JP2021503450A - プログラム可能なポリマー薬 - Google Patents
プログラム可能なポリマー薬 Download PDFInfo
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- JP2021503450A JP2021503450A JP2020526505A JP2020526505A JP2021503450A JP 2021503450 A JP2021503450 A JP 2021503450A JP 2020526505 A JP2020526505 A JP 2020526505A JP 2020526505 A JP2020526505 A JP 2020526505A JP 2021503450 A JP2021503450 A JP 2021503450A
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Abstract
Description
標的化薬物コンジュゲートは、例えば化学療法とは異なり、罹患細胞しか標的とせず、かつ健常な細胞を害さないよう意図されている。通常、コンジュゲートは、生物学的に活性なペイロードまたは薬物に連結されている標的指向性分子から構成される。コンジュゲートは、固有の標的能力と生物学的に活性な薬物の治療有効性とを組み合わせることにより、意図する標的だけに薬物を送達し、潜在的な副作用を最小化することができる。
抗体−薬物コンジュゲート(ADC)は、がん処置に特に関心がもたれる標的化薬物コンジュゲートのクラスの1つである。ADCは、モノクローナル抗体の標的指向性特徴と、細胞毒性剤のがん死滅能とを組み合わせて、他の化学療法剤よりもいくつかの利点を有する治療を実現する。しかし、ADC構築の複雑さ、具体的には、抗体と薬物との間の化学リンカーに関わる難題により、新規かつ有効な治療剤の開発はかなり困難である。最初のADCは、2001年に承認されたが、次のADCが承認されるまでに、ほとんど10年間が費やされた。現時点において、Adcetris(登録商標)およびKadcyla(登録商標)しか、世界中で市販されていない(Zevalin(登録商標)は、中国でしか承認されてない)。先駆者のPfizer/Wyethは、比較臨床試験の間に安全性問題が観察された後の2010年にMylotarg(登録商標)を取り消した。
したがって、大きな治療指数を有する強力な標的薬物コンジュゲートが当分野において必要とされている。理想的には、このような薬物コンジュゲートは、健常な組織と罹患組織(例えば、腫瘍細胞)との間の微妙な区別を実現すべきである。本発明は、この必要性に応え、さらなる関連する利点を実現する。
現在開示されている化合物の実施形態は、リンカー(「L」)によって共有結合により連結されている、1つまたは複数の生物学的に活性な部分を含む。有利には、本発明の実施形態は、ポリマー合成の間に組み込まれ得るか、または合成後に結合され得る化合物を提供する。さらに、本明細書に記載されている実施形態は、同一化合物内の複数の生物学的に活性な部分の取り込み、および標的指向性部分の任意の含有を可能にする。
一実施形態では、以下の構造(I)を有する化合物:
別の実施形態では、それを必要とする対象に、治療有効量の構造(I)の化合物または構造(I)の化合物を含む組成物を投与するステップを含む、疾患を処置する方法であって、Mはそれぞれ、独立して、疾患を処置するのに有効な生物活性部分を含む、方法が提供される。
本発明のこれらの態様および他の態様が、以下の詳細説明を参照すると明白になろう。
文脈上異なる解釈を要する場合を除き、本明細書および特許請求の範囲の全体を通して、語「含む(comprise)」、ならびに「含む(comprises)」および「含むこと(comprising)」などのその変化形は、オープンな包括的な意味で、すなわち、「以下に限定されないが、含む」として解釈されるべきである。
「アミノ」とは、−NH2基を指す。
「カルボキシ」とは、−CO2H基を指す。
「シアノ」とは、−CN基を指す。
「ホルミル」」とは、−C(=O)H基を指す。
「ヒドロキシ」または「ヒドロキシル」とは、−OH基を指す。
「イミノ」とは、=NH基を指す。
「ニトロ」とは、−NO2基を指す。
「オキソ」とは、=O置換基を指す。
「スルフヒドリル」とは、−SH基を指す。
「チオオキソ」とは、=S基を指す。
「アルキニレン」または「アルキニレン鎖」とは、少なくとも1つの炭素−炭素三重結合を含有し、2〜12個の炭素原子を有する、炭素および水素のみからなる、分子の残りをラジカル基に連結する、二価の直鎖状または分岐状炭化水素鎖、例えば、エテニレン、プロペニレン、n−ブテニレンなどを指す。アルキニレン鎖は、単結合を介して分子の残りに、および二重結合または単結合を介してラジカル基に結合している。アルキニレン鎖の、分子の残りおよびラジカル基への結合点は、この鎖内の1個の炭素または任意の2個の炭素を介することができる。本明細書において特に具体的に明記しない限り、アルキニレンは、置換されていてもよい。
