JP2019535671A - ブロモドメイン阻害剤 - Google Patents
ブロモドメイン阻害剤 Download PDFInfo
- Publication number
- JP2019535671A JP2019535671A JP2019521064A JP2019521064A JP2019535671A JP 2019535671 A JP2019535671 A JP 2019535671A JP 2019521064 A JP2019521064 A JP 2019521064A JP 2019521064 A JP2019521064 A JP 2019521064A JP 2019535671 A JP2019535671 A JP 2019535671A
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- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- compound
- polymer
- methylisoquinolin
- methylsulfonylphenyl
- 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.)
- Granted
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Abstract
Description
本出願は、それぞれすべての目的のために参照により本明細書に完全に組み込まれる、米国仮特許出願第62/410,756号 (2016年10月20日出願)及び、米国仮特許出願第62/151,205号 (2015年4月22日出願)の優先権利益を主張する米国特許出願第15/136,761号 (2016年4月22日出願)の優先権利益を主張する。
本実施形態は、例えば、4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン等の、がんの処置のために有用な化合物及び医薬組成物を提供する。
がん及び新生物疾患の有効な処置に対する必要性が当技術分野に存在する。
本実施形態は、結晶形態、アモルファス形態、溶媒和物及びそれらの水和物を含む、ブロモドメイン阻害剤、化合物4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン(「化合物1」);ならびに本化合物を含む医薬組成物を提供する。
本発明が、本明細書に記載され、それ自体が変動する場合がある具体的な方法、プロトコール及び試薬等に限定されないことは理解されるべきである。本明細書において使用される用語は、具体的な実施形態を記載する目的のためだけであり、特許請求の範囲によってのみ定義される本発明の範囲を限定することは意図されない。
一部の実施形態では、化合物1はアモルファスである。一部の実施形態では、アモルファス化合物1は、結晶性の欠如を示すX線粉末回折(XRPD)パターンを有する。図2は、アモルファス化合物1のXRPDパターンを例示している。一実施形態は、アモルファス4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンを含む医薬組成物を提供する。
一部の実施形態では、化合物1は結晶である。一部の実施形態では、化合物1は結晶形態Aである。図1は、化合物1の結晶形態AのXRPDパターンを実証している。これにより一部の実施形態は、4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンの結晶形態Aを含む医薬組成物を提供する。
一部の実施形態では、4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンの結晶形態は、例に概説のとおり調製される。本明細書において提示される溶媒、温度及び他の反応条件は変動する場合があることが留意される。
ヒト等の哺乳動物に投与される治療剤は、規制ガイドラインに従って調製されなければならない。そのような政府規制ガイドラインは、Good Manufacturing Practice(GMP)と称される。GMPガイドラインは、例えば最終産物中の残存溶媒の量等の有効治療剤の許容可能な混入レベルを概説している、好ましい溶媒は、GMP施設における使用のために好適であり、産業での安全上の懸念に沿ったものである。溶媒の分類は、例えば、the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Humna Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R5), (February 2011)に規定されている。
医薬組成物、製剤又は成分に関して用語「許容される」又は「薬学的に許容される」は、処置される対象の全般的健康に持続性の有害作用を有さないことを意味し、生物学的活性又は化合物の特性を抑制せず、比較的無毒性であると見なされる。
医薬組成物は、薬学的に使用され得る調製物への活性化合物の処理を促進する賦形剤及び補助剤を含む1つ又は複数の生理学的に許容される担体を使用して、従来の様式で製剤化されてよい。適切な製剤は、選択された投与の経路に依存する。薬学的に許容されると理解される任意の周知の技術、担体及び賦形剤は、好適であれば、当技術分野において理解されるとおり使用されてよい。薬学的に許容される賦形剤及び製剤は、当技術分野において周知である。例えば、REMINGTON: SCIENCE & PRACTICE OF PHARMACY, 19th Ed. (Mack Publishing Co., Easton, PA, 1995);PHARMACEUTICAL DOSAGE FORMS (Liberman & Lachman, eds., Marcel Decker, New York, NY, 1980);PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS, 7th Ed. (Lippincott Williams & Wilkins, 1999)を参照されたい。
本明細書に記載される化合物1を含む医薬組成物は、これらに限らないが、固体経口剤形、放出制御製剤、急速溶解製剤、発泡性製剤、錠剤、粉剤、丸剤、カプセル、遅延放出製剤、持続放出製剤、パルス放出製剤、多粒子製剤ならびに即時放出及び制御放出の混合製剤を含む、任意の好適な剤形に製剤化され得る。
クロマチンは、染色体を形成しているDNAとタンパク質との複合体である。ヒストンは、クロマチンの主要なタンパク質構成成分であり、DNAが巻き付くスプールとして作用している。クロマチン構造における変化は、ヒストンタンパク質の共有結合改変によって及び非ヒストン結合タンパク質によって影響を受ける。いくつかの種類の酵素は、種々の部位でヒストンを改変することが周知である。
