JP6423804B2 - 細胞結合剤及び細胞毒性剤を含む複合体 - Google Patents
細胞結合剤及び細胞毒性剤を含む複合体 Download PDFInfo
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- JP6423804B2 JP6423804B2 JP2015560361A JP2015560361A JP6423804B2 JP 6423804 B2 JP6423804 B2 JP 6423804B2 JP 2015560361 A JP2015560361 A JP 2015560361A JP 2015560361 A JP2015560361 A JP 2015560361A JP 6423804 B2 JP6423804 B2 JP 6423804B2
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- Prior art keywords
- ala
- val
- gly
- optionally substituted
- phe
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Description
本出願は、米国特許法第119条(e)の下、2013年2月28日に提出した米国仮特許出願第61/770937号及び2013年5月6日に提出した米国仮特許出願第61/819848号の提出日に基づく優先権を主張する。該仮出願の内容は、その全体が参照により本明細書に取り込まれる。
本明細書において使用する場合、「アルキル」は、1〜20個の炭素原子の、1価の直鎖または分岐飽和炭化水素ラジカルを指す。「1価」とは、アルキルが、分子の残りの部分と1点で結合することを意味する。アルキル基の例としては、メチル、エチル、1‐プロピル、2‐プロピル、1‐ブチル、2‐メチル‐1‐プロピル、‐CH2CH(CH3)2、2‐ブチル、2‐メチル‐2‐プロピル、1‐ペンチル、2‐ペンチル、3‐ペンチル、2‐メチル‐2‐ブチル、3‐メチル‐2‐ブチル、3‐メチル‐1‐ブチル、2‐メチル‐1‐ブチル、1‐ヘキシル、2‐ヘキシル、3‐ヘキシル、2‐メチル‐2‐ペンチル、3‐メチル‐2‐ペンチル、4‐メチル‐2‐ペンチル、3‐メチル‐3‐ペンチル、2‐メチル‐3‐ペンチル、2,3‐ジメチル‐2‐ブチル、3,3‐ジメチル‐2‐ブチル、1‐ヘプチル及び1‐オクチル等が挙げられるがこれらに限定されるものではない。好ましくは、アルキル基は1〜10個の炭素原子を有する。より好ましくは、アルキル基は1〜4個の炭素原子を有する。
細胞結合剤−薬物部複合体
細胞毒性化合物
である。式中、変数は、第3実施形態もしくはその各代替実施形態またはその第1もしくは第6の具体的実施形態において規定されるとおりである。好ましくは、P及びP’は同じである。一実施形態においては、vは0で
ある。
であり;残りの変数は、第3もしくは第4実施形態もしくはそれらの各代替実施形態またはそれらの第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12、第13、第14、第15、第16、第17、第18もしくは第19の具体的実施形態において規定されるとおりである。
リンカー化合物
である。式中、変数は、第5実施形態もしくはその各代替実施形態またはその第1もしくは第6の具体的実施形態において規定されるとおりである。好ましくは、P及びP’は同じである。一実施形態においては、vは0である。
細胞結合剤−薬物複合体の作製
細胞毒性の生体外評価
組成物及び使用方法
類似体及び誘導体
本明細書及びこれに続く実施例において引用する全参考文献は、その全体が参照により明白に取り込まれる。
実施例2
実施例3
ある態様において、本発明は以下であってもよい。
[態様1]
以下の式:
CBAは細胞結合剤であり;
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)iCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
iは0〜15の整数であり;
JCB’は、
Arは任意に置換されたアリーレンまたは任意に置換されたヘテロアリーレンであり;
Cyは任意に置換されたシクロアルキンまたは任意に置換されたヘテロシクロアルキンの非アルキン残基であり;
R201、R202及びR203はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z3はピリジルまたは
Cy’は任意に置換されたひずんだシクロアルケンまたは任意に置換されたひずんだヘテロシクロアルケンの非アルケン残基であり;
R301はHまたは任意に置換されたアルキルであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z1は存在しないか、‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐CH2‐O‐、‐O‐CH2‐、‐(CH2CH2O)p‐または‐(OCH2CH2)p’‐であり、p及びp’は独立して1〜1000の整数であり;
JD’は、
A及びA’はそれぞれ独立して任意に置換されたアルキレン、任意に置換されたアルケニレン、任意に置換されたアルキニレン、任意に置換されたシクロアルキレン、任意に置換されたシクロアルケニレン、または任意に置換されたシクロアルキニレンであり;
Qは‐Z1‐P‐Z2‐であり;
Q’は‐Z1’‐P’‐Z2’‐であり;
Z1及びZ2の1個は‐C(=O)‐であり、他方は‐NRh‐であり;
Z1’及びZ2’の1個は‐C(=O)‐であり、他方は‐NRh’‐であり;
P及びP’はそれぞれ独立して存在しないか、任意に置換されたアルキレン、‐(CH2‐CH2‐O)j‐、‐(O‐CH2‐CH2)j‐または[XX]1−10であり、各XXは独立して選択されるアミノ酸残基であり;
jは1〜500の整数であり;
kは0または1であり;
Lは‐(CR5R6)v‐、‐(CR7R8)q‐N(Rg)‐(CR9R10)r‐、‐(CR7R8)q‐C(Ra)(Rg)‐(CR9R10)rまたは‐(CR11R12)s‐N(Rg)‐(CR13R14)t‐N(Rg’)‐(CR15R16)u‐であり;