「アルコキシ」とは、式−ORaの基を指し、Raは、1〜12個の炭素原子を含有する、上で定義したアルキル基である。本明細書において特に具体的に明記しない限り、アルコキシ基は、置換されていてもよい。
「ヘテロアルコキシ」とは、式−ORaの基を指し、Raは、1〜12個の炭素原子を含有する、上で定義したヘテロアルキル基である。本明細書において特に具体的に明記しない限り、ヘテロアルコキシ基は、置換されていてもよい。
「ヘテロアルケニレン」は、少なくとも1つの炭素−炭素二重結合を含む、上で定義したヘテロアルキレンである。本明細書において特に具体的に明記しない限り、ヘテロアルケニレン基は、置換されていてもよい。
「ヘテロアルキニレン」は、少なくとも1つの炭素−炭素三重結合を含む、ヘテロアルキレンである。本明細書において特に具体的に明記しない限り、ヘテロアルキニレン基は、置換されていてもよい。
「ホスフェート」とは、−OP(=O)(Ra)Rb基(Raは、OH、O-またはORcであり、Rbは、OH、O-、ORcである)、チオホスフェート基またはさらなるホスフェート基(Rcは、対イオン(例えば、Na+など)である)を指す。
「チオホスフェート」とは、−OP(=Ra)(Rb)Rc基(Raは、OまたはSであり、Rbは、OH、O-、S-、ORdまたはSRdであり、Rcは、OH、SH、O-、S-、ORd、SRd、ホスフェート基またはさらなるチオホスフェート基であり、Rdは、対イオン(例えば、Na+など)であり、ただし、i)RaはSであり、ii)RbはS-またはSRdであり、iii)Rcは、SH、S-またはSRdであり、またはiv)i)、ii)および/またはiii)の組合せであることを条件とする)を指す。
「蛍光」とは、特定の周波数の光を吸収して、異なる周波数の光を発光することが可能な分子を指す。蛍光は、当業者に周知である。
「有色の」とは、有色スペクトル(すなわち、赤色、黄色、青色など)内の光を吸収する分子を指す。
「固体支持体」とは、分子の固定相支持体に関して、当分野で公知の任意の固体基材を指し、例えば、「マイクロ粒子」とは、以下に限定されないが、ガラス製ビーズ、磁気ビーズ、ポリマー製ビーズ、非ポリマー製ビーズなどを含めた、本発明の化合物への結合に有用ないくつかの小型粒子のいずれかを指す。ある種の実施形態では、マイクロ粒子はポリスチレン製ビーズを含む。
「固体支持体残基」とは、分子が固体支持体から開裂されると、分子に結合した状態のままである官能基を指す。固体支持体残基は、当分野で公知であり、固体支持体の構造、および分子を固体支持体に連結する基に基づいて容易に誘導体化され得る。
構造(I)の同位体標識化合物は、一般に、当業者に公知の従来技法により、または以下において、および以前に使用された非標識試薬の代わりに適切な同位体標識試薬を使用する以下の実施例に記載されているものに類似した方法によって一般に調製され得る。
「安定な化合物」および「安定な構造」は、反応混合物から有用な純度の程度となるまでの単離、および有効な治療剤への製剤化の間に分解しない(survive)ほど十分に頑強な化合物を示すことが意図されている。
「塩」は、酸付加塩と塩基付加塩の両方を含む。
「互変異性体」とは、分子の1個の原子から同一分子の別の原子へのプロトン移動を指す。本発明は、任意の前記化合物の互変異性体を含む。本化合物の様々な互変異性体は、当業者によって容易に誘導可能である。
「アミノ酸側鎖」または「側鎖」とは、アミノ酸のα−炭素、β−炭素またはγ−炭素に結合している置換基を指す。アミノ酸側鎖は、天然アミノ酸または非天然アミノ酸に不随しているものであってよい。
「文字コード」、「1文字コード」または「3文字コード」とは、アミノ酸配列中のアミノ酸またはアミノ酸残基に関する表示または略称を指す。「1文字コード」および「3文字コード」の一般リスト、およびそれらが対応するアミノ酸は、以下に見いだされる:
本明細書において使用される化学命名プロトコルおよび構造略図は、ACD/命名バージョン9.07ソフトウェアプログラムおよび/またはChemDraw Ultraバージョン11.0ソフトウェア命名プログラム(CambridgeSoft)を使用する、I.U.P.A.C.命名法システムの修正版である。当業者が精通している一般名称も使用される。
Mは、出現毎に独立して、生物活性部分もしくはその断片、生物活性部分のプロドラッグもしくはその断片、蛍光色素、イメージング剤または放射性同位体結合部位を含み、ただし、出現するMの少なくとも1つは、蛍光色素ではないことを条件とし、
Lは、生理的に開裂可能なリンカーであり、
L1、L2、L3およびL4は、出現毎に独立して、任意選択のアルキレン、アルケニレン、アルキニレン、ヘテロアルキレン、ヘテロアルケニレン、ヘテロアルキニレンまたはヘテロ原子リンカーであり、
