JP2017507912A - 免疫療法のための化合物及び組成物 - Google Patents
免疫療法のための化合物及び組成物 Download PDFInfo
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Abstract
Description
本出願は、2014年1月10日に全て出願された中国特許出願第201410011324.5号、同201410011262.8号、及び同201410011362.0号の利益、及び同出願に対する優先権を主張し、これらの出願の全開示は、その全体が参照により本明細書に組み込まれる。
本発明は、標的免疫療法のための化合物、ならびにそれらを含む組成物に関する。さらに、本発明は、癌などの疾患の処置における当該化合物の使用に関する。
TM−Ln−AM(Ia)の構造を有する化合物を提供し、
式中、TMは、標的部分であり、AMは、樹状細胞、マクロファージ、単核球、骨髄由来抑制細胞、NK細胞、B細胞、T細胞または腫瘍細胞、またはそれらの組み合わせを含むがこれらに限定されないヒト免疫細胞を活性化させることができる活性化部分であり、Lnはリンカーであり、nは0及び1から選択される整数である。
TM−L−AM(Ib)
の構造を有する化合物、またはその薬学的に許容され得る塩または溶媒和物を提供し、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(I):
式中、破線は結合または結合の不在を表し、
Xは、Sまたは−NR1であり、R1は−W0―W1―W2―W3―W4であり、
W0は、結合、アルキル、アルケニル、アルキニル、アルコキシ、または−アルキル−S−アルキル−−であり、
W1は、結合、−−O−−、または−−NR2−−であり、ここでR2は、水素、アルキルまたはアルケニルであり、
W2は、結合、−−O−−、−−C(O)−−、−−C(S)−−、または−S(O)2―であり、
W3は、結合、−−NR3−−であり、ここでR3は、水素、アルキルまたはアルケニルであり、
W4は、水素、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、アリール、アリールオキシ、ヘテロアリール、またはヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
Zは、水素、アルキル、アルケニル、アルキニル、アルコキシ、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、ヘテロシクリル、ハロゲン、シアノ、ニトロ、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−O−C(O)−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;
Rは、水素、アルキル、アルコキシ、ハロアルキル、ハロゲン、アリール、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
nは、0、1、2、3、または4であり;
Yは、−NR6R7、−CR6R7R8、または−アルキル−NH2であり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、−−NH2、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、
ここでR6、R7及びR8は独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
X及びZは一緒になって、任意選択的に(5〜9)員環を形成し得る。
mは1、2、3、4、5、または6であり、各bは独立して、0または1であり、Dは独立して、式(III):
の構造により表され、
式中、各iは独立して、0または1であり;
各jは独立して、0、1、2、3、4、5、または6であり;
各Aは独立して、S、O、またはN−Raであり、ここでRaは、水素、アルキル、アルケニル、またはアルコキシであり;
各Bは独立して、アルキル、アルケニル、−−O−アルキル−、−−アルキル−O−−、−−S−アルキル−−、−−アルキル−S−−、アリール、ヘテロアリール、ヘテロシクリル、またはペプチドであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−C(O)−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NHR4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルである。
TM−L−AM(Ib)
の構造を有する化合物、またはその薬学的に許容され得る塩または溶媒和物を提供し、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(IV):
式中、
Vは、−NR6R7であり、R6及びR7のそれぞれは独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
R10及びR11は独立して、水素、アルキル、アルケニル、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリル、またはシクロアルキルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;TM及びLは、上記及び下記に定義される。
本明細書で言及する全ての刊行物、特許、及び特許出願は、各個別の刊行物、特許、または特許出願は、ここで具体的及び個別に参照により組み込まれるように示されるのと同程度に、参照により組み込まれる。
別段の定義のない限り、本明細書において使用される全ての技術用語及び科学用語は、一般に、本発明が属する当業者により一般的に理解されるものと同じ意味を有する。一般に、本明細書、及び細胞培養、分子遺伝学、有機化学、及び核酸化学及びハイブリダイゼーションにおける実験室手順に使用される命名法は、当該分野において周知であり、一般的に用いられているものである。標準的な技術が、核酸及びペプチド合成に使用される。技術及び手順は、当該分野における従来の方法、及びこの文書の全体を通して提供される種々の一般的な参照に従って一般に実施される。本明細書、及び分析化学における実験室手順、及び下記に記載されている有機合成に使用される命名法は、当該分野において周知のものであり、一般的に用いられるものである。標準的な技術またはそれらの修正が、化学合成及び化学分析に使用される。
(a)アルキル;
(b)ヒドロキシ(または保護されたヒドロキシ);
(c)ハロ;
(d)オキソ、すなわち、=O;
(e)アミノ、アルキルアミノまたはジアルキルアミノ;
(f)アルコキシ;
(g)シクロアルキル;
(h)カルボキシ;
(i)ヘテロシクロオキシ、ここでヘテロシクロオキシは酸素架橋を通して結合された複素環基を示す;
(j)アルキル−O−C(O)−−;
(k)メルカプト;
(l)ニトロ;
(m)シアノ;
(n)スルファモイルまたはスルホンアミド;
(o)アリール;
(p)アルキル−C(O)−O−−;
(q)アリール−C(O)−O−−;
(r)アリール−S−−;
(s)アリールオキシ;
(t)アルキル−S−−;
(u)ホルミル、すなわち、HC(O)−−;
(v)カルバモイル;
(w)アリール−アルキル−−;及び
(x)アルキル、シクロアルキル、アルコキシ、ヒドロキシ、アミノ、アルキル−C(O)−NH−−、アルキルアミノ、ジアルキルアミノまたはハロゲンで置換されたアリール。
一態様では、本発明は式(Ia):
TM−Ln−AM(Ia)の構造を有する化合物を提供し、
式中、TMは標的部分であり、AMは、樹状細胞、ナチュラルキラー細胞、または腫瘍細胞、またはそれらの組み合わせを活性化させる活性化部分であり、Lnはリンカーであり、nは0及び1から選択される整数である。
TM−L−AM(Ib)
の構造を有する化合物、またはその薬学的に許容され得る塩または溶媒和物を提供し、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(I):
式中、破線は結合または結合の不在を表し、
Xは、Sまたは−NR1であり、R1は−W0―W1―W2―W3―W4であり、
W0は、結合、アルキル、アルケニル、アルキニル、アルコキシ、または−アルキル−S−アルキル−−であり、
W1は、結合、−−O−−、または−−NR2−−であり、ここでR2は、水素、アルキルまたはアルケニルであり、
W2は、結合、−−O−−、−−C(O)−−、−−C(S)−−、または−S(O)2―であり、
W3は、結合、−−NR3−−であり、ここでR3は、水素、アルキルまたはアルケニルであり、
