JP4644428B2 - ヒストンデアセチラーゼの新規な阻害剤 - Google Patents
ヒストンデアセチラーゼの新規な阻害剤 Download PDFInfo
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- JP4644428B2 JP4644428B2 JP2003574621A JP2003574621A JP4644428B2 JP 4644428 B2 JP4644428 B2 JP 4644428B2 JP 2003574621 A JP2003574621 A JP 2003574621A JP 2003574621 A JP2003574621 A JP 2003574621A JP 4644428 B2 JP4644428 B2 JP 4644428B2
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- Prior art keywords
- alkyl
- compound
- amino
- alkyloxy
- hydrogen
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Classifications
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Description
nは、0、1、2または3であり、そしてnが0の時には直接結合を意図し、
tは、0、1、2、3または4であり、そしてtが0の時には直接結合を意図し、
各Qは、窒素または
各Xは、窒素または
各Yは、窒素または
各Zは、窒素または
R1は、−C(O)NR7R8、−NHC(O)R9、−C(O)−C1−6アルカンジイルSR9、−NR10C(O)N(OH)R9、−NR10C(O)C1−6アルカンジイルSR9、−NR10C(O)C=N(OH)R9または別のZn−キレート基であり、ここで、
R7およびR8は、各々独立して、水素、ヒドロキシ、C1−6アルキル、ヒドロキシC1−6アルキル、アミノC1−6アルキルまたはアミノアリールから選択され、
R9は、独立して、水素、C1−6アルキル、C1−6アルキルカルボニル、アリールC1−6アルキル、C1−6アルキルピラジニル、ピリジノン、ピロリジノンまたはメチルイミダゾリルから選択され、
R10は、独立して、水素またはC1−6アルキルから選択され、
R2は、水素、ハロ、ヒドロキシ、アミノ、ニトロ、C1−6アルキル、C1−6アルキルオキシ、トリフルオロメチル、ジ(C1−6アルキル)アミノ、ヒドロキシアミノまたはナフタレニルスルホニルピラジニルであり、
−L−は、直接結合、またはC1−6アルカンジイル、C1−6アルキルオキシ、アミノ、カルボニルまたはアミノカルボニルから選択される二価の基であり、
各R3は、独立して、水素原子を表し、そして1つの水素原子がアリールから選択される置換基に置き換わっていてもよく、
R4は、水素、ヒドロキシ、アミノ、ヒドロキシC1−6アルキル、C1−6アルキル、C1−6アルキルオキシ、アリールC1−6アルキル、アミノカルボニル、ヒドロキシカルボニル、アミノC1−6アルキル、アミノカルボニルC1−6アルキル、ヒドロキシカルボニルC1−6アルキル、ヒドロキシアミノカルボニル、C1−6アルキルオキシカルボニル、C1−6アルキルアミノC1−6アルキルまたはジ(C1−6アルキル)アミノC1−6アルキルであり、
各sは、独立して、0、1、2、3、4または5であり、
各R5およびR6は、独立して、水素;ハロ;ヒドロキシ;アミノ;ニトロ;トリハロC1−6アルキル;トリハロC1−6アルキルオキシ;C1−6アルキル;アリールおよびC3−10シクロアルキルで置換されているC1−6アルキル;C1−6アルキルオキシ;C1−6アルキルオキシC1−6アルキルオキシ;C1−6アルキルカルボニル;C1−6アルキルオキシカルボニル;C1−6アルキルスルホニル;シアノC1−6アルキル;ヒドロキシC1−6アルキル;ヒドロキシC1−6アルキルオキシ;ヒドロキシC1−6アルキルアミノ;アミノC1−6アルキルオキシ;ジ(C1−6アルキル)アミノカルボニル;ジ(ヒドロキシC1−6アルキル)アミノ;(アリール)(C1−6アルキル)アミノ;ジ(C1−6アルキル)アミノC1−6アルキルオキシ;ジ(C1−6アルキル)アミノC1−6アルキルアミノ;ジ(C1−6アルキル)アミノC1−6アルキルアミノC1−6アルキル;アリールスルホニル;アリールスルホニルアミノ;アリールオキシ;アリールオキシC1−6アルキル;アリールC2−6アルケンジイル;ジ(C1−6アルキル)アミノ;ジ(C1−6アルキル)アミノC1−6アルキル;ジ(C1−6アルキル)アミノ(C1−6アルキル)アミノ;ジ(C1−6アルキル)アミノ(C1−6アルキル)アミノC1−6アルキル;ジ(C1−6アルキル)アミノC1−6アルキル(C1−6アルキル)アミノ;ジ(C1−6アルキル)アミノC1−6アルキル(C1−6アルキル)アミノC1−6アルキル;アミノスルホニルアミノ(C1−6アルキル)アミノ、アミノスルホニルアミノ(C1−6アルキル)アミノC1−6アルキル;ジ(C1−6アルキル)アミノスルホニルアミノ(C1−6アルキル)アミノ;ジ(C1−6アルキル)アミノスルホニルアミノ(C1−6アルキル)アミノC1−6アルキル;シアノ;チオフェニル;ジ(C1−6アルキル)アミノC1−6アルキル(C1−6アルキル)アミノC1−6アルキル、ジ(C1−6アルキル)アミノC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、ヒドロキシC1−6アルキルピペラジニルC1−6アルキル、ヒドロキシC1−6アルキルオキシC1−6アルキルピペラジニルC1−6アルキル、ジ(C1−6アルキル)アミノスルホニルピペラジニルC1−6アルキル、C1−6アルキルオキシピペリジニル、C1−6アルキルオキシピペリジニルC1−6アルキル、モルホリニルC1−6アルキル、ヒドロキシC1−6アルキル(C1−6アルキル)アミノC1−6アルキルまたはジ(ヒドロキシC1−6アルキル)アミノC1−6アルキルで置換されているチオフェニル;フラニル;ヒドロキシC1−6アルキルで置換されているフラニル;ベンゾフラニル;イミダゾリル;オキサゾリル;アリールおよびC1−6アルキルで置換されているオキサゾリル;C1−6アルキルトリアゾリル;テトラゾリル;ピロリジニル;ピロリル;ピペリジニルC1−6アルキルオキシ;モルホリニル;C1−6アルキルモルホリニル;モルホリニルC1−6アルキルオキシ;モルホリニルC1−6アルキル;モルホリニルC1−6アルキルアミノ;モルホリニルC1−6アルキルアミノC1−6アルキル;ピペラジニル;C1−6アルキルピペラジニル;C1−6アルキルピペラジニルC1−6アルキルオキシ;ピペラジニルC1−6アルキル;ナフタレニルスルホニルピペラジニル;ナフタレニルスルホニルピペリジニル;ナフタレニルスルホニル;C1−6アルキルピペラジニルC1−6アルキル;C1−6アルキルピペラジニルC1−6アルキルアミノ;C1−6アルキルピペラジニルC1−6アルキルアミノC1−6アルキル;C1−6アルキルピペラジニルスルホニル;アミノスルホニルピペラジニルC1−6アルキルオキシ;アミノスルホニルピペラジニル;アミノスルホニルピペラジニルC1−6アルキル;ジ(C1−6アルキル)アミノスルホニルピペラジニル;ジ(C1−6アルキル)アミノスルホニルピペラジニルC1−6アルキル;ヒドロキシC1−6アルキルピペラジニル;ヒドロキシC1−6アルキルピペラジニルC1−6アルキル;C1−6アルキルオキシピペリジニル;C1−6アルキルオキシピペリジニルC1−6アルキル;ピペリジニルアミノC1−6アルキルアミノ;ピペリジニルアミノC1−6アルキルアミノC1−6アルキル;(C1−6アルキルピペリジニル)(ヒドロキシC1−6アルキル)アミノC1−6アルキルアミノ;(C1−6アルキルピペリジニル)(ヒドロキシC1−6アルキル)アミノC1−6