JP6297776B2 - 免疫調節薬−高分子化合物 - Google Patents
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Description
本明細書は、米国特許法第119条の下に、そのそれぞれの内容全体を参照によって本明細書に援用する、それぞれ2009年5月27日に出願された、米国仮特許出願第61/217129号、米国仮特許出願第61/217117号、米国仮特許出願第61/217124号、および米国仮特許出願第61/217116号の優先権を主張する。
式(III)、
HO−ポリマー−OH(VII)
を有するジオール、および式(IV)、
HO−ポリマー−OH(VII)
を有するジオール、および式(IV)、
HO−ポリマー−OH(VII)
を有するジオール、および式(IV)、
各R2は独立して=H、アルキル、または置換アルキルであり;
各Yは独立して=NまたはCであり;
各R3は独立してY=Nであれば不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
各R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければ、独立してHであり、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
各Xは独立してC、N、O、またはSであり;
各R6およびR7は独立してそれぞれ独立してHであるか、または置換されており;
各R9、R10、R11、およびR12は独立してそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物が提供される。
本発明者らは、意外にもそして驚いたことに、本明細書で開示される本発明を実施することにより、上記の問題および制限を克服し得ることを発見した。特に、本発明者らは、式(I)、
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R8は生分解性ポリマーまたはその単位である)の構造を含んでなる化合物を関連組成物および方法と共に提供することが可能であることを意外にも発見した。
活性化生分解性ポリマーまたはその単位、および式(III)、
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R8は生分解性ポリマーまたはその単位である)の構造を含んでなる化合物を塩基および/または溶剤に曝露するステップを含んでなる。
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R8はポリマーまたはその単位である)の構造を含んでなる化合物を共役剤および塩基および/または溶剤に曝露するステップ
を含んでなる。
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R5はポリマーまたはその単位であり;
X=C、N、O、またはSであり;
R6およびR7はそれぞれ独立して不在、H、または置換されており;R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物を関連組成物および方法と共に提供することが可能であることを意外にも発見した。
アルコールおよび触媒、および式(IV)
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R5はポリマーまたはその単位であり;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立してHであるか、または置換されており;R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物を組み合わせるステップと;
アルコール、触媒、および化合物を加熱するステップ
を含んでなる。
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R5はポリマーまたはその単位であり;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立してHであるか、または置換されており;
R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物とを組み合わせるステップと;
アルコールおよび化合物を加熱するステップと;
触媒を添加するステップ
を含んでなる。
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R5はポリマーまたはその単位であり;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立してHであるか、または置換されており;R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物を組み合わせるステップを含んでなる。
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立してHであるか、または置換されており;R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる。
R2=H、アルキル、または置換アルキルであり;
Y=NまたはCであり;
Y=NであればR3は不在であり;あるいはY=CであればH、アルキル、置換アルキルであるか、またはR4と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
R4はR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成しなければH、あるいは置換もしくは非置換アルキル、アルコキシ、アルキルチオ、またはアルキルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共に炭素環もしくは複素環を形成し;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立してHであるか、または置換されており;R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオ、NH2、あるいは置換もしくは非置換アルキル、アリール、複素環、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物とを組み合わせるステップを含んでなる方法によって作成し得る。
「投与する」または「投与」は、薬理学的に有用な様式で、本明細書で提供される化合物、抱合体、合成ナノキャリア、または組成物を患者に提供することを意味する。