ヒストンアセチル化は、静電気的状態を変化させることによって修飾がDNAとヒストン八量体との相互作用を失わせることが周知であるとおり、遺伝子転写の活性化と全般に関連している。この物理的変化に加えて、特定のタンパク質は、エピジェネティックコードに従って機能するためにヒストン内のアセチル化リジン残基に結合することが周知である。ブロモドメインは、ヒストンの文脈ではアセチル化リジン残基に共通に、だが排他的でなく結合する、タンパク質内の小さな(約110アミノ酸)別個のドメインである。およそ50個のタンパク質がブロモドメインを含有していることが周知であり、それらは細胞内でさまざまな機能を有する。
本明細書に記載される組成物は、エピジェネティック制御に関与する1つ又は複数のタンパク質の活性の阻害のために一般に有用である。したがって、少なくとも1つの実施形態は、細胞又は細胞内のクロマチン(chomatin)と化合物1とを接触させることによって、ブロモドメイン(例えばBRD2、BRD3、BRD4もしくはBRDT等のBETタンパク質、及びCBP、ATAD2A、GCN5L、BAZ2B、FALZ、TAF1もしくはBRPF1等の非BETタンパク質)又はこれらの変異体としても周知の、アセチル−リジン認識モチーフを含有する1つ又は複数のタンパク質によって媒介されるエピジェネティック制御を調節する方法を提供する。少なくとも1つの実施形態は、化合物1を含む医薬組成物を対象に投与することによって、ブロモドメイン(例えば、BRD2、BRD3、BRD4もしくはBRDT等のBETタンパク質及び、CBP、ATAD2A、GCN5L、BAZ2B、FALZ、TAF1もしくはBRPF1等の非BETタンパク質)又はこれらの変異体としても周知の、アセチル−リジン認識モチーフを含有する1つ又は複数のタンパク質によって媒介されるエピジェネティック制御を調節する方法を提供する。一部の実施形態では、ブロモドメイン含有タンパク質はBETタンパク質である。一部の実施形態では、BETタンパク質はBRD4である。
本明細書において開示される方法を実施するための次の成分、製剤、プロセス及び手順は、上に記載されるものに対応する。他の実施形態及び使用は、本開示に照らして当業者に明らかである。続く例は、種々の実施形態の単なる例示として提供され、いかなる様式においても本発明を限定すると解釈するべきでない。
4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン(化合物1)の合成
他に記される場合を除いて、試薬及び溶媒は、Acros Organics(Pittsburgh、PA)、Aldrich Chemical(Milwaukee、WI、including Sigma Chemical and Fluka)、Apin Chemicals Ltd.(Milton Park、UK)、Avocado Research(Lancashire、U.K.)、BDH Inc.(Toronto、Canada)、Bionet(Cornwall、U.K.)、Chemservice Inc.(West Chester、PA)、Crescent Chemical Co.(Hauppauge、NY)、Eastman Organic Chemicals、Eastman Kodak Company(Rochester、NY)、Fisher Scientific Co.(Pittsburgh、PA)、Fisons Chemicals(Leicestershire、UK)、Frontier Scientific(Logan、UT)、ICN Biomedicals、Inc.(Costa Mesa、CA)、Key Organics(Cornwall、U.K.)、Lancaster Synthesis(Windham、NH)、Maybridge Chemical Co.Ltd.(Cornwall、U.K.)、Parish Chemical Co.(Orem、UT)、Pfaltz & Bauer、Inc.(Waterbury、CN)、Polyorganix(Houston、TX)、Pierce Chemical Co.(Rockford、IL)、Riedel de Haen AG(Hanover、Germany)、Spectrum Quality Product、Inc.(New Brunswick、NJ)、TCI America(Portland、OR)、Trans World Chemicals、Inc.(Rockville、MD)及びWako Chemicals USA、Inc.(Richmond、VA)等の供給業者から入手して、使用した。
本明細書において開示される置換複素環誘導体化合物の合成のための追加的方法は、当業者に容易に利用可能である。
1H NMR (CDCl3, 400 MHz) δ 8.43 (d, J=7.9 Hz, 1H), 8.40 (dd, J=8.2 Hz, 0.9 Hz, 1H), 7.68 (s, 1H), 7.65 (ddd, J=8.2, 8.2, 1.1 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS: 286 (M+H)+
1H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2H), 0.29 (m, 1H), 0.35 (m, 1H), 0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J=7.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J=7.6 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.30 (d, J=8.1 Hz, 1H). LCMS: 384 (M+H)+
ステップ1:2−メチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソキノリン−1−オン
1H NMR: (CDCl3, 400 MHz) δ 8.51 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.98 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.53 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 3.88 (m, 2H), 3.66 (s, 3H), 3.09 (s, 3H), 1.02-0.98 (m, 1H), 0.44-0.38 (m, 2H), 0.11-0.09 (m, 2H). LCMS: 384.1 (M+H)+.
