JP6863742B2 - 新規アントラニルアミドとその使用 - Google Patents
新規アントラニルアミドとその使用 Download PDFInfo
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- JP6863742B2 JP6863742B2 JP2016542095A JP2016542095A JP6863742B2 JP 6863742 B2 JP6863742 B2 JP 6863742B2 JP 2016542095 A JP2016542095 A JP 2016542095A JP 2016542095 A JP2016542095 A JP 2016542095A JP 6863742 B2 JP6863742 B2 JP 6863742B2
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- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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Description
本願は、2013年9月11日に出願された米国仮出願第61/876,645号に基づく利益を主張するものであり、その全体の内容を参照により含むものである。
本発明は、国立衛生研究所により承認された政府支援(承認番号R01CA125806とR15 CA176496)により完成されたものである。米国政府は、本発明について所定の権利を有する。
別途説明がない限り、本明細書において使用される全ての技術的及び科学的用語は、本開示された主題が属する分野の当業者が通常理解するものと同じ意味を持つ。化学用語の一般用語の定義については、The McGraw−Hill Dictionary of Chemical Terms(1985年)やThe Condensed Chemical Dictionary(1981年)などを参照されたい。分子生物学の一般用語の定義については、Benjamin Lewin著のGenes IX(Jones and Bartlet社、2008年)(ISBN0763752223)、Kendrewら編のThe Encyclopedia of Molecular Biology(Blackwell Science社、1994年)(ISBN0632021829)やRobert A. Meyers編のMolecular Biology and Biotechnology: a Comprehensive Desk Reference(VCH Publishers社、1995年)(ISBN 9780471185710)、その他の同様の参考文献を参照されたい。本明細書において、「a」、「an」、「the」などの単数形の単語は、別途文脈上明白に示されていない限り、複数の場合も包含するものである。同様に、「または」という単語は、別途文脈上明白に示されていない限り、複数の場合も包含するものである。また、本明細書では、「comprises」は「includes」と同じ意味である。よって、「AまたはBを含む」は、A、B、またはA及びBを有することを意味する。別途記載が無い限り、全ての数値は、「約」や「およそ」等の単語がある場合でもない場合でも近似値である。本明細書で示された物質、方法、及び例は、説明のためだけに挙げられているもので、本発明を限定するものではない。全ての分子量は近似値であり、説明のためだけに挙げられているものである。別段記載が無い限り、本発明の方法と手法の実施は、本分野で公知の従来の方法に基づいて通常実施でき、また本明細書において引用され、言及される様々な一般的またはより専門的な文献で説明されているように実施可能である。例えばLoudon著Organic Chemistry 第4版(ニューヨーク、Oxford University Press社、2002年、pp.360−361,1084−1085);Smith and March著、March’s Advanced Organic Chemistry:Reactions, Mechanisms, and Structure 第5版(Wiley−Interscience社、2001年、またはVogel著、A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis 第4版(ニューヨーク:Longman社、1978年)などを参照されたい。
