JP5385125B2 - MDM2とp53の間の相互作用の阻害剤 - Google Patents
MDM2とp53の間の相互作用の阻害剤 Download PDFInfo
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- JP5385125B2 JP5385125B2 JP2009500841A JP2009500841A JP5385125B2 JP 5385125 B2 JP5385125 B2 JP 5385125B2 JP 2009500841 A JP2009500841 A JP 2009500841A JP 2009500841 A JP2009500841 A JP 2009500841A JP 5385125 B2 JP5385125 B2 JP 5385125B2
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012440 retinoic acid metabolism blocking agent Substances 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000010233 scurvy Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
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- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 108091035539 telomere Proteins 0.000 description 1
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- 210000003411 telomere Anatomy 0.000 description 1
- YVSQVYZBDXIXCC-INIZCTEOSA-N telomestatin Chemical compound N=1C2=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(=C(O1)C)N=C1C(=C(O1)C)N=C1[C@@]1([H])N=C2SC1 YVSQVYZBDXIXCC-INIZCTEOSA-N 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- 230000002103 transcriptional effect Effects 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Classifications
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Description
2によるp53のフィードバック阻害を妨害すると、機能的p53の濃度が増加することでアポトーシスをもたらす野生型p53の機能が回復しそして/またはp53に関連した薬剤耐性が無効になることでそのような薬剤が示す治療効果が向上するであろう。生体内でMDM2阻害とDNA損傷治療を組み合わせると相乗的抗腫瘍効果がもたらされることが示された(非特許文献1)。
本発明は、癌を治療する目的でMDM2とp53の間の相互作用を阻害する化合物、組成物および方法を提供するものである。その上、本発明の化合物および組成物は化学療法および放射線療法の効果を向上させようとする時に用いるにも有用である。
mは、0、1または2であり、そしてmが0の時には直接結合を意図し、
nは、0、1、2、3または4であり、そしてnが0の時には直接結合を意図し、
pは、0または1であり、そしてpが0の時には直接結合を意図し、
sは、0または1であり、そしてsが0の時には直接結合を意図し、
tは、0または1であり、そしてtが0の時には直接結合を意図し、
R1およびR2は、各々独立して、水素、ハロ、C1−6アルキル、C1−6アルキルオキシ、アリールC1−6アルキルオキシ、ヘテロアリールC1−6アルキルオキシ、フェニルチオ、ヒドロキシC1−6アルキルカルボニル;アミノ、アリールおよびヘテロアリールから選択される置換基で置換されているC1−6アルキル;またはアミノ、アリールおよびヘテロアリールから選択される置換基で置換されているC3−7シクロアルキルであり、
Aは、
R4およびR5は、各々独立して、水素、ハロ、C1−6アルキル、ポリハロC1−6アルキル、シアノ、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、アミノ、C1−6アルキルオキシ、C1−6アルキルカルボニル、メチルスルホニルアミノ、アリールまたはヘテロアリールから選択され、
Zは、
R6またはR7は、各々独立して、水素、ハロ、ヒドロキシ、アミノ、C1−6アルキル、ニトロ、ポリハロC1−6アルキル、シアノ、シアノC1−6アルキル、テトラゾロC1−6アルキル、アリール、ヘテロアリール、アリールC1−6アルキル、ヘテロアリールC1−6アルキル、アリール(ヒドロキシ)C1−6アルキル、ヘテロアリール(ヒドロキシ)C1−6アルキル、アリールカルボニル、ヘテロアリールカルボニル、C1−6アルキルカルボニル、アリールC1−6アルキルカルボニル、ヘテロアリールC1−6アルキルカルボニル、C1−6アルキルオキシ、C3−7シクロアルキルカルボニル、C3−7シクロアルキル(ヒドロキシ)C1−6アルキル、アリール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アルキルオキシC1−6アルキル、
C1−6アルキルカルボニルオキシC1−6アルキル、C1−6アルキルオキシカルボニルC1−6アルキルオキシ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、C1−6アルキルオキシカルボニルC2−6アルケニル、C1−6アルキルオキシC1−6アルキル、C1−6アルキルオキシカルボニル、C1−6アルキルカルボニルオキシ、アミノカルボニル、ヒドロキシC1−6アルキル、アミノC1−6アルキル、ヒドロキシカルボニル、ヒドロキシカルボニルC1−6アルキルおよび−(CH2)v−(C(=O)r)−(CHR10)u−NR8R9から選択され、かつ
vは、0、1、2、3、4、5または6であり、そしてvが0の時には直接結合を意図し、
rは、0または1であり、そしてrが0の時には直接結合を意図し、
uは、0、1、2、3、4、5または6であり、そしてuが0の時には直接結合を意図し、
R10は、水素またはC1−6アルキルであり、
R8およびR9は、各々独立して、水素、C1−12アルキル、C1−6アルキルカルボニル、C1−6アルキルスルホニル、アリールC1−6アルキルカルボニル、C3−7シクロアルキル、C3−7シクロアルキルカルボニル、−(CH2)k−NR11R12;ヒドロキシ、ヒドロキシカルボニル、シアノ、C1−6アルキルオキシカルボニル、C1−6アルキルオキシ、アリールまたはヘテロアリールから選択される置換基で置換されているC1−12アルキル;またはヒドロキシ、C1−6アルキルオキシ、アリール、アミノ、アリールC1−6アルキル、ヘテロアリールまたはヘテロアリールC1−6アルキルから選択される置換基で置換されているC3−7シクロアルキルから選択されるか、或は場合により、R8とR9がこれらが結合している窒素と一緒になって、モルホリニル、ピペリジニル、ピロリジニル、ピペラジニル;またはC1−6アルキル、アリールC1−6アルキル、アリールC1−6アルキルオキシカルボニル、ヘテロアリールC1−6アルキル、C3−7シクロアルキルおよびC3−7シクロアルキルC1−6アルキルから選択される置換基で置換されているピペラジニルを形成していてもよく、かつ
kは、0、1、2、3、4、5または6であり、そしてkが0の時には直接結合を意図し、
R11およびR12は、各々独立して、水素、C1−6アルキル、アリールC1−6アルキルオキシカルボニル、C3−7シクロアルキル;ヒドロキシ、C1−6アルキルオキシ、アリールおよびヘテロアリールから選択される置換基で置換されているC1−12アルキル;およびヒドロキシ、C1−6アルキルオキシ、アリール、アリールC1−6アルキル、ヘテロアリールおよびヘテロアリールC1−6アルキルから選択される置換基で置換されているC3−7シクロアルキルから選択されるか、或は
場合により、R11とR12がこれらが結合している窒素と一緒になって、モルホリニル、ピペラジニル;またはC1−6アルキルオキシカルボニルで置換されているピペラジニルを形成していてもよく、
アリールは、各々が場合によりハロ、ヒドロキシ、ヒドロキシC1−6アルキル、C1−6アルキル、アミノ、ポリハロC1−6アルキルおよびC1−6アルキルオキシから各々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てもよいフェニルもしくはナフタレニルであり、かつ各フェニルもしくはナフタレニルは場合によりメチレンジオキシおよびエチレンジオキシから選択される二価基で置換されていてもよく、
ヘテロアリールは、ピリジニル、インドリル、キノリニル、イミダゾリル、フラニル、チエニル、オキサジアゾリル、テトラゾリル、ベンゾフラニルまたはテトラヒドロフラニルであり、
各ピリジニル、インドリル、キノリニル、イミダゾリル、フラニル、チエニル、オキサジアゾリル、テトラゾリル、ベンゾフラニルまたはテトラヒドロフラニルは場合によりハロ、ヒドロキシ、C1−6アルキル、アミノ、ポリハロC1−6アルキル、アリール、アリールC1−6アルキルまたはC1−6アルキルオキシから各々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てもよく、かつ各ピリジニル、インドリル、キノリニ
ル、イミダゾリル、フラニル、チエニル、ベンゾフラニルまたはテトラヒドロフラニルは場合によりメチレンジオキシまたはエチレンジオキシから選択される二価基で置換されていてもよい]
で表される化合物、これらのN−オキサイド形態物、付加塩または立体化学異性体形態物に関する。
トリウム、過酸化カリウムなどが含まれ、適切な有機過酸化物には、ペルオキシ酸、例えば過安息香酸またはハロ置換過安息香酸、例えば3−クロロ過安息香酸など、ペルオキソアルカン酸、例えばペルオキソ酢酸など、アルキルヒドロパーオキサイド、例えばt−ブチルヒドロパーオキサイドなどが含まれ得る。適切な溶媒は、例えば水、低級アルコール、例えばエタノールなど、炭化水素、例えばトルエンなど、ケトン、例えば2−ブタノンなど、ハロゲン置換炭化水素、例えばジクロロメタンなど、そしてそのような溶媒の混合物である。
a)mが0であるか、
b)nが0または2であるか、
c)pが1であるか、
d)sが0であるか、
e)tが0であるか、
f)R1およびR2が各々独立して水素であるか、
g)Aが(a−15)、(a−21)、(a−30)、(a−39)または(a−40)から選択される基であるか、
h)R4およびR5が各々独立して水素またはC1−6アルキルオキシから選択されるか、
i)Zが基(b−2)であるか、或は
j)R6およびR7が各々独立して水素から選択される。
a)mが0であるか、
b)nが2であるか、
c)pが1であるか、
d)sが0であるか、
e)tが0であるか、
f)R1およびR2が各々独立して水素であるか、
g)Aが(a−21)、(a−39)または(a−40)から選択される基であるか、
h)R4およびR5が各々独立して水素またはC1−6アルキルオキシから選択されるか、
i)Zが基(b−2)であるか、或は
j)R6およびR7が各々独立して水素から選択される。
される式(I)で表される化合物またはこれらのサブグループのいずれかで構成させる。
ミン中で反応させることで実施可能である。
語「MDM2」を用いる。この用語の意味の範囲内で、MDM2は、mdm2がコードする蛋白質、それらの変異体、代替スライス蛋白質および燐酸化蛋白質の全部を包含する。加うるに、本明細書で用いる如き用語「MDM2」には、MDM2類似物、例えばMDMX(またMDM4としても知られる)および他の動物のMDM2相同体および類似物、例えばヒト相同HDM2またはヒト類似HDMXなども含まれる。
− p53とMDM2の間の相互作用の阻害、
− MDM2またはp53蛋白質のいずれかとの直接的結合、
− 上流もしくは下流の標的、例えばキナーゼまたはユビキチン化またはSUMO修飾に関与する酵素の活性に相互作用を及ぼす、
− MDM2およびp53を異なる細胞内コンパートメントの中に封じ込めるか或は輸送する、
− MDM2と結合する蛋白質、例えば(これらに限定するものでないが)p73、E2F−1、Rb、p21waf1またはcip1のモジュレーション、
− MDM2の発現および/またはMDM2の活性を下方調節または妨害、例えば(これらに限定するものでないが)、それの細胞内位置、翻訳後修飾、核外輸送またはユビキチンリガーゼ活性に影響を及ぼす、
− p53蛋白質を直接または間接的に安定化、例えばそれを機能的構造形態に保持するか或は誤った折り畳みを防止することなどで安定化、
− p53の発現またはp53ファミリー員、例えばp63およびp73などの発現の増加、
− p53の活性の向上、例えば(これらに限定するものでないが)、それの転写活性などの向上、そして/または
− p53シグナル伝達経路の遺伝子および蛋白質、例えば(これらに限定するものでないが)p21waf1、cip1、MIC−1(GDF−15)、PIG−3およびATF−3などの発現の増加。
白質の間の相互作用の阻害を結果としてもたらすか或はそのような阻害の結果としてもたらされる望ましくないか或は有害な状態のいずれかを意味する。
連した病気の治療で用いるにも有用であり得る。立体配座的に不安定であるか或は誤って折り畳まれた蛋白質に関連した病気の例には、これらに限定するものでないが、嚢胞性線維症(CFTR)、マルファン症候群(フィブリリン)、筋萎縮性側索硬化症(スーパーオキシドジスムターゼ)、壊血病(コラーゲン)、メープルシロップ尿症(アルファ−ケト酸デヒドロゲナーゼ複合体)、骨形成不全症(1型プロコラーゲンプロ−アルファ)、クロイツフェルト・ヤコブ病(プリオン)、アルツハイマー病(ベータ−アミロイド)、家族性アミロイドーシス(リゾチーム)、白内障(クリスタリン)、家族性高コレステロール血症(LDL受容体)、αI−抗トリプシン欠乏症、テイ・サックス病(ベータ−ヘキソサミニダーゼ)、網膜色素変性症(ロドプシン)および妖精症(インスリン受容体)が含まれる。
− 白金配位化合物、例えばシスプラチン、カルボプラチン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またはドセタキセル;
− 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またはトポテカン;
− トポイソメラーゼII阻害剤、例えば抗腫瘍性エピポドフィロトキシン(epipodophyllotoxins)またはポドフィロトキシン誘導体、例えばエトポシドまたはテニポシド;
− 抗腫瘍性ビンカアルカロイド、例えばビンブラスチン、ビンクリスチンまたはビノレルビン;
− 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、ロイコボリン、ゲムシタビン(gemcitabine)またはカペシタビン;
− アルキル化剤、例えばナイトロジェンマスタードまたはニトソロ尿素、例えばシクロホスファミド、クロラムブシル、カルマスチン、チオテパ、メファラン(mephala
n)またはロムスチン;
− 抗腫瘍性アントラサイクリン誘導体、例えばダウノルビシン、ドキソルビシン、ドキシル(doxil)、イダルビシンまたはミトキサントロン;
− IGF−1受容体を標的にする分子、例えばピクロポドフィリン(picropodophilin);
− テトラカルシン(tetracarcin)誘導体、例えばテトロカルシン(tetrocarcin)A;
− グルココルチコイデン(glucocorticoiden)、例えばプレドニゾン;
− 抗体、例えばトラスツズマブ(trastuzumab)(HER2抗体)、リツキシマブ(CD20抗体)、ゲムツザマブ(gemtuzamab)、セチュキマブ、ペルツズマブ(pertuzumab)またはベバシズマブ(bevacizumab);
− 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モジュレーター、例えばタモキシフェン、フルベストラント(fulvestrant)、トレミフェン、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;
− アロマターゼ阻害剤、例えばエキセメスタン、アナストロゾール、レトラゾール(letrazole)およびボロゾール(vorozole);
− 分化誘導薬、例えばレチノイド、ビタミンDまたはレチノイン酸およびレチノイン酸代謝遮断薬(RAMBA)、例えばアキュテイン;
− 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またはデシタビン(decitabine);
− 抗葉酸剤、例えばプレメトレキセドジナトリウム(premetrexed disodium);
− 抗生物質、例えばアンチノマイシン(antinomycin)D、ブレオマイシン、マイトマイシンC、ダクチノマイシン、カルミノマイシン(carminomycin)またはダウノマイシン;
− 代謝拮抗剤、例えばクロファラビン(chlofarabine)、アミノプテリン、シトシンアラビノシドまたはメトトレキサート;
− アポトーシス誘発剤および抗血管新生薬、例えばBc1−2阻害剤、例えばYC 137、BH 312、ABT 737、ゴシポール、HA 14−1、TW 37またはデカン酸;
− チュブリン結合剤(tubuline−binding agents)、例えばコンブレスタチン(combrestatin)、コルヒチンまたはノコダゾール(nocodazole);
− キナーゼ阻害剤、例えばフラボペリドール(flavoperidol)、メシル酸イマチニブ、エルロチニブ(erlotinib)またはゲフィチニブ;
− ファルネシルトランスフェラーゼ阻害剤、例えばチピファルニブ(tipifarnib);
− ヒストンデアセチラーゼ(HDAC)阻害剤、例えば酪酸ナトリウム、スベロイルアニリドヒドロキサミド(suberoylanilide hydroxamide)酸(SAHA)、デプシペプチド(FR 901228)、NVP−LAQ824、R306465、JNJ−26481585またはトリコスタチン(trichostatin)A;
− ユビキチン−プロテアソーム経路の阻害剤、例えばPS−341、MLN.41またはボルテゾミブ;
− ヨンデリス(Yondelis);
− テロメラーゼ阻害剤、例えばテロメスタチン(telomestatin);
− マトリクスメタロプロテイナーゼ阻害剤、例えばバチマスタット(batimasta)、マリマスタット(marimastat)、プリノスタット(prinostat
)またはメタスタット(metasta)。
から300mg(mg/m2)、例えば50から250mg/m2の投薬量、特にエトポシドの場合には1治療過程当たり約35から100mg/m2の投薬量そしてテニポシドの場合には約50から250mg/m2の投薬量で投与する。
チド、蛋白質、酵素または受容体の間の複合体形成を検出または測定することを含んで成る。
本明細書では以降、「DCM」はジクロロメタンであると定義し、「DIPE」はジイソプロピルエーテルであると定義し、「EtOAc」は酢酸エチルであると定義し、「EtOH」はエタノールであると定義し、「MeOH」はメタノールであると定義しそして「THF」はテトラヒドロフランであると定義する。
線形温度勾配の加熱プレート、スライディングポインター(sliding pointer)および温度スケール(摂氏度)で構成されているKoflerホットベンチ(hot bench)を用いていろいろな化合物が示す融点を得て、それらを(Kofler)で示す。
一般的手順
脱気装置付き4元ポンプ、オートサンプラーおよびダイオードアレイ検出器(DAD)が備わっているAlliance HT 2795(Waters)装置を用いてHPLC勾配をかけた。カラムから出る流れを分割してMS検出器に送った。そのMS検出器にはエレクトロスプレーイオン化源が備わっていた。毛細管針電圧を3kVにしそしてLCT(WatersのTime of Flight−Z−スプレー質量分析計)の源の温度を100℃に維持した。窒素をネブライザーガスとして用いた。データの取得をWaters−Micromass MassLynx−Openlynxデータシステムを用いて実施した。
前記一般的手順に加えて、Xterra−RP C18カラム(5μm、3.9x150mm)を用いた逆相HPLCを1.0ml/分の流量で温度を30℃にして実施した。2種類の可動相(可動相A:7mMの酢酸アンモニウムが100%、可動相B:アセトニトリルが100%)を用いてAが85%でBが15%(3分間保持)から5分かけてAが20%でBが80%にしてAが20%でBが80%の状態を6分間保持しそして再び初期条件の平衡状態に3分間置くことによる勾配条件で流した。20μlの注入体積を用いた。正および負イオン化モードの場合のコーン電圧を20Vにした。走査間の遅延を0.08秒にして0.8秒間に100から900まで走査することで質量スペクトルを取得した。
前記一般的手順に加えて、Xterra−RP C18カラム(5μm、3.9x150mm)を用いた逆相HPLCを1.0ml/分の流量で温度を30℃にして実施した。2種類の可動相(可動相A:7mMの酢酸アンモニウムが100%、可動相B:アセトニトリルが100%)を用いてAが100%(1分間保持)から4分かけてAが50%でBが50%にしてAが50%でBが50%の状態を9分間保持しそして再び初期条件の平衡状態に3分間置くことによる勾配条件で流した。20μlの注入体積を用いた。コーン電圧を正イオン化モードの場合には20Vにしそして負イオン化モードの場合にも20Vにした。走査間の遅延を0.08秒にして0.8秒間に100から900まで走査することで質量スペクトルを取得した。
実施例A1
中間体1の製造
1H NMR(300MHz,CDCl3)δ7.63(m,2H),7.46(d,1H,J=7.1),7.25(m,2H),3.84(s,2H),3.70(s,3H),3.22(s,3H)。
MS(ES+)m/z220(M+1)。
実施例A2
a)中間体2の製造
)が201℃の中間体2を0.152g(28%)得た。
b)中間体3の製造
実施例A3
a)中間体4の製造
b)中間体5の製造
c)中間体6の製造
実施例A4
a)中間体7の製造
b)中間体8の製造
実施例A5
a)中間体9の製造
ル(40−63μm)使用カラムクロマトグラフィー(溶離剤:EtOAc/シクロヘキサンを50/50)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9を無色の油として410mg(85%)得た。
1H NMR(300MHz,CDCl3)δ7.54(m,2H),6.99(s,1H),6.88(d,1H,J=6.4),3.83(s,3H),3.79(s,2H),3.69(s,3H),3.21(s,3H)。
実施例A6
a)中間体10の製造
b)中間体11の製造
c)中間体12の製造
d)中間体13の製造
実施例B1
化合物1の製造
カラムクロマトグラフィー(溶離剤:DCM/MeOHを95/5)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152℃−154℃の化合物1を41mg(20%)得た。
1H NMR(300MHz,MeOH−d4)δ7.98(d,2H,J=6.6),7.59(m,2H),7,43(d,1H,J=7.4),7.24(m,2H),7.00(dd,2H,J=8.7,J=3.3),6.68(m,4H),3.45(t,2H,J=7.2),2.98(t,2H,J=7.2)。
MS(ES+)m/z330(M+1)。
実施例B2
化合物2の製造
1H NMR(DMSO−d6)δ2.96(2H,t,J=7.7Hz),3.30(2H,t,J=7.7Hz),5.6(1H,br,t,J=7.6Hz),6.58(4H,m),6.95(2H,d,J=7.7Hz),7.03(1H,m),7.33(1H,m),7.96(1H,d,J=7.7Hz),8.03(2H,d,J=7.6Hz),8.17−8.21(1H,m),8.22(1H,br,s),11.38(1H,br,s)
LCMS(ES+)m/z330(M+1),Rt=7.10,方法A。
実施例B3
化合物3の製造
/10/0.5から90/10/1)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化合物3を0.63g(48%)得た。
1H NMR(DMSO−d6)δ1.75−1.93(4H,m),2.65−2.78(4H,m),3.32(2H,s),3.70(2H,t,J=6.1Hz),5.62(1H,br,t,J=7.6Hz),6.58−6.53(5H,m),6.95(2H,d,J=7.7Hz),8.05(2H,d,J=7.6Hz),8.24(1H,s)
LCMS(ES+)m/z334(M+1),Rt5.18,方法B。
融点256℃(Kofler)。
実施例B4
化合物4の製造
1H NMR(DMSO−d6)δ6.32(1H,br s),6.68(1H,d,J=5.6Hz),6.9(1H,dd,J=10.2Hz,J=2.5Hz),6.55(2H,d,J=10.2Hz),7.0(2H,d,J=10.2Hz),7.27(1H,m),7.32(1H,d,J=10.2Hz),7.7(1H,br s),8.17(1H,dd,J=10.2Hz,J=2.5Hz),8.37(1H,br s),10.9(1H,br s)。
LCMS(ES+)m/z301(M+1),Rt7.73,方法A。
実施例B5
化合物5の製造
1H NMR(300MHz,DMSO−d6)δ8.23(s,1H),8.01(dd,2H,J=6.3,J=1.5),7,71(s,1H),7.51(d,1H,J=8.5),7.14(d,1H,J=2.1),6.92(d,2H,J=8.6),6.85(dd,1H,J=8.5,J=2.2),6.58(m,4H),5.64(t,1H,J=5.6),3.77(s,3H),3.30(t,2H,J=7.0),2.48(t,2H,J=7.0)。
MS(ES+)m/z360(M+1)。
実施例B6
化合物6の製造
本化合物がA2780細胞内のp53を保存する能力の測定をp53酵素免疫測定法を用いて実施した。このp53測定法は2種類のポリクローナル抗体を用いた「サンドイッチ」酵素免疫測定法である。p53蛋白質に特異的なポリクローナル抗体をプラスチックの穴の表面に固定した。測定すべきサンプルにいくらか存在するp53はその捕捉用抗体と結合するであろう。また、ビオチニル化検出体であるポリクローナル抗体もp53を認識しそして前記捕捉用抗体がいくらか保持しているp53と結合するであろう。次に、その検出体である抗体を西洋ワサビペルオキシダーゼ接合ストレプトアビジンと結合させる。その西洋ワサビペルオキシダーゼは発色基質であるo−フェニレンジアミンの変換に触媒作用を及ぼすが、それの強度は前記プレートと結合したp53蛋白質の量と比例する。その着色した反応生成物を分光光度計で量化する。精製しておいた組換え型HIS標識付きp53蛋白質を既知濃度で用いて標準曲線を作成することで量化を達成する(実施例C.1を参照)。
A2780細胞(ATCC)をウシ胎仔血清(FCS)を10%とゲンタマイシンとL−グルタミンを2mM補充しておいたRPMI1640に入れてCO2が5%の湿気のある37℃のインキュベーター内で培養した。
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液を作成した。細胞増殖測定時の最終的なDMSO濃度が0.1%(体積/体積)を超えないようにした。対照には化合物を入れないでU87MG細胞とDMSOを入れ、そしてブランクには細胞を入れないでDMSOを入れた。
錠剤中心部の調製
式(I)で表される化合物(100g)とラクトース(570g)と澱粉(200g)の混合物を充分に混合した後、ドデシル硫酸ナトリウム(5g)とポリビニルピロリドン(10g)を水(約200ml)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(100g)および水添植物油(15g)を加える。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。
メチルセルロース(10g)を変性エタノール(75ml)に入れることで生じさせた
溶液に、エチルセルロース(5g)をジクロロメタン(150ml)に入れることで生じさせた溶液を加える。次に、ジクロロメタン(75ml)および1,2,3−プロパントリオール(2.5ml)を加える。ポリエチレングリコール(10g)を溶融させてジクロロメタン(75ml)に溶解させる。後者の溶液を前者に加えた後、オクタデカン酸マグネシウム(2.5g)、ポリビニルピロリドン(5g)および濃カラー懸濁液(concentrated colour suspension)(30ml)を加えて、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被覆する。
Claims (10)
- nが2であるか、またはAが(a−21)、(a−39)および(a−40)から選択される基である請求項1記載の化合物。
- 薬剤として用いるための請求項1から4のいずれかに記載の化合物。
- 製薬学的に許容される担体および請求項1から4のいずれかに記載の化合物を有効成分として治療的に有効な量で含有して成る製薬学的組成物。
- 請求項6記載の製薬学的組成物を製造する方法であって、製薬学的に許容される担体と請求項1から4のいずれかに記載の化合物を密に混合する方法。
- p53−MDM2の相互作用が媒介する障害を治療する薬剤を製造するための請求項1から4のいずれかに記載の化合物の使用。
- 抗癌剤と請求項1から4のいずれかに記載の化合物の組み合わせ物。
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KR101730407B1 (ko) * | 2009-02-04 | 2017-04-26 | 얀센 파마슈티카 엔.브이. | 항암제로서의 인돌 유도체 |
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