米国特許出願第14/517,705号も参照されたい。
複素環誘導体BRD4阻害剤化合物1についてのIC50の決定を次のとおり実施した。Hisタグ化BRD4をクローニングし、発現させ、均一に精製した。Filipakopoulos et al., 468 Nature 1067-73 (2010)。BRD4結合及び阻害をビオチン化H4−テトラアセチルペプチド(AnaSpec、H4K5/8/12/16(Ac)、ビオチン−標識)の標的との相互作用をAlphaScreen technology(Life Technologies)を使用してモニタリングすることによって評価した。384ウエルProxiPlateでBRD4(BD1)(最終2nM)を50mM HEPES(pH7.3)、10mM NaCl、0.25mM TCEP、0.1%(w/v)BSA及び0.005%(w/v)Brij−35中で、DMSO(最終0.4%DMSO)又はDMSO中の化合物1の希釈系列のいずれかの存在下で、ペプチド(最終15nM)と組み合わせた。20分間、RTでのインキュベーション後、アルファストレプトアビジンドナービーズ及びニッケルキレート受容体ビーズを最終濃度5μg/mLまで加えた。2時間の平衡化後、プレートをEnvision装置で読み取り、IC50を4パラメーター非線形曲線フィットを使用して算出した。BRD4活性を阻害する化合物1の能力を定量し、相対的IC50値を決定した。比較のために関連化合物、2−メチル−4−フェニルイソキノリン−1−オンは本アッセイにおいてIC502.782μMを有した。化合物1は表1に示すとおり、本アッセイにおいて≦0.5μMのIC50値を示した。
比色分析細胞増殖アッセイ(細胞MTSアッセイ)を、確立されたがん細胞株の増殖に影響を与える本明細書で開示される複素環誘導体BRD4阻害剤の能力を評価するために実施した。
細胞MTSアッセイは、検査化合物の存在下又は非存在下で新たに生成されたNADHの量を定量する7日プレートベース比色分析アッセイである。NADHレベルは、がん細胞増殖の定量のために使用される。
種々の駆動変異(driving mutation)を有する確立されたがん細胞株をAmerican Type Culture Collection(ATCC)から得て、ATCCプロトコールに従って日常的に継代した。日常的アッセイのために、これらの細胞を7日間培養後に約90%コンフルエンスを可能にする密度で播種した。Raji、ヒトバーキットリンパ腫細胞(cMYC)を96ウエルあたり細胞15,000個で播種した。HL−60、ヒトプロ白血病細胞(NRAS、p16、p53、c−Myc増幅)を96ウエルあたり細胞5,000個で播種した。NCI−H460、ヒト非小細胞肺がん細胞(KRAS、PIK3CA、STLK11、p16)を96ウエルあたり細胞3,000個で播種した。プレートに蒔いた細胞を24時間インキュベートし、その後、細胞は最終濃度範囲100μMから2.0nMまでの化合物1の11点希釈物を受けた。細胞を薬物の存在下で168時間、37℃、5%CO2でインキュベートした。このインキュベーション期間の最後に培地80μLを除去し、20μLのCellTiter96(登録商標)AQueous Non−Radioactive Cell Proliferation Assayアッセイ溶液(Promega)を加えた。細胞をOD490>0.6に達するまでインキュベートした。IC50値をIDBS XLfitソフトウェアパッケージを使用し、バックグラウンド減算OD490値及びDMSO対照への標準化を含めて算出した。Chem Biography Platformを使用して細胞増殖IC50値をアップロードし、記録した。表1は、化合物1を用いて実施したin vitro酵素阻害アッセイ実験及びin vitro細胞ベースアッセイ実験の結果を提供する。
化合物1のシリカゲルカラムクロマトグラフィー精製(60:40 Hex/EtOAcから100%EtOAc)から純粋画分を回収し、ポリッシュフィルター(polish filter)を通してろ過し、約800mL〜1000mLに濃縮した。得られたスラリーをHex/EtOAc(50:50、2x200mL)の混合物を用いてろ過及び洗浄した。痰黄色固体を真空下、室温で乾燥させ、128.6gの精製化合物1を得た。
XRPDパターンもCuKα放射線(40kV、40mA)、θ−2θ角度計ならびにV4の発散及び受光スリット(receiving slit)、GeモノクロメーターならびにLynxeye検出機を使用してBruker AXS D8 Advance回折計で回収した。データ回収のために使用したソフトウェアはDiffrac Plus XRD Commander v2.6.1であり、データはDiffrac Plus EVA v15.0.0.0を使用して分析し、提示した。