Rg及びRg’はそれぞれ独立して‐(CR17R18)p‐Z‐Vであり;
pは1〜5の整数であり;
VはH、電荷をもつ置換基、またはイオン化できる基であり;
Zは存在しないか、‐C(=O)NRh‐アルキレン‐または‐NRh‐C(=O)‐アルキレン‐であり;
Rh及びRh’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
R5〜R18はそれぞれ独立してHまたは任意に置換されたアルキルであり;
q、r、s、t、u及びvはそれぞれ独立して0〜10の整数であり;ならびに
wは1〜20の整数である
複合体またはその薬学的に許容できる塩。
[態様2]
以下の式:
R19〜R22はそれぞれ独立してHまたは任意に置換されたアルキルであり;
m及びnはそれぞれ独立して0〜10である
前記複合体またはその薬学的に許容できる塩。
[態様3]
態様1または2に記載の複合体であって、前記イオン化できる基が‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12または‐Z’‐NR11R12であり、前記電荷をもつ基は‐N+R23R24R25X−または‐Z’‐N+R23R24R25X−であり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R23〜R25はそれぞれ独立して任意に置換されたアルキルであり;X−は薬学的に許容できる陰イオンである前記複合体。
[態様4]
VがHもしくは‐CH2CH2SO3Hである態様1もしくは2に記載の複合体、またはその薬学的に許容できる塩。
[態様5]
以下の式:
[態様6]
以下の式:
[態様7]
Lが‐(CR7R8)q‐N(Rg)‐(CR9R10)r‐または‐(CR11R12)s‐N(Rg)‐(CR13R14)t‐N(Rg’)‐(CR15R16)u‐である態様1〜4及び6のいずれか1項に記載の複合体。
[態様8]
[態様9]
R19、R20、R21及びR22がそれぞれHである態様2〜8のいずれか1項に記載の複合体。
[態様10]
R5及びR6がそれぞれHである態様1〜4及び6〜9のいずれか1項に記載の複合体。
[態様11]
P及びP’がそれぞれ独立して[XX]1−10である態様1〜10のいずれか1項に記載の複合体。
[態様12]
各XXが、天然アミノ酸、合成アミノ酸、アミノ酸類似体または天然アミノ酸と同様の方法で機能するアミノ酸擬似物より独立して選択されるアミノ酸の残基である態様1〜11のいずれか1項に記載の複合体。
[態様13]
各XXが、それぞれ独立してLまたはD異性体であるヒスチジン、アラニン、イソロイシン、アルギニン、ロイシン、アスパラギン、リジン、アスパラギン酸、メチオニン、システイン、フェニルアラニン、グルタミン酸、スレオニン、グルタミン、トリプトファン、グリシン、バリン、プロリン、セリン、チロシン、N‐メチル‐ヒスチジン、N‐メチル‐アラニン、N‐メチル‐イソロイシン、N‐メチル‐アルギニン、N‐メチル‐ロイシン、N‐メチル‐アスパラギン、N‐メチル‐リジン、N‐メチル‐アスパラギン酸、N‐メチル‐メチオニン、N‐メチル‐システイン、N‐メチル‐フェニルアラニン、N‐メチル‐グルタミン酸、N‐メチル‐スレオニン、N‐メチル‐グルタミン、N‐メチル‐トリプトファン、N‐メチル‐グリシン、N‐メチル‐バリン、N‐メチル‐プロリン、N‐メチル‐セリン、N‐メチル‐チロシン、ヒドロキシプロリン、γ‐カルボキシグルタミン酸、セリノシステイン(selinocysteine)、O‐リン酸化セリン、ホモセリン、ノルロイシン、メチオニンスルホキシド、メチオニンメチルスルホニウム、シトルリン、オルニチン、システインスルホン酸、システインスルフィン酸、3‐アミノアラニン、3‐ジメチルアミノアラニン、2‐アミノ‐4‐(ジメチルアミノ)ブタン酸、2,4‐ジアミノブタン酸、2‐アミノ‐6‐(ジメチルアミノ)ヘキサン酸、2‐アミノ‐5‐(ジメチルアミノ)ペンタン酸及びβ‐アラニンから成る群より独立して選択されるアミノ酸の残基である態様12記載の複合体。
[態様14]
各XXが、独立して選択されるグリシンまたはアラニンの残基である態様13記載の複合体。
[態様15]
P及びP’がそれぞれ、プロテアーゼによって切断可能なペプチドである態様1〜14のいずれか1項に記載の複合体。
[態様16]
P及びP’がそれぞれ、腫瘍組織において発現するプロテアーゼによって切断可能なペプチドである態様15記載の複合体。
[態様17]
P及びP’がそれぞれ、リソソームプロテアーゼによって切断可能なペプチドである態様15記載の複合体。
[態様18]
P及びP’がそれぞれ、Val−Cit、Val−Lys、Phe−Lys、Lys−Lys、Ala−Lys、Phe−Cit、Leu−Cit、Lle−Cit、Trp、Cit、Phe−Ala、Phe−N9−トシル−Arg、Phe−N9−ニトロ−Arg、Phe−Phe−Lys、D−Phe−Phe−Lys、Gly−Phe−Lys、Leu−Ala−Leu、Ile−Ala−Leu、Val−Ala−Val、Ala−Leu−Ala−Leu、β−Ala−Leu−Ala−Leu、Gly−Phe−Leu−Gly、Val−Arg、Arg−Val、Arg−Arg、Val−D−Cit、Val−D−Lys、Val−D−Arg、D−Val−Cit、D−Val−Lys、D−Val−Arg、D−Val−D−Cit、D−Val−D−Lys、D−Val−D−Arg、D−Arg−D−Arg、Ala−Ala、Ala−D−Ala、D−Ala−Ala及びD−Ala−D−Ala、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Ala−D−Ala、Ala−Val−Cit、Ala−Val−Alaならびにβ−Ala−Gly−Gly−Glyから成る群より選択される態様1〜17のいずれか1項に記載の複合体。
[態様19]
P及びP’がそれぞれ、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Val−Alaまたはβ−Ala−Gly−Gly−Glyである態様1〜18のいずれか1項に記載の複合体。
[態様20]
以下の式:
[態様21]
R7〜R10がそれぞれHである態様1〜4、6、7及び9〜20のいずれか1項に記載の複合体。
