JP6998969B2 - (s)-2-((2-((s)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドの多形体及び固体形態と、生産方法 - Google Patents
(s)-2-((2-((s)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドの多形体及び固体形態と、生産方法 Download PDFInfo
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- JP6998969B2 JP6998969B2 JP2019558502A JP2019558502A JP6998969B2 JP 6998969 B2 JP6998969 B2 JP 6998969B2 JP 2019558502 A JP2019558502 A JP 2019558502A JP 2019558502 A JP2019558502 A JP 2019558502A JP 6998969 B2 JP6998969 B2 JP 6998969B2
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- crystalline
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- oxazepine
- difluoromethyl
- oxooxazolidine
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- 235000002906 tartaric acid Nutrition 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Description
本出願は、2017年4月28日に出願された米国仮許出願第62/491812号の優先権の利益を主張し、その出願の内容全体は参照により本明細書に組み込まれる。
本発明は、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドと名付けられるPI3K阻害剤化合物GDC-0077の多形形態に関する。本発明は、GDC-0077の多形形態を得るためのプロセスにも関する。
の構造、又はその立体異性体、幾何異性体、互変異性体、及び薬学的に許容される塩を含む。
用語「含む(comprise/comprising/include/includinge及びincludes)」は、本明細書及び特許請求の範囲で使用される場合、記載される特徴、整数、成分、又は工程の存在を特定することを意図しているものの、一又は複数の他の特徴、整数、成分、工程若しくはそれらの群の存在又は付加を排除するものではない。
本発明は、式I(CAS Registry Number 2060571-02-8):
として示され、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドと名付けられたGDC-0077の多形体と、GDC-0077の多形体の生成のためのプロセス、方法、及び試薬とを含む(国際公開第2017/001645号、米国特許出願公開第2017/0015678号、参照により明示的に組み込まれる)。本明細書で使用されるGDC-0077には、すべての立体異性体、幾何異性体、互変異性体、及びその薬学的に許容される塩が含まれる。GDC-0077は、乳がん及びその他障害の臨床治療のために開発されている製剤中のAPI(医薬品有効成分)である。
X線粉体回折(XRPD)パターンの分析が、市販の分析ソフトウェアを用いて実施された。XRPDは、異なる結晶相、多形体、水和物又は溶媒和物の、それらに固有の回折パターンによるフィンガープリンティングのために有用である。横座標(横軸)には、いわゆる2シータ値(入射ビームと回折ビームの間の一連の角度)がとられている。縦座標(縦軸)は、検出器によって記録された拡散X線の強度が記録されている。ピークの組は、結晶質物質内部の結晶学的単位細胞の固有のフィンガープリントとして機能する。結晶学的単位細胞は、結晶全体にわたって三次元で周期的に繰り返される最小原子スケールの3D断片である。すべての結晶質物質は、その結晶学的単位細胞(及びそれゆえそのピーク位置)によって区別される。測定されたピーク位置とデータベースに保持されているものとを比較することにより、結晶質物質を一意に同定することができる。純粋な物質に関して、すべてのピークの位置は、通常、結晶学的単位細胞を構成する基本の平行六面体を画定する三つのパラメーター:a、b、c及び三つの角度:アルファ、ベータ、ガンマ(α、β、γ)の関数である。