アルキルアミノC1−6アルキル;ヒドロキシC1−6アルキルオキシC1−6アルキルピペラジニル;ヒドロキシC1−6アルキルオキシC1−6アルキルピペラジニルC1−6アルキル;(ヒドロキシC1−6アルキル)(C1−6アルキル)アミノ;(ヒドロキシC1−6アルキル)(C1−6アルキル)アミノC1−6アルキル;ヒドロキシC1−6アルキルアミノC1−6アルキル;ジ(ヒドロキシC1−6アルキル)アミノC1−6アルキル;ピロリジニルC1−6アルキル;ピロリジニルC1−6アルキルオキシ;ピラゾリル;チオピラゾリル;C1−6アルキルまたはトリハロC1−6アルキルから選択される2個の置換基で置換されているピラゾリル;ピリジニル;C1−6アルキルオキシ、アリールオキシまたはアリールで置換されているピリジニル;ピリミジニル;テトラヒドロピリミジニルピペラジニル;テトラヒドロピリミジニルピペラジニルC1−6アルキル;キノリニル;インドール;フェニル;ハロ、アミノ、ニトロ、C1−6アルキル、C1−6アルキルオキシ、ヒドロキシC1−4アルキル、トリフルオロメチル、トリフルオロメチルオキシ、ヒドロキシC1−4アルキルオキシ、C1−4アルキルスルホニル、C1−4アルキルオキシC1−4アルキルオキシ、C1−4アルキルオキシカルボニル、アミノC1−4アルキルオキシ、ジ(C1−4アルキル)アミノC1−4アルキルオキシ、ジ(C1−4アルキル)アミノ、ジ(C1−4アルキル)アミノカルボニル、ジ(C1−4アルキル)アミノC1−4アルキル、ジ(C1−4アルキル)アミノC1−4アルキルアミノC1−4アルキル、ジ(C1−4アルキル)アミノ(C1−4アルキル)アミノ、ジ(C1−4アルキル)アミノ(C1−4アルキル)アミノC1−4アルキル、ジ(C1−4アルキル)アミノC1−4アルキル(C1−4アルキル)アミノ、ジ(C1−4アルキル)アミノC1−4アルキル(C1−4アルキル)アミノC1−4アルキル、アミノスルホニルアミノ(C1−4アルキル)アミノ、アミノスルホニルアミノ(C1−4アルキル)アミノC1−4アルキル、ジ(C1−4アルキル)アミノスルホニルアミノ(C1−4アルキル)アミノ、ジ(C1−4アルキル)アミノスルホニルアミノ(C1−4アルキル)アミノC1−6アルキル、シアノ、ピペリジニルC1−4アルキルオキシ、ピロリジニルC1−4アルキルオキシ、アミノスルホニルピペラジニル、アミノスルホニルピペラジニルC1−4アルキル、ジ(C1−4アルキル)アミノスルホニルピペラジニル、ジ(C1−4アルキル)アミノスルホニルピペラジニルC1−4アルキル、ヒドロキシC1−4アルキルピペラジニル、ヒドロキシC1−4アルキルピペラジニルC1−4アルキル、C1−4アルキルオキシピペリジニル、C1−4アルキルオキシピペリジニルC1−4アルキル、ヒドロキシC1−4アルキルオキシC1−4アルキルピペラジニル、ヒドロキシC1−4アルキルオキシC1−4アルキルピペラジニルC1−4アルキル、(ヒドロキシC1−4アルキル)(C1−4アルキル)アミノ、(ヒドロキシC1−4アルキル)(C1−4アルキル)アミノC1−4アルキル、ジ(ヒドロキシC1−4アルキル)アミノ、ジ(ヒドロキシC1−4アルキル)アミノC1−4アルキル、フラニル、−CH=CH−CH=CH−で置換されているフラニル、ピロリジニルC1−4アルキル、ピロリジニルC1−4アルキルオキシ、モルホリニル、モルホリニルC1−4アルキルオキシ、モルホリニルC1−4アルキル、モルホリニルC1−4アルキルアミノ、モルホリニルC1−4アルキルアミノC1−4アルキル、ピペラジニル、C1−4アルキルピペラジニル、C1−4アルキルピペラジニルC1−4アルキルオキシ、ピペラジニルC1−4アルキル、C1−4アルキルピペラジニルC1−4アルキル、C1−4アルキルピペラジニルC1−4アルキルアミノ、C1−4アルキルピペラジニルC1−4アルキルアミノC1−6アルキル、テトラヒドロピリミジニルピペラジニル、テトラヒドロピリミジニルピペラジニルC1−4アルキル、ピペリジニルアミノC1−4アルキルアミノ、ピペリジニルアミノC1−4アルキルアミノC1−4アルキル、(C1−4アルキルピペリジニル)(ヒドロキシC1−4アルキル)アミノC1−4アルキルアミノ、(C1−4アルキルピペリジニル)(ヒドロキシC1−4アルキル)アミノC1−4アルキルアミノC1−4アルキル、ピリジニルC1−4アルキルオキシ、ヒドロキシC1−4
アルキルアミノ、ヒドロキシC1−4アルキルアミノC1−4アルキル、ジ(C1−4アルキル)アミノC1−4アルキルアミノ、アミノチアジアゾリル、アミノスルホニルピペラジニルC1−4アルキルオキシまたはチオフェニルC1−4アルキルアミノから独立して選択される1、2または3個の置換基で置換されているフェニルから選択され、
各R5およびR6は窒素上に水素の代わりに位置していてもよく、
この上に示したアリールはフェニル、または各々がハロ、C1−6アルキル、C1−6アルキルオキシ、トリフルオロメチル、シアノまたはヒドロキシカルボニルから独立して選択される1個以上の置換基で置換されているフェニルである]
で表される化合物、これのN−オキサイド形態、薬学的に受け入れられる付加塩および立体化学異性体形態に関する。
a)nが1または2であり、
b)tが0、1、2または4であり、
c)各Qが
d)R1が−C(O)NH(OH)であり、
e)R2が水素またはニトロであり、
f)−L−が直接結合またはC1−6アルカンジイルから選択される二価の基であり、
g)R4が水素であり、
h)
i)各sが独立して0、1、2または4であり、
j)各R5およびR6が独立して水素;ハロ;トリハロC1−6アルキル;C1−6アルキル;アリールおよびC3−10シクロアルキルで置換されているC1−6アルキル;C1−6アルキルオキシ;C1−6アルキルカルボニル;ベンゾフラニル;ナフタレニルスルホニル;アリールオキシで置換されているピリジニル;フェニル;ヒドロキシC1−4アルキルまたはモルホリニルC1−4アルキルから独立して選択される1個の置換基で置換されているフェニルから選択される、
の中の1つ以上が当てはまる前記式(I)で表される化合物で構成される群である。
a)nが1であり、
b)tが0、1または2であり、
c)各Qが
d)各Xが窒素であり、
e)各Yが窒素であり、
f)R1が−C(O)NH(OH)であり、
g)R2が水素であり、
h)−L−が直接結合であり、
i)各R3が独立して水素原子を表し、
j)R4が水素であり、
k)
l)各sが独立して0、1または4であり、
m)各R5およびR6が独立して水素;C1−6アルキル;C1−6アルキルオキシ;ナフタレニルスルホニル;またはヒドロキシC1−4アルキルまたはモルホリニルC1−4アルキルで置換されているフェニルから選択される、
の中の1つ以上が当てはまる前記式(I)で表される化合物で構成される群である。
a)R1が−C(O)NH(OH)であり、
b)L−が直接結合である、
の中の1つ以上が当てはまる前記式(I)で表される化合物で構成される群である。
a)tが1、2、3または4であり、
b)R1が−C(O)NR7R8、−C(O)−C1−6アルカンジイルSR9、−NR10C(O)N(OH)R9、−NR10C(O)C1−6アルカンジイルSR9、−NR10C(O)C=N(OH)R9または別のZn−キレート基であり、ここで、R7およびR8が各々独立して水素、ヒドロキシ、ヒドロキシC1−6アルキルまたはアミノC1−6アルキルから選択され、
c)R2が水素、ハロ、ヒドロキシ、アミノ、ニトロ、C1−6アルキル、C1−6アルキルオキシ、トリフルオロメチルまたはジ(C1−6アルキル)アミノであり、
d)−L−が直接結合、またはC1−6アルカンジイル、C1−6アルカンジイルオキシ、アミノ、またはカルボニルから選択される二価の基であり、
e)R4が水素、ヒドロキシ、アミノ、ヒドロキシC1−6アルキル、C1−6アルキル、C1−6アルキルオキシ、アリールC1−6アルキル、アミノカルボニル、アミノC1−6アルキル、C1−6アルキルアミノC1−6アルキルまたはジ(C1−6アルキル)アミノC1−6アルキルであり、
