JP4836405B2 - ヒストンデアセチラーゼの新規な阻害剤としてのアミノカルボニル誘導体 - Google Patents
ヒストンデアセチラーゼの新規な阻害剤としてのアミノカルボニル誘導体 Download PDFInfo
- Publication number
- JP4836405B2 JP4836405B2 JP2003574640A JP2003574640A JP4836405B2 JP 4836405 B2 JP4836405 B2 JP 4836405B2 JP 2003574640 A JP2003574640 A JP 2003574640A JP 2003574640 A JP2003574640 A JP 2003574640A JP 4836405 B2 JP4836405 B2 JP 4836405B2
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- JP
- Japan
- Prior art keywords
- alkyl
- amino
- hydroxy
- alkyloxy
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 108090000353 Histone deacetylase Proteins 0.000 title claims abstract description 32
- 102000003964 Histone deacetylase Human genes 0.000 title claims abstract description 32
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 title claims description 12
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
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- 125000000217 alkyl group Chemical group 0.000 claims description 326
- -1 hydroxy, amino Chemical group 0.000 claims description 106
- 125000003545 alkoxy group Chemical group 0.000 claims description 105
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 59
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 28
- 125000003282 alkyl amino group Chemical group 0.000 claims description 26
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000002757 morpholinyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004104 aryloxy group Chemical group 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
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- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000002971 oxazolyl group Chemical group 0.000 claims description 10
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
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- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 7
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
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- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
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- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
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- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
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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、
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、−N(H)C(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、
R3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、
Zが窒素に相当する時には−L−は直接結合であり、
Zが
R4は、水素、C1−6アルキル、C3−10シクロアルキル、ヒドロキシC1−6アルキル、C1−6アルキルオキシC1−6アルキル、ジ(C1−6アルキル)アミノC1−6アルキルまたはアリールであり、
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;インドリル;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であり、
b)各Qが
c)R1が−C(O)NR7R8または−NHC(O)C1−6アルカンジイルSHであり、ここで、R7およびR8が各々独立して水素、ヒドロキシまたはヒドロキシC1−6アルキルから選択され、
d)R2が水素またはニトロであり、
e)R3が水素であり、
f)Zが
g)R4が水素、C1−6アルキルまたはアリールであり、
h)
i)各sが独立して0、1または2であり、
j)各R5が独立して水素;ハロ;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;アリールオキシ;シアノまたは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)各Qが
c)各Xが窒素であり、
d)各Yが窒素であり、
e)R1が−C(O)NH(OH)であり、
f)R2が水素であり、
g)R3が水素であり、
h)Zが
i)R4が水素、C1−6アルキルまたはアリールであり、
j)
k)各R5が独立して水素または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)各Zが窒素であり、
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)R3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、