[態様22]
以下の式:
[態様23]
R11〜R16がそれぞれHである態様1〜4、6、7、9〜19及び22のいずれか1項に記載の複合体。
[態様24]
以下の式:
CBAは細胞結合剤であり;
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)iCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
iは0〜15の整数であり;
n’は1〜500の整数であり;
n1’は1〜20の整数であり;
R401及びR402はそれぞれ独立してHまたは任意に置換されたアルキルであり;
JCB’は、
Arは任意に置換されたアリーレンまたは任意に置換されたヘテロアリーレンであり;
Cyは任意に置換されたシクロアルキンまたは任意に置換されたヘテロシクロアルキンの非アルキン残基であり;
R201、R202及びR203はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z3はピリジルまたは
Cy’は任意に置換されたひずんだシクロアルケンまたは任意に置換されたひずんだヘテロシクロアルケンの非アルケン残基であり;
R301はHまたは任意に置換されたアルキルであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z1は存在しないか、‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐CH2‐O‐、‐O‐CH2‐、‐(CH2CH2O)p‐または‐(OCH2CH2)p’‐であり、p及びp’は独立して1〜1000の整数であり;
JD’は、
wは1〜20の整数である
複合体またはその薬学的に許容できる塩。
[態様25]
JCB’が、
[態様26]
JD’が
[態様27]
Ra、Rb、Rc及びReがそれぞれHである態様1〜26のいずれか1項に記載の複合体。
[態様28]
[態様29]
Rh及びRh’がそれぞれ独立してHまたはメチルである態様1〜28のいずれか1項に記載の複合体。
[態様30]
Rh及びRh’がそれぞれHである態様29記載の複合体。
[態様31]
R1及びR2がそれぞれ独立してHまたは任意に置換されたアルキルであり;R3及びR4がそれぞれHであり;iが0〜10の整数である態様1〜30のいずれか1項に記載の複合体。
[態様32]
Yが‐CH2‐CH2‐である態様1〜30のいずれか1項に記載の複合体。
[態様33]
前記薬物部DMが以下の式:
[態様34]
前記細胞結合剤が抗体、単鎖抗体、標的細胞に特異的に結合する抗体断片、モノクローナル抗体、単鎖モノクローナル抗体、標的細胞に特異的に結合するモノクローナル抗体断片、キメラ抗体、標的細胞に特異的に結合するキメラ抗体断片、ドメイン抗体、標的細胞に特異的に結合するドメイン抗体断片、リンホカイン、ホルモン、ビタミン、増殖因子、コロニー刺激因子または栄養輸送分子である態様1〜33のいずれか1項に記載の複合体。
[態様35]
前記細胞結合剤がモノクローナル抗体、単鎖モノクローナル抗体または標的細胞に特異的に結合するモノクローナル抗体断片である態様34記載の複合体。
[態様36]
前記抗体が表面再形成抗体、表面再形成単鎖抗体または表面再形成抗体断片である態様34または35に記載の複合体。
[態様37]
前記抗体がヒト化抗体、ヒト化単鎖抗体またはヒト化抗体断片である態様34〜36のいずれか1項に記載の複合体。
[態様38]
前記細胞結合剤がミニボディ、二重特異性抗体(diabody)、三重特異性抗体、四重特異性抗体、ナノボディ、プロボディ、ドメインボディ、ユニボディ、二重特異性抗体(bispecific antibody)、アンキリン反復タンパク質(例えば、DARPin)、センチリンまたはAvibodyである態様1〜33のいずれか1項に記載の複合体。
[態様39]
以下の式:
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)iCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
iは0〜15の整数であり;
JCBは、マレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、Ra‐C(=O)‐、Ra‐C(=O)‐Ar‐、NH2‐NRe‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐Ar‐、NH2‐O‐、
Arは任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
X’はハロゲンであり;
R201、R202及びR203はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z3はピリジルまたは
R301はHまたは任意に置換されたアルキルであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z1は存在しないか、‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐CH2‐O‐、‐O‐CH2‐、‐(CH2CH2O)p‐または‐(OCH2CH2)p’‐であり、p及びp’は独立して1〜1000の整数であり;
JD’は、
A及びA’はそれぞれ独立して任意に置換されたアルキレン、任意に置換されたアルケニレン、任意に置換されたアルキニレン、任意に置換されたシクロアルキレン、任意に置換されたシクロアルケニレン、または任意に置換されたシクロアルキニレンであり;
Qは‐Z1‐P‐Z2‐であり;
Q’は‐Z1’‐P’‐Z2’‐であり;
Z1及びZ2の1個は‐C(=O)‐であり、他方は‐NRh‐であり;
Z1’及びZ2’の1個は‐C(=O)‐であり、他方は‐NRh’‐であり;
P及びP’はそれぞれ独立して存在しないか、任意に置換されたアルキレン、‐(CH2‐CH2‐O)j‐、‐(O‐CH2‐CH2)j‐または[XX]1−10であり、各XXは独立して選択されるアミノ酸残基であり;
jは1〜500の整数であり;
kは0または1であり;