図4は、無水物形態I(形態A)GDC-0077のXRPDを示している。表2は、GDC-0077形態I/Aの、XRPDピークのサーチレポートである。図5Aは、無水物形態I(形態A)GDC-0077の、倍率1000Xでの走査電子顕微鏡検査(SEM)を示している。図5Bは、無水物形態I(形態A)GDC-0077の、倍率200Xでの偏光顕微鏡検査(PLM)を示している。形態Iは、長さ 30-40μm(ミクロン)の小さなロッド形状の結晶を有する、実質的に結晶質であることが分かった。無水物形態I(形態A)GDC-0077の熱解析は、TGAによる無視できる重量減少(~0.25% w/w)と、DSCによる214℃での融解吸熱を示し、したがって無水物であるとみなされた(図6A)。質量変化率(dm/dt)の厳格なプロトコールを使用した25℃での水収着は、実験時間スケールにわたり、<0.3% w/wという無視できる程度の吸湿を示した(実施例5)。形態Iは、無水結晶質形態であることがかなりよく特徴づけられたため、形態Aと呼ばれる。
形態Aの粉砕は特定のPK特性を最適化しうる。スケールアップした形態Aロットを粉砕し、さらに安定性試験に供した(40℃/75% RH、25℃/60% RH、開放バイアル)。さらに三つのロットを粉砕した。これらは粉砕時に類似の挙動を示した。代表的な粉砕ロットを特徴づけ、物理的形態を決定した。このロットを100%エタノール中でスラリー化して形態Aを得て、ジェットミルを用いて3.5時間にわたり60 psiの圧力で粉砕した。収率は91%であった。粒度分析(PSD)は、D10=0.7μm、D50=2.7μm、D90=6.7μmであると決定された。粉砕後、API(医薬品有効成分、即ちGDC-0077)バッチの一部分を、開放バイアル中において40℃/75% RH及び25℃/60% RHで安定させた。固体状態データを4及び8週目に収集し、物理形体に対する温度及び湿度の影響を評価した。粉砕した安定性試料を、XRPD、PLM、DSC、TGA、水収着分析及び表面積分析により特徴づけた。DSCの実行は、非ハーメチックにクリンプされたパン、0-175℃にわたり1℃/分の加熱速度、調節振幅±1℃及び60秒の期間を用いて、調節モードで実施された。
本明細書に詳述されるGDC-0077の結晶質形態は、PI3Kに関連する異常な細胞の増殖、機能又は挙動に起因する、がんのような疾患又は障害に罹患しているヒト又は動物の患者を治療するために有用である。つまり、そのような疾患又は障害は、本明細書に詳述されるGDC-0077の結晶質多形体(例えば、結晶質無水物形態A、結晶質無水物形態D、又は結晶質三水和物形態B)の前記患者への投与を含む方法により治療されうる。また、がんに罹患しているヒト又は動物の患者は、本明細書に詳述されるGDC-0077の結晶質多形体の前記患者への投与を含む方法によって治療される。それにより、患者の状態を改善又は回復させることができる。
GDC-0077の多形体は、炎症又は過剰増殖性障害(例えばがん)といった本明細書に記載される疾患又は障害を治療するために、単独で、又は追加の治療剤と組み合わせて使用することができる。特定の実施態様では、本明細書に詳述されるGDC-0077の結晶質多形体(例えば、結晶質無水物形態A、結晶質無水物形態D、又は結晶質三水和物形態B)は、抗炎症性又は抗過剰増殖特性を有するか、又は 炎症、免疫応答障害若しくは過剰増殖性障害(例えばがん)を治療するために有用な、追加の第2の治療化合物と、併用療法としての組み合わせ医薬製剤又は投薬レジメンにおいて組み合わせられる。追加の治療剤は、CDK4/6阻害剤、Bcl-2阻害剤、JAK阻害剤、抗炎症剤、免疫調節剤、化学療法剤、アポトーシス促進剤、神経栄養因子、心血管疾患治療剤、肝疾患治療剤、抗ウイルス剤、血液疾患治療剤、糖尿病治療剤、及び免疫不全障害治療剤でありうる。第2の治療剤は、NSAID抗炎症剤であってもよい。第2の治療剤は、化学療法剤であってもよい。組み合わせ医薬製剤又は投薬レジメンの第2の化合物は、好ましくは、互いに悪影響を与えないように、GDC-0077を補完する活性を有する。このような化合物は、意図した目的に有効な量で組み合わされて、適切に存在する。一実施態様において、本発明の組成物は、CDK4/6阻害剤といった治療剤との組み合わせで、本明細書に詳述されるGDC-0077の結晶質多形体(例えば、結晶質無水物形態A、結晶質無水物形態D、又は結晶質三水和物形態B)を含む。