A.序文
マイトジェン活性化タンパク質キナーゼ(MAPK)は、タンパク質セリン/トレオニンキナーゼの一群である。これらキナーゼは、胚形成、細胞分化、細胞増殖、及び細胞死を制御する経路の主成分である。MEK5シグナル経路は、細胞に酸化的ストレスを生き延びさせるもので、マイトジェン(EGF及びG−CSF)、サイトカイン(LIF及びCT−1)及びストレス(H2O2、及びソルビトール)により活性化される。MEK/ERK経路を含むいくつかのシグナル経路は、ある種のがんでは顕著に上方制御されており、より侵襲性の間葉表現型への移行において役割を担っていると考えられている。
本明細書にて総称してアントラニルアミド誘導体と称される化合物を開示する。これらアントラニルアミド誘導体は、例えば乳がん、膵臓がん、扁平上皮がん、前立腺がん及び/または初期またはトリプルネガティブな乳がんなどの固形腫瘍等のがんの治療に使用可能である。上記化合物は、例えば、がんの進行時、特にがんの転移時において、特に上皮間葉間転換の防止、予防及び/または逆行に効果的である。上記化合物の他の使用としては、下記のように、インビトロ及びインビボアッセイ両方での上皮間葉(EMT)遺伝子の発現の抑制が挙げられる。具体的な実施例において、化合物は小分子治療用である。
上記の化合物(例えば、アントラニルアミド誘導体や、その水和物や薬学的に許容可能な塩)または、その組み合わせのいずれもがんの治療薬の製造において使用されることを意図するものである。そのような薬剤に好適な処方と、その貢献を受けえる対象者、そしてその他の特徴は、本明細書の他の箇所に記載されている。
上記開示されたアントラニルアミド誘導体は、本技術分野において公知の任意の方法で合成してもよい。上記開示された化合物の合成に使用可能な一般的な化学合成スキームと条件を記載した一般的な参考文献は多い(例えば、Smith and March著、March’s Advanced Organic Chemistry:Reactions, Mechanisms, and Structure第5版(Wiley−Interscience、2001年)、またはVogel著、A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis、第4版(New York:Longman,1978年を参照)。方法の例をいくつか下記と実施例に示す。
ジハロアミドの合成
カルボン酸71の酸塩化物を介して進行する一般的合成戦略は有効だったが、複雑なものであった。ジハロ酸71から開始する化学的経路は、上述のテトラハロ酸(39)よりも収率が低かった。これは、結合したジフェニルアミンが(39)より(71)において電子欠損が低いことが原因である可能性がある。カルボン酸(71)が、上記のテトラハロ酸(39)に誘導するように反応すると予想されたが、電子欠損が低いジフェニルアミンは、分子内または分子間でのジフェニルアミンと塩化アシルの縮合を伴う副反応に参加したであろう。
N−メチルジフェニルアミンコアの合成:
エシュバイラー・クラーク反応を、3,4−ジフルオロ−2−((2−フルオロ−4−ヨードフェニル)(メチル)アミノ)安息香酸である化合物76を調製する初期戦略として検討した。標準のマイクロ波反応条件を用いることを検討したが、所望の生成物は単離できなかった。ヨウ化メチルを用いたアルキル化の前にジフェニルアミンの窒素原子からプロトンを分離する水酸化ナトリウム分離を利用する他の戦略を試した。粗TLC分析では多くのスポットが見られ、カラムクロマトグラフィによる分離は失敗したことが分かった。
その他の合成スキームを図4〜図8に示す。
がんの対象者、がんの疑いのある対象者、またはがんを発症するリスクが高い対象者を、上記開示されたアントラニルアミド誘導体で治療する方法を本明細書で開示する。本方法は、例えば乳がん腫瘍、前立腺がん腫瘍及び/または膵臓腫瘍などの固形腫瘍と診察された対象者、がんの対象者などの必要のあるまたは治療の個人を選択することを含む。開示されたアントラニルアミド誘導体での治療の対象となる典型的な対象者は、ヒトや非ヒト霊長類やマウスなどその他の動物を含む。選択後、対象者は、開示されたアントラニルアミド誘導体の治療有効量を投与され、がんを治療する。いくつかの例では、上記開示されたアントラニルアミド誘導体は、薬学的組成物として提供される。また、例えば、対象者に開示されたアントラニルアミド誘導体の効果的補正を投与するなどの、対象者においてMEK1/2及び/またはMEK5を抑制する方法を開示する。さらに、例えばがん細胞などにおいて上皮間葉間転換を抑制及び/または逆行する方法を開示する。
