JP4725944B2 - ヒストンデアセチラーゼの阻害剤 - Google Patents
ヒストンデアセチラーゼの阻害剤 Download PDFInfo
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- JP4725944B2 JP4725944B2 JP2003574203A JP2003574203A JP4725944B2 JP 4725944 B2 JP4725944 B2 JP 4725944B2 JP 2003574203 A JP2003574203 A JP 2003574203A JP 2003574203 A JP2003574203 A JP 2003574203A JP 4725944 B2 JP4725944 B2 JP 4725944B2
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- Prior art keywords
- alkyl
- compound
- formula
- amino
- acid
- 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
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- 239000003814 drug Substances 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 76
- -1 hydroxy, amino Chemical group 0.000 claims description 73
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
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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、
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)NR5R6、−N(H)C(O)R7、−C(O)−C1−6アルカンジイルSR7、−NR8C(O)N(OH)R7、−NR8C(O)C1−6アルカンジイルSR7、−NR8C(O)C=N(OH)R7または別のZn−キレート基であり、ここで、
R5およびR6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、
R7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、
R8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、C1−6アルキル、アリールC2−6アルケンジイル、フラニルカルボニル、ナフタレニルカルボニル、−C(O)フェニルR9、C1−6アルキルアミノカルボニル、アミノスルホニル、アリールアミノスルホニル、アミノスルホニルアミノ、ジ(C1−6アルキル)アミノスルホニルアミノ、アリールアミノスルホニルアミノ、アミノスルホニルアミノ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、アリールアミノスルホニルアミノC1−6アルキル、ジ(C1−6アルキル)アミノC1−6アルキル、C1−12アルキルスルホニル、ジ(C1−6アルキル)アミノスルホニル、トリハロC1−6アルキルスルホニル、ジ(アリール)C1−6アルキルカルボニル、チオフェニルC1−6アルキルカルボニル、ピリジニルカルボニルまたはアリールC1−6アルキルカルボニルであり、ここで、
各R9は、独立して、フェニル;ハロ、アミノ、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、ヒドロキシC1−4アルキルオキシ、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(C1−6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C1−6アルキル、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、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アルキルピペラジニルC1−4アルキル、ジ(ヒドロキシC1−4アルキル)アミノ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C1−4アルキルオキシ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、2または3個の置換基で置換されているフェニル;チオフェニル;またはジ(C1−4アルキル)アミノC1−4アルキルオキシ、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(C1−6アルキル)アミノC1−6アルキル、ピロリジニル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、ジ(ヒドロキシC1−4アルキル)アミノC1−4アルキルまたはモルホリニルC1−4アルキルオキシで置換されているチオフェニルから選択され、
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、
R3とR4が同じ炭素原子上に存在する時にはR3とR4が一緒になって式
−C(O)−NH−CH2−NR10− (a−1)
(式中、R10は水素またはアリールである)
で表される二価の基を形成していてもよく、
R3とR4が隣接する炭素原子上に存在する時にはR3とR4が一緒になって式
=CH−CH=CH−CH= (b−1)
で表される二価の基を形成していてもよく、
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0または1であり、
b)各Qが
c)R1が−C(O)NH(OH)または−NHC(O)C1−6アルカンジイルSHであり、
d)R2が水素またはニトロであり、
e)R3がC1−6アルキル、アリールC2−6アルケンジイル、フラニルカルボニル、ナフタレニルカルボニル、C1−6アルキルアミノカルボニル、アミノスルホニル、ジ(C1−6アルキル)アミノスルホニルアミノC1−6アルキル、ジ(C1−6アルキル)アミノC1−6アルキル、C1−12アルキルスルホニル、ジ(C1−6アルキル)アミノスルホニル、トリハロC1−6アルキルスルホニル、ジ(アリール)C1−6アルキルカルボニル、チオフェニルC1−6アルキルカルボニル、ピリジニルカルボニルまたはアリールC1−6アルキルカルボニルであり、
f)R4が水素であり、
g)R3とR4が同じ炭素原子上に存在する時にはR3とR4が一緒になって式(a−1)[式中、R10はアリールである]で表される二価の基を形成していてもよく、
h)R3とR4が隣接する炭素原子上に存在する時にはR3とR4が一緒になって式(b−1)で表される二価の基を形成していてもよい、
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Zが窒素であり、
d)R1が−C(O)NH(OH)であり、
e)R2が水素であり、
f)R3がナフタレニルカルボニル、C1−12アルキルスルホニルまたはジ(アリール)C1−6アルキルカルボニルであり、
g)R4が水素である、
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)R1が−C(O)NR5R6、−C(O)−C1−6アルカンジイルSR7、−NR8C(O)N(OH)R7、−NR8C(O)C1−6アルカンジイルSR7、−NR8C(O)C=N(OH)R7または別のZn−キレート基であり、ここで、
R5およびR6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、
b)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、