Lは‐(CR5R6)v‐、‐(CR7R8)q‐N(Rg)‐(CR9R10)r‐、‐(CR7R8)q‐C(Ra)(Rg)‐(CR9R10)rまたは‐(CR11R12)s‐N(Rg)‐(CR13R14)t‐N(Rg’)‐(CR15R16)u‐であり;
Rg及びRg’はそれぞれ独立して‐(CR17R18)p‐Z‐Vであり;
pは1〜5の整数であり;
VはH、電荷をもつ置換基、またはイオン化できる基であり;
Zは存在しないか、‐C(=O)NRh‐アルキレン‐または‐NRh‐C(=O)‐アルキレン‐であり;
Rh及びRh’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
R5〜R18はそれぞれ独立してHまたは任意に置換されたアルキルであり;ならびに
q、r、s、t、u及びvはそれぞれ独立して0〜10の整数である
細胞毒性化合物またはその塩。
[態様40]
以下の式:
R19〜R22はそれぞれ独立してHまたは任意に置換されたアルキルであり;ならびに
m及びnはそれぞれ独立して0〜10である
前記細胞毒性化合物。
[態様41]
態様39または40に記載の細胞毒性化合物であって、前記イオン化できる基が‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12または‐Z’‐NR11R12であり、前記電荷をもつ基は‐N+R23R24R25X−または‐Z’‐N+R23R24R25X−であり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R23〜R25はそれぞれ独立して任意に置換されたアルキルであり;X−は陰イオンである前記細胞毒性化合物。
[態様42]
VがHもしくは‐CH2CH2SO3Hである態様39もしくは40に記載の細胞毒性化合物、またはその塩。
[態様43]
以下の式:
[態様44]
以下の式:
[態様45]
Lが‐(CR7R8)q‐N(Rg)‐(CR9R10)r‐または‐(CR11R12)s‐N(Rg)‐(CR13R14)t‐N(Rg’)‐(CR15R16)u‐である態様39〜42及び44のいずれか1項に記載の細胞毒性化合物。
[態様46]
[態様47]
R19、R20、R21及びR22がそれぞれHである態様40〜46のいずれか1項に記載の細胞毒性化合物。
[態様48]
R5及びR6がそれぞれHである態様39〜42及び44〜47のいずれか1項に記載の細胞毒性化合物。
[態様49]
P及びP’がそれぞれ独立して[XX]1−10である態様39〜48のいずれか1項に記載の細胞毒性化合物。
[態様50]
各XXが、天然アミノ酸、合成アミノ酸、アミノ酸類似体または天然アミノ酸と同様の方法で機能するアミノ酸擬似物より独立して選択されるアミノ酸の残基である態様39〜49のいずれか1項に記載の細胞毒性化合物。
[態様51]
各XXが、それぞれ独立してLまたはD異性体であるヒスチジン、アラニン、イソロイシン、アルギニン、ロイシン、アスパラギン、リジン、アスパラギン酸、メチオニン、システイン、フェニルアラニン、グルタミン酸、スレオニン、グルタミン、トリプトファン、グリシン、バリン、プロリン、セリン、チロシン、N‐メチル‐ヒスチジン、N‐メチル‐アラニン、N‐メチル‐イソロイシン、N‐メチル‐アルギニン、N‐メチル‐ロイシン、N‐メチル‐アスパラギン、N‐メチル‐リジン、N‐メチル‐アスパラギン酸、N‐メチル‐メチオニン、N‐メチル‐システイン、N‐メチル‐フェニルアラニン、N‐メチル‐グルタミン酸、N‐メチル‐スレオニン、N‐メチル‐グルタミン、N‐メチル‐トリプトファン、N‐メチル‐グリシン、N‐メチル‐バリン、N‐メチル‐プロリン、N‐メチル‐セリン、N‐メチル‐チロシン、ヒドロキシプロリン、γ‐カルボキシグルタミン酸、セリノシステイン(selinocysteine)、O‐リン酸化セリン、ホモセリン、ノルロイシン、メチオニンスルホキシド、メチオニンメチルスルホニウム、シトルリン、オルニチン、システインスルホン酸、システインスルフィン酸、3‐アミノアラニン、3‐ジメチルアミノアラニン、2‐アミノ‐4‐(ジメチルアミノ)ブタン酸、2,4‐ジアミノブタン酸、2‐アミノ‐6‐(ジメチルアミノ)ヘキサン酸、2‐アミノ‐5‐(ジメチルアミノ)ペンタン酸及びβ‐アラニンから成る群より独立して選択されるアミノ酸の残基である態様50記載の細胞毒性化合物。
[態様52]
各XXが、独立して選択されるグリシンまたはアラニンの残基である態様51記載の細胞毒性化合物。
[態様53]
P及びP’がそれぞれ、プロテアーゼによって切断可能なペプチドである態様39〜52のいずれか1項に記載の細胞毒性化合物。
[態様54]
P及びP’がそれぞれ、腫瘍組織において発現するプロテアーゼによって切断可能なペプチドである態様53記載の細胞毒性化合物。
[態様55]
P及びP’がそれぞれ、リソソームプロテアーゼによって切断可能なペプチドである態様53記載の細胞毒性化合物。
[態様56]
P及びP’がそれぞれ、Val−Cit、Val−Lys、Phe−Lys、Lys−Lys、Ala−Lys、Phe−Cit、Leu−Cit、Lle−Cit、Trp、Cit、Phe−Ala、Phe−N9−トシル−Arg、Phe−N9−ニトロ−Arg、Phe−Phe−Lys、D−Phe−Phe−Lys、Gly−Phe−Lys、Leu−Ala−Leu、Ile−Ala−Leu、Val−Ala−Val、Ala−Leu−Ala−Leu、β−Ala−Leu−Ala−Leu、Gly−Phe−Leu−Gly、Val−Arg、Arg−Val、Arg−Arg、Val−D−Cit、Val−D−Lys、Val−D−Arg、D−Val−Cit、D−Val−Lys、D−Val−Arg、D−Val−D−Cit、D−Val−D−Lys、D−Val−D−Arg、D−Arg−D−Arg、Ala−Ala、Ala−D−Ala、D−Ala−Ala及びD−Ala−D−Ala、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Ala−D−Ala、Ala−Val−Cit、Ala−Val−Alaならびにβ−Ala−Gly−Gly−Glyから成る群より選択される態様39〜55のいずれか1項に記載の細胞毒性化合物。
[態様57]