R1は、出現毎に独立して、天然または非天然アミノ酸側鎖であり、
R2およびR3は、それぞれ独立して、−H、−OH、−SH、アルキル、アルコキシ、アルキルエーテル、ヘテロアルキル、アルキルアミニル、アルキルカルボニル、アルコキシカルボニル、Qもしくはそれらの保護形態、またはL’であり、アルキル、アルコキシ、アルキルエーテル、ヘテロアルキル、アルキルアミニル、アルキルカルボニルおよびアルキルオキシカルボニルは、ヒドロキシル、アミノ、スルフヒドリル、ホスフェート、チオホスフェート、ホスホアルキル、チオホスホアルキル、ホスホアルキルエーテルもしくはチオホスホアルキルエーテル、またはそれらの組合せにより置換されていてもよく、
Qは、出現毎に独立して、標的指向性部分の相補性反応性基Q’と共有結合の形成が可能な、反応性基、またはその保護形態を含む部分であり、
L’は、出現毎に独立して、Qへの共有結合を含むリンカー、標的指向性部分、標的指向性部分への共有結合を含むリンカー、固体支持体もしくは固体支持体残基への共有結合を含むリンカー、固体支持体もしくは固体支持体残基への共有結合を含むリンカー、または構造(I)のさらなる化合物への共有結合を含むリンカーであり、
mは、出現毎に独立して、0以上の整数であり、
nは、1以上の整数である)。
一部の実施形態では、出現するMの少なくとも1つは、生物活性部分を含む。他の実施形態では、Mは、出現毎に独立して、生物活性部分を含む。
一部の実施形態では、L4は、出現毎に独立して、ヘテロアルキレンリンカーである。
別の実施形態では、R1、L1およびmは、
一部の実施形態では、L2およびL3は、独立して存在しないか、またはヘテロアルキレンリンカーである。より具体的な実施形態では、ヘテロアルキレンリンカーは、ペプチジルリンカーである。一部の実施形態では、R2は、−NH2である。
ある種の実施形態では、R2またはR3の1つは、L’であり、L’は、固体支持体への共有結合を含むリンカーである。そのような実施形態の一部では、固体支持体は、ポリマー製ビーズまたは非ポリマー製ビーズである。
ある種の他の実施形態では、R2またはR3の1つは、L’であり、L’は、標的指向性部分、または標的指向性部分へのリンカーである。それらの実施形態の一部では、L’は、標的指向性部分へのリンカーであり、このリンカーは、ヘテロアルキレンリンカーを含む。
他の実施形態では、出現するLの少なくとも1つについては、官能基は、アルキンおよびアジドの反応によって形成され得る。他の実施形態では、出現するLの少なくとも1つについては、官能基は、アミン(例えば、一級アミン)およびN−ヒドロキシスクシンイミドエステルまたはイソチオシアネートの反応によって形成され得る。
一部の実施形態は、適切な条件(例えば、生理的条件)下で、開裂可能なLを提供する。したがって、一部の実施形態では、Lは、アミド結合、エステル結合、ジスルフィド結合、ヒドラゾン、ホスホトリエステル、ジエステル、β−グルクロニド、二重結合、三重結合、エーテル結合、ケトンもしくはオキソ、ジオール、シアノ、ニトロまたはそれらの組合せを含む。
Rは、H、メチル、エチル、イソプロピル、tert−ブチルまたはフェニルであり、
Xは、OまたはCH2であり、
nは、0より大きな整数である)を含む。
上述の様々な実施形態では、L1aもしくはL1b、またはそれらの両方が、存在しない。他の実施形態では、L1aもしくはL1b、またはそれらの両方が存在する。
さらなる実施形態では、L2およびL3は、出現毎に独立して、C1−C6アルキレン、C2−C6アルケニレンまたはC2−C6アルキニレンである。
上述の化合物のいずれかの一部の異なる実施形態では、R1は、出現毎に、Hである。
他の様々な実施形態では、R2およびR3は、それぞれ独立して、OHまたは−OP(=Ra)(Rb)Rcである。一部の異なる実施形態では、R2またはR3は、OHまたは−OP(=Ra)(Rb)Rcであり、R2またはR3の他方は、QまたはL’である。
構造(I)の上述の化合物のいずれかのさらなる異なる実施形態では、R2およびR3は、それぞれ独立して、−OP(=Ra)(Rb)Rcである。これらの実施形態の一部では、Rcは、OL’である。
他の実施形態では、R2およびR3は、それぞれ独立して、−OP(=Ra)(Rb)OL’であり、L’は、Q、標的指向性部分、分析対象(例えば、分析対象分子)、固体支持体、固体支持体残基、アミノ酸、ヌクレオシド、または構造(I)のさらなる化合物へのアルキレンまたはヘテロアルキレンリンカーである。
m”およびn”は、独立して、1〜10の整数であり、
Reは、H、電子対または対イオンであり、
L”は、標的指向性部分または標的指向性部分への連結基である)を有する。
一部の実施形態では、m”は、4〜10の整数、例えば、4、6または10である。他の実施形態では、n”は、3〜6の整数、例えば、3、4、5または6である。
Q基のタイプ、および構造(I)の化合物の残りへのQ基の結合性は、特に限定されないが、ただし、Qは、所望の結合を形成するために適切な反応性を有する部分を含むことを条件とする。
