JP6714664B2 - ペプチドエポキシケトンを用いた併用療法 - Google Patents
ペプチドエポキシケトンを用いた併用療法 Download PDFInfo
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- JP6714664B2 JP6714664B2 JP2018181939A JP2018181939A JP6714664B2 JP 6714664 B2 JP6714664 B2 JP 6714664B2 JP 2018181939 A JP2018181939 A JP 2018181939A JP 2018181939 A JP2018181939 A JP 2018181939A JP 6714664 B2 JP6714664 B2 JP 6714664B2
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- 210000003905 vulva Anatomy 0.000 description 1
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- 230000003442 weekly effect Effects 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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Description
本出願は、引用をもってその教示全体をここに援用することとする、2008年10月21日に提出された米国仮特許出願第61/196,945号に基づく優先権を主張するものである。
真核生物においてタンパク質分解は主にユビキチン経路を通じて媒介されるが、該経路では、分解の標的となるタンパク質は76個のアミノ酸から成るポリペプチドであるユビキチンに連結される。標的化されたユビキチン化タンパク質はその後、タンパク質をその三つの主要なタンパク質分解活性の作用によりより短いペプチドに切断する多重触媒性プロテアーゼである26Sプロテアソームの基質として働く。プロテアソーム媒介型の分解はまた、細胞内タンパク質のターンオーバーにおいて一般的な機能を有する一方で、主要組織適合複合体 (MHC) クラスI提示、アポトーシス、細胞***、及びNF-κB活性化など、数多くのプロセスでも鍵となる役割を果たす。
本発明の局面の一つは、ペプチドエポキシケトン又はその薬学的に許容可能な塩を一種以上の他の治療薬と一緒に投与し、その併用が、いずれかの作用薬を単独で投与した場合の効験よりも高い効験(例えば相乗的又は付加的な抗腫瘍効果など)を示すような併用療法に関する。このような併用処置は、当該処置の個々の成分の同時、逐次、又は別々の投薬により行われてよい。
いくつかの実施態様では、ペプチドエポキシケトンが1乃至7群のいずれかひとつの化合物から選択される。以下の群のそれぞれにおいて、多様な部分の数値(例えばR1など)は群内で統一されていると考えられるが、ある群(例えば第1群)にとっての数値が別の群にもあてはまることはない。
ある実施例では、当本ペプチドエポキシケトンは式(1)又はその薬学的に許容可能な塩の構造を有し、
いくつかの実施態様では、当該のペプチドエポキシケトンは式(2)又はその薬学的に許容可能な塩の構造を有し;
Aは選択的に、Zの位置に隣接する場合には共有結合であり;
L は存在しないか、あるいはC=O、C=S、及びSO2から選択され、好ましくはL は存在しないか又はC=Oであり;
M は存在しないか、あるいはC1-12アルキルであり、好ましくはC1-8アルキルであり;
Q は存在しないか、あるいはO、NH、及びN-C1-6アルキルから選択され、好ましくはQ は存在しないか、O又はNHであり、最も好ましくはQは存在しないか又はOであり;
X はOであり;
Y は存在しないか、又はO、NH、N-C1-6アルキル、S、SO、SO2、CHOR10、及びCHCO2R10から選択され;
各ZはO、S、NH、及びN-C1-6アルキルから個別に選択され、好ましくはOであり;あるいはZは選択的に、Aの位置に隣接する場合には共有結合であり;
R1、R2、R3、及びR4 はそれぞれ個別に、選択的に置換されたC1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、一つ以上のアミド、アミン、カルボン酸(又はその塩)、エステル(C1-5アルキルエステル及びアリールエステルを含む)、チオール、又はチオエーテル置換基が含まれてもよく;