P及びP’がそれぞれ、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Val−Alaまたはβ−Ala−Gly−Gly−Glyである態様39〜56のいずれか1項に記載の細胞毒性化合物。
[態様58]
以下の式:
[態様59]
R7〜R10がそれぞれHである態様39〜42、44、45及び47〜58のいずれか1項に記載の細胞毒性化合物。
[態様60]
以下の式:
[態様61]
R11〜R16がそれぞれHである態様39〜42、44、45、47〜57及び60のいずれか1項に記載の細胞毒性化合物。
[態様62]
以下の式:
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)iCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
iは0〜15の整数であり;
n’は1〜500の整数であり;
nl’は1〜20の整数であり;
R401及びR402はそれぞれHまたは任意に置換されたアルキルであり;
JCBは、マレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、Ra‐C(=O)‐、Ra‐C(=O)‐Ar‐、NH2‐NRe‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐Ar‐、NH2‐O‐、
Arは任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
X’はハロゲンであり;
R201、R202及びR203はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z3はピリジルまたは
R301はHまたは任意に置換されたアルキルであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z1は存在しないか、‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐CH2‐O‐、‐O‐CH2‐、‐(CH2CH2O)p‐または‐(OCH2CH2)p’‐であり、p及びp’は独立して1〜1000の整数であり;ならびに
JD’は、
細胞毒性化合物またはその塩。
[態様63]
JCBが、マレイミド、Ra‐C(=O)‐、Ra‐C(=O)‐フェニレン‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐フェニレン‐、NH2‐O‐、‐N3、‐C≡CH、
[態様64]
JD’が、
[態様65]
Ra、Rb、Rc及びReがそれぞれHである態様39〜64のいずれか1項に記載の細胞毒性化合物。
[態様66]
[態様67]
Rh及びRh’がそれぞれ独立してHまたはメチルである態様39〜66のいずれか1項に記載の細胞毒性化合物。
[態様68]
Rh及びRh’がそれぞれHである態様67記載の細胞毒性化合物。
[態様69]
R1及びR2がそれぞれ独立してHまたは任意に置換されたアルキルであり;R3及びR4がそれぞれHであり;iが0〜10の整数である態様39〜68のいずれか1項に記載の細胞毒性化合物。
[態様70]
Yが‐CH2‐CH2‐である態様39〜68のいずれか1項に記載の細胞毒性化合物。
[態様71]
前記薬物部DMが以下の式:
[態様72]
以下の式:
JCBは、マレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、Ra‐C(=O)‐、Ra‐C(=O)‐Ar‐、NH2‐NRe‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐Ar‐、NH2‐O‐、
Arは任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
X’はハロゲンであり;
R201、R202及びR203はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z3はピリジルまたは
R301はHまたは任意に置換されたアルキルであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z1は存在しないか、‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐CH2‐O‐、‐O‐CH2‐、‐(CH2CH2O)p‐または‐(OCH2CH2)p’‐であり、p及びp’は独立して1〜1000の整数であり;ならびに
JDはマレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、
A及びA’はそれぞれ独立して任意に置換されたアルキレン、任意に置換されたアルケニレン、任意に置換されたアルキニレン、任意に置換されたシクロアルキレン、任意に置換されたシクロアルケニレン、または任意に置換されたシクロアルキニレンであり;
Qは‐Z1‐P‐Z2‐であり;
Q’は‐Z1’‐P’‐Z2’‐であり;
Z1及びZ2の1個は‐C(=O)‐であり、他方は‐NRh‐であり;
Z1’及びZ2’の1個は‐C(=O)‐であり、他方は‐NRh’‐であり;
P及びP’はそれぞれ独立して存在しないか、任意に置換されたアルキレン、‐(CH2‐CH2‐O)j‐、‐(O‐CH2‐CH2)j‐または[XX]1−10であり、各XXは独立して選択されるアミノ酸残基であり;
jは1〜500の整数であり;
kは0または1であり;
Lは‐(CR5R6)v‐、‐(CR7R8)q‐N(Rg)‐(CR9R10)r‐、‐(CR7R8)q‐C(Ra)(Rg)‐(CR9R10)rまたは‐(CR11R12)s‐N(Rg)‐(CR13R14)t‐N(Rg’)‐(CR15R16)u‐であり;
Rg及びRg’はそれぞれ独立して‐(CR17R18)p‐Z‐Vであり;
pは1〜5の整数であり;
VはH、電荷をもつ置換基、またはイオン化できる基であり;
Zは存在しないか、‐C(=O)NRh‐アルキレン‐または‐NRh‐C(=O)‐アルキレン‐であり;
Rh及びRh’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
R5〜R18はそれぞれ独立してHまたは任意に置換されたアルキルであり;ならびに