結晶化合物1(516mg)をジクロロメタン(11mL)に溶解した。溶媒を真空(40℃、30mbar)下で除去した。残存固体を真空(25℃、0mbar)下、30分間さらに乾燥させ、XRPDによって分析した。XRPDディフラクトグラムは、回折ピークを示していない。図2は、アモルファス化合物1のXRPDディフラクトグラムを示している。
DSCデータを34位オートサンプラーを備えたMettler DSC 823Eで回収した。装置は、認証されたインジウムを使用してエネルギー及び温度について較正した。典型的には、各試料0.5mg〜5mg(例えば、4.877mg)をピンホールを付けたアルミニウムパン中で、10℃/分、25℃から350℃に加熱した。50mL/分での窒素パージを試料にわたって維持した。装置管理及びデータ分析ソフトウェアは、STARe v12.1. Wg−1、Integral −599.85 mJ normalized −122.99 Jg−1であった。発生は224.33℃で示され;試料の融解に起因する急な吸熱が224.95℃に見られ、図3に例示されている。
吸着等温線(Sorption isotherm)をDVS Intrinsic Control ソフトウェア v1.0.1.2(又はv1.0.1.3)によって管理しているSMS DVS Intrinsic水分吸着分析機(moisture sorption analyser)を使用して得た。試料温度を装置制御によって25℃に維持した。湿度は、200mL/分の合計流速での乾燥及び湿潤窒素の混合流によって調節した。相対湿度は、試料近くに位置させた較正Rotronicプローブ(ダイナミックレンジ1.0%RH〜100%RH)によって測定した。%RHの関数としての試料の重量変化(質量緩和(mass relaxation))は、微量天秤(精度±0.005mg)によって常にモニターした。
キネティック振とうフラスコ法(kinetic shake flask method)を使用して、化合物1形態Aの、pH=7.4、50mMリン酸緩衝液中の溶解度を2.6μg/mL〜3.7μg/mLであると決定した。
化合物1の結晶形態Aは、1%Tween、40%PEG400及び59%の0.5%HPMC中の懸濁物として10mg/kg、30mg/kg、100mg/kg又は300mg/kgでメスSprague Dawleyラットに経口投与された場合に非線形曝露レベル(AUC 0〜24時間)をもたらした。本研究の概要を図5に例示する。
噴霧乾燥分散物(SDD)を、ジクロロメタン中の化合物1の溶液をポリビニルピロリドン(PVP K12 PF)又はヒロドキシプロピルメチルセルロース(Methocel E5 LV)のいずれかと、化合物1:ポリマーの比が1:1又は1:3のいずれかとなるよう混合し、4つの固有の組合せを得て、続いて各調製物をラボスケールBuchi Spray Dryer(Buchi B290 パラメーター:注入口T° 80℃;出口 T° 57℃;アスピレーター100%;ノズルエア30mm;ポンプ速度25%;セットアップ:オープンループ)を使用して噴霧乾燥することによって調製した。
上に記載のとおり調製された4つのSDDの血漿曝露レベルを決定するために、それぞれの調製物をメスCD−1マウスに0.5%MC中の懸濁物として経口投与した。図6は、本実験の結果を例示している。要約:
1:1の化合物1:ポリマー比でPVPポリマーを含む組成物では、化合物1は平均AUC 0〜6時間、7,193hr ng/mLを有した。
1:3の化合物1:ポリマー比でPVPポリマーを含む組成物では、化合物1は平均AUC 0〜6時間、8,872hr ng/mLを有した。
1:1の化合物1:ポリマー比でHPMCポリマーを含む組成物では、化合物1は平均AUC 0〜6時間、10,484hr ng/mLを有した。
1:3の化合物1:ポリマー比でHPMCポリマーを含む組成物では、化合物1は平均AUC 0〜6時間、24,430hr ng/mLを有した。
噴霧乾燥分散物をジクロロメタン中の化合物1の溶液をヒドロキシプロピルメチルセルロース(Methocel E5 LV)(HPMC)と、1:3の化合物1:ポリマーの比で混合し、混合物を一晩撹拌し、次いでラボスケールBuchi spray dryerを使用して噴霧乾燥することによって調製した。
実施例12においてのとおり調製された25%化合物1:HPMC(すなわち、比1:3)噴霧乾燥分散物のXRPDディフラクトグラムを図7に示す。
実施例12において記載されるとおり25%化合物1:HPMC SDDとして調製された化合物1は、経口剤形(0.5%メチルセルロース(MC)懸濁物)としてメスSprague Dawleyラットに投与された場合に、用量範囲10mg/kgから300mg/kgを通しておよその用量比例性を示した。結果を図8aに示す。およその用量比例性は、実施例12に記載されたとおり25%化合物1:HPMC SDDとして調製された化合物1が経口剤形(0.5%MC懸濁物)としてオスビーグルイヌに投与された場合、用量範囲1mg/kg〜10mg/kgを通して証明されている。結果を図8bに示す。