W4は、水素、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、アリール、アリールオキシ、ヘテロアリール、またはヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
Zは、水素、アルキル、アルケニル、アルキニル、アルコキシ、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、ヘテロシクリル、ハロゲン、シアノ、ニトロ、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−O−C(O)−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;
Rは、水素、アルキル、アルコキシ、ハロアルキル、ハロゲン、アリール、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
nは、0、1、2、3、または4であり;
Yは、−NR6R7、−CR6R7R8、または−アルキル−NH2であり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、−−NH2、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、
ここでR6、R7及びR8は独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
X及びZは一緒になって、任意選択的に(5〜9)員環を形成し得る。
TM−L−AM(Ib)、
の構造を有する化合物、またはそれらの薬学的に許容され得る塩または溶媒和物を提供し、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(Ic):
式中、破線は結合または結合の不在を表し、
R1は、−W0―W1―W2―W3―W4であり、
W0は、結合、アルキル、アルケニル、アルキニル、アルコキシ、または−アルキル−S−アルキル−−であり、
W1は、結合、−−O−−、または−−NR2−−であり、ここでR2は、水素、アルキルまたはアルケニルであり、
W2は、結合、−−O−−、−−C(O)−−、−−C(S)−−、または−S(O)2―であり、
W3は、結合、−−NR3−−であり、ここでR3は、水素、アルキルまたはアルケニルであり、
W4は、水素、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、アリール、アリールオキシ、ヘテロアリール、またはヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
Zは、水素、アルキル、アルケニル、アルキニル、アルコキシ、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、ヘテロシクリル、ハロゲン、シアノ、ニトロ、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−O−C(O)−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;
Rは、水素、アルキル、アルコキシ、ハロアルキル、ハロゲン、アリール、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
nは、0、1、2、3、または4であり;
Yは、−NR6R7、−CR6R7R8、または−アルキル−NH2であり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、−−NH2、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、
ここでR6、R7及びR8は独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
X及びZは一緒になって、任意選択的に(5〜9)員環を形成し得る。
TM−L−AM(Ib)
の構造を有する化合物、またはその薬学的に許容され得る塩または溶媒和物を提供し、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(IV):
式中、
Vは、−NR6R7であり、R6及びR7のそれぞれは独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
R10及びR11は独立して、水素、アルキル、アルケニル、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリル、またはシクロアルキルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;
TM及びLは、上記及び下記に定義される。
式中、Rは、―NH(R5)及びイソチオシアネート(―NCS)からなる群より選択され;
R5は、水素(―H)、アセチル、―CO−tert−Bu(−Boc)、―CO―(CH2)X―R6、C1〜C16アルキル、―CO−4−(フェニルボロン酸)、―C(S)―NH―(CH2)X―NH―(CH2)X―NH―(CH2)X―NH2、
R6は、水素、アルキン、アジド、カルボン酸、及び―CONH―(CH2)X―O―(CH2)X―O―(CH2)X―O―(CH2)X―R7からなる群より選択され;
R7は、アミノ、イソチオシアネート、及び―NH―CO―(CH2)X―CO2Hからなる群より選択され;
R8は、ペプチド抗原部分またはタンパク質抗原部分から選択され;
xは、1から10の任意の整数である。
式中、R1及びR3はそれぞれ独立して、水素、ハロゲン、ニトロ、―NH2、アジド、ヒドロキシル、―CF3、カルボン酸(carboylic acid)、及び―CO2R2からなる群より選択され;
R2は、C2〜C5アルキルであり、
R4は、―NH(R5)及びイソチオシアネートからなる群より選択され;
R5は、水素、アセチル、―CO−tert−Bu(−Boc)、―CO―(CH2)X―R6、C1〜C16アルキル、―CO−4−(フェニルボロン酸)、―C(S)―NH―(CH2)X―NH―(CH2)X―NH―(CH2)X―NH2、
R6は、水素、アルキン、アジド、カルボン酸、及び―CONH―(CH2)X―O―(CH2)X―O―(CH2)X―O―(CH2)X―R7からなる群より選択され;
R7は、アミノ、イソチオシアネート、及び―NH―CO―(CH2)X―CO2Hからなる群より選択され;
R8は、ペプチド抗原部分またはタンパク質抗原部分から選択され;
Xは、1から10の任意の整数である。その開示がその全体において参照により組み込まれる、米国特許出願公開第20140256922A1。
一般に、本発明の化合物は、標的部分を含む。
一般に、本発明の化合物は、標的部分と活性化部分を結合するリンカーを含む。しかし、いくつかの化合物において、リンカーが存在せず、活性化部分と標的部分は直接結合する。
−Ta−Ww−Yy−
を有し、
式中、−T−は、ストレッチャー単位であり;aは、0または1であり;各−W−は独立して、アミノ酸単位であり;wは、独立して2〜12の範囲の整数であり;−Y−は、スペーサー単位であり;yは、0、1、または2である。
ストレッチャー単位(−T−)は、存在する場合、標的部分をアミノ酸単位(−W−)に結合させる。天然型または化学操作を介したいずれかの抗体などの標的部分に存在し得る有用な官能基には、スルフヒドリル、アミノ、ヒドロキシル、炭水化物のアノマーヒドロキシル基、及びカルボキシルが含まれるが、これらに限定されない。好適な官能基は、スルフヒドリル及びアミノである。スルフヒドリル基は、抗体の分子内ジスルフィド結合の還元により生成することができる。あるいは、スルフヒドリル基は、抗体のリシン部分のアミノ基と、2−イミノチオラン(トラウト試薬)または他のスルフヒドリル生成試薬との反応により、生成することができる。いくつかの実施形態では、抗体は、組み換え抗体であり、1つまたは複数のリシンを有するように操作される。他の実施形態では、組み換え抗体は、追加のスルフヒドリル基、例えば追加のシステインを有するように操作される。
アミノ酸単位(−W−)は、スペーサー単位が存在する場合には、ストレッチャー単位(−T−)をスペーサー単位(−Y−)に結合させ、スペーサー単位が不在の場合には、ストレッチャー単位を細胞障害剤または細胞増殖抑制剤(活性化部分;D)に結合させる。−Ww−は、ジペプチド、トリペプチド、テトラペプチド、ペンタペプチド、ヘキサペプチド、ヘプタペプチド、オクタペプチド、ノナペプチド、デカペプチド、ウンデカペプチド、またはドデカペプチド単位である。各−W−単位は、独立して、角括弧内に下記に示す式:
式中、R2は、水素、メチル、イソプロピル、イソブチル、sec−ブチル、ベンジル、p−ヒドロキシベンジル、―CH2OH、―CH(OH)CH3、―CH2CH2SCH3、―CH2CONH2、―CH2COOH、―CH2CH2CONH2、―CH2CH2COOH、―(CH2)3NHC(=NH)NH2、―(CH2)3NH2、―(CH2)3NHCOCH3、―(CH2)3NHCHO、―(CH2)4NHC(=NH)NH2、―(CH2)4NH2、―(CH2)4NHCOCH3、―(CH2)4NHCHO、―(CH2)3NHCONH2、―(CH2)4NHCONH2、―CH2CH2CH(OH)CH2NH2、2−ピリジルメチル−、3−ピリジルメチル−、4−ピリジルメチル−、フェニル、シクロヘキシル、
スペーサー単位(−Y−)は、存在する場合、アミノ酸単位を薬物単位に結合させる。スペーサー単位には、自己犠牲型及び非自己犠牲型の2つの一般的な種類がある。非自己犠牲型スペーサー単位は、スペーサー単位の一部または全てが、TM−リンカー−AMコンジュゲートまたは薬物−リンカー化合物からのアミノ酸単位の酵素切断の後、活性化部分単位に結合したままであるものである。非自己犠牲型スペーサー単位の例には、(グリシン−グリシン)スペーサー単位及びグリシンスペーサー単位が挙げられるが、これらに限定されない。グリシン−グリシンスペーサー単位またはグリシンスペーサー単位を含有するTM−リンカー−AMコンジュゲートが、腫瘍細胞関連プロテアーゼ、癌細胞関連プロテアーゼ、またはリンパ球関連プロテアーゼを介して酵素切断を受ける場合、グリシン−グリシン−薬物部分またはグリシン−薬物部分は、A−T−Ww−から切断される。AMを遊離するため、独立した加水分解反応が、グリシン−薬物単位結合を切断するために標的細胞内で生じるべきである。
式中、Qは、C1〜C8アルキル、C1〜C8アルコキシ、ハロゲン、ニトロ、またはシアノであり;mは、0〜4の範囲の整数である。
の構造により表され、mは、1、2、3、4、5、または6であり、各bは独立して、0または1であり、Dは独立して、式(III):
式中、各iは独立して、0または1であり;
各jは独立して、0、1、2、3、4、5、または6であり;
各Aは独立して、S、O、またはN−Raであり、ここでRaは、水素、アルキル、アルケニル、またはアルコキシであり;
各Bは独立して、アルキル、アルケニル、−−O−アルキル−、−−アルキル−O−−、−−S−アルキル−−、−−アルキル−S−−、アリール、ヘテロアリール、ヘテロシクリル、またはペプチドであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−C(O)−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NHR4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルである。
一般に、式(I)の構造により表される活性化部分は、以下に概略する、合成手法を用いて作製することができる。ステップ(1)では、式Aの4−クロロ−3−ニトロキノリンを式R1NH2のアミンと反応させて式Bの3−ニトロキノリン−4−アミンを提供する。ステップ2では、式Bの3−ニトロキノリン−4−アミンを還元させて式Cのキノリン(quinoine)−3−4−ジアミンを提供する。ステップ3では、式Cのキノリン(quinoine)−3−4−ジアミンをカルボン酸またはその等価物と反応させて式Dの1H−イミダゾ[4,5c]キノリンを提供する。
本発明は、本明細書の化合物またはその薬学的に許容され得る塩、及び1つまたは複数の薬学的に許容され得る担体を含む、医薬製剤にさらに関する。
別の態様では、本発明は、1つまたは複数の本発明の化合物または組成物と、当該化合物または組成物の使用指示書とを含有するキットを提供する。例示的な実施形態では、本発明は、本発明のリンカーアームを別の分子とコンジュゲートするためのキットを提供する。キットは、リンカーと、リンカーを特定の官能基に付着させるための指示書とを含む。キットは、1つまたは複数の細胞障害薬、標的剤、検出可能標識、薬学的塩または緩衝液も含み得る。キットは、容器、及び任意選択的に1つまたは複数のバイアル、試験管、フラスコ、ボトル、またはシリンジも含み得る。キットの他の形式は、当業者に明白であり得、本発明の範囲内である。
別の態様では、本発明は、疾患状態の処置を必要とする対象内の疾患状態を処置するための方法であって、治療有効量の本発明の化合物、その薬学的に許容され得る塩、及び薬学的に許容され得る担体を含む医薬組成物を対象に投与することを含む、前記方法を提供する。
本発明での使用に好適な医薬組成物には、活性成分が治療有効量、すなわち、その意図される目的を達成するのに有効な量で含有される組成物が含まれる。特定の用途のための実際の有効量は、とりわけ、処置される状態に依存するだろう。有効量の決定は、特に本明細書の詳細な開示を考慮すると、十分に当業者の能力の範囲内である。
her2またはegfrトランスフェクトL細胞系の生成
試薬:L細胞は、ATCC(バージニア州マナサス;カタログ番号CRL2648)からのものであり、Her2/pEZ−Lv105またはegfr/pCMV cDNAは、Sino Biological Inc.,(カタログ番号H10004)またはGeneCopoeia(カタログ番号Z2866)から購入した、グルコースDMEM、L−グルタミン、リポフェクタミン2000(Invitrogen;カリフォルニア州カールスバッド)。
コンジュゲートトラスツズマブの結合能を決定するため、ヒトHer2を発現するL細胞のFACS分析を実施した。簡潔には、her2を一過的にトランスフェクトした100μl中おおよそ106個のL細胞を、様々な量のトラスツズマブコンジュゲート抗体と共にインキュベートし、PBSまたは二次抗体単独または無関係のhuIgGを陰性対照として使用した。洗浄後、細胞をFACS緩衝液に再懸濁し、100μLの反応容量中のフィコエリトリン(μ抗ヒトPE)二次抗体にコンジュゲートした20μLのマウス抗ヒトIgGと共に室温で30分間インキュベートした。洗浄後、細胞を200μLの2%パラホルムアルデヒド/PBSにて固定し、フローサイトメトリーを実施した。同じ手順をアイソタイプ対照として無関係のヒトIgG抗体に対して使用して、細胞系毎にベースラインPMTを設定した。フローサイトメトリーを、BD FACSCalibur(登録商標)により実施し、幾何平均蛍光強度をそれぞれの試料に対して記録した。記録したデータを、FlowJoソフトウエアを使用して分析した。結果を図1に示す。
試薬:トラスツズマブ(Roche/Genentech Corporation、カリフォルニア州サウスサンフランシスコ)、セツキシマブ(Merck)、レシキモドと結合したMC−val−cit−PAB(MC−vc−PAB−TLRL)またはレシキモドと結合したMC(MC−TLRL)(Contract Research Organization、中国において合成)、ホウ酸ナトリウム、塩化ナトリウム、ジチオスレイトール(DTT)、Sephadex G25、DTPA、DTNB、及びマレイミドカプロイル−モノメチル(Sigma−Aldrich、ウィスコンシン州ミルウォーキー)。
トラスツズマブを、20mg/mLでの緩衝液交換によりHERCEPTIN(登録商標)から精製し、pH8.0の500mMのホウ酸ナトリウム及び500mMの塩化ナトリウム中に溶解した抗体を、過剰量の100mMジチオスレイトール(DTT)で処理する。37℃で約30分間インキュベートした後、緩衝液をSephadex G25樹脂での溶出により交換し、1mMのDTPAを有するPBSで溶出する。チオール/Ab値は、溶液の280nmでの吸光度からの還元された抗体の濃度、及びDTNB(Sigma−Aldrich、ウィスコンシン州ミルウォーキー)との反応によるチオール濃度を決定すること、及び412nmにおける吸光度の決定によって、調べる。PBS中に溶解した還元抗体を氷上で冷却する。DMSO中に溶解した、レシキモドとMc結合した薬物リンカー試薬を、既知の濃度でアセトニトリル及び水中に希釈し、PBS中の冷却還元抗体に添加する。約1時間後、過剰量のマレイミドを添加して、反応をクエンチし、あらゆる未反応抗体チオール基をキャップする。いくつかの場合では、標準的な手順を用いた免疫グロブリンのリシンへの結合を実施した。反応混合物を遠心分離限外濾過により濃縮し、コンジュゲート抗体を精製し、PBS中でG25樹脂を通す溶出により脱塩し、0.2μmフィルターを通して滅菌条件下で濾過し、凍結保存する。セツキシマブMC−TLRLの調製は同じ手法を使用した。