R5 はN(R6)LQR7であり;
R6、R12、R13及びR14 は個別に 水素、OH、C1-6アルキル、及び式(3)の基から選択され;好ましくは、R6 は水素、OH、及びC1-6アルキルから選択され、そしてR12、R13、及びR14は個別に水素及びC1-6アルキルから選択され、好ましくは水素であり;
R6 及びR7 は共にC1-6アルキル-Y-C1-6アルキル、C1-6アルキル-ZAZ-C1-6アルキル、ZAZ-C1-6アルキル-ZAZ-C1-6アルキル、ZAZ-C1-6アルキル-ZAZ、又はC1-6アルキル-Aであることで一個の環を形成し;好ましくはC1-2アルキル-Y-C1-2アルキル、C1-2アルキル-ZA-C1-2アルキル、A-C1-2アルキル-ZA-C1-2アルキル、A-C1-3アルキル-A、又はC1-4アルキル-Aであり、但しこの場合、Z及びAはそれぞれ存在する箇所において個別に共有結合以外であり;
R8 及びR9 は個別に水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され、好ましくは水素、金属陽イオン、及びC1-6アルキルから選択され、あるいはR8 及びR9 は共にC1-6アルキルであることで一個の環を形成し;
各々のR10 は個別に水素及びC1-6アルキルから選択され、好ましくはC1-6アルキルであり;
R11 は個別に水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され;
R15 及びR16 は個別に水素及びC1-6アルキルから選択され、あるいはR15及びR16 は共に3-乃至6-員環の炭素環又は複素環の環を形成し;そして
R17 及びR18 は個別に水素、金属陽イオン、C1-6アルキル、及びC1-6アラルキルから選択され、あるいはR17 及びR18 は共にC1-6アルキルを表すことで一個の環を形成し;
但し条件として、R6、R12、R13、及びR14 がH 又はCH3であり、Q が存在しない場合、LR7 は水素、非置換C1-6アルキルC=O、アミノ酸の更なる鎖、t-ブトキシカルボニル (Boc)、ベンゾイル (Bz)、フルオレン-9-イルメトキシカルボニル (Fmoc)、トリフェニルメチル(トリチル)、ベンジルオキシカルボニル (Cbz)、トリクロロエトキシカルボニル (Troc);又は置換もしくは非置換アリールもしくはヘテロアリールではなく;そして
配列ZAZが存在する箇所では必ず、該配列の少なくとも一つのメンバーは共有結合以外でなくてはならない。
Aは、Zの存在する箇所に隣接する場合には選択的に共有結合であり;
Lは存在しないか、又はC=O、C=S、及びSO2から選択され、好ましくはLは存在しないか、又はC=Oであり;
Mは存在しないか、又はC1-12アルキルであり、好ましくはC1-8アルキルであり;
Qは存在しないか、又はO、NH、及びN-C1-6アルキルから選択され、好ましくはQは存在しないか、O、又はNHであり、最も好ましくはQは存在しないか、又はOであり;
XはOであり;
Yは存在しないか、又はO、NH、N-C1-6アルキル、S、SO、SO2、CHOR10、及びCHCO2R10から選択され;
各Zは個別にO、S、NH、及びN-C1-6アルキルから選択され、好ましくは Oであり;あるいは
Z は、Aの存在する箇所に隣接する場合には選択的に共有結合であり;
R2 及び R4 はそれぞれ個別に置換C1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及び C1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、一つ以上のアミド、アミン、カルボン酸 (又はその塩)、エステル(C1-5アルキルエステル及びアリールエステルを含む)、チオール、又はチオエーテル置換基が含まれてもよく;
R5 はN(R6)LQR7であり;
R6 は水素、OH、及び C1-6アルキルから選択され、好ましくは C1-6アルキルであり;