GDC-0077(式I)多形形態は、ヒトを含む哺乳動物の過剰増殖性障害の治療的処置(予防処置を含む)のための治療の組合せにおいて使用される、標準の薬務に従って製剤設計される。本発明は、一又は複数の薬学的に許容される担体、流動促進剤、希釈剤、又は添加剤と併せてGDC-0077を含む薬学的組成物を提供する。
本発明の薬学的組成物は、治療される状態に適切な任意の経路により投与することができる。適切な経路には、経口、非経口(皮下、筋肉内、静脈内、動脈内、吸入、皮内、髄腔内、硬膜外、及び点滴技術を含む)、経皮、直腸内、鼻腔内、局所(頬側及び舌下を含む)、膣内、腹腔内、肺内及び鼻腔内が含まれる。局所投与は、経皮パッチ又はイオントホレシス装置といった経皮投与の使用も含むことができる。薬物の製剤は、Remington’s Pharmaceutical Sciences, 18th Ed., (1995)Mack Publishing Co., Easton, PAにおいて検討されている。製剤の他の例は、Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2nd Ed., New York, NYに見ることができる。局所的な免疫抑制治療のために、化合物は、移植前に移植片を潅流適用するか、又は他の方法で阻害剤と接触させることを含む病巣内投与によって投与されうる。好ましい経路は、例えばレシピエントの状態によって変わりうることが理解されよう。化合物は、経口投与される場合、薬学的に許容される担体、流動促進剤、又は添加剤とピル、カプセル、錠剤などとして製剤化されうる。化合物は、非経口投与される場合、薬学的に許容される非経口ビヒクル又は希釈剤と共に、後述のような注射可能な単位投与形態で製剤化されうる。
GDC-0077は、国際公開第2017/001645号、米国特許出願公開第2017/0015678号(それぞれ参照により取り込まれる)に従って調製された。
Symyx CM2システム(Freeslate Inc.,CA)を用いる96ウェルプレート自動化HTSを実施して、GDC-0077の存在しうる多形体を同定した。概ね20mgのAPIを各ウェルに加え、それに800μl(マイクロタイター)の溶媒(ニート又は混合物)を加え、スラリーを50℃で2時間撹拌した。溶媒は、水、1,2-ジクロロエタン、ヘプタン、シクロヘキサン、エタノール、1-プロパノール、アセトニトリル、ブチルアミン、ニトロメタン、1,4-ジオキサン、ベンゼン、ペルフルオロヘプタン、酢酸エチル,(トリフルオロメチル)ベンゼン、ブタン-2-オン(MEK)、1,2-ジメトキシエタン、2-メチルテトラヒドロフラン、四塩化炭素、ジメチルアセトアミド、テトラヒドロフラン(THF)、アセトン、アニソール、トルエン、及び2-エトキシエタノールを含んでいた。この「マスター」プレートから、上清を濾過し、三つの別々のプレートに分配し、エバポレーション、抗溶媒の付加による沈殿及び8-10時間にわたる50-20℃の制御冷却を行った。溶媒及び抗溶媒の詳細は図2にまとめられている。いずれの場合も、残留溶媒をエバポレートするか又は吸い上げて、偏光顕微鏡及びX線粉末回折測定を用いて固体を調査した。結晶質ヒットのXRPDパターンを比較し、続いて「異なっている」可能性のあるヒットをスケールアップし、それらを特徴づけた。
水分が0-100%の範囲の異なる組成物の脱イオン(DI)水-エタノール(無水アルコール)混合物を調製し、水分活性メーターを用いてそれらの水分活性を測定した。GDC-0077の三水和物と無水物形態の1:1混合物(合計40mg)をこれら溶媒混合物(液体1.5mL)に加え、RTで4日間撹拌するスラリー実験をRTで設定した。4日後、試料を等分し、遠心分離した。固体をXRPDにより分析し、上清を水分活性について分析した。形態AとDの1:1混合物を、in-プロパノール中において一晩RTで撹拌した。スラリーを遠心分離し、固体形態をXRPDにより分析した。