抗体を、マレイミドカプロイル−バリン−シトルリン(vc)−p−アミノベンジルオキシカルボニル(MC−vc−PAB)によりシステインを通してTLRLに結合した。MC−vc−PABリンカーは、カテプシンBなどの細胞間プロテアーゼにより切断可能であり、切断されると、遊離薬物を放出し(Doroninaら、Nat.Biotechnol.,21:778−784(2003))、一方でMCリンカーは、細胞内プロテアーゼによる切断に対して抵抗性である。精製したトラスツブマブを、pH8.0の500mMのホウ酸ナトリウム及び500mMの塩化ナトリウム中に溶解し、過剰量の100MMジチオスレイトール(DTT)でさらに処理した。37℃で約30分間インキュベートした後、緩衝液をSephadex G25樹脂での溶出により交換し、1mMのDTPAを有するPBSで溶出する。チオール/Ab値を、溶液の280nmでの吸光度からの還元された抗体の濃度、及びDTNB(Sigma−Aldrich、ウィスコンシン州ミルウォーキー)との反応によるチオール濃度を決定すること、及び412nm(吸光係数=13600cm−1M−1)における吸光度の決定によって、調べた。PBS中に溶解した還元抗体を氷上で冷却した。DMSO中でレシキモドと結合したMC−val−cit−PAB−PNPを、アセトニトリル及び水中に溶解し、PBS中の冷却還元抗体に添加した。1時間のインキュベーションの後、過剰量のマレイミドを添加して、反応をクエンチし、あらゆる未反応抗体チオール基をキャップした。いくつかの場合では、標準的な手順を用いた免疫グロブリンのリシンへの結合を実施した。反応混合物を遠心分離限外濾過により濃縮し、抗体薬物複合体を精製し、PBS中でG25樹脂を通す溶出により脱塩し、0.2μmフィルターを通して滅菌条件下で濾過し、凍結保存した。セツキシマブMC−vc−TLRLの調製は同じ手法を使用した。
試薬:SKBR3細胞(ATCC、カタログ番号HTB−30)、マッコイ5A(Invitrogen、カタログ番号22400、ロット番号747809);RPMI−1640(Invitrogen、カタログ番号11835、ロット番号764956);FCS(Hyclone、カタログ番号SH30084.03、ロット番号GRH0054);フィコール・ハイパック(Amersham Biosciences、ニュージャージー州ピスカタウェイ;カタログ番号17−1440−02)、96ウエルプレート(Costar、カタログ番号3599、カタログ番号3916);トリパンブルー(Invitrogen カタログ番号15250−061);LDHキット(Promega、カタログ番号G7891)、ELISAリーダーMD5(Molecule device)、ヒト化抗体Herceptin(登録商標)(Genentech Corporation、カリフォルニア州サウスサンフランシスコ;トラスツズマブの商標名)は水で再構成して、使用前に10mg/mlの貯蔵液を作製した。
ヒトPBMCを、Ficoll遠心分離により、健常な志願提供者から得たバフィーコートから調製した。樹状細胞を、ヒトPBMCからの抗CD3、CD19、CD20、CD14、及びCD16抗体の混合物を伴う磁気ビーズ(Miltenyi Biotec)を用いる陰性枯渇を使用することにより濃縮した。DCの濃縮を、ヤギ抗マウスFITC(系列)、HLA−DR−APCCy7、CD123−BV421及びCD11C−APCで染色した。染色された細胞をBDLSR Fortessaにより分析した。抗CD3、CD4、CD11C、CD19、CD14、CD16、CD123モノクローナル抗体は、BD BiosciencesまたはBiolgendから購入した。
1〜2×105濃縮DCを、96ウエルプレート、100μLの培地に播種し、100μLの希釈刺激薬をプレートに加え、37℃のインキュベーター中で20〜22時間培養した。上清を採取し、ヒトIFN−α、IL−6、IL−12(p70)、及びTNF−αをELISA(Mabtech AB)により分析した。
全ての比較の有意性は、モックと試料群との間の不等分散を推定し、スチューデント両側t検定を使用して算出され、結果は、p<0.05の場合に有意であるとした。パラメーター間の相関関係は、スピアマンの順位相関検定を使用して評価し、P値<0.05を統計学的に有意であるとした。
患者由来胃癌腫異種移植片(PDX)マウスモデルの作製のため、6〜8週齢の雌Balb/cヌードマウス(SLAC,中国上海から入手)を、腫瘍断片埋め込みに使用した。動物に、通常のヌードマウス食餌を与え、実験動物の管理と使用に関する指針(Guide for Care and Use of Laboratory Animals)、及び動物実験委員会(Institutional Animal Care and Use Committee)の規制に従って、SPF動物施設に収容した。大きさが約15〜30mm3の特許STO番号69胃腫瘍断片をBalb/cヌードマウスの腹部右側(皮下)に埋め込んだ。
(付記1)
式(Ib):
TM−L−AM(Ib)
の構造を有する化合物であって、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(I):
式中、破線は結合または結合の不在を表し、
Xは、Sまたは−NR1であり、R1は−W0―W1―W2―W3―W4であり、
W0は、結合、アルキル、アルケニル、アルキニル、アルコキシ、または−アルキル−S−アルキル−−であり、
W1は、結合、−−O−−、または−NR2−−であり、ここでR2は、水素、アルキルまたはアルケニルであり、
W2は、結合、−−O−−、−−C(O)−−、−−C(S)−−、または−S(O)2―であり、
W3は、結合、−−NR3−−であり、ここでR3は、水素、アルキルまたはアルケニルであり、
W4は、水素、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、アリール、アリールオキシ、ヘテロアリール、またはヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
Zは、水素、アルキル、アルケニル、アルキニル、アルコキシ、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、ヘテロシクリル、ハロゲン、シアノ、ニトロ、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−O−C(O)−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;
Rは、水素、アルキル、アルコキシ、ハロアルキル、ハロゲン、アリール、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
nは、0、1、2、3、または4であり;
Yは、−NR6R7、−CR6R7R8、または−アルキル−NH2であり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、−−NH2、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、
ここでR6、R7及びR8は独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
X及びZは一緒になって、任意選択的に(5〜9)員環を形成し得る、
化合物、またはその薬学的に許容され得る塩もしくは溶媒和物。
Lが式(II):
mは、1、2、3、4、5、または6であり、各bは独立して、0または1であり、Dは独立して、式(III):
式中、各iは独立して、0または1であり;
各jは独立して、0、1、2、3、4、5、または6であり;
各Aは独立して、S、O、またはN−Raであり、ここでRaは、水素、アルキル、アルケニル、またはアルコキシであり;
各Bは独立して、アルキル、アルケニル、−−O−アルキル−、−−アルキル−O−−、−−S−アルキル−−、−−アルキル−S−−、アリール、ヘテロアリール、ヘテロシクリル、またはペプチドであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−C(O)−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NHR4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルである、
付記1に記載の化合物。
Xが−NR1であり、R1がアルキル、−−アルキル−W4、−−アルキル−O−W4、−−アルキル−NH−C(O)−W4、−−アルコキシ−NH−C(O)−W4、−−アルキル−NH−C(O)−NH−W4、−−アルコキシ−NH−C(O)−NH−W4、−−アルキル−S(O)2−W4、または−−アルキル−NH−C(S)−W4である、付記1に記載の化合物。
XがSである、付記1に記載の化合物。