R7 は水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、C1-6アラルキル、ヘテロアリール、C1-6ヘテロアラルキル、R8ZAZ-C1-8アルキル-、R11Z-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、R8ZAZ-C1-8アルキル-ZAZ-C1-8アルキル-、ヘテロシクリルMZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-、(R10)2N-C1-12アルキル-、(R10)3N+-C1-12アルキル-、ヘテロシクリルM-、カルボシクリルM-、R11SO2C1-8アルキル-、及び R11SO2NHから選択され; 好ましくは C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、C1-6アラルキル、ヘテロアリール、C1-6ヘテロアラルキル、R8ZA-C1-8アルキル-、R11Z-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-Z-C1-8アルキル-、R8ZA-C1-8アルキル-ZAZ-C1-8アルキル-、ヘテロシクリルMZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-、(R10)2N-C1-8アルキル-、(R10)3N+-C1-8アルキル-、ヘテロシクリルM-、カルボシクリルM-、R11SO2C1-8アルキル-、及び R11SO2NHであり、但しこの場合、Z 及び Aはそれぞれ存在する箇所において個別に共有結合以外であり;あるいは
R6 及び R7は共にC1-6アルキル-Y-C1-6アルキル、C1-6アルキル-ZAZ-C1-6アルキル、ZAZ-C1-6アルキル-ZAZ-C1-6アルキル、ZAZ-C1-6アルキル-ZAZ、又はC1-6アルキル-Aであることで一個の環を形成し;好ましくは C1-2アルキル-Y-C1-2アルキル、C1-2アルキル-ZA-C1-2アルキル、A-C1-2アルキル-ZA-C1-2アルキル、A-C1-3アルキル-A、又はC1-4アルキル-Aであり、但しこの場合、Z及びAはそれぞれ存在する箇所において個別に共有結合以外であり;
R8及びR9 は水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから、好ましくは水素、金属陽イオン、及び C1-6アルキルから、個別に選択され、あるいはR8及びR9 は共にC1-6アルキルであることで一個の環を形成し;
各R10 は個別に水素及び C1-6アルキルから選択され、好ましくはC1-6アルキルであり;そして
R11 は個別に水素、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから選択され、
但し条件としてR6 がH又はCH3 であり、そしてQが存在しない場合、LR7 は水素、非置換C1-6アルキルC=O、アミノ酸の更なる鎖、t-ブトキシカルボニル (Boc)、ベンゾイル (Bz)、フルオレン-9-イルメトキシカルボニル(Fmoc)、トリフェニルメチル(トリチル)、ベンジルオキシカルボニル(Cbz)、トリクロロエトキシカルボニル (Troc);あるいは置換もしくは非置換アリールもしくはヘテロアリールではなく;そして
配列ZAZが存在する箇所では必ず、該配列の少なくとも一つのメンバーは共有結合でなくてはならない。
いくつかの実施態様では、本ペプチドエポキシケトンは式(5)又はその薬学的に許容可能な塩の構造を有し:
R1、R2、R3、及びR4 は、個別に、水素及び式(6)の基から選択され、但し条件としてR1、R2、R3、及びR4 のうちの少なくとも一つは式(6)の基であり;
R9 は、アミノ酸の更なる鎖、水素、C1-6アシル、保護基、アリール、又はヘテロアリールであり、但しこの場合の置換基にはハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、及びC1-5アルキルが含まれてよく;
R10 及びR11 は、個別に、水素及びC1-6アルキルから選択され、あるいはR10及びR11 は共に3- 乃至6-員環の炭素環又は複素環の環を形成し;
R12 及びR13 は、個別に、水素、金属陽イオン、C1-6アルキル、及びC1-6アラルキルから選択され、あるいはR12 及びR13 は共にC1-6アルキルを表すことで一個の環を形成し;そして
Lは存在しないか、あるいは-CO2 又は-C(=S)Oから選択される。
R1、R2、R3、及びR4 は、個別に、水素 及び式(6)の基から選択され、但し条件としてR1、R2、R3、及びR4 のうちの少なくとも一つは式(6)の基であり;
R6 及びR8 は、個別に、選択的に置換されたC1-6アルキル、C1-6ヒドロキシ アルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、アミド、アミン、カルボン酸 又はその薬学的に許容可能な塩、カルボキシルエステル、チオール、及びチオエーテルが含まれてよく;