e)R4が水素であり、
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。
各Zが窒素であり、
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、
R3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、
R4が水素であり、
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、そして
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、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) 4−(1−ピペラジニル)−安息香酸エチルエステル(0.043モル)とトリエチルアミン(0.051モル)をDCMp.a.(75ml)に入れることで生じさせた溶液を0℃(氷)で撹拌しながら1−イソシアナト−4−メチル−ベンゼン(0.051モル)をDICp.a.(75ml)に入れることで生じさせた溶液を20分かけて滴下した。この反応混合物を室温で1時間撹拌した後、水で抽出した。その有機層を飽和NaCl溶液そして再び水で抽出した後、分離し、乾燥(MgSO4)させ、濾別した後、その濾液に蒸発を受けさせた。その残留物をDIPEに入れて撹拌し、生じた沈澱物を濾別し、DIPEで洗浄した後、乾燥させた。その残留物(14.3g、90%)の一部(0.5g)を2−プロパノール(10ml)から結晶化させ、生じた沈澱物を濾別した後、乾燥させることで、4−[4−[[(4−メチルフェニル)アミノ]カルボニル]−1−ピペラジニル]−安息香酸エチルエステル(中間体1)を0.42g得た。
b) 中間体1(0.021モル)と36%のHCl(150ml)の混合物を撹拌しながら3時間還流させた後、水(400ml)の中に注ぎ出して30分間撹拌した。その沈澱物を濾別し、水で洗浄した後、乾燥させることで、4−[4−[[(4−メチルフェニル)アミノ]カルボニル]−1−ピペラジニル]−安息香酸・HCl(1:1)(中間体2)を6.57g(92%)得た。
c) 中間体2(0.0009モル)とDIC(0.002モル)と4−メチルモルホリン(0.44モル)をDIC(50ml)に入れることで生じさせた混合物を撹拌した。塩酸O−(フェニルメチル)−ヒドロキシルアミン(0.002モル)を加えた。この混合物を室温で24時間撹拌した。水(50ml)を加えた。この混合物を濾過した。層分離を起こさせた。その有機層を乾燥させ、濾過した後、溶媒を蒸発させた。その残留物を2−プロパノールの下で磨り潰した。その沈澱物を濾別した後、乾燥させることで、N−(4−メチルフェニル)−4−[4−[[(フェニルメトキシ)アミノ]カルボニル]フェニル]−1−ピペラジンカルボキサミド(中間体3)を0.133g(33%)得た。
実施例A2
a)
ピペラジン(0.5モル)をアセトニトリル(500ml)と炭酸カリウム(50g)に入れることで生じさせた混合物を室温で撹拌した後、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(0.10モル)をアセトニトリル(200ml)に入れることで生じさせた溶液を室温で滴下した。この反応混合物を室温で1時間撹拌した後、水で希釈した。その有機溶媒を蒸発させ(CH3CNを除去し)た後、その水性濃縮液にDCMによる抽出を3回受けさせた。その有機層を一緒にし、水で洗浄した後、乾燥(MgSO4)させた。溶媒を蒸発させた後、その残留物に結晶化をDIPEを用いて受けさせ、その結果として生じた沈澱物を濾別した後、乾燥させることで中間体4を3.8g得た。その濾液に蒸発を受けさせた後、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が95/5)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4を11.9g得た。中間体4の全収量は15.7gであった。
b)
中間体4(0.0002モル)とジフェニルカルバミン酸クロライド(0.0003モル)とモルホリノメチル−PS−捕捉剤(供給業者:Novabiochem カタログ番号01−64−0171:モルホリノメチルポリスチレンHL(200−400メッシュ)、2%ジビニルベンゼン)(0.150g)をDCM(5ml)に入れることで生じさせた混合物を室温で20時間撹拌した後、トリス(2−アミノエチル)アミン−PS捕捉剤(供給業者:Novabiochem カタログ番号01−64−0170:トリス−(2−アミノメチル)−アミンポリスチレンHL(200−400メッシュ)、1%ジビニルベンゼン)(0.150g)を加えて、この反応混合物を更に4時間撹拌した。前記捕捉剤を濾別し、DCMで洗浄した後、溶媒を蒸発させることで、中間体5を得た。
c)
中間体5(0.0003モル)を1Nの水酸化ナトリウム(1.5ml)とTHF(4ml)とMeOH(1ml)に入れることで生じさせた混合物を室温で3日間撹拌した後、この反応混合物を1NのHCl(1.5ml)で中和した。この混合物をExtrelut(商標)NT(供給業者:Merck)に通して濾過した後、N2流下で乾燥させることで中間体6を得た。
d)
中間体6(0.0003モル)とHOBT−6−カルボキサミドメチル−PS−捕捉剤(0.200g;Novabiochemカタログ番号01−64−0425)とN,N−ジメチル−4−ピリジンアミン(0.00015モル)をDCM/DMF(5ml)に入れることで生じさせた混合物を室温で15分間撹拌した後、N,N’−メタンテトライルビス−2−プロパンアミン(0.070ml)を加えて、この反応混合物を4時間振とうした。この樹脂をDCMで3回、DMFで3回そして再びDCMで3回そしてDMFで3回、最後にDCMで6回洗浄した。O−(テトラヒドロ−2H−ピラン−2−イル)−ヒドロキシルアミン(0.00026モル)をDCM(5ml)に入れることで生じさせた溶液を加えた後、この反応混合物を20時間振とうし、次に、PS結合メチルイソシアネート(0.150g)を加えて、この混合物を4時間振とうした。前記捕捉剤を濾別し、DCMで2回洗浄した後、その濾液に蒸発を受けさせることで、中間体7を得た。
実施例A3
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8を3.7g(32%)得た。
b)
中間体8(0.0049モル)と4−イソシアナト−1,1’−ビフェニル(0.0074モル)をTHF(30ml)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、室温に冷却して、氷水の中に注ぎ出した。その沈澱物を濾過し、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、中間体9を2.215g(98%)得た。
B. 最終化合物の調製
実施例B1
中間体3(0.0013モル)に水添をDMF(10ml)中で10%Pd/C(0.2g)を触媒として用いて受けさせた。H2(1当量)の吸収が起こった後、前記触媒をジカライト(dicalite)で濾別した後、溶媒を蒸発させた。その残留物をDCM/MeOH(300ml;50/50)に溶解させた後、濾紙を用いて濾過した。その濾液の溶媒を蒸発させた。その残留物をDCM下で磨り潰した。その沈澱物を濾別した後、乾燥させることで化合物1を0.35g(76%)得た。
実施例B2