q、r、s、t、u及びvはそれぞれ独立して0〜10の整数である
リンカー化合物またはその塩。
[態様73]
以下の式:
R19〜R22はそれぞれ独立してHまたは任意に置換されたアルキルであり;ならびに
m及びnはそれぞれ独立して0〜10である
前記リンカー化合物。
[態様74]
態様72または73に記載のリンカー化合物であって、前記イオン化できる基が‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12または‐Z’‐NR11R12であり、前記電荷をもつ基は‐N+R23R24R25X−または‐Z’‐N+R23R24R25X−であり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R23〜R25はそれぞれ独立して任意に置換されたアルキルであり;X−は陰イオンである前記リンカー化合物。
[態様75]
VがHもしくは‐CH2CH2SO3Hである態様72もしくは73に記載のリンカー化合物、またはその塩。
[態様76]
以下の式:
[態様77]
以下の式:
[態様78]
Lが‐(CR7R8)q‐N(Rg)‐(CR9R10)r‐または‐(CR11R12)s‐N(Rg)‐(CR13R14)t‐N(Rg’)‐(CR15R16)u‐である態様72〜75及び77のいずれか1項に記載のリンカー化合物。
[態様79]
[態様80]
R19、R20、R21及びR22がそれぞれHである態様73〜79のいずれか1項に記載のリンカー化合物。
[態様81]
R5及びR6がそれぞれHである態様72〜75及び77〜79のいずれか1項に記載のリンカー化合物。
[態様82]
P及びP’がそれぞれ独立して[XX]1−10である態様72〜81のいずれか1項に記載のリンカー化合物。
[態様83]
各XXが、天然アミノ酸、合成アミノ酸、アミノ酸類似体または天然アミノ酸と同様の方法で機能するアミノ酸擬似物より独立して選択されるアミノ酸の残基である態様72〜82のいずれか1項に記載のリンカー化合物。
[態様84]
各XXが、それぞれ独立してLまたはD異性体であるヒスチジン、アラニン、イソロイシン、アルギニン、ロイシン、アスパラギン、リジン、アスパラギン酸、メチオニン、システイン、フェニルアラニン、グルタミン酸、スレオニン、グルタミン、トリプトファン、グリシン、バリン、プロリン、セリン、チロシン、N‐メチル‐ヒスチジン、N‐メチル‐アラニン、N‐メチル‐イソロイシン、N‐メチル‐アルギニン、N‐メチル‐ロイシン、N‐メチル‐アスパラギン、N‐メチル‐リジン、N‐メチル‐アスパラギン酸、N‐メチル‐メチオニン、N‐メチル‐システイン、N‐メチル‐フェニルアラニン、N‐メチル‐グルタミン酸、N‐メチル‐スレオニン、N‐メチル‐グルタミン、N‐メチル‐トリプトファン、N‐メチル‐グリシン、N‐メチル‐バリン、N‐メチル‐プロリン、N‐メチル‐セリン、N‐メチル‐チロシン、ヒドロキシプロリン、γ‐カルボキシグルタミン酸、セリノシステイン(selinocysteine)、O‐リン酸化セリン、ホモセリン、ノルロイシン、メチオニンスルホキシド、メチオニンメチルスルホニウム、シトルリン、オルニチン、システインスルホン酸、システインスルフィン酸、3‐アミノアラニン、3‐ジメチルアミノアラニン、2‐アミノ‐4‐(ジメチルアミノ)ブタン酸、2,4‐ジアミノブタン酸、2‐アミノ‐6‐(ジメチルアミノ)ヘキサン酸、2‐アミノ‐5‐(ジメチルアミノ)ペンタン酸及びβ‐アラニンから成る群より独立して選択されるアミノ酸の残基である態様83記載のリンカー化合物。
[態様85]
各XXが、独立して選択されるグリシンまたはアラニンの残基である態様84記載のリンカー化合物。
[態様86]
P及びP’がそれぞれ、プロテアーゼによって切断可能なペプチドである態様72〜85のいずれか1項に記載のリンカー化合物。
[態様87]
P及びP’がそれぞれ、腫瘍組織において発現するプロテアーゼによって切断可能なペプチドである態様86記載のリンカー化合物。
[態様88]
P及びP’がそれぞれ、リソソームプロテアーゼによって切断可能なペプチドである態様86記載のリンカー化合物。
[態様89]
P及びP’がそれぞれ、Val−Cit、Val−Lys、Phe−Lys、Lys−Lys、Ala−Lys、Phe−Cit、Leu−Cit、Lle−Cit、Trp、Cit、Phe−Ala、Phe−N9−トシル−Arg、Phe−N9−ニトロ−Arg、Phe−Phe−Lys、D−Phe−Phe−Lys、Gly−Phe−Lys、Leu−Ala−Leu、Ile−Ala−Leu、Val−Ala−Val、Ala−Leu−Ala−Leu、β−Ala−Leu−Ala−Leu、Gly−Phe−Leu−Gly、Val−Arg、Arg−Val、Arg−Arg、Val−D−Cit、Val−D−Lys、Val−D−Arg、D−Val−Cit、D−Val−Lys、D−Val−Arg、D−Val−D−Cit、D−Val−D−Lys、D−Val−D−Arg、D−Arg−D−Arg、Ala−Ala、Ala−D−Ala、D−Ala−Ala及びD−Ala−D−Ala、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Ala−D−Ala、Ala−Val−Cit、Ala−Val−Alaならびにβ−Ala−Gly−Gly−Glyから成る群より選択される態様72〜88のいずれか1項に記載のリンカー化合物。
[態様90]
P及びP’がそれぞれ、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Val−Alaまたはβ−Ala−Gly−Gly−Glyである態様72〜89のいずれか1項に記載のリンカー化合物。
[態様91]
以下の式:
[態様92]
R7〜R10がそれぞれHである態様72〜75、77、78及び80〜91のいずれか1項に記載のリンカー化合物。
[態様93]
以下の式:
[態様94]
R11〜R16がそれぞれHである態様72〜75、77、78、80〜90及び93のいずれか1項に記載のリンカー化合物。
[態様95]
以下の式:
n’は1〜500の整数であり;
nl’は1〜20の整数であり;
R401及びR402はそれぞれHまたは任意に置換されたアルキルであり;