ある種の実施形態では、Qは、水性条件下で加水分解を受けにくいが、分析対象分子または固体支持体に対応する基と結合を形成するのに十分な反応性のある部分(例えば、アミン、アジドまたはアルキン)である。
R1、R2、R3、L、L1、L2、L3、L4、M、mおよびnは出現毎に、独立して、構造(I)の化合物に関して定義されている通りであり、
L”は、Q部分と対応するQ’部分との反応から生じる官能基を含むリンカーであり、
αは、1より大きな整数、例えば1〜100、または1〜10である)を有する。
構造(I’)の他の化合物は、当業者によって、例えば、本明細書において提供されている構造(I)の化合物を二量化または重合することにより誘導可能である。
mに関する値は、所望の溶解度、浸透作用または治療用途に基づいて選択され得る別の可変因子である。一部の実施形態では、mは、出現毎に独立して、1〜20の整数である。一部の実施形態では、mは、出現毎に独立して、1〜10の整数である。他の実施形態では、mは、出現毎に独立して、1〜5、例えば、1、2、3、4または5の整数である。
一部の実施形態では、Mは、出現毎に独立して、NSAID、キナーゼ阻害剤、アントラサイクリン、EGFR阻害剤またはアルキル化剤である。
抗がん薬は、本明細書で使用する場合、誘導体を含む。これは、修飾または誘導体化された抗がん薬であり、こうしてこの薬物は、コンジュゲートされ得るか、または別の分子(例えば、Q部分を含むよう)に結合され得る。例えば、マイタンシンはがん薬であり、マイタンシノイドは、がん薬の誘導体である。
修飾され得る抗がん薬、および本開示の化合物の実施形態に組み込まれ得る抗がん薬には、例えば、オーリスタチンF、オーリスタチンE、マイタンシン、カリチアマイシン、パクリタキセル、ドキソルビシン、クリプトフィシン;エルロチニブ、CC−1065、カルゼレシン、SJG−136、DSB−120、アファチニブ、イレッサまたはメトトレキサートが含まれる。
上述のいずれかのさらなる実施形態では、Mは、同じである。他の実施形態では、Mはそれぞれ、異なる。さらなる実施形態では、1つまたは複数のMは同じであり、1つまたは複数のMは異なる。
Mは、M上の任意に位置(すなわち、原子)から分子の残りに結合し得る。当業者は、Mが分子の残りに結合するための手段を認識していよう。例示的な方法には、本明細書に記載されている「クリック」反応が含まれる。
構造(I)または(I’)の上述の化合物のいずれかの他の実施形態では、少なくとも1つのMは、少なくとも1個のヘテロ原子を含む。例えば、一部の実施形態では、ヘテロ原子は、窒素、酸素または硫黄である。
上述のいずれかのさらなる実施形態では、少なくとも1つのMは、少なくとも1つの置換基を含む。例えば、一部の実施形態では、置換基は、フルオロ、クロロ、ブロモ、ヨード、アミノ、アルキルアミノ、アリールアミノ、ヒドロキシ、スルフヒドリル、アルコキシ、アリールオキシ、フェニル、アリール、メチル、エチル、プロピル、ブチル、イソプロピル、t−ブチル、カルボキシ、スルホネート、アミドまたはホルミル基である。
カルボン酸基を含むM部分は、上記の陰イオン性形態(CO2 -)で図示されているが、当業者は、これは、pHに応じて様々になること、およびプロトン化形態(CO2H)は、様々な実施形態に含まれることを理解するであろう。
Gは、出現毎に独立して、相補性反応性基と共有結合を形成することが可能な、反応性基またはその保護類似体を含む部分であり、
L1a、L1、L2、L3およびL4は、出現毎に独立して、任意選択のアルキレン、アルケニレン、アルキニレン、ヘテロアルキレン、ヘテロアルケニレン、ヘテロアルキニレンまたはヘテロ原子リンカーであり、
R1は、出現毎に独立して、天然または非天然アミノ酸側鎖であり、
R2およびR3は、それぞれ独立して、−H、−OH、−SH、アルキル、アルコキシ、アルキルエーテル、ヘテロアルキル、アルキルアミニル、アルキルカルボニル、アルコキシカルボニル、Qもしくはそれらの保護形態、またはL’であり、アルキル、アルコキシ、アルキルエーテル、ヘテロアルキル、アルキルアミニル、アルキルカルボニルおよびアルキルオキシカルボニルは、ヒドロキシル、アミノ、スルフヒドリル、ホスフェート、チオホスフェート、ホスホアルキル、チオホスホアルキル、ホスホアルキルエーテルもしくはチオホスホアルキルエーテル、またはそれらの組合せにより置換されていてもよく、
Qは、出現毎に独立して、標的指向性部分の相補性反応性基Q’と共有結合の形成が可能な、反応性基、またはその保護形態を含む部分であり、
L’は、出現毎に独立して、Qへの共有結合を含むリンカー、標的指向性部分、標的指向性部分への共有結合を含むリンカー、固体支持体への共有結合を含むリンカー、固体支持体への共有結合を含むリンカー、または構造(I)の化合物もしくは構造(II)のさらなる化合物への共有結合を含むリンカーであり、