c)R3が水素、C1−6アルキル、アリールC2−6アルケンジイル、フラニルカルボニル、ナフタレニルカルボニル、−C(O)フェニルR9、C1−6アルキルアミノカルボニル、アミノスルホニル、アリールアミノスルホニル、アミノスルホニルアミノ、ジ(C1−6アルキル)アミノスルホニルアミノ、ジ(C1−6アルキル)アミノC1−6アルキル、C1−12アルキルスルホニル、ジ(C1−6アルキル)アミノスルホニルまたはピリジニルカルボニルであり、
ここで、各R9が独立してフェニル;ハロ、C1−6アルキル、C1−6アルキルオキシ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;またはチオフェニルから選択され、
d)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。
R1が−C(O)NR5R6、−C(O)−C1−6アルカンジイルSR7、−NR8C(O)N(OH)R7、−NR8C(O)C1−6アルカンジイルSR7、−NR8C(O)C=N(OH)R7または別のZn−キレート基であり、ここで、
R5およびR6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、C1−6アルキル、アリールC2−6アルケンジイル、フラニルカルボニル、ナフタレニルカルボニル、−C(O)フェニルR9、C1−6アルキルアミノカルボニル、アミノスルホニル、アリールアミノスルホニル、アミノスルホニルアミノ、ジ(C1−6アルキル)アミノスルホニルアミノ、ジ(C1−6アルキル)アミノC1−6アルキル、C1−12アルキルスルホニル、ジ(C1−6アルキル)アミノスルホニルまたはピリジニルカルボニルであり、
ここで、各R9が独立してフェニル;ハロ、C1−6アルキル、C1−6アルキルオキシ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;またはチオフェニルから選択され、そして
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0または1であり、各Qが
R1が−C(O)NH(OH)または−NHC(O)C1−6アルカンジイルSHであり、R2が水素またはニトロであり、R3がC1−6アルキル、アリールC2−6アルケンジイル、フラニルカルボニル、ナフタレニルカルボニル、C1−6アルキルアミノカルボニル、アミノスルホニル、ジ(C1−6アルキル)アミノスルホニルアミノC1−6アルキル、ジ(C1−6アルキル)アミノC1−6アルキル、C1−12アルキルスルホニル、ジ(C1−6アルキル)アミノスルホニル、トリハロC1−6アルキルスルホニル、ジ(アリール)C1−6アルキルカルボニル、チオフェニルC1−6アルキルカルボニル、ピリジニルカルボニルまたはアリールC1−6アルキルカルボニルであり、R4が水素であり、R3とR4が同じ炭素原子上に存在する時にはR3とR4が一緒になって式(a−1)[式中、R10はアリールである]で表される二価の基を形成していてもよいか、或はR3とR4が隣接する炭素原子上に存在する時にはR3とR4が一緒になって式(b−1)で表される二価の基を形成していてもよい前記式(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)NH(OH)であり、R2が水素であり、R3がナフタレニルカルボニル、C1−12アルキルスルホニルまたはジ(アリール)C1−6アルキルカルボニルであり、そしてR4が水素である前記式(I)で表される化合物で構成される群である。
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)
炭酸カリウム(0.18モル)と2−(メタンスルホニル)−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15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)を加えた後、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 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1を15.1g得た。
b)
中間体1(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、そして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/MH3) 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2を6.8g(>96%)得た。
c)
中間体2(0.0012モル)とTEA(0.0017モル)をDCM(1ml)に入れることで生じさせた5℃の混合物にN2流下でジメチル−スルファモイルクロライド(0.0015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18時間撹拌した。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(0.69g)をジエチルエーテルで取り上げた。その沈澱物を濾別した後、乾燥させることで、融点が193℃の中間体3を0.64g(73%)得た。
実施例A2
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 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4を3.7g(32%)得た。
実施例A3
a)
中間体2(0.0002モル)とα−フェニル−ベンゼンアセチルクロライド(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。
b)
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)で中性にした。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。
c)
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 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(供給業者:Novabiochem カタログ番号01−64−0289:メチルイソチオシアネートポリスチレン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、その濾液を用いることで、中間体7を得た。
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。TEAを4当量入れておいたDMFで膨潤させておいた樹脂にアリールスルホニルクロライド(2当量)を一度に加えた。反応物を一晩撹拌し、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
説明の目的で本明細書の以下のスキームを含める。
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時間振とうした。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 1つの実施例である化合物1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 ある場合には、また、異なる洗浄手順でMeOHも用いた(化合物1)。
3 樹脂の充填率を基準
4 ある場合にはPyBrOPの代わりにPyBOPを用いた(化合物1)。
実施例B3
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時間振とうした。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、DCMおよびDIEAを樹脂と一緒にして室温で一晩振とうした。この樹脂に排出を受けさせた後、それを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。
実施例B4
a)