治療的または医薬組成物などの組成物は、開示されたアントラニルアミド誘導体の1つまたは複数を含んで提供される。MEK1/2及び/またはMEK5活性の抑制剤を医薬組成物、例えば、細胞増殖または細胞の移動、または細胞の普及障害を抑制または治療する目的に適切な医薬組成物として準備するのが望ましい。よって、開示されたアントラニルアミド誘導体を含む薬剤や医薬組成物を製造する方法も本発明は包含する。上記開示されたアントラニルアミド誘導体のみを投与するために生成されてもよく、他の化学治療薬などの他の活性成分と共に投与されるために生成されてもよい。
実験
図1及び図2は、MAPKシグナル経路とMEK5シグナル経路をそれぞれ示す。MEK5を抑制する化合物を設計する戦略を開発するため、EGFを介したpERKイソ型の形成の抑制の細胞アッセイをHEK293(腎臓)とBT−474細胞株の合成済みの抑制剤で行った。設計戦略は、図3に示す4つのエリアについて検討した。側鎖のバリエーションを、溶解度を変化させるためにターゲットとし、MEK5の予想された反応を調べるために使用した。設計戦略エリア2及び3は、それぞれ、アミド変化形と中央のアレーンに集中した。第4のエリアは、末端アレーンであり、ゴールは置換の必要性を最小限にすることと、MEK5の選択的相互反応を促進することである。
合成方法
全ての溶媒と試薬は、別途記載がないかぎり、受領された状態そのままで使用された。全ての反応は、別途記載が無い限り乾いたガラス器具を用いて、アルゴン雰囲気下で行われた。シールしたチューブ内でマイクロ波反応を行い、マルチモードマイルストーンスタート装置を使用して、記載の電力と制御パラメータで放射を行った。融点は、MelTemp装置で測定され、修正は行わなかった。全てのプロトンNMRスペクトルは、ブルーカーアヴァンスシステム(Bruker Avance system)で制御されたオックスフォードスペクトロスピンクリオスタット(Oxford spectrospin cryostat)を用いて500MHzまたは400MHzで測定され、ブルーカートップスピン2.0取得ソフト(Bruker TOPSPIN2.0 acquisition software)で取得された。取得したFIDを、MestReC3.2を用いて分析した。元素分析は、アトランティックマイクロラブを用いて実施され、理論的に±0.4である。全ての1H NMRスペクトルは、別途記載が無い限りCDCl3を用いて測定された。内部標準であるTMSに対するppmとして報告する。カップリング値をヘルツで報告する。全てのTLCは、厚さ200μmのソルベントテクノロジーポリエステルバックドシリカG TLCプレートで測定された。
3,4−ジフルオロ−2−((2−フルオロ−4−ヨードフェニル)アミノ)安息香酸(SC−1−180)(39) 250mLの丸底フラスコに2−フルオロ−4−ヨードアニリン(38;2.38g、10.0mmol)、2,3,4−トリフルオロ安息香酸(37;1.80g,10.2mmol)、そして無水THF(30mL)を仕込んだ。該反応混合液を氷水浴で0℃に冷却し、LiNH2(561.2mg,24.45mmol)を3回に分けて10分かけて添加した。その後、反応は、内部温度58℃まで温め、12時間攪拌した。該混合液を0℃まで冷却し、反応混合液の温度を0℃に保ちながら1NのHClを添加して、最終pH1.0を得た(ピハイドリン紙(pHydrion paper)で赤)。次に反応混合液を10mLのEt2Oを用いて3回抽出し、5mLの1NのHClで3回洗浄し、NaCl(飽和水溶液)で洗浄し、Na2SO4で乾燥した。抽出物をデカントし、溶媒を減圧下で除去した。粗生成物を2:1ヘキサン/EAを用いてSiO2で単離し、白色の固体を2.11g(53%)得た。MP=199.0−200.1℃(lit.MP=200−201℃) SiO2 TLC Rf 0.51(2:1へキサン/EA) 1H NMR(400MHz,MeOD−d4):δ6.74(m, 1H, Ar),6.91(m, 1H, Ar),7.38−7.45(d, 1H, J=8.5Hz,Ar),7.47(dd,1H,J1=1.8Hz and J2=10.5Hz,Ar),7.89(br, 1H, Ar) 計算値 C13H7F3INO2:C,39.72;H,1.79;N,3.56.実測値:C,39.41;H,1.91;N,3.52.
乾燥した100mLの丸底フラスコに3,4−ジフルオロ−2−((2−フルオロ−4−ヨードフェニル)アミノ)安息香酸(39)及びDCMを5mL仕込んだ。該反応混合液を氷水浴で0℃に冷却した。無水DMFを100μL添加し、純粋な塩化オキサリル(2当量)を5分かけて滴下した。該反応液を23℃で4時間攪拌した。次に溶媒を減圧下で除いた。余剰の塩化オキサリルを、減圧下で2x5mLのDCMと共沸させて除去した。該粗生成物を5mLのDCMに溶解し、適切なアミンを精確に0℃で添加した。10分後氷水浴を除き、該反応液を放置して室温にした。その後該反応液を23℃で6時間攪拌し、反応が終了したことをTLCで確認した。10mLのH2Oと10mLのEt2Oの混合液を添加し、結果得られた混合液をEt2Oで抽出し、NaCl(飽和水溶液)で洗浄し、Na2SO4で乾燥した。抽出物をデカントし、溶媒を減圧下で除去した。粗生成物をヘキサン/EAを用いてSiO2で単離した。
2−((2−フルオロ−4−ヨードフェニル)アミノ)安息香酸(SC−1−14)(98):マイクロ波反応器チューブにオルト−ヨード安息香酸(496mg, 2mmol)、2−フルオロ−4−ヨードアニリン(237mg, 1mmol)、K2CO3(416mg,3mmol)、CuI(200mg,1.04mmol)及び5mLのDMF/H2O(9:1)を仕込んだ該反応液を、内部温度を100℃に保ちながら2時間300Wのマイクロ波放射に晒した。完了後、該反応液をTLCで分析し、1NのHCl(約4 mL)を該反応混合液に添加して、最終的な溶液pH6.0を得た。その後溶媒を減圧下で除去した。 粗生成物をSiO2で1:1ヘキサン/EAを用いて単離し、217mg(61%)の白色の固体を得た。MP=186.2−186.5℃。SiO2 TLC Rf 0.70(1:1 ヘキサン/EA)。1H NMR (400 MHz, CDCl3): δ 6.85 (t, 1 H, J = 7.1 Hz, Ar), 7.11(d, 1 H, J = 8.6 Hz, Ar), 7.20 (t, 1 H, J = 8.4 Hz, Ar), 7.42 (m, 2 H, Ar), 7.50 (dd, 1 H, J = 2.0 Hz and J = 9.8 Hz, Ar), 8.06 (dd, 1 H, J = 1.6 Hz and J = 8.1 Hz, Ar), 9.25 (s, 1 H, CO2H).計算値 C13H9FINO2:C, 43.72; H, 2.54; N, 3.92.実測値:C, 43.81; H, 2.65; N, 3.80.
(4−メチルピペラジン−1−イル)(2−(フェニルアミノ)フェニル)メタノン(SC−1−177アミド)(75):乾燥させた100mLの丸底フラスコに化合物25(1.00g, 4.69mmol)と12mLのDCMを仕込んだ。N−メチルピペラジン(2.59mL, 23.45mmol)とDMAP(9mg,0.07mmol)を添加し、その後、DIC(1.08mL,7mmol)を添加した。該反応混合液を23℃で22時間攪拌した。溶媒を減圧下で除去した。10mLのエーテルとHClの混合液を添加し、得られた混合液をHCl(3x5mL)に抽出して、エーテル(2x5mL)で洗浄した。水相を5%Na2CO3でアルカリ化し、粗生成物をDCM(3x8mL)に抽出した。粗生成物をSiO2に充填し、クロロフォルム:メタノール(95:5)で溶出した。適切な分画を採取し、溶媒を除去して、高温のエタノールから再結晶させて、232mg(17%)の透明無色の針状の物質を得た。MP=105.9−108.0℃。 SiO2 TLC Rf 0.35 (chloroform/ 1% メタノール).1H NMR(400 MHz, MeOD−d4):δ 2.23 (s, 3 H, CH3), 2.35 (br, 4 H, 2CH2), 3.73−3.82 (m, 4 H, 2CH2), 6.88 (t, 1 H, J = 7.3 Hz), 6.97−7.01 (m, 3 H, Ar), 7.19−7.26 (m, 4 H, Ar), 7.30−7.34 (m, 1 H, Ar).計算値 C18H21N3O:C, 73.19; H, 7.17; N, 14.23.実測値:C, 73.14; H, 7.22; N, 14.23.
3,4−ジフルオロ−2−(フェニルアミノ)フェニル)(4−メチルピペラジン−1−イル)メタノン(SC−1−181)(72):化合物71(249mg,1mmol)、N−メチルピペラジン(0.25mL, 2mmol)及びDMAP(6mg, 0.05mmol)の溶液を10mLの無水THFに溶解して準備し、EDCI(382mg, 2mmol)を一度に添加した。反応混合液を23℃で12時間攪拌した。溶媒を減圧下で除去し、エーテル50mLとH2O1mLを添加した。得られた混合液を1mLのH2Oで3回洗浄し、5mLの飽和NaClで洗浄し、その後無水Na2SO4で乾燥させた。粗生成物をSiO2でCHCl3、1%MeOH、1%TEAを用いて単離し、204mg(62%)の白色の固体を得た。MP=153.0−155.3℃。 1H NMR (400 MHz, CDCl3):δ 2.22 (s, 4 H, 2CH2), 2.27(br, 3 H, CH3),3.47 (br, 4 H, 2CH2), 6.60 (s, 1 H, NH), 6.82−6.95 (m, 4 H, Ar), 6.99−7.03 (m, 1 H, Ar), 7.22−7.24 (m, 2 H, Ar).計算値 C18H19F2N3O:C, 65.24; H, 5.78; N, 12.68; F, 11.47.実測値:C, 65.38; H, 5.89; N, 12.72; F, 11.46.
生物的評価
細胞の培養と処理
MDA−MB−231細胞を、10cm細胞培養プレート[Sarstedt]中のダルベッコ改変イーグル培地(DMEM; Gibco)にハムF12栄養混合物(1:1)(Invitrogen)、10%熱不活性化FBS[Atlanta Biological及び0.5%ペニシリン/ストレプトマイシン[Gibco]を添加した培地にて培養した。細胞を5%CO2の雰囲気下37℃で保持された。処理の36時間前に35mmの培養プレート[Sarstedt]への細胞の播種を行い、コンフルエンスさせた。MEK−5抑制剤をテストする為、化合物での処理の前に30分、細胞を上皮成長因子(EGF; Sigma−Aldrich)にて処理した。EGFの添加15分後に、細胞を1XPBS [Sigma−Aldrich]で洗浄し、20mMトリス(pH 6.8)、137mMのNaCl、25mMのベータグリセロリン酸エステル、2mMのNaPPi、2mMのEDTA、1mMのNa3VO4、10%のグリセロール、5μg/mLのロイペプチン、5μg/mLのアプロチニン、2mMのベンズアミジン、0.5mMのDTT、及び1mMのPMSFを含有した1%Triton X−100バッファーで溶解した。溶解物を4℃において10,000rpmで10分間遠心分離した。
トータルタンパク質含有量をブラッドフォードバイオラドタンパク質アッセイ(Cat.No.500−0006, Bio−Rad, Hercules, CA)で分析し、30μgのタンパク質を8%SDS−PAGEジェルに充填して、リン酸化とトータルERK1/2及びERK5タンパク質とした。試料を準備後、ジェルをニトロセルロース薄膜(Cat.No. 926−31092, Licor Biosciences, Lincoln, NE)に移した。移動後、該薄膜を5分間1xPBSで洗浄し、1時間カゼインブロッキングバッファー(Cat.No.927−40200,Licor Biosciences)で室温にてブロックした。該薄膜を0.2% Tween−20を添加したCBB中にて第1抗体と共に一晩4℃で培養した。抗体はラビットアンチフォスフォ−ERK1/2(希釈 1:1000, Cat.No. 9101, Cell Signaling, Beverly, MA)マウスアンチ−トータルERK1/2 (希釈 1:1000, Cat.No. 9107, Cell Signaling)、及びラビットアンチートータルERK5(希釈 1:1,000, Cat.No. 3372, Cell Signaling)を含んでいた。マウスアンチα−チューブリン(希釈 1:10,000, Cat.No.T5168, Sigma−Aldrich)をローディングコントロールとして用いた。第1抗体との培養後、ブロットを0.2% Tween−20を添加した1xPBS溶液(1xPBS−T)で洗浄し、ゴートアンチ−ラビット(希釈 1:10,000, Cat.No. 926−68021, LICOR Biosciences)と、ゴートアンチ−マウス(希釈 1: 10,000, Cat.No. 926−32210, LICOR Biosciences)第2抗体で、1時間室温にて培養した。該薄膜を1xPBS−Tで洗浄し、タンパク質バンドをオデッセイ赤外線撮像装置で可視化して、オデッセイソフト(LICOR Biosciences)で定量化した。
トリネガティブ乳がん(TNBC)細胞MDA−MB−231を96ウェルプレートに5%活性炭処理無フェノールDMEMが入った各ウェルに2,000個播種した。一晩放置して付着させた後、DMSOとMEK抑制剤化合物で2回処理した。プレートは、3日目、5日目、7日目に採取され、クリスタルバイオレットで染色された。細胞の形態の変化を倒立顕微鏡で観察した。細胞を洗浄し、33%の酢酸で溶解して、バイオテックシナジープレートリーダー(Biotek Synergy plate reader)を用いて吸光度を630nmにて測定した。データを、各2回測定した3回の実験からの賦形剤処理±SEMで正常化した平均細胞生存率として得た。
TNBC細胞を5%CS無フェノールDMEMにて48時間培養し、SC−1−151または賦形剤で処理して、3日間培養した。その後、2.5x104個の細胞をトランスウェルインサートで播種した。24時間後、細胞を固定化し、クリスタルバイオレットで染色して、移動した細胞数をカウントした。データを200xの視野中のコントロールに対する移動した細胞±SEMとして得た。実験は3回行った。
免疫低下したSCID/ベージュのメスのマウス(生後29日〜32日目)をチャールズリバーラボラトリー(Wilmington, MA)から得た。該動物を消毒済みの無菌の環境にて食料と水を不断給餌して適応させた。乳がん細胞MDA−MB−231を5%FBS無フェノールDMEMにて5日間培養し、採取した。生存細胞をPBSとマトリゲル減衰因子(BD Biosciences, San Jose, CA)と混合した。0日(13年7月5日)に乳腺脂肪体の両側に注射した(1x106細胞/注射)。動物に対する全ての手順は、マスクで供給されたイソフルレンと酸素の混合気を用いた麻酔状態で行われた。動物は0日にDMSOまたはSC−1−151(25mg/kg)で処理された。腫瘍サイズを、30日間デジタルキャリパーを使用して2週間毎に測定した。腫瘍体積を以下の式で算出した。4/3πLM2、式中Lは最大半径であり、Mは最小半径である。31日目に、腫瘍を切除し、OCT化合物でブロックした。マウスを毎日観察し、手術後の生存を確認した。マウスを14日間観察下に置き、転移に対する薬剤治療の効果を調べた。
グラフパッドプリズムソフト(Graph−Pad Software, Inc., San Diego, CA)を用いて統計分析を行った。データをペアにしていないスチューデントテストにて分析した。p<0.05を統計的に顕著だと判断した。
対象者の処理
本実施例は、開示されたアントラニルアミド誘導体で治療可能な、がんなどの具体的な疾患や状態を有する対象者の治療に使用できる方法を説明するものである。その様な治療は、単独でも他の治療(化学的治療など)と組み合わされて使用されてもよい。
Claims (11)
- R6はフッ素である、請求項1に記載の医薬組成物。
- 前記化合物が、(3,4−ジフルオロ−2−((2−フルオロフェニル)アミノ)フェニル)(4−メチルピペラジン−1−イル)メタノンモノフマル酸塩(SC−2−45)である、請求項1に記載の医薬組成物。
- 経口投与、静脈投与、経皮投与、筋内投与、及び皮下投与用に製剤化された、請求項1〜3のいずれか一項に記載の医薬組成物。
- 濃縮物、乾燥粉末、液体、カプセル、丸薬、及び錠剤を含む経口デリバリー用の製品を含む、請求項4に記載の医薬組成物。
- 薬剤の製造における請求項1〜3のいずれか一項に記載の医薬組成物の使用。
- 前記乳がんはトリプルネガティブな乳がんを含む請求項1〜5のいずれか一項に記載の医薬組成物。
- 前記乳がんは初期の乳がんを含む、請求項1〜5のいずれか一項に記載の医薬組成物。
- 前記がんは転移がんを含む、請求項1〜5のいずれか一項に記載の医薬組成物。
- 対象者における上皮間葉細胞転換を抑制または逆行させるための、請求項1〜5のいずれか一項に記載の医薬組成物。
- 対象者におけるMEK1/2及び/またはMEK5酵素活性を抑制するための、
請求項1〜5のいずれか一項に記載の医薬組成物。
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CN108947879B (zh) * | 2017-05-17 | 2022-06-28 | 中国科学院上海药物研究所 | Prmt i型抑制剂及其制备方法和用途 |
CN107954893A (zh) * | 2017-11-28 | 2018-04-24 | 兰州纬寰生物科技有限公司 | 邻氨基苯甲酰胺衍生物及制备方法和用途 |
WO2019111792A1 (ja) * | 2017-12-05 | 2019-06-13 | 国立研究開発法人産業技術総合研究所 | GTPセンサータンパク質PI5P4Kβの阻害剤 |
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