JP2014132027A - (e)−n−(2−アミノ−フェニル)−3−{1−[4−(1−メチル−1h−ピラゾール−4−イル)−ベンゼンスルホニル]−1h−ピロール−3−イル}−アクリルアミド塩 - Google Patents
(e)−n−(2−アミノ−フェニル)−3−{1−[4−(1−メチル−1h−ピラゾール−4−イル)−ベンゼンスルホニル]−1h−ピロール−3−イル}−アクリルアミド塩 Download PDFInfo
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- JP2014132027A JP2014132027A JP2014063486A JP2014063486A JP2014132027A JP 2014132027 A JP2014132027 A JP 2014132027A JP 2014063486 A JP2014063486 A JP 2014063486A JP 2014063486 A JP2014063486 A JP 2014063486A JP 2014132027 A JP2014132027 A JP 2014132027A
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- methyl
- amino
- phenyl
- benzenesulfonyl
- acrylamide
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Abstract
【解決手段】臭化水素酸塩、メタンスルホン酸塩、ヘミエタン-1,2-ジスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩及び2-ナフタレンスルホン酸塩からなる群から選ばれる(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドの塩。
【選択図】なし
Description
本発明は、医薬産業において医薬組成物の製造のために用いられる、(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド塩に関する。
細胞内の転写制御は複雑な生体プロセスである。その基本原理の一つは、ヒストンタンパク質、つまり八量体ヒストンコア複合体を形成するヒストンタンパク質H2A/B、H3及びH4、の翻訳後修飾による制御である。リシン残基のアセチル化又はメチル化、及びセリン残基のリン酸化による、これら複雑なN末端修飾は、いわゆる“ヒストンコード”の一部を構成する(Strahl & Ellis,Nature 403,41-45,2000)。一つの簡単なモデルにおいては、正に荷電したリシン残基がアセチル化されると、負に荷電したDNAへの親和性が低下し、こうして転写因子の結合が可能になる。
(i)ルビンスタイン・テイビー症候群に関連するHAT cAMP応答エレメント結合タンパク質(CBP)の突然変異、癌素因(Murataet al.Hum Mol Genet 10,1071-1076,2001)、
(ii)PML-レチノイン酸受容体α融合遺伝子による、急性前骨髄球性白血病(APL)における転写因子によるHDAC1活性の異常亢進(He et al. Nat genet 18,126-135,1998)、
(iii)非ホジキンリンパ腫で過剰発現されたBCL6タンパク質によるHDAC活性の異常亢進(Dhordain et al.Nuceic Acid Res 26,4645−4651,1998)、及び最後に
(iv)急性骨髄性白血病におけるAML-ETO融合タンパク質によるHDAC活性の異常亢進(AML M2サブタイプ;Wang et al.Proc Natl Acad Sci USA 95,10860-10865,1998)。このAMLサブタイプでは、HDAC1活性の亢進が原因となって遺伝子サイレンシング、分化阻害、及び発癌性形質転換が引き起こされる。
(v)HDAC1遺伝子をマウスにおいてノックアウトすることで、HDAC1は、サイクリン依存性キナーゼインヒビターであるp21waf1及びp27kip1を抑制することによって、胚性幹細胞において重大な機能を果たすことが示された(Lagger et al.Embo J.21,2672-2681,2002)。p21waf1はHDIによって多くの癌細胞系統で誘導されるので、HDAC1は、癌細胞増殖においても同様に重要な成分なのだろう。初期のsiRNAを基礎とするHeLa細胞での遺伝子ノックダウン実験は、この仮説を支持している(Glaser et al.310,529-536,2003)。
(vi)近年Zhuらによって報告されたところによると、機能性腺腫性結腸ポリポーシス(APC)タンパク質の欠損によってwnt/β-カテニン/TCF-シグナル伝達経路が構成的に活性化されると、結腸癌においてHDAC2が過剰に発現される(Cancer Cell 5,455-463,2004)。
本発明の第一の観点によれば、以下に詳細に記載される、合成された新規の(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドの塩は、該化合物の遊離塩基より優れた溶解性を驚くほど示し、かつWO2006/097474に記載された(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドの塩酸塩よりも高い安定性を有する。前記の塩には異なる多形相があり、薬剤物質のより高いバイオアベイラビリティの実現につながり得る。
本発明の(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドの塩は、該化合物の遊離塩基を、所望の酸を含むか、或いは所望の酸を後から添加した適切な溶媒(例えば、アセトン、メチルエチルケトン又はメチルイソブチルケトンのようなケトン、ジエチルエーテル、テトラヒドロフラン又はジオキサンのようなエーテル、塩化メチレン又はクロロホルムのような塩素化炭化水素、又は、メタノール、エタノール又はイソプロパノールのような低分子量脂肪族アルコール)に溶かすことによって得ることができる。該塩は、濾過、再沈殿、非溶剤を用いた付加塩の沈殿、又は溶媒を蒸発させることにより得られる。得られた塩はアルカリ化、又は酸性化によって遊離の化合物に変換することができ、ひいては別の塩へと変換することもできる。この方法によって、薬学的に耐容性のない塩は耐容性の塩に変換することが可能である。