R9 はアミノ酸の更なる鎖、水素、アシル、保護基、アリール、又はヘテロアリールであり、但しこの場合の置換基には、ハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、及びC1-5アルキルが含まれてよい。ペプチド合成業で公知の適したN-保護基にはt-ブトキシ カルボニル (Boc)、ベンゾイル (Bz)、フルオレン-9-イルメトキシカルボニル (Fmoc)、トリフェニルメチル (トリチル) 及びトリクロロエトキシカルボニル (Troc) 等があり;そして。
いくつかの実施態様では、本ペプチドエポキシケトンは式(8)又はその薬学的に許容可能な塩の構造を有し;
各Bは、個別に、C=O、C=S、及びSO2から選択され、好ましくは C=Oであり;
Dは存在しないか、又はC1-8アルキルであり;
GはO、NH、及び N-C1-6アルキルから選択され;
Kは存在しないか、あるいはC=O、C=S、及び SO2から選択され、好ましくは Kは存在しないか、あるいはC=Oであり;
L は存在しないか、又はC=O、C=S、及び SO2、から選択され、好ましくは L は存在しないか、又はC=Oであり;
M は存在しないか、又は C1-8アルキルであり;
Q は存在しないか、又はO、NH、及びN-C1-6アルキルから選択され、好ましくは Q は存在しないか、O又はNHであり、最も好ましくはQ は存在せず;
X はOであり;
各V は個別に存在しないか、又はO、S、NH、及びN-C1-6アルキルから選択され、好ましくはVは存在しないか、又はOであり;
W は存在しないか、又は、個別に、O、S、NH、及び N-C1-6アルキルから選択され、好ましくはOであり;
Y は存在しないか、又はO、NH、N-C1-6アルキル、S、SO、SO2、CHOR10、及び CHCO2R10から選択され;
各Zは個別にO、S、NH、及び N-C1-6アルキルから選択され、好ましくはOであり;
R1、R2、R3、及び R4 は、それぞれ個別に、C1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、C1-6アラルキル、及び R14DVKOC1-3アルキル-から選択され、但しこの場合、R1 及び R3 の少なくとも一方はR14DVKOC1-3アルキル-であり;
R5 はN(R6)LQR7であり;
R6 は水素、OH、及び C1-6アルキルから選択され、好ましくは C1-6アルキルであり;
R7 はアミノ酸の更なる鎖、水素、保護基、アリール、又はヘテロアリールであり、この場合それらのいずれも選択的ハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、C1-5アルキルで置換され;あるいはR7はC1-6アルキル、C1-6アルケニル、C1-6アルキニル、C1-6アラルキル、C1-6ヘテロアラルキル、R8ZA-C1-8アルキル-、R11Z-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-Z-C1-8アルキル-、R8ZA-C1-8アルキル-ZAZ-C1-8アルキル-、ヘテロシクリルMZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-、(R10)2N-C1-8アルキル-、(R10)3N+-C1-8アルキル-、ヘテロシクリルM-、カルボシクリルM-、R11SO2C1-8アルキル-、及び R11SO2NHから選択され;あるいは
R6 及び R7 は共にC1-6アルキル-Y-C1-6アルキル、C1-6アルキル-ZA-C1-6アルキル、A-C1-6アルキル-ZA-C1-6アルキル、A-C1-6アルキル-A、又はC1-6アルキル-Aであり、好ましくは C1-2アルキル-Y-C1-2アルキル、C1-2アルキル-ZA-C1-2アルキル、A-C1-2アルキル-ZA-C1-2アルキル、A-C1-3アルキル-A、又はC1-4アルキル-Aであることで一個の環を形成し、好ましくは R6 は水素で、そして R7 はC1-6アルキルであり;
R8 及び R9 は、個別に、水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから、好ましくは水素、金属陽イオン、及び C1-6アルキルから、選択され、あるいはR8 及び R9 は共にC1-6アルキルであることで一個の環を形成し;
各R10は、個別に、水素及びC1-6アルキルから選択され、好ましくは C1-6アルキルであり;
各R11は、個別に、水素、OR10、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから選択され;