mは、出現毎に独立して、0以上の整数であり、
nは、1以上の整数である)を使用して形成される。
ある種の実施形態は、治療的に有効な蛍光化合物を対象とし、ただし、出現するMの少なくとも1つが蛍光色素ではなく、出現するMの少なくとも1つが蛍光色素である。治療的に有効な蛍光化合物には、少なくとも1つの生物活性部分もしくはその断片、または生物活性部分のプロドラッグもしくはその断片を含む化合物が含まれ、これらは、紫外線光などの光により励起されると、蛍光シグナルを発する。
特許請求の範囲のいずれか1項の化合物、および標的指向性部分を含む組成物も提供される。
現在開示されている化合物の実施形態は、「調節可能」であり、これは、上述の化合物のいずれかにおける可変因子を適切に選択することにより、当業者は、所望のモル蛍光度(molar fluorescence)および/または所定のモル蛍光(モル輝度(molar brightness))を有する化合物に到達することができることを意味する。本化合物のある種の実施形態の「調節可能性」により、使用者は、特定のアッセイにおいて、使用するための所望の蛍光および/または色調を有する化合物に容易に到達することが可能となる。すべての可変因子は、本明細書において開示されている化合物のある種の実施形態のモル蛍光度に影響を及ぼし得るが、M、L4、mおよびnの適切な選択が、開示化合物の実施形態のモル蛍光度において重要な役割を果たすと考えられる。したがって、一実施形態では、所望のモル蛍光度を有する化合物を得るための方法であって、公知の蛍光度を有するM部分を選択するステップ、M部分を含む構造(I)の化合物を調製するステップ、および所望のモル蛍光度に到達するためのL4、mおよびnに対する適切な可変因子を選択するステップを含む方法が提供される。
上述の化合物のいずれかおよび1つまたは複数の標的指向性部分(例えば、抗体または細胞表面受容体アンタゴニスト)を含む組成物は、様々な他の実施形態において提供される。一部の実施形態では、疾患を処置するための方法であって、それを必要とする対象に治療有効量の構造(I)の化合物または構造(I)の化合物を含む組成物を投与するステップを含む方法における、このような組成物の使用であって、Mがそれぞれ独立して、該疾患を処置するのに有効な生物活性部分である使用も提供される。
一実施形態は、本明細書において開示されている実施形態のいずれか1つおよび薬学的に許容される担体による化合物を含む組成物を提供する。
別の実施形態は、単一連結基により抗体に共有結合している請求項1に記載の化合物を含む複数のコンジュゲートを含む組成物であって、複数のコンジュゲートが少なくとも90%の構造均質性を有する、組成物を提供する。「構造均質性」は、抗体への結合点を含めて、同じ構造を有する化合物を意味する。より具体的な実施形態では、複数のコンジュゲートは、少なくとも95%の構造均質性を有する。関連する実施形態では、複数のコンジュゲートは、99%を超える構造均質性を有する。ある種の実施形態では、R2およびR3の1つは、−OP(=Ra)(Rb)OL’またはL’であり、L’は、抗体、もしくは当該抗体への共有結合を含むリンカーである。
好適な投与経路には、以下に限定されないが、経口、静脈内、直腸、エアゾール、非経口、眼、肺、経粘膜、経皮、膣、耳、鼻腔および局所投与が含まれる。さらに、単なる例として、非経口送達には、筋肉内、皮下、静脈内、髄内の注射、ならびに鞘内、心室内に直接、腹腔内、リンパ内および鼻内への注射が含まれる。
一部の実施形態では、本発明の化合物は単回用量で投与される。通常、このような投与は、薬剤を迅速に導入するため、注射によって、例えば静脈内注射になるであろう。しかし、適切な場合、他の経路が使用される。本発明の化合物の単回用量はまた、急性状態の処置に使用されることがある。
本発明の化合物の実施形態の投与は、必要な限り継続されてもよい。一部の実施形態では、本発明の化合物は、1、2、3、4、5、6、7、14または28日間を超えて、投与される。一部の実施形態では、本発明の化合物は、28、14、7、6、5、4、3、2または1日未満の間で投与される。一部の実施形態では、本発明の化合物は、例えば、作用が長期的な処置のために、継続的に長期間投与される。
一部の実施形態では、本発明の化合物は、投与量で投与される。化合物の薬物動態の対象間のばらつきのため、投与レジメンの個別化が最適治療に必要であることが当分野において公知である。本発明の化合物の実施形態のための投与は、本開示に照らし合わせて、型通りの実験により見いだすことができる。
別の実施形態では、本明細書に記載されている化合物は、経口投与向けに製剤化されている。本明細書に記載されている化合物は、活性化合物と、例えば薬学的に許容される担体または賦形剤とを組み合わせることにより製剤化される。様々な実施形態では、本明細書において記載されている化合物は、単なる例として、錠剤、散剤、丸剤、ドラジェ剤、カプセル剤、液体、ゲル剤、シロップ剤、エリキシル剤、スラリー剤、懸濁液剤などを含む経口剤形で製剤化される。