中間体3(0.0016モル)と水酸化ナトリウム(0.0033モル)をEtOH(6ml)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で洗浄した後、乾燥させることで、中間体8・Naを0.59g(>100%)得た。
b)
中間体8・Na(0.0016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(0.0021モル)と1−ヒドロキシ−1H−ベンゾトリアゾール(0.0021モル)をDCM/THF(10ml)に入れることで生じさせた混合物にN2流下で一塩酸N’−(エチルアルボニミドイル)−N,N−ジメチル−1,3−プロパンジアミン(0.0021モル)を滴下した。この混合物を室温で週末の間撹拌した。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(0.94g)をクロマシル(kromasil)使用カラムクロマトグラフィー(溶離剤:DCM/MeOH/NH4OH 97/3/0.1;15−40μm)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(0.45g、65%)をジエチルエーテルで取り上げた。その沈澱物を濾別した後、乾燥させることで、融点が183℃の中間体9を0.422g(61%)得た。
c)
中間体9(0.0009モル)をMeOH(10ml)に入れることで生じさせた混合物にトリフルオロ酢酸(0.5ml)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、DCMで洗浄した後、乾燥させることで、融点が>260℃の化合物2を0.176g(59%)得た。
実施例B5
中間体2(0.0019モル)とスルファミド(0.0021モル)を1,2−ジメトキシ−エタン(5ml)に入れることで生じさせた混合物を撹拌しながら4日間還流させた。水を加えた。この混合物を濾別した後、乾燥させることで、融点が192℃の中間体10を0.51g(83%)得た。
中間体4(0.0057モル)とTEA(0.0085モル)をDCM(5ml)に入れることで生じさせた10℃の溶液にN2流下でジメチル−スルファモイルクロライド(0.007モル)をDCM(5ml)に入れることで生じさせた溶液を加えた。この混合物を一晩撹拌し、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。その残留物をCH3CN/ジエチルエーテルから結晶化させた。その沈澱物を濾別した後、乾燥させることで、融点が142℃の中間体11を0.492g(24%)得た。
中間体7(0.0003モル)を酢酸、トリフルオロ酢酸(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5を得た。
実施例B8
中間体2(0.0025モル)と2−ナフタレンカルボニルクロライド(0.003モル)と炭酸カリウム(0.005モル)をアセトニトリル(20ml)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、室温に冷却し、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。その残留物をジエチルエーテルから結晶化させた。その沈澱物を濾別した後、乾燥させることで、融点が140℃の中間体12を0.97g(100%)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、21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。9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7個の化合物が3の等級を示し、そして2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。
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。
表F−2:表F−2に化合物に実施例C.1、C.2およびC.3に従う試験を受けさせた時の結果を挙げる。
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 (11)
- 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CHまたはR 1 もしくはR 2 が結合する場合には炭素であり、
Xは、窒素またはCHまたはR 1 もしくはR 2 が結合する場合には炭素であり、
Yは、窒素またはCHまたはR 1 もしくはR 2 が結合する場合には炭素であり、
Zは、窒素または
R1は、−C(O)NH(OH)または−NHC(O)−C1-6アルカンジイルSH基であり、
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、C1-6アルキル、アリールC2-6アルケンジイル、フラニルカルボニル、ナフタレニルカルボニル、C1-6アルキルアミノカルボニル、アミノスルホニル、ジ(C1-6アルキル)アミノスルホニルアミノC1-6アルキル、ジ(C1-6アルキル)アミノC1-6アルキル、C1-12アルキルスルホニル、ジ(C1-6アルキル)アミノスルホニル、トリハロC1-6アルキルスルホニル、ジ(アリール)C1-6アルキルカルボニル、チオフェニルC1-6アルキルカルボニル、ピリジニルカルボニルまたはアリールC1-6アルキルカルボニルであり、
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、或は
R3とR4が同じ炭素原子上に存在する時にはR3とR4が一緒になって式
−C(O)−NH−CH2−NR10− (a−1)
(式中、R10はアリールである)
で表される二価の基を形成していてもよく、
R3とR4が隣接する炭素原子上に存在する時にはR3とR4が一緒になって式
=CH−CH=CH−CH= (b−1)
で表される二価の基を形成していてもよく、
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(但し、2−(メチル−4−ピペラジニル−1)−ニコチノヒドロキサム酸を除く)、またはその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。 - nが0または1であり、QがCHまたはR 1 もしくはR 2 が結合する場合には炭素であり、
R2が水素またはニトロであり、
R4が水素であり、
R3とR4が同じ炭素原子上に存在する時にはR3とR4が一緒になって式(a−1)で表される二価の基を形成していてもよいか、或は
R3とR4が隣接する炭素原子上に存在する時にはR3とR4が一緒になって式(b−1)で表される二価の基を形成していてもよい請求項1記載の化合物。 - nが1であり、QがCHまたはR 1 もしくはR 2 が結合する場合には炭素であり、
Zが窒素であり、
R1が−C(O)NH(OH)であり、
R2が水素であり、
R3がナフタレニルカルボニル、C1-12アルキルスルホニルまたはジ(アリール)C1-6アルキルカルボニルであり、そして
R4が水素である請求項1または2記載の化合物。 - 薬剤的に受け入れられる担体および請求項1〜4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5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1〜4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1〜4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1〜4のいずれかに記載化合物の使用。
- 標識を付けた請求項1記載の化合物を有効成分として含んで成る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1〜4のいずれかに記載のHDAC阻害剤を含んで成る腫瘍細胞の増殖を抑制するための併用剤。
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