噴霧乾燥分散物(SDD)を(90:10)アセトン:水中の化合物1の溶液をヒドロキシプロピルメチルセルロースアセテートサクシネートM又はH(HPMCAS−M又はHPMCAS−H)と、1:9又は1:3のいずれかの化合物1:ポリマーの比で混合し、続いて各調製物をカスタムベンチスケールLab Spray Dryer(BLD−35;プロセスパラメーター:注入口T°93〜109℃;出口T°42〜43℃;微粒化圧110psi;供給速度29g/分;ガラス流速450g/分)を使用して噴霧乾燥することによって調製した。
上に記載のとおり調製された3つのSDDの血漿曝露レベルを決定するために、それらそれぞれを10mg/kg(化合物1に基づいて)でメスSprague Dawleyラットに、10%HPMCAS−M SDDについては0.5%MC中の懸濁物として又は25%HPMCAS−M及び25%HPMCAS−H SDDについては0.5%Methocel A4M/0.5%HPMCAS−HF/20mM Tris、pH7.4中の懸濁物として経口投与した。図9は、本実験の結果を例示する。1:9の化合物1:ポリマー比でHPMCAS−Mポリマーを含む組成物では、化合物1は、平均AUC 0〜24時間、28,069hr*ng/mLを有した。1:3の化合物1:ポリマー比でHPMCAS−Mポリマーを含む組成物では、化合物1は、平均AUC 0〜24時間、24,558hr*ng/mLを有した。1:3の化合物1:ポリマー比でHPMCAS−Hポリマーを含む組成物では、化合物1は平均AUC 0〜24時間、27,469hr*ng/mLを有した。
噴霧乾燥分散物(SDD)を(90:10)アセトン:水中の化合物1の溶液をヒドロキシプロピルメチルセルロースアセテートサクシネート(HPMCAS−HG)と、1:1、1:2.85又は1:3のいずれかの化合物1:ポリマーの比で混合し、続いて各調製物をカスタムベンチスケールLab Spray Dryer(Bend Research BLD−35;プロセスパラメーター:注入口T 84〜94℃;出口T 40〜42℃;微粒化圧120psi;ノズル−圧力回転/Schlick2.0;溶液スプレー速度25g/分;気流475g/分;セットアップ:オープンループ)を使用して噴霧乾燥することによって調製した。
10mgの化合物1を含有する即時放出錠剤を、一般に次のとおり調製した。表2(下)に記載の原材料をブレンドし、ふるいにかけ、造粒前に再度ブレンドした。ブレンドした原材料を乾式造粒プロセスを使用して造粒した。次いで乾燥造粒材料を粒外材料とブレンドした。ブレンドした材料を6mm SRC(標準丸凹型(standard round concave))工具を使用して錠剤に圧縮した。
100mgの化合物1を含有する即時放出錠剤の1つのバージョンを一般に次のとおり調製した。表3(下)に記載の原材料をブレンドし、ふるいにかけ、造粒前に再度ブレンドした。ブレンドした原材料を乾式造粒プロセスを使用して造粒した。次いで乾燥造粒材料を粒外材料とブレンドした。ブレンドした材料を凹型変形楕円(modified oval)工具(9.1mmx18.1mm)を使用して錠剤に圧縮した。
200mgの化合物1を含有する即時放出錠剤の1つのバージョンを次のとおり調製する。表4(下)に記載の原材料をブレンドし、ふるいにかけ、造粒前に再度ブレンドした。ブレンドした原材料を乾式造粒プロセスを使用して造粒する。次いで乾燥造粒材料を粒外材料とブレンドする。次いでブレンドした材料を錠剤に圧縮する。
Claims (22)
- 4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンの固体形態を含む医薬組成物。
- 結晶形態Aと名付けられた結晶4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンを含む、請求項1に記載の医薬組成物。
- 4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンの結晶形態Aが、7.8、9.0、15.7、18.0、21.1、22.0、23.6及び24.5 2シータ(2θ)にXRPD反射ピークを示す、請求項2に記載の医薬組成物。
- アモルファス4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンを含む、請求項1に記載の医薬組成物。
- 4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンが(a)噴霧乾燥、又は(b)超臨界CO2溶液の急速な膨張(RESS)による微粒子化を含むプロセスによって調製される、請求項1に記載の医薬組成物。