クロスビームオプティクス(40kV×44mA)を用いて生成されるCu Kα(1.541904Å)照射の入射ビームを用いて、Rigaku SmartLab(登録商標)回折計(Rigaku Corp.,Tokyo,Japan)によりXRPDパターンを収集した。GDC-0077の粉末試料を、トップフィル法を用いてゼロバックグラウンドホルダーに詰め、1又は3.0°/分のスキャンスピード及び2-40° 2θ(2シータ)の範囲にわたり0.02又は0.04° 2θのステップサイズで、Bragg-Brentano又は並行ビーム構成(反射配置)においてスキャンを取得した。市販のソフトウェア(JADE(登録商標)、バージョン9、Materials Data Inc.,Livermore,CA)を用いてデータを分析した。
約5-6mgの粉末試料を、25℃及び200mL/分の窒素流量で、自動化水収着分析器(Q5000SA、TA instruments,New Castle,DE)の試料パンの中に置いた。はじめに試料を0%RHで合計600分間(60℃で、続いて25℃で)「乾燥させ」、続いてRH0-90%にわたり10%刻みで、各RHにつき240分の滞留時間で、0.001%のdm/dtウィンドウで30分間RHを漸進的に上昇させた。これに続いて、同じプロトコールを用いて10%刻みで0%RHへとRHを漸進的に低下させた。水和物試料については、このプロセスを逆転させ、開始時のRHを90%に維持し、続いて漸進的且つ段階的に0%まで低下させ、続いて同様に段階的に上昇させて90%に戻した。これは、水和作用の水を確実に実験開始時に保持するために行われた。
Aqualab 4TEV(Decagon Devices,WA)を静電容量センサーモードで水分活性メーターとして使用し、溶媒混合物及びスラリー上清に関するデータを25±0.2℃で取得した。ベンダーが供給する基準を用いて(飽和食塩水)0.25-1のawレンジにわたり機器を較正した。すべてのaw値は、連続する三つの読み取りの安定化の後で取得されている。
概ね3-8mgの粉末試料を、冷蔵冷却アクセサリーを備えたDSC Q2000TM(TA Instruments,New Castle,DE)を用いて分析した。試料を、非ハーメチックにパン(TzeroTM、アルミニウム製のパン)に詰め、乾燥窒素パージ下20-250℃で一般的な加熱を行った。サファイア(ベースライン)及びインジウム(温度及びセル定数)を用いて機器を較正した。市販のソフトウェア(Universal Analysis 2000、バージョン4.7A、TA Instruments)を用いてデータを分析した。実験条件及びパンの較正は以下の通りである。
非等温実験:熱重量分析計(Discovery TGA,TA Instruments)において、3-4mgのGDC-0077試料を、開放アルミニウムパン内でRTから350℃まで10℃/分の加熱速度で、RTから350°まで乾燥窒素パージ下で加熱した。Alumel(登録商標)及びNickelを用いて温度較正を実施した。重量較正には100mg及び1gmの標準重量を使用した。
試料をシリコンオイル中に分散させ、高分解能CCDカメラ及びモーター駆動ステージを備えたビデオ強化Leica DM 4000B顕微鏡のクロスポラライザー(Clemex Technologies Inc.,Longueuil,Quebec,Canada)下において倍率200Xで観察した。Clemex Vision PEソフトウェア(Clemex Technologies Inc.,Longueuil,Quebec,Canada)を用いて顕微鏡写真を取得した。
粉末試料をSEMスタブにスパッタコーティングし、次いでベンチトップPhenom SEM(Nanoscience Instruments,Inc.,AZ)を用いて分析した。異なる倍率で顕微鏡写真を取得した。
Hydros 2000SM湿式分散アタッチメントを備えたMalvern Mastersizer 2000機器(Malvern Instruments Ltd.,Malvern、UK)を用いて粒子サイズ分析を実施した。~30mgのAPIを計量してバイアル中に入れ、ヘプタン中1mLの0.1% Span 85を加えた。バイアルを5秒間超音波処理し、約0.3mLを1500rpmの撹拌速度でサンプラーに加え、PSDを10-20%のオブスキュレーションで実施した。次いで試料をさらに10秒間(合計15秒)超音波処理し、約0.3mLをサンプラーに加え、PLM画像を取得し、PSDを実施した。