R14 は水素、(R15O)(R16O)P(=O)W-、R15GB-、ヘテロシクリル-、(R17)2N-、(R17)3N+-、R17SO2GBG-、及び R15GBC1-8アルキル- から選択され、但しこの場合のC1-8アルキル部分は選択的にOH、C1-8アルキルW (選択的にはハロゲン、好ましくはフッ素、で置換された)、アリール、ヘテロアリール、カルボシクリル、ヘテロシクリル、及び C1-6アラルキルで置換され、好ましくはR14 は存在する箇所の少なくとも一つにおいて水素以外であり;
R15 及び R16 は、個別に、水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから、好ましくは水素、金属陽イオン、及び C1-6アルキルから、選択され、あるいはR15 及び R16 は共にC1-6アルキルであることで一個の環を形成し;そして
各R17 は、個別に、水素、OR10、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから選択され;
但し条件として、R6 がHであり、L がC=Oであり、そしてQ が存在しない場合、R7 は水素、C1-6アルキル、又は置換もしくは非置換アリールもしくはヘテロアリールではなく;そして
D、G、V、K、及びWは、O-O、N-O、S-N、又はS-O結合がないように選択される。
各B は、個別に、C=O、C=S、及びSO2から選択され、好ましくはC=Oであり;
Dは存在しないか、又はC1-8アルキルであり;
GはO、 NH、及びN-C1-6アルキルから選択され;
K は存在しないか、又はC=O、 C=S、及びSO2から選択され、好ましくはKは存在しないか、又はC=Oであり;
Lは存在しないか、又はC=O、C=S、及びSO2から選択され、好ましくはLは存在しないか、又はC=Oであり;
Mは存在しないか、又はis C1-8アルキル;
Qは存在しないか、又はO、NH、及びN-C1-6アルキルから選択され、好ましくはQは存在しないか、O、又はNHであり、最も好ましくはQは存在しないか、又はOであり;
X はOであり;
各Vは、個別に、存在しないか、又はO、S、NH、及びN-C1-6アルキルから選択され、 好ましくはVは存在しないか、又はOであり;
Wは存在しないか、又は、個別に、O、S、NH、及びN-C1-6アルキルから選択され、好ましくはOであり;
Y は存在しないか、又はO、NH、N-C1-6アルキル、S、SO、SO2、CHOR10、及びCHCO2R10から選択され;
各Zは、個別に、O、S、NH、及びN-C1-6アルキルから選択され、好ましくはOであり;
R1 及びR3 は、それぞれ個別に、C1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、C1-6アラルキル、及びR14DVKOC1-3アルキル-から選択され、但しこの場合、R1 及びR3 の少なくとも一方は R14DVKOC1-3アルキル-であり;R5 はN(R6)LQR7であり;
R6は水素、OH、及びC1-6アルキルから選択され、好ましくは C1-6アルキルであり;
R7はアミノ酸の更なる鎖、水素、保護基、アリール、又はヘテロアリールであり、この場合これらのいずれかは選択的にハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、C1-5アルキルで置換され;あるいはR7はC1-6アルキル、C1-6アルケニル、C1-6アルキニル、C1-6アラルキル、C1-6ヘテロアラルキル、R8ZA-C1-8アルキル-、R11Z-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-ZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-Z-C1-8アルキル-、R8ZA-C1-8アルキル-ZAZ-C1-8アルキル-、ヘテロシクリルMZAZ-C1-8アルキル-、(R8O)(R9O)P(=O)O-C1-8アルキル-、(R10)2N-C1-8アルキル-、(R10)3N+-C1-8アルキル-、ヘテロシクリルM-、カルボシクリルM-、R11SO2C1-8アルキル-、及びR11SO2NHから選択され;あるいは
R6 及び R7 は共にC1-6アルキル-Y-C1-6アルキル、C1-6アルキル-ZA-C1-6アルキル、A-C1-6アルキル-ZA-C1-6アルキル、A-C1-6アルキル-A、又はC1-6アルキル-A、好ましくは C1-2アルキル-Y-C1-2アルキル、C1-2アルキル-ZA-C1-2アルキル、A-C1-2アルキル-ZA-C1-2アルキル、A-C1-3アルキル-A、又はC1-4アルキル-Aであることで一個の環を形成し;