一部の実施形態では、構造(I)の少なくとも1つの化合物を含む医薬組成物は、例示的に、薬剤が溶液中、懸濁液中、またはそれらの両方に存在する液体の形態をとる。通常、組成物が溶液剤または懸濁液剤として投与される場合、薬剤の第1の部分は溶液中に存在し、薬剤の第2の部分は、液体マトリックス中の懸濁液中の微粒子形態で存在する。一部の実施形態では、液体組成物はゲル製剤を含む。他の実施形態では、液体組成物は水性である。
有用な医薬組成物はまた、構造(I)の化合物の溶解を補助する可溶化剤を含んでもよい。用語「可溶化剤」は、薬剤のミセル溶液または真の溶液の形成をもたらす作用剤を一般に含む。許容されるある種の非イオン性界面活性剤、例えばポリソルベート80は、眼用として許容されるグリコール、ポリグリコール、例えば、ポリエチレングリコール400およびグリコールエーテルと同様に、可溶化剤として有用である。
他の有用な医薬組成物は、微生物活性を阻害するための1種または複数の保存剤を含んでもよい。好適な保存剤には、メルフェンおよびチオメルサールなどの水銀含有物質、安定化二酸化塩素、および塩化ベンザルコニウム、臭化セチルトリメチルアンモニウムおよび塩化セチルピリジニウムなどの四級アンモニウム化合物が含まれる。
さらに他の有用な組成物は、必要な場合、化学安定性を増強するための1つまたは複数の抗酸化剤を含む。好適な抗酸化剤は、単なる例として、アスコルビン酸およびメタ重亜硫酸ナトリウムを含む。
ある種の実施形態では、水性懸濁液組成物は、単回用量用の再密閉不可能な容器に包装される。代替的に、多回用量用の再密閉可能な容器を使用し、この場合、組成物中に保存剤を含ませるのが通例である。
代替実施形態では、疎水性医薬品化合物のための他の送達系が使用される。リポソームおよびエマルションが、本明細書において有用な送達用ビヒクルまたは担体の例である。ある種の実施形態では、N−メチルピロリドンなどの有機溶媒も使用される。追加的な実施形態では、本明細書において記載されている化合物は、治療剤を含有する固体の疎水性ポリマーの半透明マトリックスなどの、持続放出系を使用して送達される。様々な持続放出物質が、本明細書において有用である。一部の実施形態では、持続放出カプセル剤は、最大で100日間にわたり数週間、化合物を放出する。治療試薬の化学的性質および生物学的安定性に応じて、タンパク質安定化に対するさらなる戦略が使用される。
一部の実施形態では、1つまたは複数の化合物の濃度は、約0.001%〜約10%、約0.01%〜約5%、約0.02%〜約4.5%、約0.03%〜約4%、約0.04%〜約3.5%、約0.05%〜約3%、約0.06%〜約2.5%、約0.07%〜約2%、約0.08%〜約1.5%、約0.09%〜約1%、約0.1%〜約0.9%w/w、w/vまたはv/vの範囲内にある。
一部の実施形態では、1つまたは複数の化合物の量は、0.0001〜10g、0.0005〜9g、0.001〜8g、0.005〜7g、0.01〜6g、0.05〜5g、0.1〜4g、0.5〜4gまたは1〜3gの範囲である。
さらに他の実施形態では、本化合物は、疾患または状態を処置する様々な方法に有用である。したがって、一実施形態は、それを必要とする対象に、治療有効量の本明細書において開示されている実施形態のいずれか1つによる化合物、または本明細書において開示されている実施形態のいずれか1つによる組成物を投与するステップを含む、疾患を処置する方法であって、Mがそれぞれ、独立して、該疾患を処置するのに有効な生物活性部分である方法を提供する。一部の実施形態では、疾患は、がんであり、Mはそれぞれ、独立して抗がん薬である。
さらなる実施形態では、本方法は、アポトーシスを誘発することをさらに含む。
したがって、本化合物の実施形態は、以下に限定されないが、薬物送達、アポトーシスの定量化、治療薬の送達の適格化、アポトーシスの定量化、ならびに血液がんなどの疾患の診断および処置を含めた任意の数の方法において利用が見いだされる。
一部の実施形態では、処置の方法は、腫瘍細胞受容体により腫瘍細胞を有する腫瘍を処置するステップを含む。一部の実施形態では、腫瘍細胞は、細胞あたり、1,000〜100,000個、1,000〜50,000個、1,000〜25,000個の受容体、1,000〜10,000個の受容体の範囲の受容体を有する。例えば、一部の実施形態では、腫瘍細胞は、細胞あたり、約1,000個、約10,000個の受容体を有するか、または100,000個未満の受容体を有する。