次いで同じ試料をさらに15秒間(合計30秒)超音波処理し、約0.3mLを加え、PLM写真を撮り、PSDを実施した。超音波処理試験に基づいて、適切な超音波処理期間が選択された。PLM画像とPSDを用いて、塊を分散させるが結晶の破壊を防止又は最小化するために必要な、試料の超音波処理の量を決定した。~10mgのさらに三つの試料を計量してバイアル中に入れ、ヘプタン中1mLの0.1% Span 85を加えた。試料を、超音波処理試験において決定された超音波処理期間にわたって超音波処理した。所定の超音波処理期間を用いて3重に最終PSD分析を実施した。機器を、イソプロピルアルコール(IPA)で2回及びヘプタンで一回すすいだ後で、各試料についてヘプタン中0.1%のSpan 85を充填した。最後の試料の回の後、機器をIPAで1回すすいだ。
表面積測定を、Micromeritics Smart VacPrepアタッチメントを備えたMicromeritics ASAP 2460(Micromeritics Instrument Corp.,GA)を用いて実施した。500mg-1gの試料を計量して空のASAP 2460チューブに入れ、Smart VacPrepに配置し、24時間周囲条件下で脱気し、次いで25℃及び100mm Hg保持圧力でクリプトン気体吸着に曝露した。11点での測定を、0.050-0.300の相対圧力範囲で行い、ベンダーによって供給されたMicroActiveソフトウェアを用いてデータを分析した。
すべての13C(@8kHzのスピニング速度)SSNMR実験は、500MHzのBruker機器(Bruker BioSpin GmbH、Karlsruhe、Germany)を用いて実施された。13CデータはCP/TOSSシーケンスを用いて取得された。シグナル平均化のために、1-2Kのスキャンを収集した。4ms(ミリ秒)の接触時間及び5秒のリサイクル遅れを用いた。脊髄の64配列を、5.3マイクロ秒のパルス長でのデカップリングに使用した。2.9マイクロ秒の1H 90度パルス長を使用した。すべての19F(@14kHzのスピニング速度)SSNMR実験は、500MHzのBruker機器を用いて実施された。19FデータはCPシーケンスを用いて取得された。シグナル平均化のために、64-256Kのスキャンを収集した。750ミリ秒の接触時間及び7秒のリサイクル遅れを用いた。3.54マイクロ秒の1H 90度パルス長を使用した。
Claims (29)
- 2シータで表して概ね5.7、11.4、及び19.0度に特徴的ピークを有するX線粉体回折パターンを呈する、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドの結晶質無水物多形体であって、示差走査熱量測定(DSC)が212から215℃に融解吸熱を示す、結晶質無水物多形体。
- 示差走査熱量測定(DSC)が概ね214℃に融解吸熱を示す、請求項1から3のいずれか一項に記載の結晶質無水物多形体。
- 2シータで表して概ね5.4、10.5、及び25.2度に特徴的ピークを有するX線粉体回折パターンを呈する、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドの結晶質三水和物多形体。
- 治療的有効量の、請求項1から6のいずれか一項に記載の結晶質無水物多形体、及び薬学的に許容される担体、流動促進剤、希釈剤、又は添加剤を含む薬学的組成物。
- 治療的有効量の、請求項7から9のいずれか一項に記載の結晶質三水和物多形体、及び薬学的に許容される担体、流動促進剤、希釈剤、又は添加剤を含む薬学的組成物。
- 錠剤の形態の、請求項10又は11に記載の薬学的組成物。
- 治療的有効量が1から100mgである、請求項10から12のいずれか一項に記載の薬学的組成物。
- 治療的有効量が3mgから15mg又は9mgである、請求項13に記載の薬学的組成物。
- 結晶質無水物多形体又は結晶質三水和物多形体が粉砕されている、請求項10から14のいずれか一項に記載の薬学的組成物。
- 結晶質多形体を調製するための方法であって、エタノール又はn-プロパノール中、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドのスラリーを加熱することと、次いで混合物を冷却することとを含み、それにより、2シータで表して概ね5.7、11.4、17.2、19.0、19.7、及び24.4度に特徴的ピークを有するX線粉体回折パターンを呈する結晶質無水物多形体が形成される方法。