R8及びR9は、個別に、水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから、好ましくは水素、金属陽イオン、及びC1-6アルキルから、選択され、あるいはR8 及び R9 は共にC1-6アルキルであることで一個の環を形成し;
各R10 は、個別に、水素 及び C1-6アルキルから選択され、好ましくは C1-6アルキルだり;そして
各R11は、個別に、水素、OR10、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され;
R14 は水素、(R15O)(R16O)P(=O)W-、R15GB-、ヘテロシクリル-、(R17)2N-、(R17)3N+-、R17SO2GBG-、及びR15GBC1-8アルキル-から選択され、但しこの場合のC1-8アルキル部分は選択的にOH、C1-8アルキルW (選択的にはハロゲン、好ましくはフッ素で置換される)、アリール、ヘテロアリール、カルボシクリル、ヘテロシクリル、及び C1-6アラルキルで置換され、好ましくはR14 は存在する箇所の少なくとも一つにおいて水素以外であり;
R15及びR16は、個別に、水素、金属陽イオン、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、アリール、ヘテロアリール、C1-6アラルキル、及び C1-6ヘテロアラルキルから、好ましくは水素、金属陽イオン、及びC1-6アルキルから、選択され、あるいはR15 及び R16 は共にC1-6アルキルであることで一個の環を形成し;
各R17は、個別に、水素、OR10、C1-6アルキル、C1-6アルケニル、C1-6アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、C1-6アラルキル、及びC1-6ヘテロアラルキルから選択され;
但し条件として、R6 がHであり、LがC=Oであり、そしてQが存在しない場合、R7 は 水素、C1-6アルキル、又は置換もしくは非置換アリールもしくはヘテロアリールではなく;そして
D、G、V、K、及び Wは、O-O、N-O、S-N、又はS-O結合がないように選択される。
いくつかの実施態様では、本ペプチドエポキシケトンは式(10)又はその薬学的に許容可能な塩の構造を有し:
XはOであり;
Y はNH、N-アルキル、O、又はC(R9)2であり、好ましくはN-アルキル、O、又はC(R9)2であり;
Z はO 又はC(R9)2であり、好ましくはC(R9)2であり;
R1、R2、R3、及び R4 は、個別に、水素 及び式(11)の基から選択され、好ましくは、R1、R2、R3、及び R4 はすべて同じであり、より好ましくは R1、R2、R3、及び R4 はすべて水素であり;
R10 及び R11は、個別に、水素及びC1-6アルキルから選択され、あるいはR10及びR11 は共に3- 乃至6-員環の炭素環又は複素環の環を形成し;
R12及びR13 は、個別に、水素、金属陽イオン、C1-6アルキル、及びC1-6アラルキルから選択され、あるいはR12 及び R13 は共にC1-6アルキルを表すことで一個の環を形成し;
Mは0乃至2の整数であり;そして
n は0乃至2の整数であり、好ましくは0又は1である。
いくつかの実施態様では、本ペプチドエポキシケトンは式(12)又はその薬学的に許容可能な塩の構造を有し:
R1、R2、R3、及びR4 は、個別に、水素及び式(11)の基から選択され、好ましくは、R1、R2、R3、及びR4 はすべて同じであり、より好ましくは R1、R2、R3、及びR4 はすべて水素であり;そして
R5、R6、R7、及びR8 は、個別に、水素並びに選択的に置換されたC1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、アミド、アミン、カルボン酸又はその薬学的に許容可能な塩、カルボキシルエステル、チオール、及びチオエーテルが含まれてもよく、好ましくは R5、R6、R7、及びR8 は、個別に、C1-6アルキル、C1-6ヒドロキシアルキル、及びC1-6アラルキルから選択され、より好ましくは、R6及びR8 は、個別に、C1-6アルキルであり、そしてR5 及びR7 は、個別に、C1-6アラルキルである。
R1、R2、R3、及び R4 は、個別に、水素及び式(11)の基から選択され、好ましくは、R1、R2、R3、及び R4 はすべて同じであり、より好ましくは R1、R2、R3、及び R4 はすべて水素であり;そして