免疫調節薬およびポリマーまたはその単位は、アミドまたはエステル結合を通じて共有結合的に共役される。いくつかの実施形態では、これらの抱合体は、合成ナノキャリアの一部を形成する。一般に、ポリラクチド(PLA)またはポリラクチド−コ−グリコリド(PLGA)などのポリマーは、幾通りかの方法でレシキモド(R848としてもまた知られている)などの免疫賦活剤と抱合し得る。共役する方法については、下および実施例で提供される。
一般にアミド合成で使用される活性化試薬を使用して、少なくとも1つの酸末端基があるポリマー(例えばPLA、PLGA)またはその単位をアシルハロゲン化物、アシルイミダゾール、活性エステルなどの反応性アシル化剤に転換する。
酸末端基があるポリマーまたはその単位(例えばあらゆる適切な分子量を有するPLA、PLGA)は、活性化または共役試薬の存在下で免疫調節薬(例えばR848)と反応し、それはポリマーまたはその単位(例えばPLA、PLGA)を原位置で反応性アシル化剤に転換して、所望の抱合体(例えばPLA−R848、PLGA−R848)を与える。
R848などの免疫調節薬もまた、水酸基で終結するポリマーまたはその単位と共役し得る。このようなポリマーまたはその単位としては、ポリエチレングリコール、ポリラクチド、ポリラクチド−コ−グリコリド、ポリカプロラクトン、およびポリエステルなど、またはその単位が挙げられる。一般に、反応は次のように進展し、そこではラクトン開環重合で使用される触媒を使用して、一般構造(IV)のイミドを前述のポリマーまたはその単位の末端ヒドロキシルと反応させる。得られる反応生成物(II)は、ポリマーまたはその単位エステル結合を通じて薬剤のアミドを結合する。式(IV)および(II)の化合物は、次のようである。
抱合体(例えばR848−PLA)は、例えば以下のスキームに示すように、触媒存在下で、免疫調節薬(例えばR848)とポリマーまたはその単位(例えばD/L−ラクチド)とのワンポット開環重合を通じて形成され得る。
抱合体は、例えば以下のスキームに示すように、触媒存在下で、免疫調節薬(例えばR848)と1つ以上のポリマーまたはその単位(例えばD/L−ラクチドおよびグリコリド)との二段階開環重合を介して形成し得る。
本発明に従った組成物は、任意に薬学的に許容できる賦形剤と組み合わされた、本発明の化合物、抱合体、または合成ナノキャリアを含んでなる。組成物は、従来の製薬および調剤技術を使用して作成し、有用な剤形にしてもよい。実施形態では、本発明の化合物、抱合体、合成ナノキャリア、または組成物は注射のために、保存料と共に無菌の食塩溶液に懸濁される。
以下の実施例は、下のステップ1で例証される、Pulendranらに付与された国際公開第2008/127532号パンフレットで提供される方法に従った、ポリケタールPCADKの合成について記載する。
ステップ1:PCADKの調製
イミド開環を使用して、分子量2000のポリ−カプロラクトンジオールの末端アルコール基にR854を付着する。ポリカプロラクトンジオールはAldrich Chemical Company(カタログ番号189421)から購入され、以下の構造を有する。
イミド開環を使用して、分子量2000のポリ−(ヘキサメチレンカーボネート)ジオールの末端アルコール基にR848を付着する。ポリ(ヘキサメチレンカーボネート)ジオールは、Aldrich Chemical Company(カタログ番号461164)から購入されて、以下の構造を有する。
HO−[CH2(CH2)4CH2OCO2]nCH2(CH2)4CH2−OH
イミダゾキノリン(R−848)、D/Lラクチド、および関連ガラス器具を使用に先だって、全て真空下50℃で8時間乾燥させた。撹拌棒および冷却管を装着した丸底フラスコに、R−848(33mg、1.05×10−4モル)および乾燥トルエン(5mL)を入れた。これを加熱して還流し、全てのR−848を溶解した。溶液を窒素下で撹拌し、室温に冷却して超微粒子R−848の懸濁液を得た。この懸濁液にリチウムジイソプロピルアミド(THF中の2.0M、50μL、1.0×10−4モル)の溶液を添加して、その後撹拌を室温で5分間継続した。形成された淡黄色溶液に、シリンジを通じて窒素下で、D/Lラクチドの熱(120℃)溶液(1.87g、1.3×10−2モル)を添加した。淡黄色溶液を冷ましてから、室温で1時間撹拌した。溶液を塩化メチレン(200mL)で希釈して、次にそれを1%塩酸(2×50mL)で洗浄し、飽和炭酸水素ナトリウム溶液(50mL)がそれに続いた。溶液を硫酸マグネシウム上で乾燥させて濾過し、真空下で蒸発させてポリ乳酸−R−848抱合体を得た。TLC(シリカ、塩化メチレン中の10%メタノール)は、溶液が遊離R−848を含有しないことを示した。ポリマーを塩化メチレン(10mL)に溶解し、溶液を撹拌されるヘキサン(200mL)に滴下した。沈殿したポリマーをデカンテーションによって単離し、真空下で乾燥させて1.47グラムのポリ乳酸-R−848抱合体を白色固体として得た。ポリマーの一部を塩基中で加水分解し、HPLCによってR−848含量について調べた。R−848濃度の標準曲線をHPLC応答と比較することで、ポリマーは、ポリマー1gあたり10.96mgのR−848を含有すると判定された。
PLA(D/L−ポリラクチド)(Boehringer−IngelheimからのResomer R202H、KOH当量酸価0.21mmol/g、固有粘度(iv):0.21dl/g)(10g、2.1mmol、1.0当量)をジクロロメタン(DCM)(35mL)に溶解した。EDC(2.0g、10.5mmol、5当量)およびNHS(1.2g、10.5mmol、5当量)を添加した。超音波処理の助けを借りて、固形物を溶解した。得られた溶液を室温で6日間撹拌した。溶液を濃縮してDCMの大部分を除去し、残留物を250mLのジエチルエーテルおよび5mLのMeOHの溶液に添加して、活性化PLA−NHSエステルを沈殿させた。溶剤を除去して、ポリマーをエーテルで2回洗浄し(2×200mL)、真空下で乾燥させてPLA−NHS活性化エステルを白色の泡状固体として得た(約8gが回収され、1H NMRはNHSエステルの存在を確認した)。PLA−NHSエステルを−10度未満の冷凍庫内でアルゴン下において使用時まで保存した。
分子量が5000(10.5g、2.1mmol、1.0当量)であるPLA(D/L−ポリラクチド)をジクロロメタン(DCM)(35mL)に溶解する。EDC(2.0g、10.5mmol、5当量)およびNHS(1.2g、10.5mmol、5当量)を添加する。得られる溶液を室温で3日間撹拌する。溶液を濃縮してDCMの大部分を除去し、残留物を250mLのジエチルエーテルおよび5mLのMeOHの溶液に添加して、活性化PLA−NHSエステルを沈殿させる。溶剤を除去して、ポリマーをエーテルで2回洗浄し(2×200mL)、真空下で乾燥させてPLA−NHS活性化エステルを白色の泡状固体として得る(約8gが回収され、H NMRを使用してNHSエステルの存在を確認し得る)。PLA−NHSエステルを−10度未満の冷凍庫内でアルゴン下において使用時まで保存する。