部分的アモルファス
3.82gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドを水38mLに懸濁し、2.7mLのアンモニア水溶液(25%)を添加した。前記の懸濁液を1時間撹拌し、濾過した。前記の濾過ケーキを19mLの水で洗浄し、乾燥させた。オフホワイトの固体(3.09g)が得られた。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表1にまとめ、かつ図1に示した。
10.0gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド二塩酸塩(19.2mmol)をTHF300mlとNa2CO3水溶液(8%)375mlの混合液と処理した。液相を分離させ、THF100mlで抽出した。この一体となっている有機相を235mlの水で処理し、混合液の有機部分を蒸発させた。これによって、茶色がかった固体として遊離塩基が分離する。前記の水溶液をデカントして除き、その残留物をTHF120ml中に溶解させ、100gシリカゲル-60(Merck)に吸着させ、シリカゲル-60(Merck)470gとクロマトグラフィーにかけ、残留化合物をCHCl3/MeOH(20:1)に溶出させた。複数の分画を含む、前記の生成物を慎重に蒸発させた。6.00gの無色の固体を得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表2にまとめ、かつ図2に示した。
20.0gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド二塩酸塩を水100mLとエタノール100mLに懸濁した。アンモニア水溶液(25%)8.7mLを添加し、懸濁液を1時間撹拌した。前記の懸濁液を濾過し、その濾過ケーキを100mLの水で洗浄し、乾燥させた。オフホワイトの固体(8.8g)が得られた。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表3にまとめ、かつ図3に示した。
温めたメタノール20ml中、(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド(0.50mmol)225mgに対し、(4mLの4N HCl水溶液にメタノールを添加し、終量100mL=0.016mmol/mLにした)HCl/メタノール溶液(3.13mL、0.05mmol)を滴下して加えた。直ちに、黄色がかった油が分離した。ジエチルエーテル(10mL)を加えることによって、分離が完了した。得られた固体を一晩乾燥させた。収量:248mg(102%);黄色がかった固体;融点:150-164℃、分解(sinter.)。得られた化合物は、モル比で0.91のHClを含有した。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表4にまとめ、かつ図4に示した。
5.0gの[2-((E)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミノ)-フェニル]-カルバミン酸 tert-ブチルエステルを、THF90mlと水7.5mLに懸濁した。塩酸水溶液(37%)7.5mLを添加し、懸濁液を60℃で4時間撹拌した。室温に冷却後、前記の懸濁液を濾過し、濾過ケーキを20mLのTHFで洗浄して乾燥させた。オフホワイトの固体(3.7g)が得られた。その化合物は、モル比で1.82のHClを含有した。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表5にまとめ、かつ図5に示した。
THF4ml中、0.21gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドに対し、THF4mlに0.169molの48%-HBr(169μL,1.5mmol)を含む溶液を滴下して加えた。固体が分離し、それをジエチルエーテルで処理した。得られた結晶性固体を分離させ、一晩乾燥させた。収量:287mg(100%);融点:200℃、分解(sinter.)。前記の化合物は、モル比で1.86のHBrを含有した。
部分的アモルファス
(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド500mg、水10ml及びメタノール1mlを130℃に加熱した。メタンスルホン酸0.435mlを添加した。前記の混合物はほとんど溶解した。次いで、前記の混合物を直ちに冷却槽で冷却した。冷却している間に、茶色がかった固体が分離した。前記の混合物を超音波で処理した。続いて、得られた固体を回収し、乾燥させた。該固体の遊離塩基とメタンスルホン酸のモル比は、1:0.95だった。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表6にまとめ、かつ図6に示した。
(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド250g、水5ml、メタノール0.5ml、及び0.112mlメタンスルホン酸を130℃に10分加熱した。外気温で一晩撹拌した後、固体を回収し、乾燥させた。該固体の遊離塩基とメタンスルホン酸のモル比は、1:0.66だった。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表7にまとめ、かつ図7に 示した。
1.00gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドを水20mlに懸濁させた。懸濁液に、水5mlに512mgのエタンジスルホン酸水和物を溶かしたものを添加し、18時間撹拌した。懸濁液を濾過し、乾燥させた。オフホワイトの固体(1.09g)が得られた。該固体の遊離塩基とエタンスルホン酸のモル比は、1:0.5だった。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表8にまとめ、かつ図8に示した。