R6及びR8は、個別に、水素並びに選択的に置換されたC1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、アミド、アミン、カルボン酸 又はその薬学的に許容可能な塩、カルボキシルエステル、チオール、及びチオエーテルが含まれてもよく、好ましくはR6及びR8 は、個別に、C1-6アルキル、C1-6ヒドロキシアルキル、及び C1-6アラルキルから選択され、より好ましくは、R6及びR8は、個別に、C1-6アルキルである。
いくつかの実施態様では、本ペプチドエポキシケトンは式(14)又はその薬学的に許容可能な塩の構造を有し、
R1、R2、R3、及び R4 は、個別に、水素及び式IIの基から選択され、好ましくは、R1、R2、R3、及び R4 はすべて同じであり、より好ましくは R1、R2、R3、及び R4 はすべて水素であり;
R5、R6、R7、及びR8は、個別に、水素並びに選択的に置換されたC1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及びC1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、アミド、アミン、カルボン酸 又はその薬学的に許容可能な塩、カルボキシルエステル、チオール、及びチオエーテルが含まれてもよく、好ましくは R5、R6、R7、及びR8 は、個別に、C1-6アルキル、C1-6ヒドロキシアルキル、及びC1-6アラルキルから選択され、より好ましくは、R6及びR8は、個別に、C1-6アルキルであり、そしてR5 及び R7 は、個別に、C1-6アラルキルであり;そして
q は0乃至3の整数である。
R1、R2、R3、及びR4 は、個別に、水素及び式(15)の基から選択され、好ましくは、R1、R2、R3、及び R4 はすべて同じであり、より好ましくは R1、R2、R3、及び R4 はすべて水素であり;
R6 及び R8 は、個別に、水素並びに選択的に置換されたC1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシアルキル、アリール、及び C1-6アラルキルから選択され、但しこの場合の置換基には、限定はしないが、アミド、アミン、カルボン酸又はその薬学的に許容可能な塩、カルボキシルエステル、チオール、及び チオエーテルが含まれてもよく、好ましくは R6 及び R8 は、個別に、C1-6アルキル、C1-6ヒドロキシアルキル、及び C1-6アラルキルから選択され、より好ましくは、R6 及び R8 は、個別に、C1-6アルキルであり;そして
q は0乃至3の整数である。
いくつかの実施態様では、前記他の治療薬はHDAC 阻害剤(例えばトリコスタチンA、デプシペプチド、アピシジン、A-161906、スクリプタイド、PXD-101、CHAP、酪酸、デプデシン、オキサムフラチン、フェニルブチレート、バルプロ酸、SAHA (ボリノスタット)、MS275 (N-(2-アミノフェニル)-4-[N-(ピリジン-3-イルメトキシ-カルボニル)アミノメチル]ベンズアミド)、LAQ824/LBH589、CI994、及びMGCD0103)である。 いくつかのこのような実施態様では、前記他の薬剤はSAHA(スベロイルアニリドヒドロキサム酸)である。
秩序あるタンパク質分解は、正常な細胞機能の維持にとって必須であり、プロテアソームはこのタンパク質分解プロセスと一体である。プロテアソームは、例えばサイクリン、カスパーゼ、BCL2及びnF-kB など、正常及び悪性の細胞における細胞周期の進行及びアポトーシスにとって重要なタンパク質レベルを制御する(Kumatori et al., Proc. Natl. Acad. Sci. USA (1990) 87:7071-7075; Almond et al., Leukemia (2002) 16: 433-443)。このように、関与する細胞に依っては、プロテアソーム活性の阻害を悪性、非悪性及び自己免疫疾患などの多様な疾患状態を処置する治療法に変えることができることは驚くほどのことではない。
実施例1