- 医薬組成物が少なくとも1つの固体マトリクスポリマーを含む、請求項1に記載の医薬組成物。
- 4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンの固体マトリクスポリマーに対する比が約1:1から約1:9までである、請求項6に記載の医薬組成物。
- 4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オンの固体マトリクスポリマーに対する比が約1:1、約1:2、約1:3、約1:4、約1:5、約1:6、約1:7、約1:8又は約1:9である、請求項6に記載の医薬組成物。
- 固体マトリクスポリマーがポリビニルピロリドン又はポリビニルピロリドン誘導体である、請求項6に記載の医薬組成物。
- 固体マトリクスポリマーがセルロース誘導体である、請求項6に記載の医薬組成物。
- セルロース誘導体がヒドロキシプロピルメチセルロース、ヒドロキシプロピルメチセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートステアレート及びヒドロキシプロピル−メチルセルロースアセテートサクシネートからなる群から選択される、請求項10に記載の医薬組成物。
- (a)噴霧乾燥、又は(b)RESSによる微粒子化を含むプロセスによって調製される、請求項6に記載の医薬組成物。
- (a)アモルファス4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン、及び(b)ポリビニルピロリドン、ヒロドキシプロピルメチルセルロース又はヒドロキシプロピルメチルセルロース−アセテート−サクシネートから選択されるポリマーを含む固体ポリマーマトリクスを含み;
前記固体ポリマーマトリクスが噴霧乾燥分散物である、請求項6に記載の医薬組成物。 - ポリマーが、約1:3の4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン:ポリマーの比で存在するヒロドキシプロピルメチルセルロースである、請求項13に記載の医薬組成物。
- ポリマーが、約1:1の4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン:ポリマーの比で存在するヒロドキシプロピルメチルセルロースである、請求項14に記載の医薬組成物。
- ポリマーが、約1:3の4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン:ポリマーの比であるポリビニルピロリドンである、請求項13に記載の医薬組成物。
- ポリマーが、約1:1の4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン:ポリマーの比であるポリビニルピロリドンである、請求項13に記載の医薬組成物。
- ポリマーが、約1:3の4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン:ポリマーの比で存在するヒドロキシプロピルメチルセルロース−アセテート−サクシネートである、請求項13に記載の医薬組成物。
- ポリマーが、約1:1の4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン:ポリマーの比で存在するヒドロキシプロピルメチルセルロース−アセテート−サクシネートである、請求項14に記載の医薬組成物。
- 請求項1に記載の医薬組成物を対象に投与するステップを含む、そのような処置を必要とする対象においてがん又は他の新生物疾患を処置するための方法。
- 請求項6に記載の医薬組成物を対象に投与するステップを含む、そのような処置を必要とする対象においてがん又は他の新生物疾患を処置するための方法。
- 医薬組成物が、(a)アモルファス4−[2−(シクロプロピルメトキシ)−5−メチルスルホニルフェニル]−2−メチルイソキノリン−1−オン、及び(b)ポリビニルピロリドン、ヒロドキシプロピルメチルセルロース又はヒドロキシプロピルメチルセルロース−アセテート−サクシネートから選択されるポリマーを含む固体ポリマーマトリクスを含み、
前記固体ポリマーマトリクスが噴霧乾燥分散物である、請求項21に記載の方法。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003519698A (ja) * | 2000-01-07 | 2003-06-24 | トランスフォーム ファーマスーティカルズ,インコーポレイテッド | 多様な固体形態のハイスループットでの形成、同定および分析 |
WO2015058160A1 (en) * | 2013-10-18 | 2015-04-23 | Quanticel Pharmaceuticals, Inc. | Bromodomain inhibitors |