Zが、水素、アルキル、アルコキシ、アリール、ヘテロアリール、ハロアルキルであり、そのそれぞれがヒドロキシル、アルキル、アリール、ヘテロアリール、ヘテロシクリル、シアノ、−−アルコキシ−アルキル、ニトロ、及び−N(R5)2からなる群より選択される1〜3個の置換基により任意選択的に置換され、ここで各R5が独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールである、付記1〜4のいずれか1つに記載の化合物。
nが1または2であり、Rがアリールまたはヘテロアリールであり、そのそれぞれが、ヒドロキシル、アルコキシ、−−アルキル−ヒドロキシル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1〜3個の置換基により任意選択的に置換され、ここでR4が独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルである、付記1〜5のいずれか1つに記載の化合物。
Yが−NH2、−−アルキル−NH2であり、そのそれぞれが、アルキル、アルコキシ、アルケニル、及びアルキニルからなる群より選択される1〜3個の置換基により任意選択的に置換される、付記1〜6のいずれか1つに記載の化合物。
AMが、2−プロピルチアゾロ[4,5−c]キノリン−4−アミン、1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、4−アミノ−2−(エトキシメチル)−a,a−ジ−メチル−1H−イミダゾ[4,5−c]キノリン−1−エタノール、1−(4−アミノ−2−エチルアミノメチルイミダゾ−[4,5−c]キノリン−1−イル)−2−メチルプロパン−2−オール、N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル−]メタンスルホンアミド、4−アミノ−2−エトキシメチル−aa−ジメチル−6,7,8,9−テトラヒドロ−1H−イミダゾ[4,5−c]キノリン−1−エタノール、4−アミノ−aa−ジメチル−2−メトキシエチル−1H−イミダゾ[4,5−c]キノリン−1−エタノール、1−{2−[3−(ベンジルオキシ)プロポキシ]エチル}−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、N−[4−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c][1,5]ナフチリジン−1−イル)ブチル]−n’−ブチル尿素、N1−[2−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c][1,5]ナフチリジン−1−イル)エチル]−2−アミノ−4−メチルペンタンアミド、N−(2−{2−[4−アミノ−2−(2−メトキシエチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]エトキシ}エチル)−n’−フェニル尿素、1−(2−アミノ−2−メチルプロピル)−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、1−{4−[(3,5−ジクロロフェニル)スルホニル]ブチル}−2−エチル−1H−イミダゾ[4,5−c]キノリン−4−アミン、N−(2−{2−[4−アミノ−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]エトキシ}エチル)−n’−シクロヘキシル尿素、N−{3−[4−アミノ−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]プロピル}−n’−(3−シアノフェニル)チオ尿素、N−[3−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル)−2,2−ジメチルプロピル]ベンズアミド、2−ブチル−1−[3−(メチルスルホニル)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン、N−{2−[4−アミノ−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−1,1−ジメチルエチル}−2−エトキシアセトアミド、1−[4−アミノ−2−エトキシメチル−7−(ピリジン−4−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、1−[4−アミノ−2−(エトキシメチル)−7−(ピリジン−3−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、N−{3−[4−アミノ−1−(2−ヒドロキシ−2−メチルプロピル)−2−(メトキシエチル)−1H−イミダゾ[4,5−c]キノリン−7−イル]フェニル}メタンスルホンアミド、1−[4−アミノ−7−(5−ヒドロキシメチルピリジン−3−イル)−2−(2−メトキシエチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、3−[4−アミノ−2−(エトキシメチル)−7−(ピリジン−3−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]プロパン−1,2−ジオール、1−[2−(4−アミノ−2−エトキシメチル−1H−イミダゾ[4,5−c]キノリン−1−イル)−1,1−ジメチルエチル]−3−プロピル尿素、1−[2−(4−アミノ−2−エトキシメチル−1H−イミダゾ[4,5−c]キノリン−1−イル)−1,1−ジメチルエチル]−3−シクロペンチル尿素、1−[(2,2−ジメチル−1,3−ジオキソラン−4−イル)メチル]−2−(エトキシメチル)−7−(4−ヒドロキシメチルフェニル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、4−[4−アミノ−2−エトキシメチル−1−(2−ヒドロキシ−2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−7−イル]−N−メトキシ−N−メチルベンズアミド、2−エトキシメチル−N1−イソプロピル−6,7,8,9−テトラヒドロ−1H−イミダゾ[4,5−c]キノリン−1,4−ジアミン、1−[4−アミノ−2−エチル−7−(ピリジン−4−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]メタンスルホンアミド、及びN−[4−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c][1,5]ナフチリジン−1−イル)ブチル]−n’−シクロヘキシル尿素からなる群より選択される化合物である、付記1に記載の化合物。
前記リンカー部分内のDが式(V)〜(VII):
TMが、免疫グロブリン、タンパク質、小分子、ナノ粒子、または核酸を含む、付記1〜9のいずれか1つに記載の化合物。
TMが、非腫瘍細胞と比較して特異的または優先的に腫瘍細胞に結合する、付記10に記載の化合物。
TMが、前記腫瘍細胞上の腫瘍抗原に特異的に結合する、付記11に記載の化合物。
前記腫瘍抗原が、CD2、CD19、CD20、CD22、CD27、CD33、CD37、CD38、CD40、CD44、CD47、CD52、CD56、CD70、CD79、CD137、4−1BB、5T4、AGS−5、AGS−16、アンジオポエチン2、B7.1、B7.2、B7DC、B7H1、B7H2、B7H3、BT−062、BTLA、CAIX、癌胎児性抗原、CTLA4、クリプト、ED−B、ErbB1、ErbB2、ErbB3、ErbB4、EGFL7、EpCAM、EphA2、EphA3、EphB2、FAP、フィブロネクチン、葉酸受容体、ガングリオシドGM3、GD2、グルココルチコイド誘発性腫瘍壊死因子受容体(GITR)、gp100、gpA33、GPNMB、ICOS、IGF1R、インテグリン(Integrin)、KIR、LAG−3、ルイスY、メソテリン、c−MET、MN炭酸脱水酵素IX、MUC1、MUC16、ネクチン−4、NKGD2、NOTCH、OX40、OX40L、PD−1、PDL1、PSCA、PSMA、RANKL、ROR1、ROR2、SLC44A4、シンデカン−1、TACI、TAG−72、テネイシン、TIM3、TRAILR1、TRAILR2、VEGFR−1、VEGFR−2、VEGFR−3、及びそれらの変異体からなる群より選択される、付記12に記載の化合物。
TMが、抗体またはその機能性断片を含む、付記10に記載の化合物。
TMが、Rituxan(リツキシマブ)、Herceptin(トラスツズマブ)、Erbitux(セツキシマブ)、Vectibix(パニツムマブ)、Arzerra(オファツムマブ)、Benlysta(ベリムマブ)、Yervoy(イピリムマブ)、Perjeta(ペルツズマブ)、トレメリムマブ、ニボルマブ、ダセツズマブ、ウレルマブ、MPDL3280A、ランブロリズマブ、ブリナツモマブ、アルデスロイキン;アレムツズマブ(aemtuzumab);アリトレチノイン;アロプリノール;アルトレタミン;アミフォスチン;アナストロゾール;三酸化ヒ素;アスパラギナーゼ;BCG生菌;ベキサロテンカプセル;ベキサロテンゲル;ブレオマイシン;静注用ブスルファン;経口用ブスルファン;カルステロン;カペシタビン;カルボプラチン;カルムスチン;ポリフェプロサン20インプラントを伴うカルムスチン;セレコキシブ;クロラムブシル;シスプラチン;クラドリビン;シクロホスファミド;シタラビン;シタラビンリポソーム;ダカルバジン;ダクチノマイシン;アクチノマイシンD;ダルベポエチンα(dabepoetin alfa);ダウノルビシンリポソーム;ダウノルビシン、ダウノマイシン;デニロイキンジフチトックス、デクスラゾキサン;ドセタキセル;ドキソルビシン;ドキソルビシンリポソーム;プロピオン酸ドロモスタノロン;エリオットB液;エピルビシン;エポエチン(eoetin)αエストラムスチン;リン酸エトポシド;エトポシド(VP−16);エキセメスタン;フィルグラスチム;フロクスウリジン(動注用);フルダラビン;フルオロウラシル(5−FU);フルベストラント;ゲムツズマブオゾガマイシン;ゴセレリン酢酸塩;ヒドロキシ尿素;イブリツモマブチウキセタン;イダルビシン;イホスファミド;イマチニブメシル酸塩;インターフェロンα−2a;インターフェロンα−2b;イリノテカン;レトロゾール;ロイコボリン;レバミゾール;ロムスチン(CCNU);メクロレタミン(ナイトロジェンマスタード);酢酸メゲストロール;メルファラン(L−PAM);メルカプトプリン(6−MP);メスナ;メトトレキセート;メトキサレン;マイトマイシンC;ミトタン;ミトキサントロン;ナンドロロンフェンプロピオナート;ノフェツモマブ(nfetumomab);LOddC;オプレルベキン(orelvekin);オキサリプラチン;パクリタキセル;パミドロネート;ペガデマーゼ;ペガスパルガーゼ;ペグフィルグラスチム;ペントスタチン;ピポブロマン;プリカマイシン;ミトラマイシン;ポルフィマーナトリウム;プロカルバジン;キナクリン;ラスブリカーゼ;サルグラモスチム;ストレプトゾシン;テルビブジン(talbuvidine)(LDT);タルク;タモキシフェン;テモゾロミド;テニポシド(VM−26);テストラクトン;チオグアニン(6−TG);チオテパ;トポテカン;トレミフェン;トシツモマブ;トレチノイン(ATRA);ウラシルマスタード;バルルビシン;バルトルシタビン(モノバルLDC);ビンブラスチン;ビノレルビン;ゾレドロネート;及びそれらの混合物を含む、付記10に記載の化合物。
有効量の付記1〜15のいずれか1つに記載の化合物及び1つまたは複数の薬学的に許容され得る担体を含む、医薬組成物。
有効量の追加の治療剤をさらに含む、付記16に記載の医薬組成物。
前記追加の治療剤が抗癌剤である、付記17に記載の医薬組成物。
前記抗癌剤が、代謝拮抗薬、トポイソメラーゼI及びIIの阻害剤、アルキル化剤、微小管阻害剤、抗アンドロゲン剤、GNRhモジュレータまたはそれらの混合物である、付記17に記載の医薬組成物。
腫瘍細胞の増殖を阻害する方法であって、前記腫瘍細胞に付記1〜15のいずれか1つに記載の化合物を投与することを含む、方法。
対象における疾患を処置する方法であって、前記対象に付記1〜15のいずれか1つに記載の化合物を投与することを含む、方法。
前記疾患が、胃、結腸、直腸、肝臓、膵臓、肺、乳房、子宮頚部、子宮体部、卵巣、精巣、膀胱、腎臓部、脳/CNS、頭頸部、喉、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、白血病、黒色腫、非黒色腫皮膚癌、急性リンパ性白血病、急性骨髄性白血病、ユーイング肉腫、小細胞肺癌、絨毛癌、横紋筋肉腫、ウィルムス腫瘍、神経芽腫、有毛細胞白血病、口腔/咽頭、食道、喉頭、腎臓癌またはリンパ腫から選択された癌である、付記21に記載の方法。
対象内の疾患を処置するための医薬品の製造における付記1〜15のいずれか1つに記載の化合物の使用。
対象内の疾患を処置するための医薬品の製造における付記16〜19のいずれか1つに記載の医薬組成物の使用。
式(Ib):
TM−L−AM(Ib)
の構造を有する化合物であって、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(IV):
式中、
Vは、−NR6R7であり、R6及びR7のそれぞれは独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
R10及びR11は独立して、水素、アルキル、アルケニル、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリル、またはシクロアルキルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールである、化合物、またはその薬学的に許容され得る塩もしくは溶媒和物。
有効量の付記25に記載の化合物及び1つまたは複数の薬学的に許容され得る担体を含む医薬組成物。
有効量の追加の治療剤をさらに含む、付記26に記載の医薬組成物。
Claims (27)
- 式(Ib):
TM−L−AM(Ib)
の構造を有する化合物であって、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(I):
式中、破線は結合または結合の不在を表し、
Xは、Sまたは−NR1であり、R1は−W0―W1―W2―W3―W4であり、
W0は、結合、アルキル、アルケニル、アルキニル、アルコキシ、または−アルキル−S−アルキル−−であり、
W1は、結合、−−O−−、または−NR2−−であり、ここでR2は、水素、アルキルまたはアルケニルであり、
W2は、結合、−−O−−、−−C(O)−−、−−C(S)−−、または−S(O)2―であり、
W3は、結合、−−NR3−−であり、ここでR3は、水素、アルキルまたはアルケニルであり、
W4は、水素、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、アリール、アリールオキシ、ヘテロアリール、またはヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
Zは、水素、アルキル、アルケニル、アルキニル、アルコキシ、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、ヘテロシクリル、ハロゲン、シアノ、ニトロ、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−O−C(O)−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり;
Rは、水素、アルキル、アルコキシ、ハロアルキル、ハロゲン、アリール、ヘテロアリール、ヘテロシクリルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−−NH2、ニトロ、−−アルキル−ヒドロキシル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルであり;
nは、0、1、2、3、または4であり;
Yは、−NR6R7、−CR6R7R8、または−アルキル−NH2であり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、−−NH2、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換されることができ、
ここでR6、R7及びR8は独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールであり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
X及びZは一緒になって、任意選択的に(5〜9)員環を形成し得る、
化合物、またはその薬学的に許容され得る塩もしくは溶媒和物。 - Lが式(II):
mは、1、2、3、4、5、または6であり、各bは独立して、0または1であり、Dは独立して、式(III):
式中、各iは独立して、0または1であり;
各jは独立して、0、1、2、3、4、5、または6であり;
各Aは独立して、S、O、またはN−Raであり、ここでRaは、水素、アルキル、アルケニル、またはアルコキシであり;