1.65gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドを水30mlに懸濁させ、642mgのベンゼンスルホン酸を添加した。懸濁液を26時間撹拌した後、濾過し、乾燥させた。オフホワイトの固体(2.04g)が得られた。該固体の遊離塩基とベンゼンスルホン酸のモル比は、1:0.99だった。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表9にまとめ、かつ図9に示した。
結晶性多形体A
5.0gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドをメタノール150mlに懸濁させ、p-トルエンスルホン酸水和物2.38gを添加した。この溶液を1時間撹拌し、ハイフロー(hyflow)で濾過した。濾液を真空中で濃縮させて50mlにし、2時間撹拌した。得られた沈澱を濾過し、乾燥させた。オフホワイトの固体(5.4g)として、多形体Aを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表10にまとめ、かつ図10に示した。
100.0gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドをイソプロパノール800mLに懸濁させた。イソプロパノール200mLにp-トルエンスルホン酸水和物46.8gを含む溶液を添加し、懸濁液を22時間撹拌した。懸濁液を濾過し、乾燥させてオフホワイトの固体(139.4g)として多形体Bを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表11にまとめ、かつ図11に示した。
1.0gの多形体Bの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド トルエン-4-スルホン酸塩をメタノール10mLに懸濁させ、60℃で48時間撹拌した。懸濁液を室温に冷却し、濾過し、乾燥させた。オフホワイトの固体(825mg)として、多形体Cを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表12にまとめ、かつ図12に示した。
5.0gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドをMIBK75mlに懸濁させ、p-トルエンスルホン酸水和物2.34gを添加した。懸濁液を4時間撹拌し、濾過し、乾燥させた。オフホワイトの固体(6.6g)として、多形体Dを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表13にまとめ、かつ図13に示した。
1.0gの多形体Bの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド トルエン-4-スルホン酸塩をメタノール9mLと水1mL中に懸濁させ、室温で24時間撹拌した。懸濁液を濾過し、乾燥させた。オフホワイトの固体(826mg)として、多形体Eを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表14にまとめ、かつ図14に示した。
200gの多形体Aの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド トルエン-4-スルホン酸塩をエチルメチルケトン1.8mLと水0.2mL中に懸濁させ、18時間撹拌した。懸濁液を濾過し、乾燥させた。オフホワイトの固体(101mg)として、多形体Fを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表15にまとめ、かつ図15に示した。
1.00gの多形体Cの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド トルエン-4-スルホン酸塩をアセトン9mLと水1mL中に懸濁させ、24時間撹拌した。懸濁液を濾過し、乾燥させた。オフホワイトの固体(867mg)として、多形体Gを得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表16にまとめ、かつ図16に示した。
7.0gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミド(15.6mmol)を、アセトンと水を5:1で含む混合物126mlに懸濁させた。全物質が溶けるまで懸濁液を加熱還流した。この熱溶液をガラス繊維フィルターで濾過し、フィルターを加熱した前記の混合物からなる溶媒4mLで洗浄した。濾液を一つに合わせ、この溶媒107mlを真空中で蒸留したところ、遊離塩基が再結晶化した。この沈殿物を濾過し、乾燥させずに用いた。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表17にまとめ、かつ図17に示した。
結晶性多形体A+B
2.00gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドをイソプロパノール40mLに懸濁させた。ナフタレン-2-スルホン酸(70%)1.46gを添加し、懸濁液を24時間撹拌した。懸濁液を濾過し、濾過ケーキをイソプロパノール20mLで洗浄して乾燥させた。オフホワイトの固体(2.72g)を得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表18にまとめ、かつ図18に示した。
2.00gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドをイソプロパノール40mLに懸濁させた。ナフタレン-2-スルホン酸(70%)1.46gを添加し、懸濁液を21時間撹拌した。懸濁液を濾過し、乾燥させた。オフホワイトの固体(2.82g)を得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表19にまとめ、かつ図19に示した。
1.00gの(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドをメタノール15mLに懸濁させた。ナフタレン-2-スルホン酸(70%)1.46gを添加し、懸濁液を濾過した。濾液に種晶を添加し、懸濁液を1時間撹拌した。懸濁液を濾過し、乾燥させた。オフホワイトの固体(1.28g)を得た。
この塩のX線粉末回折パターンの特徴的なピークを、実質的に表20にまとめ、かつ図20に示した。
本発明による(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドの塩は、有用な薬理学的特性及び作用を有し、それゆえ産業上の応用が可能である。例えば、ヒストンヒストンデアセチラーゼ活性とその機能の阻害に関する特性に基づいて、前記の塩は産業上利用性を有する。
(i)関節症及び骨病理学的疾患、例えばリウマチ様関節炎、変形性関節症、痛風、多発関節炎及び乾癬性関節炎、
(ii)全身性エリテマトーデス及び移植拒絶反応のような自己免疫疾患、
(iii)過剰増殖性疾患、例えば乾癬、又は血管増殖疾患、アテローム性動脈硬化症及び再狭窄のような平滑筋細胞増殖、
(iv)急性及び慢性の炎症症状及び皮膚疾患、例えば潰瘍性結腸炎、クローン病、アレルギー性鼻炎、アレルギー性皮膚炎、嚢胞性線維症、慢性気管支炎及び喘息、
(v)子宮内膜症、子宮類線維腫、子宮内膜増殖症及び良性前立腺肥大症、
(vi)心不全、
(vii)HIV感染症のような免疫抑制状態の阻害、
(viii)パーキンソン病、アルツハイマー病又はポリグルタミン関連疾患のような神経病理学的な疾患、
(ix)内因性遺伝子の発現増強並びに遺伝子治療における導入遺伝子の発現増強により寛解されうる病態
が含まれる。
本発明の(E)-N-(2-アミノ-フェニル)-3-{1-[4-(1-メチル-1H-ピラゾール-4-イル)-ベンゼンスルホニル]-1H-ピロール-3-イル}-アクリルアミドの塩は、組合せ療法において、別々に、連続的に、同時に、併用して又は時差で(例えば組合せ単位投与形態として、別々の単位投与形として、隣接した不連続な単位投与形として、固定又は非固定の組合せ剤として、パーツ・キットとして、又は混合剤として)、1種以上の標準的な治療剤、特に当該技術分野で知られる抗癌剤(化学療法薬及び/又は標的特異的な抗癌剤)、例えば前記のいずれかと一緒に投与してよい。
Claims (13)
- 臭化水素酸塩、メタンスルホン酸塩、ヘミエタン‐1,2‐ジスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩及び2‐ナフタレンスルホン酸塩からなる群から選ばれる(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩。
- これらに限定されるものではないが、3.9、16.4及び16.9±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる、多形Aの形の請求項1に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドメタンスルホン酸塩。
- これらに限定されるものではないが、16.0、22.7及び25.1±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる、多形Aの形の請求項1に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドヘミエタン‐1,2‐スルホン酸塩。
- これらに限定されるものではないが、19.1、20.4及び22.7±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる、多形Aの形の請求項1に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドベンゼンスルホン酸塩。
- 下記の多形のいずれかの形である、請求項1に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドトルエンスルホン酸塩:
これらに限定されるものではないが、7.0、19.6及び19.9±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形A;
これらに限定されるものではないが、18.1、21.2及び22.9±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形B;
これらに限定されるものではないが、8.9、11.7及び20.3±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形C;
これらに限定されるものではないが、17.1、18.7及び22.5±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形D;
これらに限定されるものではないが、6.9、13.0及び19.8±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形E;
これらに限定されるものではないが、5.3、10.5及び18.6±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形F;
これらに限定されるものではないが、6.6、19.2及び20.4±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形G;
これらに限定されるものではないが、6.7、19.5及び19.8±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形H。 - 下記:の多形のいずれかの形である、請求項1に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミド‐2‐ナフタレンスルホン酸塩:
これらに限定されるものではないが、4.6、18.5及び23.8±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形A+B;
これらに限定されるものではないが、4.7、6.8及び18.5±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形A+B;
これらに限定されるものではないが、5.8、17.3及び22.9±0.1(°2θ)を含む粉末X線回折ピークによって特徴づけられる多形C。 - 疾患の治療に用いられる、請求項1〜6のいずれかに記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩。
- 良性及び/又は悪性の新生組織形成、例えば癌の治療、予防又は改善に用いられる、請求項1〜6のいずれかに記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩。
- ヒストンデアセチラーゼの活性阻害に応答性又は感受性である疾患の治療に用いられる、請求項1〜6のいずれか1項に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩。
- 1種以上の請求項1〜6のいずれか1項に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩と共に、通常の医薬用賦形剤、希釈剤及び/又は担体を含む医薬組成物。
- 良性及び/又は悪性の新生組織形成、例えば癌の治療、予防又は改善に用いられる医薬組成物の製造のための、請求項1〜6のいずれか1項に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩の使用。
- ヒストンデアセチラーゼの活性阻害に応答性又は感受性である疾患の治療に用いられる医薬組成物の製造のための、請求項1〜6のいずれか1項に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩の使用。
- 患者に治療上有効かつ許容される量の請求項1〜6のいずれか1項に記載の(E)‐N‐(2‐アミノ‐フェニル)‐3‐{1‐[4‐(1‐メチル‐1H‐ピラゾール‐4‐イル)‐ベンゼンスルホニル]‐1H‐ピロール‐3‐イル}‐アクリルアミドの塩を投与することを含む、良性及び/又は悪性の過剰増殖性疾患、及び/又はアポトーシスの誘導に応答性の疾患、例えば良性及び/又は悪性の新生組織形成、例えば癌を治療、予防又は改善するための方法。
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JP2014063486A Active JP5952328B2 (ja) | 2008-03-12 | 2014-03-26 | (e)−n−(2−アミノ−フェニル)−3−{1−[4−(1−メチル−1h−ピラゾール−4−イル)−ベンゼンスルホニル]−1h−ピロール−3−イル}−アクリルアミド塩 |
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CN102716465B (zh) * | 2012-06-18 | 2014-01-15 | 贵州金桥药业有限公司 | 治疗肿瘤的药物组合物及其制备方法 |
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CN111432884A (zh) * | 2017-09-08 | 2020-07-17 | 4Sc股份公司 | Hdac抑制剂与免疫检查点调节剂组合用于癌症治疗 |
WO2019185598A1 (en) | 2018-03-26 | 2019-10-03 | 4Sc Ag | Combination comprising hdac inhibitor and cd137 agonist for cancer therapy |
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TW202114659A (zh) | 2019-10-02 | 2021-04-16 | 德商4Sc製藥公司 | 用於癌症治療之含hdac抑制劑、ctla—4抑制劑及pd—1抑制劑或pd—l1抑制劑之組合 |
CN111973590A (zh) * | 2020-07-06 | 2020-11-24 | 江苏省人民医院(南京医科大学第一附属医院) | 新型hdac抑制剂laq824在治疗弥漫大b细胞淋巴瘤药物中的应用 |
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BRPI0908917A2 (pt) | 2021-04-13 |
CN104803988A (zh) | 2015-07-29 |
HK1256310A1 (zh) | 2019-09-20 |
EA201001269A1 (ru) | 2011-06-30 |
EP2262775A1 (en) | 2010-12-22 |
NZ587823A (en) | 2012-05-25 |
KR101657718B1 (ko) | 2016-09-19 |
IL207994A (en) | 2015-10-29 |
WO2009112522A1 (en) | 2009-09-17 |
HK1186736A1 (en) | 2014-04-17 |
MX2010010014A (es) | 2011-04-05 |
CN110183425A (zh) | 2019-08-30 |
CN103360371A (zh) | 2013-10-23 |
JP2011513466A (ja) | 2011-04-28 |
US8557858B2 (en) | 2013-10-15 |
US20110086897A1 (en) | 2011-04-14 |
UA106351C2 (en) | 2014-08-26 |
AU2009224710B2 (en) | 2013-05-02 |
CA2719071C (en) | 2016-07-12 |
IL207994A0 (en) | 2010-12-30 |
CN103360371B (zh) | 2015-03-25 |
CN108101890A (zh) | 2018-06-01 |
CN101970411A (zh) | 2011-02-09 |
AU2009224710A1 (en) | 2009-09-17 |
ZA201006523B (en) | 2011-09-28 |
KR20100133422A (ko) | 2010-12-21 |
CA2719071A1 (en) | 2009-09-17 |
EP2100882A1 (en) | 2009-09-16 |
EA017533B1 (ru) | 2013-01-30 |
HK1208219A1 (en) | 2016-02-26 |
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