WO2015078929A1 (en) * | 2013-11-27 | 2015-06-04 | Oncoethix Sa | Method of treating leukemia using pharmaceutical formulation containing thienotriazolodiazepine compounds |
JP2016529246A (ja) * | 2013-08-06 | 2016-09-23 | オンコエシックス ゲーエムベーハー | Betブロモドメイン阻害剤を用いるびまん性大細胞型b細胞性リンパ腫(dlbcl)の治療方法 |
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US9884806B2 (en) * | 2013-08-30 | 2018-02-06 | Icahn School Of Medicine At Mount Sinai | Cyclic vinylogous amides as bromodomain inhibitors |
TW201642860A (zh) * | 2015-04-22 | 2016-12-16 | 塞爾基因定量細胞研究公司 | 布羅莫結構域抑制劑 |
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-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003519698A (ja) * | 2000-01-07 | 2003-06-24 | トランスフォーム ファーマスーティカルズ,インコーポレイテッド | 多様な固体形態のハイスループットでの形成、同定および分析 |
JP2016529246A (ja) * | 2013-08-06 | 2016-09-23 | オンコエシックス ゲーエムベーハー | Betブロモドメイン阻害剤を用いるびまん性大細胞型b細胞性リンパ腫(dlbcl)の治療方法 |
WO2015058160A1 (en) * | 2013-10-18 | 2015-04-23 | Quanticel Pharmaceuticals, Inc. | Bromodomain inhibitors |
WO2015078929A1 (en) * | 2013-11-27 | 2015-06-04 | Oncoethix Sa | Method of treating leukemia using pharmaceutical formulation containing thienotriazolodiazepine compounds |
Non-Patent Citations (8)
Title |
---|
BYRN S: "PHARMACEUTICAL SOLIDS: A STRATEGIC APPROACH TO REGULATORY CONSIDERATIONS", PHARMACEUTICAL RESEARCH, vol. V12 N7, JPN5013009960, 1 July 1995 (1995-07-01), US, pages 945 - 954, XP055307460, ISSN: 0004661955, DOI: 10.1023/A:1016241927429 * |
PHARM STAGE, vol. 6, JPN6011001457, 2007, pages 48 - 53, ISSN: 0004661952 * |
医薬審発第568号, JPN6010021254, 2001, ISSN: 0004661951 * |
有機合成化学協会誌, vol. 65, JPN6010003277, 2007, pages 907 - 913, ISSN: 0004661954 * |
森部久仁一、山本恵司: "非晶質医薬品の調製と評価", 低温生物工学会誌, vol. 51, no. 1, JPN6020007587, 2005, pages 19 - 24, ISSN: 0004661949 * |
生活工学研究, vol. 4, JPN6014015069, 2002, pages 310 - 317, ISSN: 0004661950 * |
難水溶性薬物の経口製剤化技術最前線, JPN6021026509, July 2016 (2016-07-01), pages 64 - 127, ISSN: 0004661948 * |
高田則幸: "創薬段階における原薬Formスクリーニングと選択", PHARM STAGE, vol. 6, no. 10, JPN6009053755, 15 January 2007 (2007-01-15), pages 20 - 25, ISSN: 0004661953 * |
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