JCBは、マレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、Ra‐C(=O)‐、Ra‐C(=O)‐Ar‐、NH2‐NRe‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐Ar‐、NH2‐O‐、
Arは任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
X’はハロゲンであり;
R201、R202及びR203はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z3はピリジルまたは
R301はHまたは任意に置換されたアルキルであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Z1は存在しないか、‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐CH2‐O‐、‐O‐CH2‐、‐(CH2CH2O)p‐または‐(OCH2CH2)p’‐であり、p及びp’は独立して1〜1000の整数であり;ならびに
JDはマレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、
リンカー化合物またはその塩。
[態様96]
JCBがマレイミド、Ra‐C(=O)‐、Ra‐C(=O)‐フェニレン‐、NH2‐NRe‐C(=O)‐またはNH2‐NRe‐フェニレン‐である態様72〜95のいずれか1項に記載のリンカー化合物。
[態様97]
JDがマレイミドである態様72〜96のいずれか1項に記載のリンカー化合物。
[態様98]
Ra、Rb、Rc及びReがそれぞれHである態様72〜97のいずれか1項に記載のリンカー化合物。
[態様99]
[態様100]
Rh及びRh’がそれぞれ独立してHまたはメチルである態様72〜99のいずれか1項に記載のリンカー化合物。
[態様101]
Rh及びRh’がそれぞれHである態様100記載のリンカー化合物。
[態様102]
態様1〜38のいずれか1項に記載の複合体または態様39〜71のいずれか1項に記載の化合物;及び薬学的に許容できる担体を含む医薬組成物。
[態様103]
異常細胞増殖の阻害方法または哺乳動物における増殖性障害、自己免疫性障害、破壊性骨障害、感染症、ウイルス性疾患、線維性疾患、神経変性障害、膵炎または腎疾患の治療方法であって、該方法が、態様1〜38のいずれか1項に記載の複合体、態様39〜71のいずれか1項に記載の化合物、または態様102記載の組成物;及び任意に第2治療薬の治療有効量を、前記哺乳動物に投与することを含む方法。
[態様104]
前記第2治療薬を前記哺乳動物に、順次にまたは連続して投与する態様103記載の方法。
[態様105]
前記方法が、がん、関節リウマチ、多発性硬化症、移植片対宿主疾患、移植片拒絶、狼瘡、筋炎、感染症及び免疫不全から成る群より選択される状態の治療方法である態様103または104記載の方法。
[態様106]
前記状態ががんである態様105記載の方法。
[態様107]
前記がんが乳癌、結腸癌、脳癌、前立腺癌、腎臓癌、膵癌、卵巣癌、頭部及び頸部癌、メラノーマ、結腸直腸癌、胃癌、扁平上皮癌、小細胞肺癌、非小細胞肺癌、精巣癌、メルケル細胞癌、神経膠芽腫、神経芽細胞腫、リンパ器官癌、ならびに造血器腫瘍から成る群より選択される態様106記載の方法。
Claims (24)
- 以下の式:
CBAは細胞結合剤であり;
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)iCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
iは0〜15の整数であり;
JCB’は、
J D’は、
Pは[XX] 1−10 であり、各XXは独立して選択されるアミノ酸残基であり;
R h はHまたは任意に置換されたアルキルであり;
R 19 〜R 22 はそれぞれ独立してHまたは任意に置換されたアルキルであり;
m及びnはそれぞれ独立して0〜10であり;ならびに
wは1〜20の整数である
複合体またはその薬学的に許容できる塩。 - R 19 、R 20 、R 21 及びR 22 がそれぞれHである請求項1に記載の複合体。
- Pが、プロテアーゼによって切断可能なペプチドである請求項1または2に記載の複合体。
- Pが、腫瘍組織において発現するプロテアーゼによって切断可能なペプチドである請求項1または2に記載の複合体。
- Pが、リソソームプロテアーゼによって切断可能なペプチドである請求項1または2に記載の複合体。
- Pが、Val−Cit、Val−Lys、Phe−Lys、Lys−Lys、Ala−Lys、Phe−Cit、Leu−Cit、Lle−Cit、Trp、Cit、Phe−Ala、Phe−N 9 −トシル−Arg、Phe−N 9 −ニトロ−Arg、Phe−Phe−Lys、D−Phe−Phe−Lys、Gly−Phe−Lys、Leu−Ala−Leu、Ile−Ala−Leu、Val−Ala−Val、Ala−Leu−Ala−Leu、β−Ala−Leu−Ala−Leu、Gly−Phe−Leu−Gly、Val−Arg、Arg−Val、Arg−Arg、Val−D−Cit、Val−D−Lys、Val−D−Arg、D−Val−Cit、D−Val−Lys、D−Val−Arg、D−Val−D−Cit、D−Val−D−Lys、D−Val−D−Arg、D−Arg−D−Arg、Ala−Ala、Ala−D−Ala、D−Ala−Ala及びD−Ala−D−Ala、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Ala−D−Ala、Ala−Val−Cit、Ala−Val−Alaならびにβ−Ala−Gly−Gly−Glyから成る群より選択される請求項1または2に記載の複合体。
- Pが、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Val−Alaまたはβ−Ala−Gly−Gly−Glyである請求項6に記載の複合体。
- 以下の式:
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)iCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
