,HC=OCH2),4.34(app q,4H,OCH2),4.48(t,J=6.4Hz,HC=OCH2CH 2),9.79(br s,1H,CHO)。
1HNMR(400MHz,CDCl3):δ=1.55(s,3H,CCH3),1.95(s,12H,(CH 3)2CBr),2.84(broad s,4H,O=CCH 2CH 2C=O),4.49(s,4H,CH 2OC=OCBr)。
「リビング」制御フリーラジカル法[原子移動ラジカル重合(ATRP)]を用いて、双性イオン単量体のテーラーメイド親水性重合体[2-メタクリロイルオキシエチルホスホリルコリン(HEMA-PC)]の高分子量を製造する代表的プロトコルは、以下の通りである。
ムアミド又はジメチルスルホキシドを滴下して加え、開始剤及びリガンドとの重量パーセントを約20%にした。得られた溶液を、乾燥氷/アセトン混合物を用いて-78℃で冷却し、10分間真空下で脱ガスした。前記管を窒素下で再充填し、窒素下に維持した触媒(特に断らない限りCuBr)をシュレンク管に加えた(ブロマイド/触媒/リガンドのモル比を1/1/2に維持する)。溶液は、すぐに、暗褐色に変化した。シュレンク管を密封し、-78℃に維持した。真空/窒素サイクルを3回適用することにより、前記溶液をパージした。HEMA-PC溶液は、窒素下に維持された単量体の規定量と、200プルーフ脱ガスエタノールとを混合することによって調製した。単量体溶液をシュレンク管に滴下して加え、軽く攪拌して均質化した。温度を-78℃に維持した。溶液からのバブリングが停止するまで、少なくとも10~15分間、反応混合物に十分な真空を適用した。次に、前記管を窒素で再充填し、室温に暖めた。溶液を攪拌し、重合が進行するのに従って、溶液が粘稠化した。3から8時間後、Cu(I)からCu(II)に酸化するために、反応物を空気に直接さらすことによって急冷し、混合物が青-緑色に変色し、シリカカラムに通して銅触媒を除去した。収集した溶液を回転留去により濃縮し、得られた混合物を、テトラヒドロフランを用いて沈殿、又は水、続いて凍結乾燥に対する透析をし、流通白色粉末を得た。
リン酸バッファー中の濃度10mg/mLでのヒト成長ホルモン(hGH)のサンプルを調製した。分離フラスコ中で、シアノ水素化ホウ素ナトリウムを、100mM濃度に量り、リン酸ナトリウムバッファー(pH6)10mL中で希釈した。PBSで希釈した後これをすぐに使用した。溶液中のシアノ水素化ホウ素ナトリウムの等容量を実施例26及びhGHからのアルデヒド官能化重合体を含有する反応混合物に加えた。反応物を1晩室温又は4℃で混合した。反応物の割合コンジュゲートを、Shodex・Protein・KW-803カラム及び移動相としてPBSを用いてHPLCによってモニタリングした。
1-10mg/mL間濃縮でのヘマチドの溶液を、PD-10脱塩カラム(GE・Healthcare)を用いて0.1Mホウ酸ナトリウムバッファー(pH9)にバッファー交換をした。実施例26からのNHSエステル官能化重合体を10モル過剰量に加え、室温でヘマチドのサンプルを常にかき攪拌した。反応物を室温で2時間又は1晩4℃で進行させた。コンジュゲートの程度を測定するためにサンプルをShodex・KW-803カラム又はPBS移動相を有するHPLCにより分析した。コンジュゲート後にサンプルのアリコートをタイム0、1及び2時間後に取った。2時間後、又は1晩後に1Mグリシンを加え、反応物を冷却した。
高圧下のHEMA-PC単量体の重合を、ガラスで内側を覆って、ステンレススチール圧力容器中で実施した。その割合HEMA-PC/2-アームはマレイミド開始剤を保護した(実施例から8/CuBr/ビピリジルの割合は500~10000/1/2/4であり;エタノール中でT=22℃であり;DMF(エタノール中の1-1.5%w/w)を用いたエタノール中で[HEMA-PC]0=0.86M)であった。圧力は1barから6kbarまでの範囲であった。
NMR(CD3OD):δ6.546(t,2H,CH=CH,J=0.8Hz),5.158(t,2H,CH-O,J=0.8Hz),4.180(m,2H,CH2-CH 2-O-C=O,J=4.9Hz),3.63(m,10H,N-CH2 and N-CH2-CH 2 and CH 2-CH2-O-C=O and CH2-OH),2.936(s,2H,CH-CH),1.147(s,3H,CH3)。
NMR(CD3OD):δ6.55(t,2H,CH=CH,J=0.8Hz),5.17(t,2H,CH-O,J=0.8Hz),3.34(m,12H,CCH2),4.23(m,2H,CH2-CH 2-O-C=O,J=4.7Hz),3.68(m,2H,N-CH2,J=4.7Hz),3.64(app q,4H,N-CH2-CH 2
and CH 2-CH2-O-C=O),2.95(s,2H,CH-CH),1.907(s,24H,Br-C-CH3),1.34(s,6H,CH3),1.308(s,3H,CH3)。
NMR(CDCl3):δ6.19(s,2H,CH=CH),4.37(app q,4H,CCH2O,J=10.9,29.7Hz),4.23(t,2H,CH2CH 2O,J=6.3Hz),4.15(t,2H,CH2CH 2O,J=6.3 Hz),3.62(t,2H,NCH2,J=7.4Hz),3.22(s,2H,CHC=O),2.48(t,2H,CH2C=O,J=7.4Hz),2.00(m,2H,CH2CH 2CH2,J=6.3Hz),1.92(s,12H,Br-C(CH3)2)1.78(s,6H,CH3),1.35(s,3H,CH3)。
NMR(CDCl3):δ6.70(t,1H,NH,J=5.4Hz),4.33(app q,4H,CH2O,J=16.3,11.4Hz),3.51(q,2H,NCH2,J=6.0Hz),2.46(t,2H,CH2CO,J=6.0Hz),1.93(s,12H,Br-C(CH3)2),1.45(s,9H,C(CH3)3),1.33(s,3H,CH3)。
NMR(CD3OD):δ4.38(app q,4H,CCH2,J=11.2,30.2Hz),4.20(t,2H,CH 2OH,J=5.0Hz),3.75(t,2H,CH 2CH2OH,J=5.0Hz),1.90(s,12H,Br-CCH3),1.36(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2O,J=11.2Hz),4.31(t,2H,CH2CH 2O,J=6.3Hz),3.71(q,2H,CH2OH,J=5.9Hz),1.92(s,12H,Br-C(CH3)2),1.9(m,2H,CH2CH 2CH2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2O,J=31.8,11.2Hz),4.31(t,2H,CH2CH 2OC=O,J=5.0Hz),3.6-3.73(m,14H,CH2O),2.46(t,1H,OH,J=6.3Hz),1.92(s,12H,Br-C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.47(m,2H,CH2O(C=O)O),4.37(app q,4H,CCH2O,J=11.2,31.6Hz),4.30(m,2H,CH2CH 2O(C=O)C),3.79(m,2H,CH 2CH2O(C=O)C),3.71(t,2H,CH 2CH2O(C=O)O,J=5.0Hz),3.67(s,4H,CH2O),3.65(s,4H,CH2O),2.84(s,4H,CH2C=O),1.92(s,12H,Br-C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2O),4.32(m,1H,OCH),4.19(m,2H,CHCH 2OC=O),4.07(d of d,1H,OCH 2CH,J=6.7,8.6Hz),3.76(d of d,1H,OCH 2CH,J=5.7,8.6Hz),1.92(s,12H,Br-C(CH3)2),1.43(s,3H,(CH3)2CO),1.36(s,3H,CH3),1.35(s,3H,(CH3)2CO)。
NMR(CDCl3+D2O):δ4.40(app q of d,4H,CCH2O,J=2.8,11.5,30.2Hz),4.24(app q of d,2H,CHCH 2OC=O,J=4.5,6.6,11.5Hz),3.96(m,1H,CH),3.66(app q of d,2H,HOCH 2CH,J=3.8,5.6,11.5,37.9Hz),1.92(s,12H,Br-C(CH3)2),1.37(s,3H,CH3)。
NMR(CDCl3):δ4.39(app q of d,4H,CCH2O,J=4.1,11.1,3.0,37.6Hz),4.31(t,2H,OCH2CH 2OC=O,J=4.7Hz),3.87(m,1H,CH-OH),3.54-3.77(m,2H,CH 2-OH),3.72(m,2H,OCH 2CH),3.58(app t,2H,OCH 2CH2OC=O),2.68(d,1H,CH-OH,J=5.1Hz),2.15(app t,1H,CH2-OH,J=6.1Hz),1.92(s,12H,Br-C(CH3)2),1.36(s,3H,CH3)。
NMR(CDCl3):δ5.87-5.97(m,1H,CH2CH=CH2),5.28(dq,1H,H-CH=CH),5.18(dq,1H,H-CH=CH),4.37(app q,CH 2OC=O),4.30(dd,2H,CH2CH 2OC=O),4.02(d,2H,CH2=CHCH 2),3.60-3.72(m,14H,CH2CH 2OCH2),1.92(s,12H,Br-C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2OC=O),4.30(t,2H,CH2CH 2OC=O,J=5.0Hz),3.85(p,1H,CHOH,J=5Hz),3.71(t,2H,OCH 2CHOH,J=4.8Hz),3.72-3.55(m,16H,OCH 2CH 2O and CH 2OH),3.12(s,1H,CHOH),2.37(s,1H,CH2OH),1.92(s,12H,Br-C(CH3)2),1.35(s,3H,CH3)。
1HNMR(400MHz,CDCl3):δ=1.23(s,3H,C=OCCH3),1.39(s,3H,CH3),1.43(s,3H,CH3),3.66(m,4H),4.02(dd,2H,CH2=CHCH 2),4.20(d,2H),4.31(t,2H,C=OOCH 2),5.18(dd,1H,=CH),5.28(dd,1H,=CH),5.89(m,=CHCH 2)。
1HNMR(400MHz,CDCl3):δ=5.84-5.94(ddt,1H,H2C=CHCH2),5.28(dq,1H,HHC=CHCH2),5.22(dq,1H,HHC=CHCH2),4.36(app t,2H,OCH 2CH2),4.02(dt,2H,H2C=CHCH 2),3.86(dd,2H,CH2OH),3.74(dd,2H,CH2OH),3.68(app t,2H,OCH2CH 2),2.90(br d,2H,OH),1.11(s,CH3)。
NMR(CDCl3):δ5.89(m,1H,CH2CH=CH2),5.28(d of q,1H,H-CH=CH,J=17.2,1.7Hz),5.20(d of q,1H,H-CH=CH,J=10.5,1.5Hz),4.38(app q,4H,CH2OC=O),4.31(t,2H,OCH2,J=4.7Hz),4.01(d of t,2H,OCH2,J=5.6,1.5Hz),3.65(t,2H,OCH2,J=4.7Hz),1.91(s,12H,Br-C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ5.88(m,1H,CH2CH=CH2),5.28(d of q,1H,H-CH=CH,J=17.4,1.6 Hz),5.20(d of q,1H,H-CH=CH,J=10.3,1.3Hz),4.24-4.44(m,14H,CH2OC=O),4.01(d,2H,CH2=CHCH 2,J=5.6),3.65(t,2H,CH2CH 2OCH2,J=4.7Hz),1.91(s,24H,Br-C(CH3)2),1.33(s,6H,CH3),1.30(s,3H,CH3).
NMR(CDCl3):δ4.28-4.41(m,14H,CCH2OC=O),3.86(m,1H,CH2CHOHCH2),3.69-3.75(m,3H),3.56-3.65(m,3H),2.78(dd,1H,OH),2.23(a ppt,1H,OH),1.92(s,24H,CH3CBr),1.34(s,6H,CH3),1.31(s,3H,CH3)。
NMR(CDCl3):δ4.39(app q,4H,CCH2O,J=11.1,33.8Hz),4.31(t,2H,OCH2CH 2OC=O,J=5Hz),3.72(t,2H,CH2N3,J=5Hz),3.67(t,2H,CH 2CH2N3,J=5Hz),3.38(t,2H,OCH 2CH2OC=O,J=5Hz),1.92(s,12H,Br-C(CH3)2),1.36(s,3H,CH3)。
1HNMR(400MHz,CDCl3):δ=2.08(s,12H,CH3),7.29(t,1H,J=2.4Hz,ArH),7.61(d,J=2.4Hz,2H,ArH),10.0(s,1H,CHO)。
NMR(DMSO-d6):δ7.70-7.82(m,6H,PhH),7.26-7.51(m,9H,PhH),3.69-3.75(m,3H),3.56-3.65(m,3H),2.78(dd,1H,OH),2.23(app t,1H,OH),1.92(s,24H,CH3CBr),1.34(s,6H,CH3),1.31(s,3H,CH3)。
NMR(DMSO-d6):δ7.75(m,6H,CCH),7.44(m,6H,CCHCH),7.30(m,3H,CCHCHCH),5.86(m,1H,CH2=CH),5.70(s,1H,NCH(equatorial)),5.250(s,2H,NCH(axial)),5.23(d of q,1H,CH 2=CH),5.11(d of q,1H,CH 2=CH),3.93(d of t2H,CH-CH 2-O),3.55-3.25(m,16H,OCH 2CH 2O),3.26(m,2H,NCH2),3.19(d,2H,NCH2),2.88(s,2H,NCH2),2.719(s,2H,CCH2O)。
NMR(DMSO-d6):δ8.004(t,3H,NH),5.87(m,1H,CH),5.23(d of q,1H,CH 2=CH),5.12(d of q,1H,CH 2=CH),3.93(d of t,2H,CH 2-CH),3.6-3.45(m,16H,OCH 2CH 2O),3.289(s,2H,CCH2O),3.12(d,6H,CCH2N),1.907(s,18H,CH3)。
NMR(CDCl3):δ7.91(t,3H,NH),3.88(m,1H,HOCH2CHOHCH2),3.55-3.72(complex m,21H),3.35(s,1H,OCH 2C(CH2)3),3.19(d,6H,J=6.4Hz,CH2NH),1.99(s,18H,CH3)。
NMR(CDCl3):δ7.76(t,3H,NH,J=6.3Hz),3.68(m,4H,OCH 2CH 2O),3.63(m,2H,N3CH2CH 2O),3.40(t,2H,N3CH2,J=5.0Hz),3.37(s,2H,CCH2O),3.19(d,6H,CCH2N,J=6.8Hz),1.99(s,18H,CH3)。
NMR(CDCl3):δ7.78(t,3H,NH,J=6.5Hz),5.91(m,1H,CH),5.27(d of q,1H,CH 2=CH,J=17.4,1.6Hz),5.18(d of q,1H,CH 2=CH,J=10.4,1.4Hz),4.38(app q,12H,CH2OC=O),4.01(d of t,2H,CH-CH 2,J=5.7,1.4Hz),3.61(two m,16H,OCH 2CH 2O),3.30(s,2H,CCH2O),3.14(d,6H,CH2N,J=6.1Hz),1.92(d,36H,BrC(CH3)2,J=1.2Hz),1.38(s,9H,CH3)。
NMR(CDCl3):δ7.78(t,3H,NH,J=6.0Hz),4.39(app q,12H,CH2OC=O),3.86 (broad s,1H,OH-CH),3.62(m,20H,OCH 2CH 2O and OHCHCH 2O and OH-CH 2),3.27(s,2H,CCH2O),3.13(s,6H,NCH2),2.40(s,2H,OH),1.92(s,36H,BrC(CH3)2),1.38(s,9H,CH3)。
NMR(CDCl3):δ6.41(dd,1H,J=1.6,17.2Hz,vinyl CH),6.18(dd,1H,J=10.6,17.2Hz,vinyl CH),5.90(dd,1H,J=1.6,10.4Hz, vinyl CH),4.35(m,2H),4.27(m,2H),4.11(m,2H),3.63(m,2H),3.22(s,9H,N(CH3)3)。
NMR(CDCl3):δ2.89(d of d,2H,CH 2C=O,J=7.9,6.4Hz),2.85(s,4H,O=CCH 2CH 2C=O),2.62(app d of d of d,2H,CHCCH 2,J=8.6,6.9,2.7Hz),2.06(t,1H,CH,J=2.7Hz)。
NMR(CDCl3):δ6.77(s,2H,CHC=O),4.30(d,2H,NCH2,J=2.4Hz),2.22(t,1H,CCH,J=2.5Hz)。
NMR(CDCl3):δ9.81(t,1H,CH=O,J=2.6Hz),2.61(t of d,2H,CH 2CH=O,J=7.1,1.2Hz),2.28(t of d,2H,CCH2,J=7.1,2.6Hz),1.99(t,1H,CCH,J=2.6Hz),1.86(p,2H,CCH2CH 2,J=7.0Hz)。
1HNMR(400MHz,CDCl3):δ=1.35(s,3H,CH 3CC=O),1.92(s,12H,(CH3)2CBr),2.43(t,J=2.4,1H,CCH),3.64-3.72(m,14H,OCH2CH2O),4.21(d,2H,J=2.4,HCCCH 2),4.30(app q,2H,OCH2CH 2OC=O),4.34(dd,2H,CH 2OC=OCBr)。
1HNMR(400Mhz,Cdcl3):δ=2.54(t,1H,J=2.4,CCH),3.23(app t,2H,CH 2NH2),3.66(m,8H,OCH2CH2O),3.74(m,4H,OCH2CH2O),3.86(app t,2H,CH 2CH2NH2),4.26(d,J=2.4,2H,CH 2CCH)。
1HNMR(400MHz,CDCl3):δ=2.68(s,2H,NCH2 adjacent to equatorial phenyls),2.92(s,2H,CCH2),3.28(d,J=13.4Hz,2H,NCH2 between axial and equatorial phenyls),3.51(d,J=13.4Hz,2H,NCH2 nearest axial phenyl),3.73(d of t,J=1.5,5.4Hz,2H,CHCH 2O),5.04(d of q,J=1.5,10.4Hz,1H,CH 2=CH),5.07(d of q,J=1.7,17.2Hz,1H,CH 2=CH),5.42(s,2H,NCH axial),5.65(s,1H,NCH equatorial),5.71(m,J=5.4,10.4,17.2Hz,1H, CH2=CH),7.2-7.9(m,15H,phenyl)。
1HNMR(400MHz,D2O):δ=3.34(s,6H,CH 2NH3),3.76(s,2H,OCH 2C(CH2)3),4.11(m,2H,CH2=CHCH 2),5.28-5.39(m,2H,CH 2=CHCH2),5.92-6.03(m,CH2=CHCH2)。
1HNMR(400MHz,CDCl3):δ=1.99(s,18H,CH3),3.20(d,6H,J=6.8,CH 2NH2),3.34(s,2H,OCH 2C(CH2)3),3.99(m,2H,CH2=CHCH 2),5.19-5.30(m,2H,CH 2=CHCH2),5.87-5.97(m,1H,CH2=CHCH2),7.72(app t,J=6.8,3H,NH)。
1HNMR(400MHz,CDCl3):d=2.00(s,18H,CH3),3
.19(d,6H,J=6.8,CH 2NH),3.31(s,2H,OCH 2C(CH2)3),4.32(s,2H,CHOCH 2),8.01(app t,J=6.8,3H,NH),9.70(s,1H,CHO)。
1HNMR(400MHz,CDCl3):δ=2.01(s,18H,CH3),3.21(d,6H,J=2.8,CH 2NH),3.36(s,2H,OCH 2C(CH2)3),4.13=2(s,2H,CH 2CO2H),8.15(app t,J=2.8,3H,NH)。
1HNMR(400MHz,CDCl3):δ=1.45(s,9H,C(CH3)3),5.93(m,6H,NHS,CH 2COON),3.53(app q,2H,NHCH2),5.2(br s,1H,NH)。
1HNMR(400MHz,CDCl3):δ=2.44(t,1H,J=2.4,CCH),3.65-3.77(m,12H,OCH 2CH 2O),4.17(d,J=0.8,2H,CH 2CHO),4.21(d,2H,J=2.4,CH 2CCH),9.74=(s,1H,CHO)。
1HNMR(400MHz,CDCl3):δ=1.38(s,9H,CH3),1.92(s,36H,CH3), 3.15(d,J=6.6Hz,6H,CH 2NH),3.32(s,2H,OCH2C),3.42(t,J=5.2Hz,2H,N3CH2),3.60(m, 2H,OCH2CH2O),3.66(m,2H,OCH2CH2O),3.69(t,J=5.2Hz,2H,N3CH2),4.38(dd,J=11.1,17.0Hz,12H,CCH2O),7.57(broad t,J=6.6Hz,NH2)。
1H NMR(400MHz,CDCl3):δ=1.99(s,18H,CH3),2.87(s,4H,CH2CO),3.17(d,J=6.6Hz,6H,CH 2NH),3.39(s,2H,CCH2O),4.51(s,2H,OCH2CO),7.86(t,J=6.6Hz,3H,NH)。
1HNMR(400MHz,CDCl3):δ=2.08(d,3H,CH3),2.43(t,1H,J=2.4Hz,CHCCH2),3.58-3.72(m,18H,CH 2CH 2O),4.20(d,J=2.4Hz,2,CCH2O),6.32(q,J=1.8Hz,1H,CHCO)。
1HNMR(400MHz,CDCl3):δ=1.99(s,18H,CH3),2.46(t,1H,J=2.4Hz,CCH),3.18(d,J=6.7Hz,6H,CH 2NH),3.39(s,2H,CH2O),4.18(d,J=2.4Hz,CHCCH 2O),7.73(t,J=6.7Hz,3H,NH)。
1HNMR(400MHz,CDCl3):δ=3.34(s,2H,CCH2O),3.35(s,6H,CH2N3),3.59-3.68(m,16H,OCH2CH2O),4.03(d of t,J=1.4,5.6Hz,2H,CHCH 2O),5.18(d of q,J=1.4,10.4Hz,1H,CH2=CH),5.28(d of q,J=1.6,17.3Hz,1H,CH2=CH),5.92(m,J=5.6,10.4,17.2Hz,1H,CH)。
1HNMR(400MHz,DMSO-d6):δ=1.91(s,18H,CH3),3.05(d,6H,J=6.4Hz,CH2N),3.21(d,2H,J=4.4Hz,CH 2OH),8.17(t,J=6.4Hz,3H,NH)。
1HNMR(400MHz,CDCl3):δ=1.43(s,9H,Boc),1.95(s,18H,(CH3)2CBr),4.54(s,6H,CH2O),4.8(br s,1H,NH)。
「リビング」制御フリーラジカル法[原子移動ラジカル重合(ATRP)]を用いて、双性イオン単量体のテーラーメイド親水性重合体[ポリ(エチレングリコール)メチルエーテルメタクリル樹脂][MW475(HEMA-PEG475)]の高分子量を製造する代表的プロトコルは、以下の相違を有する、実施例98で既説されたプロトコルと本質的に同じである。単量体(HEMA-PEG475)中で溶解し、200プルーフ及び溶液をフリーズ・ポンプ・ソウ・テクニック(3サイクル)を用いて脱ガスした。得られた脱ガス混合物を開始剤、リガンド及びCuBrの脱ガスした溶液中-78℃で窒素下に導入した。得られた混合物を-78℃で脱ガスし、解凍下に置き、室温で窒素下に置いた。
「リビング」制御フリーラジカル法[原子移動ラジカル重合(ATRP)]であるの高分子量を製造する代表的プロトコルを用いたN-イソプロピルアクリルアミド(NIPAM)、アクリルアミド(AM)、N,N-ジメチルアクリルアミド(DMA)及び親水性単量体のテーラーメイド親水性重合体は、以下の相違を有する、実施例99で既説されたプロトコルと本質的に同じである。使用したリガンドは、トリス[2-ジメチルアミノ)エチル]アミン(Me6TREN)であり、3.3molx10-5をサンプル1及び2で加え、他全てのサンプル及び溶媒1.5molx10-5は水であった。ハロゲン化物/CuBr/CuBr2/Me6TRENの割合は各ケースで1/0.75/0.25/1であった。触媒の追加後、容器を密封し、0℃下で置いた。アクリルアミド誘導体、DMA、AM又はNIPAMの水溶液を、フリーズ・ポンプ・ソウ・テクニック(3サイクル)を用いて脱ガスし、開始剤、リガンド、及び窒素下のカニュラ(canula)を介した触媒を含有してシュレンク管に導入した。容器を密封し、反応を4℃で開始下に置いた。ある時間の経過後、反応物を空気に直接さらすことによって急冷した。青-緑色反応物混合物をシリカゲルのショートプラグに通過させ、褐色触媒を除去した。収集した溶液を凍結乾燥により濃縮した。
実施例102:ジオール先駆体に続くジオール官能化開始剤の重合からのアルデヒド官能基の発生
蒸留水中で溶解した過ヨウ素酸ナトリウムの大過剰を、蒸留水(10wt.%)中のジオール官能化重合体の溶液に加えた。反応を暗所で室温にて90分間進行させた。
それから、コンジュゲート濃度をFab’に加えて重合体のMWを含むことにより算出した。
下記のアルデヒド官能化共重合体(特に断らない限り実施例102による実施例98及び99による続く酸化)を使用した:
下記のアルデヒド官能化共重合体(実施例98及び99に続く実施例102による酸化による)を使用した:
312.9kDaの分子量を有する6-アームアジド官能化HEMA-PEG475重合体を実施例100中の手順に従って作った。アルデヒド官能基を実施例103中の手順に従ってアジド官能基に5-ヘキシン-1-アールを結合することにより加えた。以下の違いを有する実施例105及び106各々の手順に従って、一般に、この重合体を22kDa遺伝子組み換え型サイトカイン及び21kDa遺伝子組み換え型ヒトマルチ-ドメインタンパク質にコンジュゲートした。暗所不活性条件下で、室温での1晩のインキュべーションに続いて、20mMトリス(pH7.5)の添加により反応物を冷却し、クロマトグラム痕跡検出のためのUV検出器及び、グラディエント形態の溶媒が可能なデリバリングジュールを備えたWaters・HPLC・systemを用いた弱アニオン交換クロマトグラフィーを用いてサンプルをクロマトグラフした。9分間にわたって、80%バッファー(0.5M-NaCl含有のバッファーA)の直線的斜頚に続いてバッファーA中の5分アイソラチック洗浄をし、それに続いて1mL/分の流速で各サンプルの15μLをカラムに適用した。塩グラディエントを2分間80%で保ち、カラム再生のために100%バッファーAに下降した。クロマトグラフ分離のコースにおいて、OD220nmにより検出したタンパク質ピークフラクションを、SDS-PAGEでさらに分析するために手動で収集した。3つの主要なピークは収集された。第1のピークは、開始剤アイソクラチック洗浄の間1.8~3分間の地点で溶出し、中性荷電の重合体であることから、非コンジュゲートした遊離重合体に相当するこのフラクションは、カラムを通して流れた;第2のピークは、塩グラディエントにて早期に溶出した弱-結合コンジュゲートフラクションであった;そして、グラディエントにおいて後期に溶出した最後のフラクションを非コンジュゲート化遊離タンパク質と調和した。3つのフラクションを収集し、10K-MWCO集線装置を有するAmicon・Ultrafree4で濃縮した。濃縮したフラクションをSDS-PAGEに続いてクマシー・ブルー・ステイン、そして前記参考実施例で記載したSEC-MALSを用いてさらに分析し、データを以下の表に示した:
1HNMR(400MHz,CDCl3):δ=1.47(s,9H,Boc),1.94(s,6H,(CH3)2CBr),2.48(t,6H,J=6,CH2C=O),3.50(app q,2H,J=6,CH2NH).
1HNMR(400MHz,CDCl3):δ=1.95(s,6H,(CH3)2CBr),2.55(t,2H,J=6,CH2C=O),3.44(app q,2H,J=6,CH2NH),6.85(m,1H,PhH),7.15(m,2H,PhH),7.25-7.42(m,12H,PhH)。
ジフェニルホスフィノエステルの調製
マクジェンは、神経血管性(wet)加齢黄斑変性(AMD)の治療用の抗-血管新生薬(angiogenic medicine)である。長さが28ヌクレオチドのオリゴヌクレオチドの共有コンジュゲート(アプタマー)であり、この末端はペンチルアミノリンカーで終結し、そのリンカーに2つの20kDaモノメトキシポリエチレングリコール(PEG)ユニット単位が、リジン残渣上で2つのアミノ基を介して共有結合している。現在の実施態様において、遊離アミノ基を用いたマクジェンアプタマーを、以下の相違を有する、実施例105で既説されたプロトコルを用いたアルデヒド官能化重合体へのコンジュゲートに使用した。本発明の重合体を有するアプタマーへのコンジュゲーションは、高安定性、低粘着性、及び有利なインビボ物性(例えば、長い停留時間及びマイクロRNAやRNAiデリバリーの調査用ベースとなること)を有するコンジュゲートをもたらす。
Claims (19)
- アクリレート、メタクリレート、アクリルアミド、及びメタクリルアミド、からなる群からそれぞれ独立して選択される複数の単量体をそれぞれ含む重合体アーム少なくとも2つと、ここで各単量体は親水性基を含む;
少なくとも2つの前記重合体アームの基部末端に連結された開始剤フラグメントと、ここで開始剤フラグメントはラジカル重合の開始用である;及び
前記重合体アームのそれぞれの遠位末端に連結された末端基であって、前記末端基はラジカルスカベンジャー又は共有結合を形成することができる官能基を含む末端基と、
を含む重合体であって、
前記開始剤フラグメント及び末端基の少なくとも1つが共有結合を形成することができる官能基を含み、
前記重合体が500kDa~1500kDaの分子量、及び1.2未満の多分散性指数を有する、
重合体。 - 各親水性基が双性イオン基を含む、請求項1に記載の重合体。
- 各双性イオン基がホスホリルコリンを含む、請求項2に記載の重合体。
- 前記単量体が2-(アクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェートを含む、請求項1~3のいずれか一項に記載の重合体。
- 前記単量体が2-(メタクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェート(HEMA-PC)を含む、請求項1~3のいずれか一項に記載の重合体。
- 前記開始剤フラグメントが2~約100の重合体アームの基部末端に連結される、請求項1~5のいずれか一項に記載の重合体。
- 前記開始剤フラグメントが2、3、4、5、6、8、9又は12の重合体アームの基部末端に連結される、請求項6に記載の重合体。
- 下記式(I):
[上記式中、
R1はH原子、LG1基及びL3-LG1基からなる群から選択され、それぞれのLG1基は、共有結合を形成することができる官能基であり;
M1及びM2はそれぞれ独立して、アクリレート、メタクリレート、アクリルアミド、及びメタクリルアミド、からなる群から選択され;
各G1及びG2はそれぞれ独立して親水性基であり;
I-I’の組み合わせがラジカル重合の開始剤I1であるように、それぞれのIは開始剤フラグメントであり、そしてI’はラジカルスカベンジャーであり;
または、I’はそれぞれ独立してH原子、ハロゲン原子、ニトリル、-SCN、-NCS、又はC1-6アルキル基からなる群から選択され;
L1、L2、及びL3はそれぞれ独立して結合又はリンカーであり;
下付き文字x及びy1はそれぞれ独立して1~1000の整数であり;
下付き文字zはそれぞれ独立して0~10の整数であり;そして
下付き文字sは2~100の整数である]
で表される重合体。 - 各親水性基が双性イオン基を含む、請求項8に記載の重合体。
- 親水性基がそれぞれホスホリルコリンを含む、請求項8に記載の重合体。
- 下付き文字sが2、3、4、5、6、8、9又は12である、請求項8~10のいずれか一項に記載の重合体。
- 式中、
R1がLG1基及びL3-LG1基からなる群から選択され;
L3が-(CH2CH2O)1-10-であり;そして
LG1がマレイミド、アセタール、ビニル、アリル、アルデヒド、-C(O)O-C1-6アルキル、ヒドロキシ、ジオール、ケタール、アジド、アルキン、カルボン酸、及びスクシンイミドからなる群から選択される、
請求項16に記載の重合体。
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