ポリマー活性化について上述したのと同様に、50%〜75%のグリコリドがある低分子量PLGAを対応するPLGA−NHS活性化エステルに変換して、−10度未満の冷凍庫内でアルゴン下において使用時まで保存する。
PLA(R202H、酸価0.21mmol/g)(2.0g、0.42mmol、1.0当量)を10mLの乾燥アセトニトリルに溶解した。炭酸N,N’−ジスクシンイミジル(DSC)(215mg、1.26mmol、3.0当量)および触媒量の4−(N,N−ジメチルアミノ)ピリジン(DMAP)を添加した。得られた混合物をアルゴン下で1日間撹拌した。得られた溶液をほぼ乾燥するまで濃縮した。次に残留物を40mLのエーテルに添加してポリマーを沈殿させ、それをエーテルで2回洗浄し(2x30mL)、真空下で乾燥させてPLA−NHS活性化エステルを得た(1H NMRはNHSエステル量が約80%であることを示した)。
PLA(R202H)(5.0g、1.05mmol)を25mLの無水DCMおよび2.5mLの無水DMFに溶解した。DCC(650mg、3.15mmol、5.0当量)およびペンタフルオロフェノール(PFP)(580mg、3.15mmol、5.0当量)を添加した。得られた溶液を室温で6日間撹拌し、次に濃縮してDCMを除去した。得られた残留物を250mLのエーテルに添加して、活性化PLAポリマーを沈殿させ、それをエーテルで洗浄し(2×100mL)、真空下で乾燥させてPLA−PFP活性化エステルを白色の泡状固体(4.0g)として得た。
PLA−NHS(1.0g)、R848(132mg、0.42mmol)およびジイソプロピルエチルアミン(DIPEA)(0.073mL、0.42mmol)をアルゴン下で2mLの乾燥DMFに溶解した。得られた溶液を50〜60℃で2日間加熱した。溶液を室温に冷却し、40mLの脱イオン(DI)水に添加して、ポリマー生成物を沈殿させた。次にポリマーをDI水(40mL)およびエーテル(2×40mL)で洗浄し、真空下30℃で乾燥させて、R848−PLA抱合体を白色の泡状固体として得た(0.8g、H NMRはアミド結合を通じたR848のPLAへの共役を示した)。ポリマー上のR848の共役の程度(装填量)は、次のようにしてHPLC分析によって確認した。秤量された量のポリマーをTHF/MeOHに溶解して15%NaOHで処理した。得られた加水分解ポリマー生成物をR848の量について、HPLCによって標準曲線と比較して分析した。
PLA−NHS(1.0g、0.21mmol、1.0当量)、R848(132mg、0.42mmol、2.0当量)、DIPEA(0.15mL、0.84mmol、4.0当量)、およびDMAP(25mg、0.21mmol、1.0当量)をアルゴン下で2mLの乾燥DMFに溶解した。得られた溶液を50〜60℃で2日間加熱した。溶液を室温に冷却して、40mLの脱イオン(DI)水に添加してポリマー生成物を沈殿させた。次にポリマーをDI水(40mL)とエーテル(2×40mL)で洗浄し、真空下30℃で乾燥させてPLA−R848抱合体を白色の泡状固体として得た(0.7g;20mgのポリマーを0.2mLのTHF、0.1mLのMeOH、および0.1mLの15%NaOHの溶液中で加水分解した。ポリマー上のR848の量は、逆相HPLC分析(C18カラム、移動相A:水中の0.1%TFA、移動相B:CH3CN中の0.1%TFA、勾配)によって約35mg/gと測定された)。
PLA(R202H)(2.0g、0.42mmol、1.0当量)、DCC(260mg、1.26mmol、3.0当量)、NHS(145mg、1.26mmol、3.0当量)、R848(200mg、0.63mmol、1.5当量)、DMAP(77mg、0.63mmol、1.5当量)、およびDIPEA(0.223mL、1.26mmol、3.0当量)を4mLの乾燥DMFに溶解した。混合物を50〜55℃で3日間加熱した。混合物を室温に冷却し、DCMで希釈した。DCC−尿素を濾過して濾液を濃縮し、DCMを除去した。得られたDMF中の残留物を水(40mL)に添加して、ポリマー生成物を沈殿させ、それを水(40mL)、エーテル/DCM(40mL/4mL)、およびエーテル(40mL)で洗浄した。真空下30℃で乾燥後、所望のPLA−R848抱合体を白色の泡状固体(1.5g)として得た。
PLA(R202H)(2.0g、0.42mmol、1.0当量)、EDC(242mg、1.26mmol、3.0当量)、HOAt(171mg、1.26mmol、3.0当量)、R848(200mg、0.63mmol、1.5当量)、およびDIPEA(0.223mL、1.26mmol、3.0当量)を4mLの乾燥DMFに溶解した。混合物を50〜55℃で2日間加熱した。溶液を室温に冷却して水(40mL)に添加し、ポリマー生成物を沈殿させて、それを水(40mL)、エーテル/MeOH(40mL/2mL)、およびエーテル(40mL)で洗浄した。オレンジ色のポリマーを4mLのDCMに溶解し、得られた溶液を40mLのエーテルに添加して、ほぼオレンジ色なしのポリマーを沈殿させた。淡色のポリマーをエーテル(40mL)で洗浄した。真空下30℃で乾燥後、所望のPLA−R848抱合体を淡褐色泡状固体(1.5g)として得た。
PLA(R202H)(1.0g、0.21mmol、1.0当量)、EDC(161mg、0.84mmol、4.0当量)、HOBt.H2O(65mg、0.42mmol、2.0当量)、R848(132mg、0.42mmol、2.0当量)、およびDIPEA(0.150mL、0.84mmol、4.0当量)を2mLの乾燥DMFに溶解した。混合物を50〜55℃で2日間加熱した。溶液を室温に冷却し、水(40mL)に添加してポリマー生成物を沈殿させた。オレンジ色のポリマーを2mLのDCMに溶解し、得られた溶液を40mLのエーテルに添加してポリマーを沈殿させ、それを水/アセトン(40mL/2mL)およびエーテル(40mL)で洗浄した。真空下30℃で乾燥後、灰色がかった泡状固体として、所望のPLA−R848抱合体を得た(1.0g;ポリマー上のR848の装填量はHPLC分析に基づいて約45mg/gであり、1H NMRによって確認された)。同様にして、PLGA(75%ラクチド)−R848およびPLGA(50%ラクチド)−R848を調製した。
ステップ1:t−BOC保護ポリグリシン/R848抱合体(5g)をトリフルオロ酢酸(25mL)に溶解し、この溶液を50℃で1時間加温する。冷却後、トリフルオロ酢酸を真空下で除去し、残留物を酢酸エチル(25mL)中で磨砕する。ポリマーを濾過によって単離し、2−プロパノールで十分洗浄した。真空下で乾燥後、4.5グラムのポリマーが灰色がかった固体として得られる。
ポリ(ヘキサメチレンカーボネート)ジオールは、Aldrich Chemical Company(カタログ番号461164)から購入される。
ポリ(ヘキサメチレンカーボネート)ジオール
HO−[CH2(CH2)4CH2OCO2]nCH2(CH2)4CH2−OH
ポリ(ヘキサメチレンカーボネート)ジオール-8−オキソアデニン抱合体
3−ニコチン−PEG−PLAポリマーは、次のように合成した。
最初に分子量3.5KD(0.20g、5.7×10−5モル)のJenKem(登録商標)からのモノアミノポリ(エチレングリコール)と過剰な4−カルボキシコチニン(0.126g、5.7×10−4モル)をジメチルホルムアミド(5.0mL)に溶解した。溶液を撹拌して、ジシクロヘキシルカルボジイミド(0.124g、6.0×10−4モル)を添加した。この溶液を室温で一晩撹拌した。水(0.10mL)を添加し、さらに15分間撹拌を継続した。ジシクロヘキシル尿素沈殿物を濾過により除去して、濾液を真空下で蒸発させた。残留物を塩化メチレン(4.0mL)に溶解し、この溶液をジエチルエーテル(100mL)に添加した。溶液を冷蔵庫内で2時間冷却して、沈殿したポリマーを濾過により単離した。ジエチルエーテルでの洗浄後、固体白色ポリマーを高真空下で乾燥させた。収率は0.188gであった。このポリマーをさらなる精製なしに、次のステップで使用した。
Gersterらに付与された米国特許第5,389,640号明細書の実施例99に提供される合成に従って、カプセル化アジュバント製剤のためにレシキモド(別名R848)を合成した。
1.塩化メチレン中のレシキモド(R848)(10mg/mL)およびPLA(100mg/mL)、または塩化メチレン中のPLA−R848抱合体(100mg/mL)
2.塩化メチレン中のPLA−PEG−ニコチン(100mg/mL)
3.塩化メチレン中のPLA(100mg/mL)
4.水中のオボアルブミンペプチド323−339(10または69mg/mL)
5.水中のポリビニルアルコール(50mg/mL)
材料
オボアルブミンタンパク質のT細胞エピトープであることが知られている、アミノ酸17個のペプチドであるオボアルブミンペプチド323−339は、Bachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505)から購入した。
材料
上の実施例32で提供されるのと同じ。
R848およびペプチド(例えばovaペプチド、ヒトペプチド、TT2pDT5t)のための方法
Agilent Zorbax SB−C18カラム(3.5μm.75×4.6mm.カラム温度=40℃(パーツ番号866953−902))を装着した、Agilent 1100システム上の逆相HPLCを使用して、適切な波長(R848ではλ=254nm、ovaペプチドでは215nm)で、95%水/5%アセトニトリル/0.1%TFAの移動相A(MPA)、および90%アセトニトリル/10%水/0.09%TFAの移動相B(MPB)を使用して、R848(免疫賦活剤)およびovaペプチド(T細胞抗原)の量を測定した。(勾配:7分間でB=5〜45%;9分間で95%Bに上昇させ;9.5分間で5%のBに低下させて、終わりまで平衡を保った。総実行時間は、流速1mL/分で13分間であった)。
Waters XBridge C−18(2.5μm粒子、50×4.6mm内径(パーツ番号186003090)、カラム温度600℃)を装着した、Agilent 1100システム上の逆相HPLCを使用して、260nmで、100mM TEA−酢酸緩衝液中の2%アセトニトリル、pH約8.0の移動相A、および90%アセトニトリルと10%水の移動相Bを使用して、CpG(免疫賦活剤)量を測定した。(カラムを5%のBで平衡化させ、8.5分間で55%のBに増大させて、次に12分間で90%のBに上昇させた。Bの濃度を1分間で迅速に5%に低下させ、停止時点まで16分間平衡化させた。流速は、方法終了時まで16分間1mL/分であった)。
Waters X−Bridge C−18(5μm粒子、100×4.6mm内径、カラム温度400℃)を装着した、Agilent 1100システム上の逆相HPLCを使用して、254nmで、95%水/5%アセトニトリル/0.1%TFAの移動相A(MPA)、および90%アセトニトリル/10%水/0.09%TFAの移動相B(MPB)を使用して、ニコチン類似体を測定した。(勾配:カラムを5%のBで平衡化させ、14分間で45%のBに増大させた。次に14〜20分間で95%Bに上昇させた。移動相Bの濃度を迅速に5%に低下させ、方法終了時まで平衡化した。方法の流速は、25分間の総実行時間0.5mL/分に保った。NC懸濁液を14000rpmで粒度に応じて約15〜30分間分遠心分離した。収集されたペレットを撹拌しながら溶液が透明になるまで、200μLの濃NH4OH(8M)で2時間処理した。200μLの1%TFAを添加して混合物溶液を中和すると、ペレット溶液の総体積は200μLになった。溶液の50μLのアリコートをMPA(または水)で200μLに希釈して、上と同様にHPLC上で分析し、ペレット中に存在する量を測定した。
0.5mLのNC懸濁液を14000rpmで約15分間遠心分離した。収集されたペレットを0.3mLのアセトニトリルで溶解して、14000rpmで短時間遠心分離して、あらゆる残留不溶性物質を除去した。透明溶液をMPAの4倍相当体積でさらに希釈して、上述の逆相HPLC上でアッセイした。
製造からの330μLのNC懸濁液(PBS中の約10mg/mLの懸濁液)を14000rpmで粒度に応じて15〜30分間遠沈した。収集されたペレットを500μLの水に再懸濁し、30分間超音波処理して粒子を完全に分散させた。次にNCを600℃で10分間加熱した。追加的な200μLの1N NaOHを混合物に添加してさらに5分間加熱したところ、混合物は透明になった。加水分解されたNC溶液を14000rpmで短時間遠心分離した。次に水を使用して透明溶液の最終2倍希釈を行い、上述の逆相HPLC上でアッセイした。
製造からの330μLのNC懸濁液(PBS中の約10mg/mL懸濁液)を14000rpmで15〜30分間遠沈した。100μLのアセトニトリルをペレットに添加して、NCのポリマー構成要素を溶解した。混合物をボルテックスして1〜5分間超音波処理した。100μLの0.2%TFAを混合物に添加してペプチドを抽出し、さらに5分間超音波処理して、凝集体の崩壊を確実にした。混合物を14000rpmで15分間遠心分離して、あらゆる不溶性物質(例えばポリマー)を分離した。150μLのMPA(または水)で希釈された上清の50μLのアリコートを取って、上述のように逆相HPLCでアッセイした。
1.5mLのNC懸濁液を14000rpmで約15分間遠沈して、150μLの濃NH4OH(8M)を使用して約2〜3時間、溶液が透明になるまでペレットを加水分解した。150μLの2%TFA(aq)溶液をペレット混合物に添加して、溶液を中和した。混合物の100μLのアリコートを200μLの水で希釈し、上述の逆相HPLC上でアッセイし、製造で使用されるPLA−PEG−ニコチン前駆物質(PEG−ニコチン)を使用して確立された標準曲線に基づいて、定量化した。
以下のデータは、上に示した低分子量ポリ乳酸−R−848抱合体からできたナノ粒子からのR−848の放出速度を示す。表1は、実験の関連製剤情報を提供する。
分析法:放出されたR848およびovaペプチドの量は、λ=215nmでAgilent Zorbax SB−C18カラム(3.5μm。75×4.6mm。カラム温度=40℃(パーツ番号866953−902))を装着したAgilent 1100システム上の逆相HPLCを使用して、98%水/2%アセトニトリル/0.1%TFAの移動相A(MPA)、および90%アセトニトリル/10%水/0.09%TFAの移動相B(MPB)を使用して、7分間でB=5〜45%;9分間で95%のBに上昇させ;終わりまで再平衡化させる勾配、13分間の実行時間、流速=1mL/分で測定される。
T0サンプルでは、200μLのアリコートをNPの各サンプルから即座に取って、微量遠心機(型名:Galaxy 16)を使用して微小遠心管内で14000rpmで遠心分離した。100μLの上清を取ってHPLC移動相A(MPA)で200μLに希釈し、放出されたR848およびovaペプチドの量について逆相HPLC上でアッセイした。
T0サンプルでは、各サンプルから200μLのアリコートを取って6000rpmで20分間遠心分離し、上清を除去した。残留ナノ粒子を200μLのクエン酸緩衝液に再懸濁し、14000rpmで15分間遠心分離した。100μLの上清を取ってMPAで200μLに希釈し、上記のようにR848およびペプチドについてアッセイした。
HPLC−Agilent 1100。λ=215nm。カラム温度=40℃。
カラム−Agilent Zorbax SB−C18、3.5μm。75×4.6mm。(パーツ番号866953−902)
C18ガードカラム
移動相A(MPA)−98%水/2%アセトニトリル/0.1%TFA
移動相B(MPB)−90%アセトニトリル/10%水/0.09%TFA
勾配:7分間でB=5〜45%;9分までに95%のBに上昇;終了時まで再平衡。13分実行時間。流速=1mL/分。
PBS−100mM、pH=7.4。
クエン酸緩衝液-100mM、pH=4.5。
オーブン
微量遠心機−Galaxy 16
微小遠心管
超音波処理器
ピペット−20、200、調節可能1000μL
HPLC等級水−EMD−#WX0008−1.
NH4OH−約8M。Mallinkcrodt。
TFA、0.2%。Prep4/27/09。
TFA、1%。Prep5/13/09。
温度計
1)T=0サンプル調製
a.PBS
i.各サンプルから200μLのアリコートを取る。14000rpmで微量遠心。上清を取り出す。
ii.上清をMPA中で100μL>200μLに希釈する。(DF=2)
iii.ペプチドおよびR848についてアッセイする。
b.クエン酸
i.各サンプルから200μLのアリコートを取る。6000rpmで20分間微量遠心。上清を除去する。
ii.200μLのクエン酸緩衝液を添加して、完全に再懸濁する。
iii.14000rpmで15分間微量遠心する。上清を取り出す。
iv.上清をMPA中で100μL>200μLに希釈する。(DF=2)
v.ペプチドおよびR848についてアッセイする。
2)PBS IVR
a.9×200μL(非抱合型では3×200)の各サンプルを微小遠心管に入れる。
b.各アリコートに37℃の300μLのPBSを添加する。
c.サンプルを即座に37℃のオーブンに入れる。
3)クエン酸IVR
a.9×200μL(非抱合型では3×200)の各サンプルを微小遠心管に入れる。
b.6000rpmで20分間遠心分離する。
c.上清を除去する。
d.各試験管に500μLのクエン酸緩衝液を入れて、完全に再懸濁する。
e.サンプルを37℃のオーブンに入れる。
4)ロット1〜4および8では、以下の時点でサンプルを取り出す(ステップ6参照)。
a.抱合型
i.24時間
ii.48時間(2日間)
iii.96時間(4日間)
iv.144時間(6日間)
v.上記データに基づいて決定されるさらなる時点。
b)非抱合型
i.2時間
ii.16時間
iii.24時間
5)ロット6および7では、以下の時点でサンプルを取り出す。
a.PBS
i.24時間
ii.48時間(2日間)
iii.96時間(4日間)
iv.144時間(6日間)
v.上記データに基づいて決定されるさらなる時点。
b.クエン酸
i.2時間
ii.16時間
iii.24時間
iv.48時間(2日間)
v.72時間(3日間)
vi.96時間(4日間)
vii.120時間(5日間)
viii.上記データに基づいて決定されるさらなる時点。
6)次のようにサンプル採取する。
a.14000rpmで15分間微量遠心。
b.上清を除去する。
c.MPA中で100μLを200μLに希釈する。(DF=2)
7)ペプチドおよびR848についてアッセイする。これは各時点の放出量を与える。
完全な質量平衡を完結するために、以下を実施する。
8)残留ペレット(抱合型のみ)に200μLのNH4OHを添加する。
9)短時間ボルテックスし、超音波処理して分散する。
10)撹拌棒を入れる。透明になるまで静置する(少なくとも3時間)。
11)200μLの1%TFAを添加する(総ペレット体積=400μL)。
12)MPA中で50μLを200μLに希釈する。HPLCによって分析し、ペレット中に残留するペプチドおよびR848を測定する。(DF=4)
13)非抱合型ロットでは、典型的なAcN/TFA法によるペプチドおよびR848のアッセイ。
37℃におけるリン酸緩衝食塩水溶液(PBS)(100mM、pH=7.4)およびクエン酸緩衝液(100mM、pH=4.5)中での合成ナノキャリアからの抗原(例えばovaペプチド、T細胞抗原)および免疫賦活剤(例えばR848、CpG)の放出を次のようにして測定した。
1mLのPBS懸濁NCを微小遠心管内で14000rpmで、粒度に応じて一般に15〜30分間遠心分離した。次に収集された上清を等体積の移動相A(MPA)または水で希釈して、保存中に放出されたR848の量について逆相HPLC上でアッセイした。残留するペレットを1mLのPBS中で均質な懸濁液に再懸濁し、絶えず穏やかに撹拌しながら37℃の加温チャンバーに入れた。
pH=7.4のPBS緩衝液の代わりに100mMクエン酸ナトリウム緩衝液(pH=4.5)を用いて、元のNC保存溶液(例えばPBS)を交換した。上のPBSおよびクエン酸緩衝液中における測定からの質量平衡を完結するために、各時点で残留したペレットを溶液が透明になるまで、100μLのNH4OH(8M)で撹拌しながら2時間(または2時間以上)処理した。100μLの1%TFAを添加して混合物を中和し、ペレット溶液の総体積を200μLにした。混合物の50μLのアリコートをMPA(または水)で200μLに希釈して、上記のようにHPLC上で分析し、生体外放出後にペレット中に残留する未放出のR848量を測定して、質量平衡を閉じた。非抱合型サンプルでは、サンプルをアセトニトリル中のTFAで希釈し、上のR848と同様にしてアッセイした。
5匹のマウスのグループを2週間間隔で(0、14、および28日目)、100μgのNC−Nicで3回免疫化した(皮下、後肢)。NC−Nicはニコチンを外面に提示するナノキャリアの組成物であり、グループ1以外の全てのマウスグループで、ナノキャリアから異なる速度で放出されるCpG−1826(チオ化(thioated))アジュバントを有した。ナノキャリアは、上で提供される方法に従って調製した。次に26および40日目に、血清抗ニコチン抗体を測定した。ポリリジン−ニコチンに対して標準ELISAで測定された、抗ニコチン抗体のEC50を図4に示す。
2形態のCpGアジュバントを有するNC−Nicによる免疫化
5匹のマウスのグループを4週間間隔で(0および28日目)、100μgのNC−Nicで2回免疫化して(皮下、後肢)、次に12、24、および40日目に血清抗ニコチン抗体を測定した。NC−Nicはニコチンを外面に提示するナノキャリア組成物であり、2形態のCpG−1826アジュバントの内1つを有した。ナノキャリアは、上で提供される方法に従って調製した。ポリリジン−ニコチンに対して標準ELISAで測定された、抗ニコチン抗体のEC50を図5に示す。
5匹のマウスのグループを2週間間隔で(0、14、および28日目)、100μgのNC−Nicで3回免疫化して(皮下、後肢)、次に26、40、および54日目に血清抗ニコチン抗体を測定した。ナノキャリアは、上で提供される方法に従って調製した。ポリリジン−ニコチンに対して標準ELISAで測定された、抗ニコチン抗体のEC50を図6に示す。
Claims (44)
- 式(I)、
R2=イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R3は、Y=Nであれば不在であり;あるいはY=CであればR4と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R4は、R3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R8は生分解性ポリマーであり、該ポリマーはポリエステル、ポリカーボネートまたはポリアミドである)
の構造を含んでなる化合物。 - ポリマーが、ポリ(乳酸)、ポリ(グリコール酸)、ポリ(乳酸−コ−グリコール酸)またはポリカプロラクトンである、請求項1に記載の化合物。
- (a)ポリマーがpH=7.4および25℃で水不溶性であり、および/または、(b)ポリマーがゲル透過クロマトグラフィーを使用した測定で、800ダルトン〜10,000ダルトンの範囲の重量平均分子量を有する、請求項1または2に記載の化合物。
- 式(II)、
R2=イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R3は、Y=Nであれば不在であり;あるいはY=CであればR4と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R4は、R3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R5は、生分解性のポリマーまたはその単位であり;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立して不在またはHであり;
R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオール、NH2、あるいはアルキル、アリール、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造を含んでなる化合物。 - ポリマーあるいはその単位が、ポリエステル、ポリカーボネート、ポリアミド、またはポリエーテルあるいはその単位を含む、請求項4に記載の化合物。
- ポリマーあるいはその単位が、ポリ(乳酸)、ポリ(グリコール酸)、ポリ(乳酸−コ−グリコール酸)、ポリカプロラクトン、またはポリ(エチレングリコール)あるいはその単位を含む、請求項4または5に記載の化合物。
- (a)ポリマーがpH=7.4および25℃で水不溶性であり、および/または、(b)ポリマーがゲル透過クロマトグラフィーを使用した測定で、800ダルトン〜10,000ダルトンの範囲の重量平均分子量を有する、請求項4〜6のいずれか一項に記載の化合物。
- ポリマーまたはその単位がポリケタールまたはその単位ではない、請求項4または7に記載の化合物。
- 式(I)、
(A)生分解性ポリマーを活性化するステップと;
活性化生分解性ポリマー、および式(III)
(B)生分解性ポリマーを含んでなる組成物、および前記式(III)の構造を含んでなる化合物を共役剤および塩基および/または溶剤に曝露するステップ
を含んでなり、
前記式(I)および式(III)において、
R 1 =H、OH、エトキシメチルであり;
R 2 =イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R 3 は、Y=Nであれば不在であり;あるいはY=CであればR 4 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R 4 は、R 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R 8 は、生分解性ポリマーであり、該生分解性ポリマーはポリエステル、ポリカーボネートまたはポリアミドである、前記方法。 - ポリマーが、ポリ(乳酸)、ポリ(グリコール酸)、ポリ(乳酸−コ−グリコール酸)またはポリカプロラクトンである、請求項9に記載の方法。
- (a)ポリマーがpH=7.4および25℃で水不溶性であり、および/または、(b)ポリマーがゲル透過クロマトグラフィーを使用した測定で、800ダルトン〜10,000ダルトンの範囲の重量平均分子量を有する、請求項9または10に記載の方法。
- 式(II)、
(A)アルコール、触媒、および式(IV)、
前記アルコール、触媒、および化合物を、加熱するステップ、または
(B)アルコールおよび前記式(IV)の構造を含んでなる化合物を組み合わせるステップと、前記アルコールおよび化合物を加熱するステップと、触媒を添加するステップ、または
(C)アルコール、触媒、および前記式(IV)の構造を含んでなる化合物を組み合わせるステップ
を含んでなり、
前記アルコールは、末端水酸基があるポリマーまたはその単位であり、
前記式(II)および式(IV)において、
R 1 =H、OH、エトキシメチルであり;
R 2 =イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R 3 は、Y=Nであれば不在であり;あるいはY=CであればR 4 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R 4 は、R 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R 5 はポリマーまたはその単位であり;
XはC、N、O、またはSであり;
R 6 およびR 7 はそれぞれ独立して不在またはHであり;
R 9 、R 10 、R 11 、およびR 12 はそれぞれ独立してH、ハロゲン、OH、チオール、NH 2 、あるいはアルキル、アリール、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである、
前記方法。 - (A)において、アルコール、触媒、および化合物を、溶剤存在下で加熱する、請求項12に記載の方法。
- (B)において、アルコール、化合物、および触媒が、触媒の添加中および/または触媒の添加後に加熱される、請求項12または13に記載の方法。
- 触媒が、ホスファゼン塩基、1,8−ジアザビシクロウンデカ−7−エン、1,4,7−トリアザビシクロデセン、またはN−メチル−1,4,7−トリアザビシクロデセンである、請求項12〜14のいずれか一項に記載の方法。
- ポリマーあるいはその単位が、ポリエステル、ポリカーボネート、ポリアミド、またはポリエーテルあるいはその単位を含む、請求項12〜15のいずれか一項に記載の方法。
- ポリマーあるいはその単位が、ポリ(乳酸)、ポリ(グリコール酸)、ポリ(乳酸−コ−グリコール酸)、ポリカプロラクトン、またはポリ(エチレングリコール)あるいはその単位を含む、請求項12〜16のいずれか一項に記載の方法。
- (a)前記ポリマーはpH=7.4および25℃で水不溶性であり、および/または、(b)前記ポリマーはゲル透過クロマトグラフィーを使用した測定で、800ダルトン〜10,000ダルトンの範囲の重量平均分子量を有する、請求項12〜17のいずれか一項に記載の方法。
- ポリマーまたはその単位がポリケタールまたはその単位ではない、請求項12〜15および18のいずれか一項に記載の方法。
- 式(IV)、
R2=イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R3は、Y=Nであれば不在であり;あるいはY=CであればR4と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R4は、R3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立して不在またはHであり;
R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオール、NH2、あるいはアルキル、アリール、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)で表される化合物。 - 請求項20に記載の化合物を含んでなる組成物。
- 式(IV)、
を含み、
式(IV)、(III)および(V)において、
R 1 =H、OH、エトキシメチルであり;
R 2 =イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R 3 は、Y=Nであれば不在であり;あるいはY=CであればR 4 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R 4 は、R 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
XはC、N、O、またはSであり;
R 6 およびR 7 はそれぞれ独立して不在またはHであり;
R 9 、R 10 、R 11 、およびR 12 はそれぞれ独立してH、ハロゲン、OH、チオール、NH 2 、あるいはアルキル、アリール、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである、前記方法。 - 式(VI)、
(A)触媒、式(VII)、
HO−ポリマー−OH(VII)
を有するジオール、および式(IV)、
前記ジオール、触媒、および化合物を加熱するステップ、または
(B)前記式(VII)を有するジオール、および前記式(IV)の構造を含んでなる化合物を組み合わせるステップと;
前記ジオールおよび化合物を加熱するステップと;
触媒を添加するステップ、または
(C)触媒、前記式(VII)を有するジオール、および前記式(IV)の構造を含んでなる化合物を合わせるステップ
を含み、
式(VI)および(IV)において、
R 1 =H、OH、エトキシメチルであり;
R 2 =イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R 3 は、Y=Nであれば不在であり;あるいはY=CであればR 4 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R 4 は、R 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR 3 と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
XはC、N、O、またはSであり;
R 6 およびR 7 はそれぞれ独立して不在またはHであり;
R 9 、R 10 、R 11 、およびR 12 はそれぞれ独立してH、ハロゲン、OH、チオール、NH 2 、あるいはアルキル、アリール、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである、
前記方法。 - (A)において、ジオール、触媒、および化合物を、溶剤存在下で加熱する、請求項23に記載の方法。
- (B)において、ジオール、化合物、および触媒が、触媒の添加中および/または触媒の添加後に加熱される、請求項23または24に記載の方法。
- (a)触媒が、ホスファゼン塩基、1,8−ジアザビシクロウンデカ−7−エン、1,4,7−トリアザビシクロデセン、またはN−メチル−1,4,7−トリアザビシクロデセンであり、および/または、(b)ポリマーがゲル透過クロマトグラフィーを使用した測定で、800ダルトン〜10,000ダルトンの範囲の重量平均分子量を有し、および/または、(c)ポリマーがpH=7.4および25℃で水不溶性である、請求項23〜25のいずれか一項に記載の方法。
- 式(VII)の化合物が、ポリケタールジオール、ポリ(エチレン)グリコール、ポリカプロラクトンジオール、ジブロックポリラクチド−コ−ポリ(エチレン)グリコール、ジブロックポリラクチド/ポリグリコリド−コ−ポリ(エチレン)グリコール、ジブロックポリグリコリド−コ−ポリ(エチレン)グリコール、ポリ(プロピレン)グリコール、ポリ(ヘキサメチレンカーボネート)ジオール、およびポリ(テトラヒドロフラン)からなる群から選択される、請求項23〜26のいずれか一項に記載の方法。
- ポリマーがポリケタールまたはその単位ではない、請求項23〜26のいずれか一項に記載の方法。
- 式(VI)、
R2=イソブチル、ヒドロキシイソブチル、メタンスルホンアミドイソブチルまたはベンジルであり;
Y=NまたはCであり;
R3は、Y=Nであれば不在であり;あるいはY=CであればR4と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
R4は、R3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成しなければ、ペンチル、ブトキシ、ベンジルアミノまたはブチルアミノであり;あるいはR3と組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成し;
XはC、N、O、またはSであり;
R6およびR7はそれぞれ独立して不在またはHであり;
R9、R10、R11、およびR12はそれぞれ独立してH、ハロゲン、OH、チオール、NH2、あるいはアルキル、アリール、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、アルキルアミノ、またはアリールアミノである)の構造
を含んでなる、化合物。 - (a)ポリマーがゲル透過クロマトグラフィーを使用した測定で、800ダルトン〜10,000ダルトンの範囲の重量平均分子量を有し、および/または、(b)ポリマーがpH=7.4および25℃で水不溶性である、請求項29に記載の化合物。
- (a)ポリマーが、ポリケタールジオール、ポリ(エチレン)グリコール、ポリカプロラクトンジオール、ジブロックポリラクチド−コ−ポリ(エチレン)グリコール、ジブロックポリラクチド/ポリグリコリド−コ−ポリ(エチレン)グリコール、ジブロックポリグリコリド−コ−ポリ(エチレン)グリコール、ポリ(プロピレン)グリコール、ポリ(ヘキサメチレンカーボネート)ジオール、およびポリ(テトラヒドロフラン)からなる群から選択される、請求項29または30に記載の化合物。
- ポリマーがポリケタールまたはその単位ではない、請求項29または30に記載の化合物。
- (a)R1がHであり、R2がイソブチルであり、YがCであり、R3およびR4が組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成する、または
(b)R1がエトキシメチルであり、R2がヒドロキシイソブチルであり、Y=Cであり、R3およびR4が組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成する、または
(c)R1がエトキシメチルであり、R2がメタンスルホンアミドイソブチルであり、Y=Cであり、R3およびR4が組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成する、または
(d)R1がOHであり、R2がベンジルであり、Y=Nであり、R3が不在であり、R4がブトキシである、または
(e)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がブチルアミノである、または
(f)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がブトキシである、または
(g)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がベンジルアミノである、または
(h)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がペンチルである、
請求項1〜8、20、29〜32のいずれか一項に記載の化合物。 - 請求項33に記載の化合物を含んでなる組成物。
- (a)R1がHであり、R2がイソブチルであり、YがCであり、R3およびR4が組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成する、または
(b)R1がエトキシメチルであり、R2がヒドロキシイソブチルであり、Y=Cであり、R3およびR4が組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成する、または
(c)R1がエトキシメチルであり、R2がメタンスルホンアミドイソブチルであり、Y=Cであり、R3およびR4が組み合わさってそれらが結合するピリジン環の炭素原子と共にベンゼン環を形成する、または
(d)R1がOHであり、R2がベンジルであり、Y=Nであり、R3が不在であり、R4がブトキシである、または
(e)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がブチルアミノである、または
(f)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がブトキシである、または
(g)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がベンジルアミノである、または
(h)YがNであり、R1がOHであり、R2がベンジルであり、R3が不在であり、R4がペンチルである、
請求項9〜19、22〜28のいずれか一項に記載の方法。 - 請求項1〜8、20、29〜33のいずれか一項に記載の化合物を含んでなる、合成ナノキャリア。
- (a)B細胞抗原および/またはT細胞抗原、および/または、(b)抗原提示細胞(APC)標的特性をさらに含んでなる、請求項36に記載の合成ナノキャリア。
- 合成ナノキャリアが、デンドリマー、バッキーボール、ナノワイヤー、ペプチドもしくはタンパク質ベースナノ粒子、ナノ材料の組み合わせを含んでなるナノ粒子、球状ナノ粒子、立方体ナノ粒子、錐体のナノ粒子、長円形ナノ粒子、円柱状ナノ粒子、またはドーナツ形ナノ粒子である、請求項36または37に記載の合成ナノキャリア。
- 請求項1〜8、20、29〜33のいずれか一項に記載の化合物および/または請求項36〜38のいずれか一項に記載の合成ナノキャリアを含んでなる、組成物。
- 薬学的に許容できる賦形剤をさらに含んでなる、請求項39に記載の組成物。
- 請求項1〜8、20、29〜33のいずれか一項に記載の化合物、請求項36〜38のいずれか一項に記載の合成ナノキャリアまたは請求項34、39、40のいずれか一項に記載の組成物の1つ以上を含んでなる、ワクチン。
- 予防方法または治療方法に用いるための、対象中で免疫応答を誘発または増強するための、請求項34、39、40のいずれか一項に記載の組成物。
- 予防方法または治療方法に用いるための、対象中で免疫応答を誘発または増強するための、請求項36〜38のいずれか一項に記載の合成ナノキャリア。
- 予防方法または治療方法に用いるための、対象中で免疫応答を誘発または増強するための、請求項41に記載のワクチン。
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