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)1。前記樹脂をDCMおよびDMFで数回洗浄2した後、DMFで膨潤させた。2当量の酸3、PyBrOP4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に入れて膨潤させた後、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。3当量の酸、DICおよびDIEAを樹脂と一緒にして室温で一晩振とうした。前記樹脂を排出させた後、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 1つの実施例である化合物2ではグリシノール2−クロロトリチル樹脂(Novabiochem、01−64−0087)を用いた。1つの実施例である化合物3ではカルボキシメタンチオール4−メトキシトリチル樹脂(Novabiochem、01−64−0238)を用いた。
2 化合物2および3の2つのケースでは、また、異なる洗浄手順でMeOHも用いた。
3 樹脂の充填率を基準
4 化合物2および3の2つのケースでは、PyBrOPの代わりにPyBOPを用いた。
実施例B3
中間体7(0.0003モル)をTFA(5ml、MeOH中5%)に入れることで生じさせた混合物を室温で20時間撹拌した後、この反応混合物にブロー乾燥を受けさせる(blown dry)ことで、化合物4を得た。
実施例B4
a)
中間体9(0.0032モル)と水酸化ナトリウム(0.0128モル)をEtOH(20ml)に入れることで生じさせた混合物を80℃で24時間撹拌した後、室温に冷却した。その沈澱物を濾過し、ジエチルエーテルで洗浄した後、乾燥させることで、中間体10・Naを1.31g(90%)得た。
b)
中間体10・Na(0.0029モル)をDMF(25ml)に入れることで生じさせた室温の溶液にN2流下でEDC(0.0037モル)とHOBT(0.0037モル)を加えた。この混合物を45分間撹拌した。O−(テトラヒドロ−2H−ピラン−2−イル)−ヒドロキシルアミン(0.0037モル)を加えた。この混合物を室温で3日間撹拌した後、氷水の中に注ぎ出した。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。その沈澱物を濾過し、水で洗浄した後、乾燥させた。その残留物(0.8g)をDMF(8ml)/水(2ml)から結晶化させた。その沈澱物を濾過し、ジエチルエーテルで洗浄した後、乾燥させることで、融点が188℃の中間体11を0.734g(48%)得た。
c)
中間体11(0.0014モル)をTFA(2ml)とMeOH(20ml)とDCM(2ml)に入れることで生じさせた混合物を室温で3日間撹拌した。その沈澱物を濾別した後、乾燥させた。その残留物(0.553g)をDCM/MeOHで取り上げた。この混合物を4時間撹拌した後、室温に2日間保持した。その沈澱物を濾別した後、乾燥させることで、融点が>260℃の化合物5を0.055g得た。
実施例B5
中間体4(0.0031モル)と4−イソシアナト−1,1’−ビフェニル(0.0046モル)をTHF(20ml)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、室温に冷却して、氷水の中に注ぎ出した。その沈澱物を濾過し、水/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を1.31g(98%)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。3個の化合物が示す溶解度を測定した。1個の化合物が1の等級を示し、1個の化合物が2の等級を示し、そして1個の化合物が3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。
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。
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 (12)
- 式(I)
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、
Qは、窒素または
Xは、窒素または
Yは、窒素または
Zは、窒素または
R1は、−C(O)NR7R8または−NHC(O)C1-6アルカンジイルSHであり、ここで、
R7およびR8は、各々独立して、水素、ヒドロキシまたはヒドロキシ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、
R3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、
Zが窒素に相当する時には−L−は直接結合であり、
Zが
R4は、水素、C1-6アルキル、C3-10シクロアルキル、ヒドロキシC1-6アルキル、C1-6アルキルオキシC1-6アルキル、ジ(C1-6アルキル)アミノC1-6アルキルまたはアリールであり、
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;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;インドリル;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、または該化合物のN−オキサイド、薬学的に受け入れられる付加塩もしくは立体化学異性体。 - Zが窒素であり、
R1が−C(O)NR7R8または−NHC(O)C1-6アルカンジイルSHであり、ここで、R7およびR8が各々独立して水素、ヒドロキシまたはヒドロキシ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、
R3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、
R4が水素であり、
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;インドリル;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、そして
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、
請求項1記載の化合物。 - nが1であり、Qが
- nが1であり、Qが
- 化合物番号4、化合物番号48、化合物番号5および化合物番号6
- 薬剤的に受け入れられる担体および請求項1から5のいずれかに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6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5のいずれかに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5のいずれかに記載の化合物。
- 増殖性疾患治療用薬剤を製造するための請求項1から5のいずれかに記載化合物の使用。
- 請求項1記載の化合物であって、R1が−C(O)NH(OH)である化合物を製造する方法であって、
- 標識を付けた請求項1記載の化合物を活性材料として含む生物学的サンプルに入っているHDACを検出または同定するための試験キット。
- 抗癌剤と請求項1から5のいずれかに記載の化合物の腫瘍細胞の増殖を抑制するための併用剤。
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