f)
g)各sが独立して0、1、2、3または4であり、
h)R5が水素;ハロ;ヒドロキシ;アミノ;ニトロ;トリハロC1−6アルキル;トリハロC1−6アルキルオキシ;C1−6アルキル;C1−6アルキルオキシ;C1−6アルキルカルボニル;C1−6アルキルオキシカルボニル;C1−6アルキルスルホニル;ヒドロキシC1−6アルキル;アリールオキシ;ジ(C1−6アルキル)アミノ;シアノ;チオフェニル;フラニル;ヒドロキシC1−6アルキルで置換されているフラニル;ベンゾフラニル;イミダゾリル;オキサゾリル;アリールおよびC1−6アルキルで置換されているオキサゾリル;C1−6アルキルトリアゾリル;テトラゾリル;ピロリジニル;ピロリル;モルホリニル;C1−6アルキルモルホリニル;ピペラジニル;C1−6アルキルピペラジニル;ヒドロキシC1−6アルキルピペラジニル;C1−6アルキルオキシピペリジニル;ピラゾリル;C1−6アルキルまたはトリハロC1−6アルキルから選択される1または2個の置換基で置換されているピラゾリル;ピリジニル;C1−6アルキルオキシ、アリールオキシまたはアリールで置換されているピリジニル;ピリミジニル;キノリニル;インドール;フェニル;またはハロ、C1−6アルキル、C1−6アルキルオキシまたはトリフルオロメチルから独立して選択される1または2個の置換基で置換されているフェニルであり、
i)R6が水素;ハロ;ヒドロキシ;アミノ;ニトロ;トリハロC1−6アルキル;トリハロC1−6アルキルオキシ;C1−6アルキル;C1−6アルキルオキシ;C1−6アルキルカルボニル;C1−6アルキルオキシカルボニル;C1−6アルキルスルホニル;ヒドロキシC1−6アルキル;アリールオキシ;ジ(C1−6アルキル)アミノ;シアノ;ピリジニル;フェニル;またはハロ、C1−6アルキル、C1−6アルキルオキシまたはトリフルオロメチルから独立して選択される1または2個の置換基で置換されているフェニルである、
の中の1つ以上が当てはまる前記式(I)で表される化合物で構成される群である。
tが1、2、3または4であり、
R1が−C(O)NR7R8、−C(O)−C1−6アルカンジイルSR9、−NR10C(O)N(OH)R9、−NR10C(O)C1−6アルカンジイルSR9、−NR10C(O)C=N(OH)R9または別のZn−キレート基であり、ここで、R7およびR8が各々独立して水素、ヒドロキシ、ヒドロキシC1−6アルキルまたはアミノC1−6アルキルから選択され、
R2が水素、ハロ、ヒドロキシ、アミノ、ニトロ、C1−6アルキル、C1−6アルキルオキシ、トリフルオロメチルまたはジ(C1−6アルキル)アミノであり、
−L−が直接結合、またはC1−6アルカンジイル、C1−6アルカンジイルオキシ、アミノ、またはカルボニルから選択される二価の基であり、
R4が水素、ヒドロキシ、アミノ、ヒドロキシC1−6アルキル、C1−6アルキル、C1−6アルキルオキシ、アリールC1−6アルキル、アミノカルボニル、アミノC1−6アルキル、C1−6アルキルアミノC1−6アルキルまたはジ(C1−6アルキル)アミノC1−6アルキルであり、
各sが独立して0、1、2、3または4であり、
R5が水素;ハロ;ヒドロキシ;アミノ;ニトロ;トリハロC1−6アルキル;トリハロC1−6アルキルオキシ;C1−6アルキル;C1−6アルキルオキシ;C1−6アルキルカルボニル;C1−6アルキルオキシカルボニル;C1−6アルキルスルホニル;ヒドロキシC1−6アルキル;アリールオキシ;ジ(C1−6アルキル)アミノ;シアノ;チオフェニル;フラニル;ヒドロキシC1−6アルキルで置換されているフラニル;ベンゾフラニル;イミダゾリル;オキサゾリル;アリールおよびC1−6アルキルで置換されているオキサゾリル;C1−6アルキルトリアゾリル;テトラゾリル;ピロリジニル;ピロリル;モルホリニル;C1−6アルキルモルホリニル;ピペラジニル;C1−6アルキルピペラジニル;ヒドロキシC1−6アルキルピペラジニル;C1−6アルキルオキシピペリジニル;ピラゾリル;C1−6アルキルまたはトリハロC1−6アルキルから選択される1または2個の置換基で置換されているピラゾリル;ピリジニル;C1−6アルキルオキシ、アリールオキシまたはアリールで置換されているピリジニル;ピリミジニル;キノリニル;インドール;フェニル;またはハロ、C1−6アルキル、C1−6アルキルオキシまたはトリフルオロメチルから独立して選択される1または2個の置換基で置換されているフェニルであり、
R6が水素;ハロ;ヒドロキシ;アミノ;ニトロ;トリハロC1−6アルキル;トリハロC1−6アルキルオキシ;C1−6アルキル;C1−6アルキルオキシ;C1−6アルキルカルボニル;C1−6アルキルオキシカルボニル;C1−6アルキルスルホニル;ヒドロキシC1−6アルキル;アリールオキシ;ジ(C1−6アルキル)アミノ;シアノ;ピリジニル;フェニル;またはハロ、C1−6アルキル、C1−6アルキルオキシまたはトリフルオロメチルから独立して選択される1または2個の置換基で置換されているフェニルである、
前記式(I)で表される化合物で構成される群である。
nが1または2であり、tが0、1、2または4であり、各Qが
a)式(II)で表される中間体と適切な酸、例えばトリフルオロ酢酸などを反応させることで式(I)[式中、R1は−C(O)NH(OH)である]で表されるヒドロキサム酸[この化合物を式(I−a)で表される化合物と呼ぶ]を生じさせることができる。前記反応を適切な溶媒、例えばメタノールなど中で実施する。
a)癌を治療する目的で腫瘍に照射を受けさせる前、受けさせている間または受けさせた後に本発明に従う化合物を投与することで腫瘍を放射線療法に対して増感させる、
b)関節症および骨病理学的状態、例えば慢性関節リューマチ、変形性関節症、若年性関節炎、通風、多発性関節炎、乾癬性関節炎、強直性脊椎炎および全身性エリトマトーデスなどの治療、
c)平滑筋細胞増殖(血管増殖障害、アテローム性動脈硬化症および再狭窄を包含)の抑制、
d)炎症状態および皮膚状態、例えば潰瘍性大腸炎、クローン病、アレルギー性鼻炎、宿主対移植片病(graft vs host disease)、結膜炎、喘息、ARDS、ベーチェット病、移植拒絶、ウチカリア(uticaria)、アレルギー性皮膚炎、円形脱毛症、強皮症、発疹、湿疹、皮膚筋炎、アクネ、糖尿病、全身性エリトマトーデス、川崎病、多発性硬化症、気腫、のう胞性線維症および慢性気管支炎などの治療、
e)子宮内膜症、子宮類線維症、機能障害子宮出血および子宮内膜過形成の治療、
f)眼の血管新生[レチナールおよび絨毛膜様管に影響を与える血管病(vasculopathy)を包含]の治療、
g)心臓機能不全の治療、
h)免疫抑制状態の防止、例えばHIV感染の治療など、
i)腎臓機能不全の治療、
j)内分泌障害の抑制、
k)糖新生不全の防止、
l)神経病、例えばパーキンソン病など、または認識障害をもたらす神経病、例えばアルツハイマー病またはポリグルタミン関連ニューロン病などの治療、
m)神経節病、例えば筋委縮性側索硬化症などの防止、
n)脊髄筋萎縮症の治療、
o)遺伝子の発現を増強することで治療され得る他の病理学的状態の治療
p)遺伝子治療の強化。
− 白金配位化合物、例えばシスプラチン(cisplatin)、カルボプラチン(carboplatin)またはオキサリプラチン(oxalyplatin);
− タキサン化合物、例えばパクリタキセル(paclitaxel)またはドセタキセル(docetaxel);
− トポイソメラーゼI阻害剤、例えばカンプトテシン化合物、例えばイリノテカン(irinotecan)またはトポテカン(topotecan);
− トポイソメラーゼII阻害剤、例えば抗腫瘍性ポドフィロトキシン誘導体、例えばエトポシド(etoposide)またはテニポシド(teniposide);
− 抗腫瘍性ビンカアルカロイド、例えばビンブラスチン(vinblastine)、ビンクリスチン(vincristine)またはビノレルビン(vinorelbine);
− 抗腫瘍性ヌクレオシド誘導体、例えば5−フルオロウラシル、ゲンシタビン(gemcitabine)またはカペシタビン(capecitabine);
− アルキル化剤、例えば窒素マスタードまたはニトロソ尿素、例えばシクロホスファミド、クロラムブシル(chlorambucil)、カルムスチン(carmustine)またはロムスチン(lomustine);
− 抗腫瘍性アントラシクリン誘導体、例えばダウノルビシン(daunorubicin)、ドキソルビシン(doxorubicin)、イダルビシン(idarubicin)またはミトキサントロン(mitoxantrone);
− HER2抗体、例えばトラスツズマブ(trastuzumab);
− エストロゲン受容体拮抗薬または選択的エストロゲン受容体調節剤、例えばタモキフェン(tamoxifen)、トレミフェン(toremifene)、ドロロキシフェン(droloxifene)、ファスロデックス(faslodex)またはラロキシフェン(raloxifene);
− アロマターゼ阻害剤、例えばエキセメスタン(exemestane)、アナストロゾール(anastrozole)、レトラゾール(letrazole)およびボロゾール(vorozole);
− 分化剤、例えばレチノイド、ビタミンDおよびレチン酸代謝遮断剤(RAMBA)、例えばアクタン(accutane);
− DNAメチルトランスフェラーゼ阻害剤、例えばアザシチジン(azacytidine);
− キナーゼ阻害剤、例えばフラボペリドール(flavoperidol)、イマチニブメシレート(imatinib mesylate)またはゲフィチニブ(gefitinib);
− ファルネシルトランスフェラーゼ阻害剤;または
− 他のHDAC阻害剤。
− 短鎖脂肪酸、例えばブチレート、4−フェニルブチレートまたはバルプロイックアシッド(valproic acid);
− ヒドロキサム酸、例えばスベロイルアニリドヒドロキサム酸(SAHA)、ビアリールヒドロキサメートA−161906、二環状アリール−N−ヒドロキシカルボキサミド、ピロキサミド、CG−152、PXD−101、スルホンアミドヒドロキサム酸、LAQ−824、トリコスタチンA(TSA)、オキサムフラチン(oxamflatin)、スクリプタイド(scriptaid)、m−カルボキシ桂皮酸ビスヒドロキサム酸またはトラポキシン−ヒドロキサム酸類似物;
− 環状テトラペプチド、例えばトラポキシン(trapoxin)、アピジシン(apidicin)またはデプシペプチド;
− ベンズアミド、例えばMS−275またはCI−994;または
− デプデシン(depudecin);
を包含する。
以下の実施例は説明の目的で示すものである。
A. 中間体の調製
実施例A1
a) ヘキサヒドロ−1H−1,4−ジアゼピン(0.20モル)と1−フルオロ−4−ニトロ−ベンゼン(0.10モル)をDCM(300ml)に入れることで生じさせた溶液を窒素雰囲気下室温で24時間撹拌した。黄色の結晶が沈澱した。その沈澱物をフィルターで集め、エーテルで洗浄した後、乾燥させた。その残留物(21.1g、87%)を水で取り上げた後、3NのNaOH溶液で処理した。この混合物をDCM(3x500ml)で抽出し、乾燥(Na2SO4)させ、濾過し、溶媒を減圧下で除去した後、真空下室温で16時間乾燥させることで、融点が115−116℃のヘキサヒドロ−1−(4−ニトロフェニル)−1H−1,4−ジアゼピン(中間体1)を18.3g得た。
b) 中間体1(0.090モル)をDCM(200ml)に入れることで生じさせた溶液を冷却(氷浴)しつつ撹拌しながら、これに、ビス−(1,1−ジメチルエチル)−ジ炭酸エステル(0.090モル)をDCM(100ml)に入れて加えた。気体の発生を確認した。CO2の発生が終了した後、前記氷浴を取り外して、撹拌を室温で3時間継続した。この反応混合物を1NのHCl溶液そして水で洗浄した後、乾燥させた。溶媒を蒸発させることで、融点が128−130℃のヘキサヒドロ−4−(4−ニトロフェニル)−1H−1,4−ジアゼピン−1−カルボン酸1,1−ジメチルエチルエステル(中間体2)を20.5g(70%)得た。
c) 一水加ヒドラジン(15ml)をメタノール(700ml)とラネーニッケル(16.1g)に入れることで生じさせた混合物を還流させながらこれに中間体2(0.047モル)を分割して加えた(20分かけて)。この混合物を撹拌しながら黄色が消失するまで還流させた。この混合物の還流を更に30分間継続した。触媒を濾過で除去した。溶媒を蒸発させることで、4−(4−アミノフェニル)ヘキサヒドロ−1H−1,4−ジアゼピン−1−カルボン酸1,1−ジメチルエチルエステル(中間体3)を13.0g得た。
d) 中間体3(0.045モル)と(1−エトキシエチリデン)−ヒドラジンカルボン酸エチルエステル(0.090モル)の混合物を混ぜ物なしに撹拌しながら130℃のオイルバスで1時間加熱した。更に2時間後、その反応混合物を冷却した後、磨り潰しながら2−プロパノール(約100ml)を加えた。固体を濾過した後、乾燥させることで固体を14g得た。この固体をエーテルと一緒にして磨り潰し、濾別した後、乾燥させることで、融点が238−240℃の1H−1,4−ジアゼピン−1−カルボン酸,4−[4−(1,5−ジヒドロ−3−メチル−5−オキソ−4H−1,2,4−トリアゾール−4−イル)フェニル]ヘキサヒドロ−1H−1,4−ジアゼピン−1−カルボン酸1,1−ジメチルエチルエステル(中間体4)を13.0g(77%)得た。
e) Ar雰囲気下の反応。中間体4(0.01モル)をDMF(200ml)に入れて、これに室温で1,1,1−トリメチル−N−(トリメチルシリル)−シランアミンのナトリウム塩(0.01モル、10ml、1M/THF)を加えた(シリンジで)。固体状のナトリウム塩が生成し始めた。これを激しく撹拌しながら更にDMF(200ml)を加えた。2−ブロモブタン(0.02モル)をDMF(100ml)に入れることで生じさせた溶液を室温でゆっくり加えた。この反応混合物を室温で18時間撹拌した。DMF溶媒を除去した(真空ポンプ)。その残留物に水を加えた後、結果として生じた油状生成物をエーテル(500ml)で取り上げた。このエーテル溶液に濃縮を受けさせることで2.70g(油状材料を放置すると固化した;62%の収率)得て、これにさらなる精製をシリカゲル使用フラッシュカラムクロマトグラフィー[溶離剤:1%(10%NH4OH/CH3OH)/CH2Cl2]で受けさせるで、融点が119−120℃の4−[4−[1,5−ジヒドロ−3−メチル−1−(1−メチルプロピル)−5−オキソ−4H−1,2,4−トリアゾール−4−イル]フェニル]ヘキサヒドロ−1H−1,4−ジアゼピン−1−カルボン酸1,1−ジメチルエチルエステル(中間体5)を0.55g得た。
f) 冷TFA溶液(5ml、氷浴)に中間体5(0.0014モル)を30分かけて加えた。溶媒を減圧下で除去した。水を加えた後、この混合物を炭酸カリウムで飽和状態にした。この混合物を酢酸エチル(2x50ml)で抽出し、硫酸ナトリウムで乾燥させ、濾過した後、溶媒を除去することで、4−[4−(ヘキサヒドロ−1H−1,4−ジアゼピン−1−イル)フェニル]−2,4−ジヒドロ−5−メチル−2−(1−メチルプロピル)−3H−1,2,4−トリアゾール−3−オン(中間体6)を0.35g(65%)得た。
g) アルゴン下のグローブボックスの中で中間体6(0.00076モル)と4−ブロモ−安息香酸メチルエステル(0.00304モル)と(1R)−[1,1’−ビナフタレン]−2,2’−ジイルビス[ジフェニル−ホスフィン(0.016g)とPd2(dba)3(0.008g)とCs2CO3(0.40g)をトルエン(10ml)に入れることで生じさせた混合物を圧力管(小型の磁気撹拌子を入れておいた)の中に入れた。前記圧力管に蓋をしっかりと取り付けた後、それを撹拌しながら120℃のオイルバスで12時間加熱した。更に(1R)−[1,1’−ビナフタレン]−2,2’−ジイルビス[ジフェニル−ホスフィン(0.016g)とPd2(dba)3(0.008g)とCs2CO3(0.40g)を加えた。この混合物を120℃のオイルバスで24時間加熱した。この反応混合物を濾過することで無機固体材料を除去した後、約20mlのCHCl3で洗浄した。その濾液に濃縮を減圧下で乾燥状態になるまで受けさせた。その残留物に精製をシリカゲル使用フラッシュクロマトグラフィー[溶離剤:NH4OH/CH3OH/CH2Cl2が0.1/0.9/99]で受けさせた。所望画分を一緒にし、溶媒を蒸発させた後、真空下室温で16時間乾燥させることで、融点が152℃−153℃の4−[4−[4−[1,5−ジヒドロ−3−メチル−1−(1−メチルプロピル)−5−オキソ−4H−1,2,4−トリアゾール−4−イル]フェニル]ヘキサヒドロ−1H−1,4−ジアゼピン−1−イル]−安息香酸メチルエステル(中間体7)を0.21g(60%)得た。
実施例A2
4−[4−(フェニルメチル)−1−ピペラジニル]−安息香酸(0.0145モル)とO−(テトラヒドロ−2H−ピラン−2−イル)−ヒドロキシルアミン(0.029モル)とN,N’−メタンテトライル−ビスシクロヘキサンアミン(0.0145モル)と1−ヒドロキシ−1H−ベンゾトリアゾール(0.021モル)をDCMp.a.(200ml)に入れることで生じさせた混合物を室温で週末の間撹拌した。この反応混合物を水で洗浄し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた。その残留物をEtOAcから結晶化させ、濾別した後、乾燥させることで、3.5g得、そして別に2.0g得ることで、4−[4−(フェニルメチル)−1−ピペラジニル]−N−[(テトラヒドロ−2H−ピラン−2−イル)オキシ]−ベンズアミド(中間体8)を全体で5.5g(95%)得た。
実施例A3
a)
炭酸カリウム(0.18モル)と2−(メチルスルホニル)−5−ピリミジンカルボン酸エチルエステル(0.082モル)をアセトニトリルp.a.(135ml)に入れることで生じさせた溶液に、1−(フェニルメチル)−ピペラジン(0.068モル)をアセトニトリルp.a.(135ml)に入れることで生じさせた溶液を徐々に加えた後、この反応混合物を室温で45分間撹拌した。次に、この反応混合物を一晩放置した。DCM(400ml)を加えた。水(300ml)を加え、その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた。その残留物(28g)をシリカゲル使用カラムクロマトグラフィー(溶離剤:DCM/MeOHが95/5)で精製した。高純度画分を集めた後、溶媒を蒸発させた。その残留物をアセトニトリルから結晶化させ、濾別した後、真空下で乾燥させることで、中間体9を15.1g得た。
b)
中間体9(0.03モル)をEtOH(250ml)に入れることで生じさせた混合物に水添を10%Pd/C(2g)を触媒として用いて50℃で受けさせた。H2(1当量)の吸収が起こった後、前記触媒を濾別し、その濾液に蒸発を受けさせた。その残留物をシリカゲル使用カラムクロマトグラフィー(溶離剤:DCM/(MeOH/NH3)が90/10)で精製した。生成物画分を集めた後、溶媒を蒸発させることで、中間体10を6.8g(>96%)得た。
c)
中間体10(0.0022モル)と4−オキソ−1−ピペリジンカルボン酸1,1−ジメチルエチルエステル(0.0027モル)を1,2−ジクロロ−エタン(6ml)に入れることで生じさせた混合物にチタンテトラキス(エトキサイド)(0.0029モル)を加えた。この混合物を50℃で18時間撹拌した後、室温に冷却した。NaBH(OAc)3(0.0029モル)を分割して加えた。この混合物を室温で2時間撹拌した。水を加えた。この混合物をDCMで抽出した後、セライトで濾過した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を乾燥状態になるまで蒸発させた。その残留物(1.1g)をジエチルエーテル/DIPEから結晶化させた。その沈澱物を濾別した後、乾燥させることで、中間体11を0.49g(51%)得た。
d)
中間体11(0.0011モル)をHCl/iPrOH(5ml)に入れることで生じさせた混合物を50℃で1時間撹拌した後、室温に冷却した。その沈澱物を濾過し、EtOHに続いてジエチルエーテルで洗浄した後、乾燥させることで、中間体12(HCl塩)を0.38g(94%)得た。
e)
中間体12(0.001モル)とTEA(0.0032モル)をDCM(4ml)に入れることで生じさせた5℃の混合物にN2流下で塩化2−ナフタレンスルホニル(0.0011モル)をDCM(1ml)に入れることで生じさせた溶液を加えた。この混合物を室温で一晩撹拌した。10%の炭酸カリウムを加えた。この混合物をDCMで抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を乾燥状態になるまで蒸発させた。その残留物(0.53g)をジエチルエーテル/DIPEで取り上げた。その沈澱物を濾別した後、乾燥させることで、中間体13を0.42g(77%)得た。
実施例A4
a)
1−(2−ナフタレニルスルホニル)−ピペラジン(0.0018モル)と4−オキソ−1−ピペリジンカルボン酸1,1−ジメチルエチルエステル(0.0021モル)を1,2−ジクロロ−エタン(6ml)に入れることで生じさせた混合物にN2流下でテトラキス(2−プロパノラト)チタン(0.0023モル)を加えた。この混合物を50℃で18時間撹拌した後、室温に冷却した。NaBH(OAc)3(0.0023モル)を分割して加えた。この混合物を室温で4時間撹拌した。水を加えた。この混合物をセライトで濾過した。この混合物をDCMで抽出した。その濾液を傾斜法で取り出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を乾燥状態になるまで蒸発させた。その残留物(1.3g)をシリカゲル(70−200μm)使用カラムクロマトグラフィー(溶離剤:DCMが100からDCM/MeOHが99/1)で精製した。高純度画分を集めた後、溶媒を蒸発させることで、中間体14を0.72g(86%)得た。
b)
中間体14(0.0014モル)を5NのHCl/iPrOH(10ml)に入れることで生じさせた混合物を50℃で18時間撹拌した後、室温に冷却し、濾過し、ジエチルエーテルで洗浄した後、乾燥させることで、融点が260℃の中間体15(HCl塩)を0.53g(95%)得た。
実施例A5
テトラキス(トリフェニルホスフィン)−パラジウム(0.0045モル)を1,2−ジメトキシエタン(50ml)に入れることで生じさせた室温の溶液にN2流下で5−ブロモ−2−フランカルボキサルデヒド(0.0171モル)を1,2−ジメトキシエタン(15ml)に入れることで生じさせた溶液を滴下した。この混合物を20分撹拌した。[4−(ヒドロキシメチル)フェニル]−ホウ素酸(0.0257モル)をEtOH(18ml)に入れることで生じさせた懸濁液を加えた。この混合物を20分間撹拌した。炭酸ナトリウム(0.15モル)を加えた。この混合物を撹拌しながら4時間還流させた後、室温にもって行った。その有機層に蒸発を受けさせた。その残留物をDCMで取り上げた後、水で洗浄した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた。その残留物(4.1g)をシリカゲル(15−40μm)使用カラムクロマトグラフィー(溶離剤:DCM/MeOHが99/1)で精製した。高純度画分を集めた後、溶媒を蒸発させることで、中間体16を2.8g(82%)得た。
実施例A6
a)
4−ピペリジンメタンアミン(0.0868モル)と炭酸カリウム(0.0434モル)をアセトニトリル(200ml)に入れることで生じさせた10℃の溶液にN2流下で2−(メチルスルホニル)−5−ピリミジンカルボン酸エチルエステル(0.0434モル)をアセトニトリル(100ml)に入れることで生じさせた溶液を滴下した。この混合物を室温で2時間撹拌し、氷水の中に注ぎ出した後、DCMで抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた。その残留物(14.18g)をシリカゲル(20−45μm)使用カラムクロマトグラフィー(溶離剤:DCM/MeOH/NH4OHが90/10/1から80/20/2)で精製した。高純度画分を集めた後、溶媒を蒸発させることで、中間体17を3.7g(32%)得た。
b)
N−シクロヘキシルカルボジイミド,N’−メチルポリスチレン(153mg)(NovaBiochemカタログ番号01−64−0211)にN−アセチル−3,4,5−トリメトキシ−アントラニル酸(0.2ミリモル)をTHF(0.5ml)に溶解させて加えた後、1−ヒドロキシ−1H−ベンゾトリアゾールをTHF(0.5ml)に溶解させて加えた。この混合物を室温で10分間振とうした。次に、この懸濁液に中間体17(0.1ミリモル)をDCM(1ml)に溶解させて加えた後、窒素流を用いて溶媒を50℃で蒸発させ、次に、その反応混合物を混ぜ物なしに窒素流下で90℃に一晩放置した。その生成物をジクロロメタン(2mL)に溶解させた後、ガラスフィルターに通して濾過した。その残留物をDCM(2x2ml)で濯いだ後、その濾液に濃縮を受けさせた。次に、その生成物にTHF(1ml)と水酸化ナトリウム水溶液(1ml、1N)の混合物を用いた処理を室温で48時間受けさせた。最後に、HCl水溶液(1ml、1N)を添加して前記混合物を中和した後、窒素流下70℃で乾燥させることで、中間体18を得た。
c)
生成物である中間体18(0.1ミリモル)に、1−ヒドロキシ−1H−ベンゾトリアゾール(0.1ミリモル)とEDC(0.1ミリモル)とTEA(0.12ミリモル)をDCM/THF混合物(3/4、7ml)に入れることで生じさせた溶液を加えた。この反応混合物を室温で5分間振とうした後、O−(テトラヒドロ−2H−ピラン−2−イル)−ヒドロキシルアミン(0.1ミリモル)を加えた。その結果として生じた溶液を室温で一晩振とうした。次に、その反応混合物に濃縮を窒素流下50℃で体積が5mlになるまで受けさせた後、重合体に担持されているメチルイソシアネート(1.25ミリモル/g、0.25ミリモル、Argonaut、カタログ番号800261)および重炭酸(ポリスチリルメチル)トリメチルアンモニウム(0.6ミリモル)(NovaBiochemカタログ番号01−64−0419)を加えて、この混合物を更に2時間振とうした。この反応混合物を濾過した後、その濾液に濃縮を受けさせた。その生成物を調製用HPLCで精製することで中間体19を29mg得た。
実施例A7
中間体27(0.001モル)とTEA(0.008モル)をDCM(10ml)に入れることで生じさせた0℃の溶液にN2流下でメタンスルホニルクロライド(0.006モル)を加えた。この混合物を0℃で3時間撹拌し、氷水の中に注ぎ出した後、DCMで抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させることで、中間体20を0.44g得た。この生成物を次の反応段階で直接用いた。
実施例A8
a)
中間体のサンプル(0.1ミリモル)と2−フェニル−4H−3,1−ベンゾキサジン−4−オン(0.1ミリモル)を計り取って容器に入れた後、トルエン(2ml)を加えた。前記容器を密封して、前記混合物を90℃に10時間加熱した。次に、溶媒を蒸発させた後、その残留物をDCM(4ml)で取り上げ、次に、エタンジオイルジクロライド(1ミリモル)とDMF(1ミリモル)を加えた。その結果として得た混合物を90℃で一晩振とうした。次に、この反応混合物を10%の重炭酸ナトリウム水溶液(2X1ml)で洗浄し、相分離を起こさせた後、その有機層に濃縮を受けさせることで中間体21を得た。
b)
中間体21(粗)を室温で一晩激しく撹拌しながらTHF/1NのNaOH水溶液/MeOHの混合物(1/1/0.2、2.2ml)で処理した。次に、この溶液にHCl水溶液(1N、1ml)を加えて中和した。溶媒を真空下で蒸発させることで中間体22を得た。
c)
B. 最終化合物の調製
実施例B1
N−Fmoc−ヒドロキシルアミン2−クロロトリチル樹脂(Novabiochem、01−64−0165)に脱保護をDMF中50%のピペリジンを用いて受けさせた(室温、24時間)。前記樹脂をDCMおよびDMFで数回洗浄した後、DMFで膨潤させた。2当量の酸1、PyBrOPおよび4当量のDIEAを一度に加えた。この混合物を24時間振とうし、液体を排出させた後、その樹脂をDCMおよびDMFで数回洗浄した。その樹脂をアミンを2当量入れておいたDMFに入れて膨潤させ、室温で24時間振とうし、その液体を排出させた後、前記樹脂をDCMおよびDMFで洗浄した。DCM中5%のTFAを用いて最終生成物を開裂させ、HPLCおよびMSで分析した後、前以て重量を測定しておいた試験管に入れて蒸発させた。
1 樹脂の充填率を基準
実施例B2
中間体7(0.00075モル)と50%NH2OH/H2O(5ml)とKCN(0.001モル)とMeOH(10ml)とTHF(10ml)の混合物を室温で48時間撹拌した。溶媒を蒸発させた。その残留物をDCMで抽出した後、水で洗浄した。溶媒を除去した後、油状残留物(0.225g)をシリカゲル使用カラムクロマトグラフィー(溶離剤:NH4OH/CH3OH/CH2Cl2が0.05/0.95/99に続いてNH4OH/CH3OH/CH2Cl2が0.1/0.9/99)で精製した。高純度画分を集めた後、溶媒を蒸発させることで、融点が182−184℃の化合物1・H2Oを0.114gと融点が244−245℃の4−[4−[4−[1,5−ジヒドロ−3−メチル−1−(1−メチルプロピル)−5−オキソ−4H−1,2,4−トリアゾール−4−イル]フェニル]ヘキサヒドロ−1H−1,4−ジアゼピン−1−イル]−安息香酸を0.040g得た。
実施例B3
中間体8(0.000088モル)を5%TFA/MeOH(5ml)に入れて25℃で24時間撹拌した。次に、この反応混合物を水(5ml)+1当量のNaHCO3の中に注ぎ出した。この混合物をDCM(5ml、2x)で抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた(50℃でN2流を吹き込むことで乾燥)。その残留物を乾燥(真空下50℃)させることで、融点が196℃の化合物2を0.018g(65%)得た。
実施例B4
a)
中間体13(0.0008モル)と水酸化ナトリウム(0.0016モル)をEtOH(10ml)に入れることで生じさせた混合物を撹拌しながら2時間還流させた後、室温に冷却した。その沈澱物を濾過し、EtOHに続いてジエチルエーテルで洗浄した後、乾燥させることで、中間体24(ナトリウム塩)を0.425g(>100%)得た。
b)
中間体24(0.0008モル)とO−(テトラヒドロ−2H−ピラン−2−イル)−ヒドロキシルアミン(0.001モル)と1−ヒドロキシ−1H−ベンゾトリアゾール(0.001モル)をDCM/THF(10ml)に入れることで生じさせた混合物にN2流下でEDC(0.001モル)を加えた。この混合物を室温で18時間撹拌した。その沈澱物を濾過し、THFに続いてジエチルエーテルで洗浄した後、乾燥させることで、融点が260℃の中間体25を0.4g(83%)得た。
c)
中間体25(0.0006モル)をMeOH(10ml)に入れることで生じさせた混合物にTFA(0.5ml)を加えた。この混合物を室温で5日間撹拌した。その沈澱物を濾過し、ジエチルエーテルで洗浄した後、乾燥させた。その残留物を水で取り上げ、30分間撹拌し、濾別した後、乾燥させることで、融点が210℃の化合物3(・0.91CF3COOH)を0.143g(38%)得た。
実施例B5
中間体15(0.0013モル)と2−(メチルスルホニル)−5−ピリミジンカルボン酸エチルエステル(0.0017モル)と炭酸カリウム(0.0039モル)をアセトニトリル(10ml)に入れることで生じさせた混合物を80℃で18時間撹拌した。水を加えた。この混合物をDCMで抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を乾燥状態になるまで蒸発させた。その残留物(0.5g)をCH3CN/DIPEから結晶化させた。その沈澱物を濾別した後、乾燥させることで、中間体26を0.25g(37%)得た。
中間体10(0.0015モル)と中間体16(0.0015モル)をMeOH(6ml)に入れることで生じさせた混合物を60℃で20時間撹拌した後、0℃に冷却した。ヒドロホウ酸ナトリウム(0.0022モル)を加えた。この混合物を室温にもって行った後、4時間撹拌し、氷水の中に注ぎ出した後、DCMで抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた。その残留物(0.8g)をシリカゲル(15−40μm)使用カラムクロマトグラフィー(溶離剤:DCM/MeOH/NH4OHが97/3/0.1から95/5/0.1)で精製した。高純度画分を集めた後、溶媒を蒸発させることで、中間体27を0.28g(45%)得た。
中間体10(0.0042モル)と2−ナフタレンカルボキサルデヒド(0.005モル)を1,2−ジクロロ−エタン(10ml)に入れることで生じさせた混合物を50℃で3時間撹拌した後、室温に冷却した。NaBH(OAc)3(0.0055モル)を分割して加えた。この混合物を室温で2時間撹拌した。水を加えた。この混合物をDCMで抽出した。その有機層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を乾燥状態になるまで蒸発させた。その残留物(2g)をCH3CN/DIPEで取り上げた。その沈澱物を濾別した後、乾燥させることで、融点が147℃の中間体28を1.2g(75%)得た。
中間体10(0.0024モル)と炭酸カリウム(0.0048ル)をアセトニトリル(6ml)に入れることで生じさせた5℃の混合物に、2−ナフタレンエタノール,メタンスルホネート(0.0029モル)をアセトニトリル(3ml)に入れることで生じさせた溶液を加えた。この混合物を室温で18時間撹拌し、撹拌しながら一晩還流させた後、室温に冷却した。水を加えた。この混合物を濾過し、水に続いてジエチルエーテルで洗浄した後、乾燥させることで、融点が128℃の中間体29を0.45g(48%)得た。
中間体19(0.05ミリモル)にTFA(2ml、1/1のDCM/MeOH中)による処理を室温で10日間受けさせた。次に、溶媒を窒素流下室温で蒸発させた後、1,4−ジオキサンを加えて、蒸発手順を繰り返した。次に、このサンプルを窒素流下40℃で一晩乾燥させることで化合物8(・CF3COOH)を得た。
実施例B10
中間体20(0.001モル)とモルホリン(0.0013モル)と炭酸カリウム(0.002モル)をアセトニトリル(6ml)に入れることで生じさせた混合物を撹拌しながら一晩還流させた後、冷却して氷水の中に注ぎ出し、EtOAcで抽出した。その有層を分離し、乾燥(MgSO4)させ、濾過した後、溶媒を蒸発させた。その残留物(0.79g)をシリカゲル(10μm)使用カラムクロマトグラフィー(溶離剤:DCM/MeOH/NH4OHが96/4/0.1)で精製した。高純度画分を集めた後、溶媒を蒸発させた。その残留物(0.183g)をDIPEから結晶化させた。その沈澱物を濾別した後、乾燥させることで、融点が120℃の中間体30を0.086g(47%)得た。
中間体23にTFAの溶液(1/1のDCM/MeOH中5%、2ml)を加えた後、この反応混合物を室温で5日間撹拌した。次に、溶媒を窒素流下室温で蒸発させた後、1,4−ジオキサンを添加し、そして濃縮手順を繰り返した。次に、このサンプルを窒素流下40℃で一晩乾燥させることで化合物10(・CF3COOH)を得た。
ヒストンデアセチラーゼのインビトロ阻害検定(実施例C.1を参照)では、前記式(I)で表される化合物を用いることで得られるHDAC酵素活性抑制を測定する。
実施例C.1:ヒストンデアセチラーゼのインビトロ阻害検定:
HeLa核抽出液(供給業者:Biomol)を60μg/mlの量で2x10−8Mの放射能標識付きペプチド基質と一緒にインキュベートした。HDAC活性測定用基質として合成ペプチド、即ちヒストンH4のアミノ酸14−21を用いた。6−アミノカプロン酸であるスペーサーを用いて前記基質のNH2末端部にビオチニル化を受けさせそしてCOOH末端部をアミド基で保護する、具体的には、リシン16の所を[3H]アセチル化する。Hepesを25mMとスクロースを1MとBSAを0.1mg/mlとTriton X−100を0.01%含有する緩衝液(pH7.4)に基質であるビオチン−(6−アミノカプロン酸)Gly−Ala−([3H]−アセチル−Lys−Arg−His−Arg−Lys−Val−NH2)を加えた。30分後、HClと酢酸を添加(それぞれの最終濃度が0.035mMおよび3.8mMになるように)することで脱アセチル反応を停止させた。反応停止後、遊離3H−アセテートを酢酸エチルで抽出した。混合および遠心分離を行った後、β−カウンターを用いて、一定分量の上方(有機)相が示す放射能を計数した。各実験毎に対照(化合物なしにHeLa核抽出液とDMSOを含有)、ブランクインキュベーション(DMSOは入れたが、HeLa核抽出液も化合物も入っていない)およびサンプル(化合物をDMSOに溶解させて入れかつHeLa核抽出液も入れた)に試験を並行して受けさせた。1番目として、化合物に試験を10−5Mの濃度で受けさせた。この化合物が10−5Mの時に活性を示した場合には、その化合物に試験を10−5Mから10−12Mの濃度で受けさせて濃度応答曲線を作成した。各試験毎に対照の値およびサンプルの値の両方からブランクの値を差し引いた。対照サンプルは基質が脱アセチルを100%受けることに相当していた。各サンプル毎に放射能を対照の平均値のパーセントとして表した。適宜、段階的データ(graded data)に関してプロビット解析を用いることでIC50値(代謝産物の量を対照の50%にまで下げるに必要な薬剤の濃度)を計算した。本明細書では、試験化合物が示す効果をpIC50(IC50値の負log値)として表す。試験を受けさせたあらゆる化合物が10−5Mの試験濃度の時に酵素活性を示し、28個の化合物が示したpIC50値は≧5であった(表F−2を参照)。
実施例C.2: A2780細胞に対する抗増殖活性の測定
試験を受けさせるあらゆる化合物をDMSOに溶解させた後、培養培地でさらなる希釈を行った。細胞増殖検定では、最終DMSO濃度が0.1%(体積/体積)を超えないようにした。対照には化合物を含有させないでA2780細胞とDMSOを含有させ、そしてブランクには細胞を含有させないでDMSOを含有させた。MTTをPBSに5mg/ml溶解させた。0.1Mのグリシンと0.1MのNaClで構成させてNaOH(1N)でpHが10.5になるように緩衝させたグリシン緩衝液を調製した(あらゆる試薬をMerckから入手した)。
実施例C.3: 水性媒体中の動的溶解性
1番目の希釈段階で、100μlの燐酸塩クエン酸塩緩衝液(pH7.4)に、DMSO(5mM)に溶解させておいた活性化合物の濃ストック溶液を10μl添加して混合した。2番目の希釈段階で、前記1番目の希釈段階の一定分量(20μl)を更に100μlの燐酸塩クエン酸塩緩衝液(pH7.4)に入れて分散させて混合した。最後に、3番目の希釈段階で、前記2番目の希釈段階のサンプル(20μl)を更に100μlの燐酸塩クエン酸塩緩衝液(pH7.4)に入れて希釈して混合した。あらゆる希釈を96個ウエルプレートを用いて実施した。最後の希釈段階後直ちに、前記逐次的3希釈段階の濁度を比濁計で測定した。偶発的誤差を排除する目的で希釈を各化合物毎に三重に実施した。濁度測定値を基にして3等級に分ける等級付けを実施する。高い溶解性を示した化合物に3の等級を与え、この化合物は1番目の希釈で透明である。中間的な溶解性を示した化合物に2の等級を与えた。このような化合物は1番目の希釈で不透明であるが、2番目の希釈では透明である。溶解性が低い化合物には1の等級を与え、このような化合物は1番目および2番目の希釈の両方とも不透明である。6個の化合物が示す溶解度を測定した。これらの化合物の中で3個の化合物が3の等級を示し、2個の化合物が2の等級を示し、そして1個の化合物が1の等級を示した(表F−2を参照)。
実施例C.4: 平行人工膜透過分析
深ウエル(deep−well)またはプレミックスプレート(Pre−mix plate)を用い、これにpHが4またはpHが7.4の水性緩衝液系[PSR4 System Solution Concentrate(pION)]を2ml入れ、これにストックサンプル(100%DMSO中5mMのストック溶液の一定分量である10μl)を入れることで希釈を行った。サンプルを基準プレートに加える前に、ウエルに緩衝液を150μl加えてブランクの紫外線測定を実施した。その後、その緩衝液を廃棄した後、そのプレートを基準プレートとして用いた。あらゆる測定を耐紫外線性プレート(供給業者:CostarまたはGreiner)を用いて実施した。基準プレートのブランク測定を行った後、その基準プレートに前記希釈したサンプルを150μl加え、そしてドナープレート(donorplate)1に前記希釈したサンプルを200μl加えた。アクセプターフィルタープレート(acceptor filter plate)1(供給業者:Millipore、タイプ:MAIP N45)を人工膜形成溶液(2,6−ジ−t−ブチル−4−メチルフェノール含有量が0.1%のドデカンに入っている1,2−ジオレオイル−sn−Glycer−3−ホスホコリン)(4μl)で覆った後、ドナープレート1の上に置くことで「サンドイッチ」を生じさせた。上部のアクセプターウエルに緩衝液(200μl)を分与した。前記サンドイッチを蓋で覆った後、室温の暗所に18時間貯蔵した。
実施例C.5: 代謝安定性
Gorrod他(Xenobiotica 5:453−462、1975)に従い、組織を機械的に均一にした後に遠心分離を行うことで、細胞内組織標本(sub−cellular tissue preparations)を作成した。肝臓の組織を氷で冷却しておいた0.1MのTris−HCl(pH7.4)緩衝液で濯ぐことで余分な血液を洗い流した。次に、組織を吸い取り紙で乾燥させ、重量を測定した後、外科用ハサミを用いて粗く細断した。テフロン製乳棒が備わっているPotter−S(Braun、イタリア)またはSorvall Omni−Mixホモジェナイザーのいずれかを用いて、前記組織片を氷で冷却しておいた3倍体積の0.1M燐酸塩緩衝液(pH7.4)に入れて7x10秒間均一にした。両方の場合とも、均一化過程を行っている間、その容器を氷の中/上に保持した。
実施例C.6: p21誘導能力
ヒトA2780卵巣癌細胞の中に発現するp21蛋白質のレベルを測定する目的で下記のプロトコルを適用した。A2780細胞(180μl当たり20000個の細胞)を96個ミクロウエルのプレートに入れておいたRPMI 1640培地(L−グルタミンを2mM、ゲンタマイシンを50μg/mlおよびウシ胎児血清を10%補充)に種付けした。この細胞を溶解させる24時間前に化合物を10−5、10−6、10−7および10−8Mの最終濃度で加えた。試験を受けさせるあらゆる化合物をDMSOに溶解させた後、培養培地を用いてさらなる希釈を行った。当該化合物を添加して24時間後に上澄み液を細胞から除去した。細胞を氷で冷却しておいた200μlのPBSで洗浄した。これらのウエルに吸引を受けさせた後、溶解用緩衝液(lysisbuffer)[Tris・HCl(pH7.6)が50mMでNaClが150mMでNonidet p40が1%でグリセロールが10%]を30μl加えた。これらのプレートを−70℃で一晩インキュベートした。
錠剤中心部の調製
式(I)で表される化合物が100gでラクトースが570gで澱粉が200gの混合物を充分に混合した後、5gのドデシル硫酸ナトリウムと10gのポリビニルピロリドンを約200mlの水に入れることで生じさせた溶液で湿らせる。この湿らせた粉末混合物をふるいにかけ、乾燥させた後、再びふるいにかける。次に、微結晶性セルロースを100gおよび水添植物油を15g加える。その全体を充分に混合した後、圧縮して錠剤にすることで、各々が式(I)で表される化合物を10mg含有する錠剤を10,000個得る。
被覆
10gのメチルセルロースを75mlの変性エタノールに入れることで生じさせた溶液に、5gのエチルセルロースを150mlのジクロロメタンに入れることで生じさせた溶液を加える。次に、75mlのジクロロメタンおよび2.5mlの1,2,3−プロパントリオールを加える。10gのポリエチレングリコールを溶融させて75mlのジクロロメタンに溶解させる。後者の溶液を前者に加え、オクタデカン酸マグネシウムを2.5g、ポリビニルピロリドンを5gおよび濃カラー懸濁液(concentrated colour suspension)を30ml加えた後、その全体を均一にする。被覆装置を用いて、そのようにして得た混合物で前記錠剤中心部を覆った。
Claims (10)
- 式(I)
Xは、窒素または炭素であり、
Yは、窒素または炭素であり、
Zは、窒素または
各R3は、独立して、水素原子を表し、そして1つの水素原子がアリールから選択される置換基に置き換わっていてもよく、
nが1または2であり、tが0、1、2または4であり、Qが炭素であり、R1が−C(O)NH(OH)であり、R2が水素またはニトロであり、−L−が直接結合またはC1-6アルカンジイルから選択される二価の基であり、R4が水素であり、
各sが独立して0、1、2または4であり、
各R5およびR6が独立して水素;ハロ;トリハロC1-6アルキル;C1-6アルキル;アリールおよびC3-10シクロアルキルで置換されているC1-6アルキル;C1-6アルキルオキシ;C1-6アルキルカルボニル;ベンゾフラニル;ナフタレニルスルホニル;アリールオキシで置換されているピリジニル;フェニル;ヒドロキシC1-4アルキルまたはモルホリニルC1-4アルキルから独立して選択される1個の置換基で置換されているフェニルから選択され、
この上に示したアリールはフェニル、または各々がハロ、C1-6アルキル、C1-6アルキルオキシ、トリフルオロメチル、シアノまたはヒドロキシカルボニルから独立して選択される1個以上の置換基で置換されているフェニルである]
で表される化合物、薬学的に受け入れられる付加塩および立体化学異性体。 - nが1であり、tが0または1であり、Qが炭素であり、Xが窒素であり、Yが窒素であり、R1が−C(O)NH(OH)であり、R2が水素であり、−L−が直接結合であり、各R3が独立して水素原子を表し、R4が水素であり、
- 化合物番号8、番号5、番号7、番号6および番号9
- 薬剤的に受け入れられる担体および請求項1から3のいずれか記載の化合物を活性材料として治療有効量で含有して成る薬剤組成物。
- 請求項4記載の薬剤組成物を製造する方法であって、薬学的に受け入れられる担体と請求項1から3のいずれか記載の化合物を密に混合する方法。
- 薬剤として使用するための請求項1から3のいずれか記載の化合物。
- 増殖性疾患治療用薬剤を製造するための請求項1から3のいずれか記載化合物の使用。
- 請求項1記載の化合物を製造する方法であって、
- 生物学的サンプルに入っているHDACをインビトロで検出または同定する方法であって、標識を付けた請求項1記載の化合物とHDACの間の複合体の形成を検出または測定
することを含んで成る方法。 - 有効成分として抗癌剤と請求項1から3のいずれか記載の化合物とを含んでなる癌を治療するための医薬組成物。
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