上記の構造(I)の化合物の実施形態、ならびに上記の構造(I)の化合物中の可変因子R1、R2、R3、L、L1、L2、L3、L4、M、mおよび/またはnに関して本明細書に記載されている任意の具体的な選択は、構造(I)の化合物の他の実施形態および/または可変因子と独立して組み合わされて、上記に具体的に記載されていない本発明の実施形態を形成してもよいことが理解される。さらに、最適なリストが、特定の実施形態および/または特許請求の範囲における任意の特定のR1、R2、R3、L、L1、L2、L3、L4、M、mおよび/またはnの可変因子に関して一覧表示されている事例では、個々の選択はそれぞれ、特定の実施形態および/または特許請求の範囲から除かれ得ること、および最適な残りのリストは、本発明の範囲内にあると見なされることが理解される。
本記載では、図示されている式の置換基および/または可変因子の組合せは、このような寄与が安定な化合物をもたらす場合に許容可能となることが理解される。
さらに、遊離塩基形態または遊離酸形態で存在する本発明の化合物はすべて、当業者に公知の方法によって、適切な無機塩基もしくは有機塩基または無機酸もしくは有機酸による処理によってその塩に変換することができる。本発明の化合物の塩は、標準技法によってその遊離塩基形態または酸形態に変換することができる。
以下の実施例は、限定ではなく、例示目的で提示される。
1HおよびNMRスペクトルは、JEOL400MHz分光計で得る。1Hスペクトルは、TMSを参照する。逆相HPLC色素分析は、45℃に保持した2.1mmx50mm Acquity BEH−C18カラムを備えるWaters Acquity UHPLCシステムを使用して行う。質量スペクトル分析は、MassLynx4.1アクイジョンソフトウェアを使用する、Waters/Micromass QuattroマイクロMS/システムMS(MSモードのみ)で行う。色素に関するLC/MSに使用した移動相は、100mMの1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール(HFIP)、8.6mMのトリエチルアミン(TEA)、pH8である。ホスホロアミダイトおよび前駆体分子は、Aapptec(著作権)Spirit(商標)ペプチドC18カラム(4.6mmx100mm、5μmの粒子サイズ)を使用する、ダイオードアレイ検出器および高性能オートサンプラーを備えるAgilent Infinity1260 UHPLCシステムを使用して分析する。励起および発光プロファイル実験は、Cary Eclipseスペクトル光度計で記録する。
反応はすべて、特に明記しない限り、窒素雰囲気下、オーブン乾燥したガラス器具中で行った。
イブプロフェン−NHSおよびナプロキセン−NHSの合成
固相合成によるペプチド主鎖の一般合成
固相合成の一般サイクルは、脱保護−洗浄−カップリング−洗浄という繰り返しサイクルの1つである。固体支持体に結合したペプチドの遊離N末端アミンは、N保護アミノ酸基(例えば、FmocまたはBocを用いる)に連結される。新しく導入されたアミノ酸単位は、脱保護されて、新しいN末端アミンが現れ、このN末端アミンは、さらなるアミノ酸とさらに反応する。この工程を繰り返し、ペプチド鎖が伸長される。
イブプロフェンポリマーの合成
ナプロキセンポリマーの合成
ドキソルビシン−NHSの合成
ドキソルビシンポリマーの合成
ドキソルビシン−PEG−アジドの合成
ドキソルビシンポリマー(化合物18)の合成
Claims (36)
- 以下の構造(I)を有する化合物:
Mは、出現毎に独立して、生物活性部分もしくはその断片、生物活性部分のプロドラッグもしくはその断片、蛍光色素、イメージング剤または放射性同位体結合部位であり、ただし、出現するMの少なくとも1つは、蛍光色素ではないことを条件とし、
Lは、生理的に開裂可能なリンカーであり、
L1、L2、L3およびL4は、出現毎に独立して、任意選択のアルキレン、アルケニレン、アルキニレン、ヘテロアルキレン、ヘテロアルケニレン、ヘテロアルキニレンまたはヘテロ原子リンカーであり、
R1は、出現毎に独立して、天然または非天然アミノ酸側鎖であり、
R2およびR3は、それぞれ独立して、−H、−OH、−SH、アルキル、アルコキシ、アルキルエーテル、ヘテロアルキル、アルキルアミニル、アルキルカルボニル、アルコキシカルボニル、Qもしくはそれらの保護形態、またはL’であり、アルキル、アルコキシ、アルキルエーテル、ヘテロアルキル、アルキルアミニル、アルキルカルボニルおよびアルキルオキシカルボニルは、ヒドロキシル、アミノ、スルフヒドリル、ホスフェート、チオホスフェート、ホスホアルキル、チオホスホアルキル、ホスホアルキルエーテルもしくはチオホスホアルキルエーテル、またはそれらの組合せにより置換されていてもよく、
Qは、出現毎に独立して、標的指向性部分の相補性反応性基Q’と共有結合の形成が可能な、反応性基、またはその保護形態を含む部分であり、
L’は、出現毎に独立して、Qへの共有結合を含むリンカー、標的指向性部分、標的指向性部分への共有結合を含むリンカー、固体支持体もしくは固体支持体残基への共有結合を含むリンカー、固体支持体もしくは固体支持体残基への共有結合を含むリンカー、または構造(I)のさらなる化合物への共有結合を含むリンカーであり、
mは、出現毎に独立して、0以上の整数であり、
nは、1以上の整数である)。 - 少なくとも1つのR1が中性アミノ酸側鎖である、請求項1に記載の化合物。
- 少なくとも1つのR1が電荷を帯びたアミノ酸側鎖である、請求項1または2に記載の化合物。
- R1が、出現毎に独立して、H、アルキル、−CH2CO2 -、−CH2CH2CO2 -、−CH2CH2CH2CH2NH3 +、−CH2CH2CH2NHC(=NH2 +)NH2またはイミダゾリルである、請求項1〜3のいずれか1項に記載の化合物。
-
-
- アミノ酸配列が、(GGEEFMLVYKFARKHGG)または(GGMSMVVSGG)である、請求項6に記載の化合物。
- L1もしくはL4、またはそれらのどちらも、少なくとも1回出現する、請求項1〜7のいずれか1項に記載の化合物。
- L1もしくはL4、またはそれらのどちらも、存在する場合、ヘテロアルキレンリンカーである、請求項8に記載の化合物。
- ヘテロアルキレンリンカーが、水溶液中で3〜11の範囲のpHの値において、正電荷または負電荷を維持することが可能な官能基を含む、請求項9に記載の化合物。
- 出現するL1もしくはL4の少なくとも1つ、またはそれらの両方が、以下の構造:
- 出現するL1もしくはL4の少なくとも1つ、またはそれらの両方が、以下の構造:
- L2およびL3が、独立して、存在しないか、またはヘテロアルキレンリンカーである、請求項1〜12のいずれか1項に記載の化合物。
- ヘテロアルキレンリンカーが、ペプチジルリンカーである、請求項13に記載の化合物。
- R2が−NH2である、請求項1〜14のいずれか1項に記載の化合物。
- R2またはR3の1つがL’であり、L’が、固体支持体への共有結合を含むリンカーである、請求項1〜14のいずれか1項に記載の化合物。
- 固体支持体が、ポリマー製ビーズまたは非ポリマー製ビーズである、請求項16に記載の化合物。
- R2またはR3の1つがL’であり、L’が、標的指向性部分であるか、または標的指向部分へのリンカーである、請求項1〜14のいずれか1項に記載の化合物。
- L’が、標的指向性部分へのリンカーであり、リンカーが、ヘテロアルキレンリンカーを含む、請求項18に記載の化合物。
- 標的指向性部分が、抗体または細胞表面受容体アンタゴニストである、請求項1〜19のいずれか1項に記載の化合物。
- 抗体または細胞表面受容体アンタゴニストが、上皮成長因子受容体(EGFR)阻害剤、肝細胞成長因子受容体(HGFR)阻害剤、インスリン様成長因子受容体(IGFR)阻害剤、フォレートまたはMET阻害剤である、請求項20に記載の化合物。
- mが、出現毎に独立して、1〜20の整数である、請求項1〜21のいずれか1項に記載の化合物。
- mが、出現毎に独立して、1〜10の整数である、請求項1〜22のいずれか1項に記載の化合物。
- nが、1〜100の整数である、請求項1〜23のいずれか1項に記載の化合物。
- nが、1〜10の整数である、請求項1〜24のいずれか1項に記載の化合物。
- Lが、出現毎に独立して、アミド結合、エステル結合、ジスルフィド結合、二重結合、三重結合、エーテル結合、ケトン、ジオール、シアノ、ニトロまたはそれらの組合せを含むリンカーである、請求項1〜25のいずれか1項に記載の化合物。
- Mが、出現毎に独立して、NSAID、キナーゼ阻害剤、アントラサイクリン、EGFR阻害剤またはアルキル化剤である、請求項1〜26のいずれか1項に記載の化合物。
- Mが、出現毎に独立して、抗がん薬であり、標的指向性部分が、腫瘍細胞抗原に特異的な抗体である、請求項1〜27のいずれか1項に記載の化合物。
- 腫瘍細胞抗原が、EGFR、HER2、葉酸受容体、CD20またはCD33である、請求項28に記載の化合物。
- 請求項1〜29のいずれか1項に記載の化合物、および薬学的に許容される担体を含む組成物。
- 単一連結基により抗体に共有結合している請求項1に記載の化合物を含む複数のコンジュゲートを含む組成物であって、複数のコンジュゲートが少なくとも90%の構造均質性を有する、組成物。
- 複数のコンジュゲートが、少なくとも95%の構造均質性を有する、請求項31に記載の組成物。
- 複数のコンジュゲートが、99%を超える構造均質性を有する、請求項31に記載の組成物。
- R2およびR3の1つが、−OP(=Ra)(Rb)OL’またはL’であり、L’が、抗体、もしくは当該抗体への共有結合を含むリンカーである、請求項31〜33のいずれか1項に記載の組成物。
- それを必要とする対象に、治療有効量の請求項1〜30のいずれか1項に記載の化合物、または請求項30〜34のいずれか1項に記載の組成物を投与するステップを含む、疾患を処置する方法であって、Mがそれぞれ、独立して、疾患を処置するのに有効な生物活性部分である、方法。
- 疾患ががんであり、Mがそれぞれ、独立して抗がん薬である、請求項35に記載の方法。
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