免疫無防備状態にしたマウス(BNX、チャールズ・リバー・ラボラトリーズ)にRLヒトリンパ腫細胞 (1 x 107/マウス)の皮下投与による刺激を、右側のわき腹に総量0.1 mL リン酸緩衝生理食塩水 (PBS)にして与えた。腫瘍の大きさがほぼ50 mm3 (図1の矢印で示す)になったときに、マウスを処置群に無作為化した(9匹のマウス/群)。化合物1を10% (w/v) スルホブチルエーテル-ベータシクロデキストリンを10 mMのクエン酸緩衝液、pH 3.5に溶かした溶液にして静脈内投与(I.V.)した。投与は各週、第1日目と第2日目に行われた。SAHAを100% DMSOに調合し、各週の第1日目−第5日目に 腹腔内投与(IP)した。ツー・ウェイANOVA・アンド・ボンフェローニのポスト・ホック比較で*** = P<0.001 (化合物1 + SAHA 対 賦形剤) 。
細胞株及び試薬: ヒトリンパ腫 (RL)、非小細胞肺(A549) 及び結腸(HT-29) 腫瘍細胞株をATCC(ヴァージニア州マナサス)から購入した。当該のHDAC 阻害剤ボリノスタットはケイマン・ケミカル社(ミシシッピ州アン・アーバー)から購入した。ドセタキセルはシグマ・ケミカル社(ミシシッピ州アン・アーバー)から購入した。ドキシルの処方箋調剤は地元の薬局から購入した。
化合物1を6.58 nMにして、11.1、7.4、4.9 及び3.3 μMという4種類の様々な用量のメルファランと組み合わせて検査した。MM1.S(多発性骨髄腫、デキサメタゾン感受性細胞)を45 μL 中、200,000 細胞/mL になるようにプレートした後、メルファランで24時間、予備処置した。次に化合物1を加え、細胞を更に24時間、6.58 nMでインキュベートした。その後、1:1の比の細胞タイター・グロー溶液をこの細胞試料に加え、生存率を読み取った。併用指数値は、数値 <0.9 = 相乗的、0.9-1.0 = 相加的及び>1.1 = 拮抗的にしたカルキュシン・プログラムを用いて計算された。結果は、図11に示すように、化合物1及びメルファランはこれらの濃度のときに相乗的かつ相加的な効果を示すことが示された。
当業者であれば、ごく慣例的な実験を用いるのみで、ここに記載した化合物及びその使用法の均等物を数多く認識され、又は確認できることであろう。このような均等物は本発明の範囲内にあると考えられ、以下の請求項の網羅するところである。
Claims (16)
-
で表されるペプチドエポキシケトンプロテアソーム阻害剤、又はその薬学的に許容されるその塩を含む癌治療剤であって、
レナリドミド(lenalidomide)及びCC-4047(アクチミド)から選ばれる免疫調節剤と共に静脈注射により投与される、癌治療剤。 - 前記免疫調節剤がレナリドミドである、請求項1に記載の癌治療剤。
- 前記免疫調節剤がCC-4047(アクチミド)である、請求項1に記載の癌治療剤。
- 前記癌治療剤が、さらにデキサメタゾン及びプレドニゾンから選ばれるステロイドと共に投与される、請求項1−3のいずれか一項に記載の癌治療剤。
- 前記ステロイドがプレドニゾンである、請求項4に記載の癌治療剤。
- 前記ステロイドがデキサメタゾンである、請求項4に記載の癌治療剤。
- 前記ペプチドエポキシケトンプロテアソーム阻害剤及び前記免疫調節剤が同時に投与される、請求項1−6のいずれか一項に記載の癌治療剤。
- 前記ペプチドエポキシケトンプロテアソーム阻害剤、前記免疫調節剤及び前記ステロイドが同時に投与される、請求項4−6のいずれか一項に記載の癌治療剤。
- 前記免疫調節剤が、前記ペプチドエポキシケトンプロテアソーム阻害剤の投与前又は投与後5分以内乃至48時間以内に投与される、請求項1−6のいずれか一項に記載の癌治療剤。
- 前記免疫調節剤が、前記ペプチドエポキシケトンプロテアソーム阻害剤の投与前又は投与後5分以内乃至1時間以内に投与される、請求項1−6のいずれか一項に記載の癌治療剤。
- 前記ペプチドエポキシケトンプロテアソーム阻害剤が、レナリドミド及びデキサメタゾンと共に投与される、請求項1に記載の癌治療剤。
- 前記癌が、多発性骨髄腫である、請求項1−11のいずれか一項に記載の癌治療剤。
- 前記癌が、再発多発性骨髄腫である、請求項1−11のいずれか一項に記載の癌治療剤。
- 前記ペプチドエポキシケトンプロテアソーム阻害剤が、少なくとも15 mg/m2の投与量で投与される、請求項1−13のいずれか一項に記載の癌治療剤。
- レナリドミド及びCC-4047(アクチミド)から選ばれる免疫調節剤と共に投与される、
で表されるペプチドエポキシケトンプロテアソーム阻害剤、又はその薬学的に許容されるその塩を含む、癌治療のための静脈注射剤。 - レナリドミド及びCC-4047(アクチミド)から選ばれる免疫調節剤と共に投与される、
で表されるペプチドエポキシケトンプロテアソーム阻害剤、又はその薬学的に許容されるその塩を含む、癌治療のための点滴輸液。
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |