JP2021528368A - Ras腫瘍性タンパク質の阻害剤、その作製方法及びその使用方法 - Google Patents
Ras腫瘍性タンパク質の阻害剤、その作製方法及びその使用方法 Download PDFInfo
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Abstract
【化1】
【選択図】図1
Description
本発明は、以下の米国政府支援:米国国立衛生研究所(NIH)によって資金援助されたグラント番号RR018733を受けて行われた。米国政府は本発明に一定の権利を有する。
本明細書で用いる場合(別段の指定がない限り)、「アルキル」という用語は、1価の直鎖状又は分岐状炭化水素鎖を意味する。例えば、「C1−C7アルキル」又は「C1−C4アルキル」という用語はそれぞれ、1〜7(例えば、1、2、3、4、5、6、又は7)又は1〜4(例えば、1、2、3、又は4)の炭素原子を有する直鎖状又は分岐状鎖の飽和炭化水素基を指す。C1−C7アルキル基の例としては、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、s−ブチル、t−ブチル、n−ペンチル、s−ペンチル、n−ヘキシル、及びn−ヘプチル(n-septyl)が挙げられるが、これらに限定されない。C1−C4アルキル基の例としては、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、s−ブチル、及びt−ブチルが挙げられるが、これらに限定されない。
[実施例]
式Iの化合物は、まず、対応するアミンR1−NH2及びR2−NH2を調製し、次に環式無水物の形をしていてもよい二酸X1(CH2COOH)2との逐次反応を行うことによって調製することができる。後続の実施例において、R1及びR2は、置換フェニル基を含む。第1の実施例において、置換フェニル基はそれぞれ、「A」及び「B」で標識されている。
F3の合成は、スルホンアミド4(F3の環B)を構築することから始めた。スルホンアミドは、市販のスルホニルクロリド1を2当量のアミン2で処理することによって調製した。合成は、接触水素化条件下でニトロ3を還元することによって優れた全収率で完了した。2を好適な第二級又は第三級アミンで置き換えることによって、様々なスルホンアミド誘導体を調製した。
1−((2−メチル−5−ニトロフェニル)スルホニル)アゼパン3。0℃で75mLのTHF中2.50g(10.6mmol)のスルホニルクロリド1の溶液に、2.4mL(2.1g、21.2mmol)のヘキサメチレンイミン2を滴下して加えた。得られた溶液を0℃で1.5時間、及び室温で2時間撹拌すると、その時点で、TLCによって、反応が完了したことが示された。90mLの水をゆっくり添加し、5分間撹拌することによって、反応を停止させた。分液し、水性相を酢酸エチル100mLずつで2回抽出した。合わせた有機層をブラインで洗浄し、乾燥し(硫酸ナトリウム)、(酢酸エチルですすいだ)シリカゲルプラグで濾過した。溶媒を真空中で除去して、3.04g(96%)の3を暗黄色油として得た。
スルホンアミド4を得た上で、F3の合成は、市販のイミノ二酢酸5をマイクロ波照射により無水酢酸と共に加熱することによって、反応性の環式無水物を生成することから始めた(Burke, M. D.; Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Klubnick, J. A. “Methods for forming protected organoboronic acids.” US 20110201806 A1. Aug 18, 2011)。アニリン4を用いて開環すると、所望の酸(6)が好収率で得られた(Henry, D. W. “A facile synthesis of piperazines from primary amines.” J. Heterocyclic Chem. 1966, 3, 503-511、Yamaoka, N.; Kodama, H.; Izuhara, Y.; Miyata, T.; Meguro, K. “Structure-activity relationships of new N-acylanthranilic acid derivatives as plasminogen activator inhibitor-1 inhibitors.”Chem.Pharm. Bull.. 2011, 59, 215-224)。F3の合成は、HATU/TEAプロトコルを使用して、酸6をアニリン7とカップリングさせることによって完了した。本発明者らは、EDCIが不十分な収率をもたらすことを見出した。また、アミド形成ステップにおけるアニリン4及び7を交換することができる(すなわち、アニリン4又は7を第1のステップにおいて使用することができる)。
2−((2−((3−(アゼパン−1−イルスルホニル)−4−メチルフェニル)アミノ)−2−オキソエチル)(メチル)アミノ)酢酸6。3mLの無水酢酸中500mg(3.40mmol)のイミノ二酢酸5の溶液を、マイクロ波照射により150℃で1時間撹拌した。室温に冷却した後、溶媒を真空中で除去し、粗中間体を高真空下にて5時間乾燥した。中間体を20mLのTHFに溶解し、得られた溶液に、913mg(3.40mmol)のアニリン4を添加した。反応物を、マイクロ波照射により100℃で4時間撹拌した。室温に冷却した後、混合物を、酢酸エチル、次いで酢酸エチル−メタノール1:1溶液ですすいだシリカゲルプラグで濾過した。酢酸エチル−メタノール1:1溶液を含む画分を真空中で濃縮して、350mgの6(26%)を淡褐色固体として得た。
JAB−7−160の合成
JAB−7−160、JAB−7−160の同族体であるJAB−7−158及びJAB−7−181を含めて、いくつかの化合物を異なるプロトコルで調製した。これらは、高度に官能化されたアニリンを調製するものであった。
合成は、アリールクロリド8をクロロスルホン酸中で終夜加熱して、スルホニルクロリド9を生成することから始めた(Kil, K.-E.; Poutiainen, P.; Zhang, Z.; Zhu, A.; Kuruppu, D.; Prabhakar, S.; Choi, J.-K.; Tannous, B. A.; Brownell, A.-L. “Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.” Bioorg. Med. Chem. Lett. 2016, 26, 133-139、Aono, T.; Endo, M. “2-Chloro-5-nitrobenzenesulfonamide.” JP patent. JP 60233051, Nov 19, 1985)。ヘキサメチレンイミン2で処理して、スルホンアミド10を好収率で得た。反応を注意深くモニタリングすることが、アリールクロリドの置換を回避するために必要とされた。重要なステップにおいて、ナトリウムtert−ブトキシドの存在下でアリールを市販の2−(ジメチルアミノ)エタノールで置換すると、アリールエーテル11が好収率で得られた。合成は、アリールニトロを水素化し、次にHATU/TEAプロトコルを利用して、得られたアニリン(12)を酸13とカップリングすることによって完了した。アリールクロリド8の代わりに、アリールブロミドを使用してもよい(しかし、アリールフルオリドを使用することはできない)。
2−クロロ−5−ニトロベンゼン−1−スルホニルクロリド9。3mLのクロロスルホン酸(要注意)中1g(6.35mmol)のアリールクロリド8の溶液を120℃で18時間撹拌した。室温に冷却した後、反応物を150mLの氷に注意深く滴下して加えた(発熱あり)。水性懸濁液を酢酸エチル75mLずつで3回抽出した。合わせた有機画分をブラインで洗浄し、乾燥し(硫酸ナトリウム)、真空中で濃縮した。残渣をシリカゲル(12g、Combiflash、11分かけて0→50%ヘキサン−酢酸エチル)によるクロマトグラフィーにかけて、620mg(38%)の9を低融点の褐色固体として得た。
合成は、アリールブロミド14をクロロスルホン酸中で終夜加熱して、スルホニルクロリド15を生成することから始めた(Kil, K.-E.; Poutiainen, P.; Zhang, Z.; Zhu, A.; Kuruppu, D.; Prabhakar, S.; Choi, J.-K.; Tannous, B. A.; Brownell, A.-L. “Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.” Bioorg. Med. Chem. Lett. 2016, 26, 133-139、Aono, T.; Endo, M. “2-Chloro-5-nitrobenzenesulfonamide.” JP patent. JP 60233051, Nov 19, 1985)。ヘキサメチレンイミン2で処理して、スルホンアミド16を許容される収率で得た。反応を注意深くモニタリングすることが、アリールブロミドの置換を回避するために必要とされた。重要なステップにおいて、アリールブロミド16と1−ペンチンのパラジウム触媒クロスカップリング(薗頭カップリング)は、定量的収率で進行した。アリールニトロ及びアルキンの同時水素化後に、合成は、HATU/TEAプロトコルを利用して、得られたアニリン(18)を酸13とカップリングすることによって完了した。
2−ブロモ−5−ニトロベンゼン−1−スルホニルクロリド15。誘導体を、9の調製について記載されている通りに調製した。1.00g(4.95mmol)のアリールニトロ14から、650mg(43%)の15を低融点褐色固体として単離した。
結合アッセイ
F3/F3a誘導体の組換えK−RASタンパク質への直接結合。Thermofluorアッセイを行って、組換えK−RASタンパク質と化合物F3の間又は組換えK−RASタンパク質と化合物JAB−6−5の間に直接相互作用を検出することができるかどうかをアッセイした。組換えK−RAS12vタンパク質にガンマGTPSを加え、結合アッセイにおいて化合物200uM/タンパク質5uMの比で使用した。対照化合物C4は、異なるタンパク質を標的とし、RASを結合させるとは予想されなかった。結果は、3連で行われた3回のアッセイに由来するものである。著しい曲線のシフトがF3とJAB−6−5の両方で認められるが、C4では認められない。予測kDは、曲線から推定することができる:55.5℃で約25uM。結果を図16に示す。
固形腫瘍の大多数は、上皮細胞から生じる。身体の正常な上皮細胞は、基底膜構造体上で生存/増殖する。そのような細胞をインビトロで増殖させるために、細胞をコーティングされたプラスチック製組織培養容器で2次元培養する。プラスチックへの粘着は、基底膜上での自然な増殖と似ており、細胞に必須の生存シグナルを固体2次元表面とのインテグリン相互作用によりもたらす。これらの非がん細胞は、固体表面から離れて培地に懸濁されている場合、インテグリン生存シグナル伝達を失い、プログラム細胞死の1つのタイプであるアノイキスと呼ばれるプロセスによって死滅する。
NRGマウスにおける細胞株異種移植腫瘍を使用して、化合物F3をインビボで試験した。使用した細胞株としては、Mia−Paca−2(膵がん)、及びNCI−H441(肺がん)が挙げられる。試験によって、対照と比べて腫瘍体積が低減されたことが示された。NCI−H441の結果を図13に示す。Mia−Paca−2の結果を図14及び図15に示す(DMSO/PBS(担体)又はF3薬物の12mg/kgで3日ごとに処置したNRGマウス)。Mia−Paca−2では、F3処置動物において生じた腫瘍は、体積のおよそ半分であった(実験のP値は0.014であった)。
RAS阻害剤のクリアランス速度をインビボで決定するために、CD1マウスにF3を5mg/kgで腹腔内注射した。経時的血漿中濃度を測定した。結果を図17に示す。同様に、脳中濃度も測定した。結果を図18に示す。30mg/kgで経口投与した後の血漿中濃度を測定した。結果を図19に示す。
F3で、予備的なインビボ毒性アッセイを行った。NRGマウスに10mg/kgの薬物を1日おきに2週間腹腔内注射した。痛み又は窮迫の明らかな徴候は認められず、体重減少も認められなかった。したがって、化合物は、このレベルでインビボにおいて特に毒性を示すことはないようである。
1. Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016 Apr 1;129(7):1287-92
2. American Cancer Society. Cancer Facts and Figures 2017
3. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-RAS(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-551
4. Shima F, Yoshikawa Y, Ye M, et al. In silico discovery of small-molecule RAS inhibitors that display antitumor activity by blocking the RAS-effector interaction. Proc Natl Acad Sci U S A. 2013;110(20):8182-8187
5. Welsch ME, Kaplan A, Chambers JM, et al. Multivalent Small-Molecule Pan-RAS Inhibitors. Cell. 2017;168(5):878-889.e29
6. Han, C. G.; Kim, J. U.; Yoon, J. H.; Lee, S. U.; Kim, N. D.; Jung, Y. S.; Lee, Y. H.; Park, S. J.; Shin, J. C.; Yang, J. W. “2-Phenyl-4-[3-(substituted-sulfonyl)anilino]quinazoline derivative for the treatment of hepatitis C and preparative method thereof.” KR patent. KR 2012048223, May 15, 2012
7. Burke, M. D.; Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Klubnick, J. A. “Methods for forming protected organoboronic acids.” US 20110201806 A1. Aug 18, 2011
8. Henry, D. W. “A facile synthesis of piperazines from primary amines.”J. Heterocyclic Chem. 1966, 3, 503-511
9. Yamaoka, N.; Kodama, H.; Izuhara, Y.; Miyata, T.; Meguro, K. “Structure-activity relationships of new N-acylanthranilic acid derivatives as plasminogen activator inhibitor-1 inhibitors.” Chem.Pharm. Bull.. 2011, 59, 215-224
10. Kil, K.-E.; Poutiainen, P.; Zhang, Z.; Zhu, A.; Kuruppu, D.; Prabhakar, S.; Choi, J.-K.; Tannous, B. A.; Brownell, A.-L. “Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.” Bioorg. Med. Chem. Lett. 2016, 26, 133-139
11. Aono, T.; Endo, M. “2-Chloro-5-nitrobenzenesulfonamide.” JP patent. JP 60233051, Nov 19, 1985
12. Colburn NH, Bruegge WF, Bates JR, Gray RH, Rossen JD, Kelsey WH, et al. Correlation of anchorage-independent growth with tumorigenicity of chemically transformed mouse epidermal cells. Cancer Res 1978;38:624-34
13. Stedman, T.L. 2000. Stedman's medical dictionary. Lippincott Williams & Wilkins, Philadelphia. xxxvi, [127], 2098
14. “Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” (July 2005) by U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research CDER
Claims (17)
- RASにおける活性化変異に関連する疾患の治療における使用のための、又はRAS活性の低減によって治療可能な疾患の治療における使用のための化合物であって、式(I)の化合物
[式中、
R1は、1価のH、カルボキシ、ニトロ、スルホ、ハロゲン、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、−(C1−C3)アルキル−アリール、−(C1−C3)アルキル−シクロアルキル、−(C1−C3)アルキル−ヘテロシクリル、−(C1−C3)アルキル−ヘテロアリール、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、又はC1−C7アルコキシであり、ハロゲン、ヒドロキシ、C1−C5アルキル、C1−C4アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、
X1は、2価の−(NH)−、−(CH2)−、−(NHCH2)−、−(CH2NH)−、−(C2H4)−、−(C2H2)−、−(C2)−、−O−、−O−(CH2)−、−(CH2)−O−、−S−、−S−(CH2)−、又は−(CH2)−S−であり、ハロゲン、ヒドロキシ、−Rx、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、
Rxは、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、又はC1−C7アルコキシであり、ハロゲン、ヒドロキシ、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C1−C4アルコキシ、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、
R2は、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、−(C1−C3)アルキル−アリール、−(C1−C3)アルキル−シクロアルキル、−(C1−C3)アルキル−ヘテロシクリル、又は−(C1−C3)アルキル−ヘテロアリールであり、ハロゲン、ヒドロキシ、C1−C16アルキル、C2−C16アルケニル、C2−C16アルキニル、C1−C15アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、スルホ、−SO2−R3、−(C=O)−R3、又は−O−R3で置換されていてもよく、
R3は、−NRaRb、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、C1−C7アルキル、C2−C7アルケニル、C2−C7アルキニル、又はC1−C6アルコキシであり、ハロゲン、ヒドロキシ、C1−C5アルキル、C1−C4アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、
Raは、1価のH、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、C1−C7アルキル、C2−C7アルケニル、C2−C7アルキニル、又はC1−C6アルコキシであり、ハロゲン、ヒドロキシ、C1−C5アルキル、C1−C4アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、かつ、
Rbは、1価のH、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、C1−C7アルキル、C2−C7アルケニル、C2−C7アルキニル、又はC1−C6アルコキシであり、前記H、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、C1−C7アルキル、C2−C7アルケニル、C2−C7アルキニル、又はC1−C6アルコキシは、ハロゲン、ヒドロキシ、C1−C5アルキル、C1−C4アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、
ここで、R2が、メタノイル、カルボキシ、アミノ、C1−C16アルキル、C2−C16アルケニル、C2−C16アルキニル、C1−C15アルコキシから選択される置換を含む場合、各置換基はハロゲン、ヒドロキシ、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C1−C4アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、−NH(C1−C4アルキル)、−N(C1−C4アルキル)(C1−C4アルキル)、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、スルホ、又は−Rcで独立に置換されていてもよく、かつ、
Rcは、選択ごとに同じでも異なってもよく、−CO−OCH3、−CO−NRfRg、−SO2−NRfRg、−NRfRg、−NH−CO−CH3、−NH−CO−NRfRg、−NH−CO−OCH3、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、5〜7員の単環式ヘテロシクリル、5〜7員の単環式ヘテロアリール、テトラゾリル、トリアゾリル、イミダゾリル、ピロリル、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、ピリジル、ピラジニル、ピリミジニル、チエニル、フリル、ピラニル、ピラゾリル、イソチアゾリル、イソオキサゾリル、ピリダジニル、フラザニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、又はピラゾリニルであってもよく、ハロゲン、ヒドロキシ、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C1−C4アルコキシ、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよく、
Rfは、選択ごとに同じでも異なってもよく、H又はC1−C4アルキルであってもよく、かつ、
Rgは、選択ごとに同じでも異なってもよく、H又はC1−C4アルキルであってもよい]。 - R1が、アリール、シクロアルキル、ヘテロシクリル、又はヘテロアリールであり、ハロゲン、ヒドロキシ、C1−C5アルキル、C1−C4アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよい、請求項1に記載の化合物。
- X1が、2価の−(NH)−、−(CH2)−、−O−、又は−S−であり、ハロゲン、ヒドロキシ、−Rx、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、又はスルホで置換されていてもよい、請求項1に記載の化合物。
- X1が、−N(CH3)−、−S−、−O−、−C(CH3)2−、又は−C(HCH3)−である、請求項1に記載の化合物。
- R2が、アリール、シクロアルキル、ヘテロシクリル、ヘテロアリールであり、−SO2−R3、−(C=O)−R3で置換されており、かつ、ハロゲン、ヒドロキシ、C1−C16アルキル、C2−C16アルケニル、C2−C16アルキニル、C1−C15アルコキシ、メタノイル、カルボキシ、ニトロ、シアノ、アミノ、カルバモイル、エチニル、−CF3、−CF2CF3、−OCF3、−OCF2CF3、スルホ、−SO2−R3、−(C=O)−R3、又は−O−R3でさらに置換されていてもよい、請求項1に記載の化合物。
- 請求項1に記載の化合物と薬学的に許容される担体とを含む医薬組成物。
- がんを治療するための医薬を調製するための、請求項1〜11のいずれかに記載のいずれかの化合物の使用。
- 請求項1〜12のいずれかに記載の化合物。
- RASにおける活性化変異に関連する疾患を治療する、又はRAS活性の低減によって治療可能な疾患を治療する方法であって、その治療を必要とする患者に請求項1〜10のいずれかに記載の化合物を投与することを含む、前記方法。
- 患者が、ヒトである、請求項14に記載の方法。
- 疾患が、腫瘍又はがんである、請求項14に記載の方法。
- ペムブロリズマブ、ニボルマブ、AS1411又は金ナノ粒子にコンジュゲートしたAS1411からなる群から選択される少なくとも1つのメンバーを投与することをさらに含む、請求項14〜16のいずれかに記載の方法。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN101919842A (zh) * | 2009-06-11 | 2010-12-22 | 复旦大学 | 一种苯丙噻吩衍生物在制备抗肿瘤药物中的应用 |
JP2011506580A (ja) * | 2007-12-21 | 2011-03-03 | ピエール、ファーブル、メディカマン | アルテミシニンの二量体誘導体、および抗癌療法における用途 |
WO2012073041A2 (en) * | 2010-12-02 | 2012-06-07 | The University Of Nottingham | Compounds |
JP2017538772A (ja) * | 2014-12-16 | 2017-12-28 | エーディーティー ファーマシューティカルズ,エルエルシー | Ras媒介性疾患を処置または予防する方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4944796A (en) * | 1988-11-14 | 1990-07-31 | Ici Americas Inc. | Certain 2-(disubstituted amino) acetanilide herbicides |
JP2002517484A (ja) * | 1998-06-09 | 2002-06-18 | ノートラン・ファーマシューティカルズ・インコーポレーテッド | 鎮咳薬としての四級アンモニウム化合物 |
WO2008070831A2 (en) | 2006-12-07 | 2008-06-12 | Xavier University Of Louisiana | Bisbenzamidines and bisbenzamidoximes for the treatment of human african trypanosomiasis |
US7951806B2 (en) * | 2007-07-25 | 2011-05-31 | Renascience Co., Ltd. | Plasminogen activator inhibitor-1 inhibitor |
GB0808282D0 (en) | 2008-05-07 | 2008-06-11 | Medical Res Council | Compounds for use in stabilizing p53 mutants |
WO2011130628A1 (en) * | 2010-04-16 | 2011-10-20 | Curis, Inc. | Treatment of cancers having k-ras mutations |
JP6043290B2 (ja) * | 2011-09-22 | 2016-12-14 | 武田薬品工業株式会社 | 縮合複素環化合物 |
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US9181288B2 (en) | 2014-01-16 | 2015-11-10 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011506580A (ja) * | 2007-12-21 | 2011-03-03 | ピエール、ファーブル、メディカマン | アルテミシニンの二量体誘導体、および抗癌療法における用途 |
CN101919842A (zh) * | 2009-06-11 | 2010-12-22 | 复旦大学 | 一种苯丙噻吩衍生物在制备抗肿瘤药物中的应用 |
WO2012073041A2 (en) * | 2010-12-02 | 2012-06-07 | The University Of Nottingham | Compounds |
JP2017538772A (ja) * | 2014-12-16 | 2017-12-28 | エーディーティー ファーマシューティカルズ,エルエルシー | Ras媒介性疾患を処置または予防する方法 |
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Title |
---|
REGISTRY(STN)[ONLINE], JPN7023001938, 2008, ISSN: 0005062679 * |
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