各Bは独立して、アルキル、アルケニル、−−O−アルキル−、−−アルキル−O−−、−−S−アルキル−−、−−アルキル−S−−、アリール、ヘテロアリール、ヘテロシクリル、またはペプチドであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、シクロアルキル、−−アルキル−アリール、−−アルキル−ヘテロアリール、−−アルキル−ヘテロシクリル、−−O−R4、−−O−アルキル−R4、−−C(O)−R4、−−C(O)−O−R4、−−S−R4、−−S(O)2−R4、−−NHR4、−−NH−アルキル−R4、ハロゲン、−−CN、−−NO2、及び−SHからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここでR4は、アルキル、アルケニル、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルである、
請求項1に記載の化合物。 - Xが−NR1であり、R1がアルキル、−−アルキル−W4、−−アルキル−O−W4、−−アルキル−NH−C(O)−W4、−−アルコキシ−NH−C(O)−W4、−−アルキル−NH−C(O)−NH−W4、−−アルコキシ−NH−C(O)−NH−W4、−−アルキル−S(O)2−W4、または−−アルキル−NH−C(S)−W4である、請求項1に記載の化合物。
- XがSである、請求項1に記載の化合物。
- Zが、水素、アルキル、アルコキシ、アリール、ヘテロアリール、ハロアルキルであり、そのそれぞれがヒドロキシル、アルキル、アリール、ヘテロアリール、ヘテロシクリル、シアノ、−−アルコキシ−アルキル、ニトロ、及び−N(R5)2からなる群より選択される1〜3個の置換基により任意選択的に置換され、ここで各R5が独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールである、請求項1〜4のいずれか1項に記載の化合物。
- nが1または2であり、Rがアリールまたはヘテロアリールであり、そのそれぞれが、ヒドロキシル、アルコキシ、−−アルキル−ヒドロキシル、−−O−R4、−−O−アルキル−R4、−−アルキル−O−R4、−−C(O)−R4、−−C(O)−NH−R4、−−C(O)−NR4R4、−−アルキル−C(O)−R4、−−アルキル−C(O)−O−R4、−−C(O)−O−R4、−−O−C(O)−R4、−−S−R4、−−C(O)−S−R4、−−S−C(O)−R4、−−S(O)2−R4、−−NH−S(O)2−R4、−−アルキル−S−R4、−−アルキル−S(O)2−R4、−−NHR4、−−NR4R4、−−NH−アルキル−R4、ハロゲン、−−CN、及び−SHからなる群より選択される1〜3個の置換基により任意選択的に置換され、ここでR4が独立して、水素、アルキル、アルケニル、アルコキシ、−−アルキル−ヒドロキシル、アリール、ヘテロアリール、ヘテロシクリル、またはハロアルキルである、請求項1〜5のいずれか1項に記載の化合物。
- Yが−NH2、−−アルキル−NH2であり、そのそれぞれが、アルキル、アルコキシ、アルケニル、及びアルキニルからなる群より選択される1〜3個の置換基により任意選択的に置換される、請求項1〜6のいずれか1項に記載の化合物。
- AMが、2−プロピルチアゾロ[4,5−c]キノリン−4−アミン、1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、4−アミノ−2−(エトキシメチル)−a,a−ジ−メチル−1H−イミダゾ[4,5−c]キノリン−1−エタノール、1−(4−アミノ−2−エチルアミノメチルイミダゾ−[4,5−c]キノリン−1−イル)−2−メチルプロパン−2−オール、N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル−]メタンスルホンアミド、4−アミノ−2−エトキシメチル−aa−ジメチル−6,7,8,9−テトラヒドロ−1H−イミダゾ[4,5−c]キノリン−1−エタノール、4−アミノ−aa−ジメチル−2−メトキシエチル−1H−イミダゾ[4,5−c]キノリン−1−エタノール、1−{2−[3−(ベンジルオキシ)プロポキシ]エチル}−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、N−[4−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c][1,5]ナフチリジン−1−イル)ブチル]−n’−ブチル尿素、N1−[2−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c][1,5]ナフチリジン−1−イル)エチル]−2−アミノ−4−メチルペンタンアミド、N−(2−{2−[4−アミノ−2−(2−メトキシエチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]エトキシ}エチル)−n’−フェニル尿素、1−(2−アミノ−2−メチルプロピル)−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、1−{4−[(3,5−ジクロロフェニル)スルホニル]ブチル}−2−エチル−1H−イミダゾ[4,5−c]キノリン−4−アミン、N−(2−{2−[4−アミノ−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]エトキシ}エチル)−n’−シクロヘキシル尿素、N−{3−[4−アミノ−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]プロピル}−n’−(3−シアノフェニル)チオ尿素、N−[3−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル)−2,2−ジメチルプロピル]ベンズアミド、2−ブチル−1−[3−(メチルスルホニル)プロピル]−1H−イミダゾ[4,5−c]キノリン−4−アミン、N−{2−[4−アミノ−2−(エトキシメチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−1,1−ジメチルエチル}−2−エトキシアセトアミド、1−[4−アミノ−2−エトキシメチル−7−(ピリジン−4−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、1−[4−アミノ−2−(エトキシメチル)−7−(ピリジン−3−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、N−{3−[4−アミノ−1−(2−ヒドロキシ−2−メチルプロピル)−2−(メトキシエチル)−1H−イミダゾ[4,5−c]キノリン−7−イル]フェニル}メタンスルホンアミド、1−[4−アミノ−7−(5−ヒドロキシメチルピリジン−3−イル)−2−(2−メトキシエチル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、3−[4−アミノ−2−(エトキシメチル)−7−(ピリジン−3−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]プロパン−1,2−ジオール、1−[2−(4−アミノ−2−エトキシメチル−1H−イミダゾ[4,5−c]キノリン−1−イル)−1,1−ジメチルエチル]−3−プロピル尿素、1−[2−(4−アミノ−2−エトキシメチル−1H−イミダゾ[4,5−c]キノリン−1−イル)−1,1−ジメチルエチル]−3−シクロペンチル尿素、1−[(2,2−ジメチル−1,3−ジオキソラン−4−イル)メチル]−2−(エトキシメチル)−7−(4−ヒドロキシメチルフェニル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、4−[4−アミノ−2−エトキシメチル−1−(2−ヒドロキシ−2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−7−イル]−N−メトキシ−N−メチルベンズアミド、2−エトキシメチル−N1−イソプロピル−6,7,8,9−テトラヒドロ−1H−イミダゾ[4,5−c]キノリン−1,4−ジアミン、1−[4−アミノ−2−エチル−7−(ピリジン−4−イル)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オール、N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]メタンスルホンアミド、及びN−[4−(4−アミノ−2−ブチル−1H−イミダゾ[4,5−c][1,5]ナフチリジン−1−イル)ブチル]−n’−シクロヘキシル尿素からなる群より選択される化合物である、請求項1に記載の化合物。
- 前記リンカー部分内のDが式(V)〜(VII):
- TMが、免疫グロブリン、タンパク質、小分子、ナノ粒子、または核酸を含む、請求項1〜9のいずれか1項に記載の化合物。