iは0〜15の整数であり;
JCBは、マレイミドであり、
J D’は、
Pは[XX] 1−10 であり、各XXは独立して選択されるアミノ酸残基であり;
R h はHまたは任意に置換されたアルキルであり;
R 19 〜R 22 はそれぞれ独立してHまたは任意に置換されたアルキルであり;ならびに
m及びnはそれぞれ独立して0〜10である
細胞毒性化合物またはその塩。 - R 19 、R 20 、R 21 及びR 22 がそれぞれHである請求項8に記載の細胞毒性化合物。
- Pが、プロテアーゼによって切断可能なペプチドである請求項8または9に記載の細胞毒性化合物。
- Pが、腫瘍組織において発現するプロテアーゼによって切断可能なペプチドである請求項8または9に記載の細胞毒性化合物。
- Pが、リソソームプロテアーゼによって切断可能なペプチドである請求項8または9に記載の細胞毒性化合物。
- Pが、Val−Cit、Val−Lys、Phe−Lys、Lys−Lys、Ala−Lys、Phe−Cit、Leu−Cit、Lle−Cit、Trp、Cit、Phe−Ala、Phe−N 9 −トシル−Arg、Phe−N 9 −ニトロ−Arg、Phe−Phe−Lys、D−Phe−Phe−Lys、Gly−Phe−Lys、Leu−Ala−Leu、Ile−Ala−Leu、Val−Ala−Val、Ala−Leu−Ala−Leu、β−Ala−Leu−Ala−Leu、Gly−Phe−Leu−Gly、Val−Arg、Arg−Val、Arg−Arg、Val−D−Cit、Val−D−Lys、Val−D−Arg、D−Val−Cit、D−Val−Lys、D−Val−Arg、D−Val−D−Cit、D−Val−D−Lys、D−Val−D−Arg、D−Arg−D−Arg、Ala−Ala、Ala−D−Ala、D−Ala−Ala及びD−Ala−D−Ala、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Ala−D−Ala、Ala−Val−Cit、Ala−Val−Alaならびにβ−Ala−Gly−Gly−Glyから成る群より選択される請求項8または9に記載の細胞毒性化合物。
- Pが、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Val−Alaまたはβ−Ala−Gly−Gly−Glyである請求項13に記載の細胞毒性化合物。
- R19、R20、R21及びR22がそれぞれHである請求項15に記載のリンカー化合物。
- Pが、プロテアーゼによって切断可能なペプチドである請求項15または16に記載のリンカー化合物。
- Pが、腫瘍組織において発現するプロテアーゼによって切断可能なペプチドである請求項17記載のリンカー化合物。
- Pが、リソソームプロテアーゼによって切断可能なペプチドである請求項17記載のリンカー化合物。
- Pが、Val−Cit、Val−Lys、Phe−Lys、Lys−Lys、Ala−Lys、Phe−Cit、Leu−Cit、Lle−Cit、Trp、Cit、Phe−Ala、Phe−N9−トシル−Arg、Phe−N9−ニトロ−Arg、Phe−Phe−Lys、D−Phe−Phe−Lys、Gly−Phe−Lys、Leu−Ala−Leu、Ile−Ala−Leu、Val−Ala−Val、Ala−Leu−Ala−Leu、β−Ala−Leu−Ala−Leu、Gly−Phe−Leu−Gly、Val−Arg、Arg−Val、Arg−Arg、Val−D−Cit、Val−D−Lys、Val−D−Arg、D−Val−Cit、D−Val−Lys、D−Val−Arg、D−Val−D−Cit、D−Val−D−Lys、D−Val−D−Arg、D−Arg−D−Arg、Ala−Ala、Ala−D−Ala、D−Ala−Ala及びD−Ala−D−Ala、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Ala−D−Ala、Ala−Val−Cit、Ala−Val−Alaならびにβ−Ala−Gly−Gly−Glyから成る群より選択される請求項15または16に記載のリンカー化合物。
- Pが、Gly−Gly−Gly、Ala−Ala−Ala、D−Ala−Ala−Ala、Ala−D−Ala−Ala、Ala−Val−Alaまたはβ−Ala−Gly−Gly−Glyである請求項15または16に記載のリンカー化合物。
- 請求項1〜7のいずれか1項に記載の複合体または請求項8〜14のいずれか1項に記載の化合物;及び薬学的に許容できる担体を含む医薬組成物。
- 哺乳動物におけるがんを治療するための医薬組成物であって、請求項1〜7のいずれか1項に記載の複合体、請求項8〜14のいずれか1項に記載の化合物、または請求項23に記載の組成物;及び任意に第2治療薬;の治療有効量を含む、前記医薬組成物。
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2014
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- 2014-02-28 US US14/763,612 patent/US9901647B2/en active Active
- 2014-02-28 JP JP2015560361A patent/JP6423804B2/ja active Active
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US20150359904A1 (en) | 2015-12-17 |
US9901647B2 (en) | 2018-02-27 |
EP2961435B1 (en) | 2019-05-01 |
HK1219423A1 (zh) | 2017-04-07 |
WO2014134486A3 (en) | 2015-03-26 |
WO2014134486A2 (en) | 2014-09-04 |
EP2961435A2 (en) | 2016-01-06 |
JP2016510730A (ja) | 2016-04-11 |
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