- エタノール又はn-プロパノールが水と一緒に使用される、請求項16に記載の方法。
- エタノール又はn-プロパノールが水なしで使用される、請求項16に記載の方法。
- 40%未満の水の存在下において、エタノール中、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドのスラリーを加熱することを含む、請求項16に記載の方法。
- 混合物に結晶質(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドを蒔く(seed)ことをさらに含む、請求項16から19のいずれか一項に記載の方法。
- 混合物に結晶質THF溶媒和物としての結晶質(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドを蒔くことをさらに含む、請求項20に記載の方法。
- 2シータで表して概ね5.4、10.5、及び25.2度に特徴的ピークを有するX線粉体回折パターンを呈する、(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドの結晶質三水和物多形体を調製するための方法であって、水中で(S)-2-((2-((S)-4-(ジフルオロメチル)-2-オキソオキサゾリジン-3-イル)-5,6-ジヒドロベンゾ[f]イミダゾ[1,2-d][1,4]オキサゼピン-9-イル)アミノ)プロパンアミドをスラリー化することを含む、方法。
- DI水中、4日間、室温で、請求項1から6のいずれか一項に記載の結晶質無水物多形体をスラリー化することを含む、請求項22に記載の方法。
- がんの治療を必要とする対象におけるがんの治療のための医薬であって、有効量の、請求項1から6のいずれか一項に記載の結晶質無水物多形体、請求項7から9のいずれか一項に記載の結晶質三水和物多形体、又は請求項10から15のいずれか一項に記載の薬学的組成物を含む医薬。
- がんが、PIK3CA変異を発現する、HR陽性及びHER2陰性乳がんである、請求項24に記載の医薬。
- 一又は複数の追加の治療剤をさらに含む、請求項24に記載の医薬。
- がんの治療のための医薬の調製における、請求項1から6のいずれか一項に記載の結晶質無水物多形体、請求項7から9のいずれか一項に記載の結晶質三水和物多形体、又は請求項10から15のいずれか一項に記載の薬学的組成物の使用。
- がんが、PIK3CA変異を発現する、HR陽性及びHER2陰性乳がんである、請求項27に記載の使用。
- 医薬が、一又は複数の追加の治療剤をさらに含む、請求項27に記載の使用。
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JP2021181446A (ja) * | 2017-04-28 | 2021-11-25 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | (s)−2−((2−((s)−4−(ジフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)アミノ)プロパンアミドの多形体及び固体形態と、生産方法 |
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AU2018259089A9 (en) | 2019-10-10 |
WO2018197653A9 (en) | 2019-09-19 |
JP2021181446A (ja) | 2021-11-25 |
MX2019012507A (es) | 2019-12-19 |
KR20190133724A (ko) | 2019-12-03 |
KR102342776B1 (ko) | 2021-12-23 |
CN110650963B (zh) | 2022-09-27 |
US20210094970A1 (en) | 2021-04-01 |
EP3615541A1 (en) | 2020-03-04 |
TW201843160A (zh) | 2018-12-16 |
IL267464B2 (en) | 2023-05-01 |
WO2018197653A1 (en) | 2018-11-01 |
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