- TMが、非腫瘍細胞と比較して特異的または優先的に腫瘍細胞に結合する、請求項10に記載の化合物。
- TMが、前記腫瘍細胞上の腫瘍抗原に特異的に結合する、請求項11に記載の化合物。
- 前記腫瘍抗原が、CD2、CD19、CD20、CD22、CD27、CD33、CD37、CD38、CD40、CD44、CD47、CD52、CD56、CD70、CD79、CD137、4−1BB、5T4、AGS−5、AGS−16、アンジオポエチン2、B7.1、B7.2、B7DC、B7H1、B7H2、B7H3、BT−062、BTLA、CAIX、癌胎児性抗原、CTLA4、クリプト、ED−B、ErbB1、ErbB2、ErbB3、ErbB4、EGFL7、EpCAM、EphA2、EphA3、EphB2、FAP、フィブロネクチン、葉酸受容体、ガングリオシドGM3、GD2、グルココルチコイド誘発性腫瘍壊死因子受容体(GITR)、gp100、gpA33、GPNMB、ICOS、IGF1R、インテグリン(Integrin)、KIR、LAG−3、ルイスY、メソテリン、c−MET、MN炭酸脱水酵素IX、MUC1、MUC16、ネクチン−4、NKGD2、NOTCH、OX40、OX40L、PD−1、PDL1、PSCA、PSMA、RANKL、ROR1、ROR2、SLC44A4、シンデカン−1、TACI、TAG−72、テネイシン、TIM3、TRAILR1、TRAILR2、VEGFR−1、VEGFR−2、VEGFR−3、及びそれらの変異体からなる群より選択される、請求項12に記載の化合物。
- TMが、抗体またはその機能性断片を含む、請求項10に記載の化合物。
- TMが、Rituxan(リツキシマブ)、Herceptin(トラスツズマブ)、Erbitux(セツキシマブ)、Vectibix(パニツムマブ)、Arzerra(オファツムマブ)、Benlysta(ベリムマブ)、Yervoy(イピリムマブ)、Perjeta(ペルツズマブ)、トレメリムマブ、ニボルマブ、ダセツズマブ、ウレルマブ、MPDL3280A、ランブロリズマブ、ブリナツモマブ、アルデスロイキン;アレムツズマブ(aemtuzumab);アリトレチノイン;アロプリノール;アルトレタミン;アミフォスチン;アナストロゾール;三酸化ヒ素;アスパラギナーゼ;BCG生菌;ベキサロテンカプセル;ベキサロテンゲル;ブレオマイシン;静注用ブスルファン;経口用ブスルファン;カルステロン;カペシタビン;カルボプラチン;カルムスチン;ポリフェプロサン20インプラントを伴うカルムスチン;セレコキシブ;クロラムブシル;シスプラチン;クラドリビン;シクロホスファミド;シタラビン;シタラビンリポソーム;ダカルバジン;ダクチノマイシン;アクチノマイシンD;ダルベポエチンα(dabepoetin alfa);ダウノルビシンリポソーム;ダウノルビシン、ダウノマイシン;デニロイキンジフチトックス、デクスラゾキサン;ドセタキセル;ドキソルビシン;ドキソルビシンリポソーム;プロピオン酸ドロモスタノロン;エリオットB液;エピルビシン;エポエチン(eoetin)αエストラムスチン;リン酸エトポシド;エトポシド(VP−16);エキセメスタン;フィルグラスチム;フロクスウリジン(動注用);フルダラビン;フルオロウラシル(5−FU);フルベストラント;ゲムツズマブオゾガマイシン;ゴセレリン酢酸塩;ヒドロキシ尿素;イブリツモマブチウキセタン;イダルビシン;イホスファミド;イマチニブメシル酸塩;インターフェロンα−2a;インターフェロンα−2b;イリノテカン;レトロゾール;ロイコボリン;レバミゾール;ロムスチン(CCNU);メクロレタミン(ナイトロジェンマスタード);酢酸メゲストロール;メルファラン(L−PAM);メルカプトプリン(6−MP);メスナ;メトトレキセート;メトキサレン;マイトマイシンC;ミトタン;ミトキサントロン;ナンドロロンフェンプロピオナート;ノフェツモマブ(nfetumomab);LOddC;オプレルベキン(orelvekin);オキサリプラチン;パクリタキセル;パミドロネート;ペガデマーゼ;ペガスパルガーゼ;ペグフィルグラスチム;ペントスタチン;ピポブロマン;プリカマイシン;ミトラマイシン;ポルフィマーナトリウム;プロカルバジン;キナクリン;ラスブリカーゼ;サルグラモスチム;ストレプトゾシン;テルビブジン(talbuvidine)(LDT);タルク;タモキシフェン;テモゾロミド;テニポシド(VM−26);テストラクトン;チオグアニン(6−TG);チオテパ;トポテカン;トレミフェン;トシツモマブ;トレチノイン(ATRA);ウラシルマスタード;バルルビシン;バルトルシタビン(モノバルLDC);ビンブラスチン;ビノレルビン;ゾレドロネート;及びそれらの混合物を含む、請求項10に記載の化合物。
- 有効量の請求項1〜15のいずれか1項に記載の化合物及び1つまたは複数の薬学的に許容され得る担体を含む、医薬組成物。
- 有効量の追加の治療剤をさらに含む、請求項16に記載の医薬組成物。
- 前記追加の治療剤が抗癌剤である、請求項17に記載の医薬組成物。
- 前記抗癌剤が、代謝拮抗薬、トポイソメラーゼI及びIIの阻害剤、アルキル化剤、微小管阻害剤、抗アンドロゲン剤、GNRhモジュレータまたはそれらの混合物である、請求項17に記載の医薬組成物。
- 腫瘍細胞の増殖を阻害する方法であって、前記腫瘍細胞に請求項1〜15のいずれか1項に記載の化合物を投与することを含む、方法。
- 対象における疾患を処置する方法であって、前記対象に請求項1〜15のいずれか1項に記載の化合物を投与することを含む、方法。
- 前記疾患が、胃、結腸、直腸、肝臓、膵臓、肺、乳房、子宮頚部、子宮体部、卵巣、精巣、膀胱、腎臓部、脳/CNS、頭頸部、喉、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、白血病、黒色腫、非黒色腫皮膚癌、急性リンパ性白血病、急性骨髄性白血病、ユーイング肉腫、小細胞肺癌、絨毛癌、横紋筋肉腫、ウィルムス腫瘍、神経芽腫、有毛細胞白血病、口腔/咽頭、食道、喉頭、腎臓癌またはリンパ腫から選択された癌である、請求項21に記載の方法。
- 対象内の疾患を処置するための医薬品の製造における請求項1〜15のいずれか1項に記載の化合物の使用。
- 対象内の疾患を処置するための医薬品の製造における請求項16〜19のいずれか1項に記載の医薬組成物の使用。
- 式(Ib):
TM−L−AM(Ib)
の構造を有する化合物であって、
式中、TMは標的部分であり、Lはリンカーであり、AMは式(IV):
式中、
Vは、−NR6R7であり、R6及びR7のそれぞれは独立して、水素、アルキル、アルケニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、アリールチオ、−−アルキル−ヒドロキシル、−−アルキル−C(O)−O−R9、−−アルキル−C(O)−R9、または−アルキル−O−C(O)−R9であり、ここでR9は、水素、アルキル、アルケニル、ハロゲン、またはハロアルキルであり;
R10及びR11は独立して、水素、アルキル、アルケニル、アリール、ハロアルキル、ヘテロアリール、ヘテロシクリル、またはシクロアルキルであり、そのそれぞれは、ヒドロキシル、アルコキシ、アルキル、アルケニル、アルキニル、ハロゲン、−−N(R5)2、−−アルコキシ−アルキル、−−アルコキシ−アルケニル、−−C(O)−アルキル、−−C(O)−O−アルキル、−−C(O)−N(R5)2、アリール、ヘテロアリール、−−CO−アリール、及び−CO−ヘテロアリールからなる群より選択される1つまたは複数の置換基により任意選択的に置換され、ここで各R5は独立して、水素、アルキル、ハロアルキル、−−アルキル−アリール、または−アルキル−ヘテロアリールである、化合物、またはその薬学的に許容され得る塩もしくは溶媒和物。 - 有効量の請求項25に記載の化合物及び1つまたは複数の薬学的に許容され得る担体を含む医薬組成物。
- 有効量の追加の治療剤をさらに含む、請求項26に記載の医薬組成物。
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JP2020114836A (ja) * | 2014-01-10 | 2020-07-30 | バーディー バイオファーマシューティカルズ インコーポレイテッド | 免疫療法のための化合物及び組成物 |
JPWO2019172210A1 (ja) * | 2018-03-03 | 2021-02-25 | 国立大学法人 東京大学 | がん特異的酵素活性を利用したプロドラッグ型抗がん剤 |
JP7442192B2 (ja) | 2018-03-03 | 2024-03-04 | 国立大学法人 東京大学 | がん特異的酵素活性を利用したプロドラッグ型抗がん剤 |
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