JP2020531463A - Tg02の多形形態 - Google Patents
Tg02の多形形態 Download PDFInfo
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- JP2020531463A JP2020531463A JP2020508985A JP2020508985A JP2020531463A JP 2020531463 A JP2020531463 A JP 2020531463A JP 2020508985 A JP2020508985 A JP 2020508985A JP 2020508985 A JP2020508985 A JP 2020508985A JP 2020531463 A JP2020531463 A JP 2020531463A
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Abstract
Description
TG02は、JAK2およびFLT3と共にCDK 1、2、5、7、および9を阻害するピリミジンベースのマルチキナーゼ阻害剤である。TG02は、CDKを主要標的として、がん細胞中のCDK、JAK2およびFLT3の下流のシグナル伝達経路を用量依存的に阻害する。TG02は、広範囲の腫瘍細胞株において抗増殖性であり、G1細胞周期停止およびアポトーシスを誘導する。急性骨髄性白血病(AML)および真性赤血球増加症の患者由来の前駆細胞の初代培養物は、TG02に対して非常に感受性が高い。TG02の主要な標的の1つだけをブロックする参照阻害剤との比較は、細胞株および初代細胞におけるCDKとJAK2/FLT3とを組み合わせた阻害の利点を示す。Goh et al., Leukemia 26:236-43(2012)(非特許文献1)参照。TG02は、SB 1317としても、およびその化学名:(16E)-14-メチル-20-オキサ-5,7,14,26-テトラアザテトラシクロ[19.3.1.1(2,6).1(8,12)]ヘプタコサ-1(25),2(26),3,5,8(27),9,11,16,21,23-デカエンによっても知られる。
TG02遊離塩基の多形形態
一態様では、本開示は、TG02遊離塩基(FB)の結晶多形形態を提供する。
別の態様では、本開示は、6.077、17.675、17.994、18.475、19.135、および19.727度2θにピークを有する粉末X線回折(PXRD)パターンを有することを特徴とする形態I(FB)を提供する。
別の態様では、本開示は、8.238、11.607、16.683、17.153、および19.073度2θにピークを有するPXRDパターンを有することを特徴とする形態II(FB)を提供する。
別の態様では、本開示は、6.236、17.674、17.769、19.056、19.082、21.631、および25.596度2θにピークを有するPXRDパターンを有することを特徴とする形態III(FB)を提供する。
別の態様では、本開示は、8.484、17.409、18.807、19.299、および22.616度2θにピークを有するPXRDパターンを有することを特徴とする形態IV(FB)を提供する。
別の態様では、本開示は、7.151、14.299、19.114、19.185、および21.495度2θにピークを有するPXRDパターンを有することを特徴とする形態V(FB)を提供する。
別の態様では、本開示は、TG02酸付加塩の結晶多形形態を提供する。
別の態様では、本開示は、8.055、12.695、15.868、16.664、18.460、19.392、22.103、24.552、および25.604度2θにピークを有するPXRDパターンを有することを特徴とする形態VI(HCl)を提供する。
別の態様では、本開示は、6.601、12.691,13.364、21.785、23.554、および27.007度2θにピークを有するPXRDパターンを有することを特徴とする形態VII(HCl)を提供する。
別の態様では、本開示は、12.994、16.147、22.211、23.305、および24.586度2θにピークを有するPXRDパターンを有することを特徴とする形態VIII(HCl)を提供する。
別の態様では、本開示は、15.2、15.5、21.7、22.1、23.0、26.2、および29.9度2θにピークを有するPXRDパターンを有することを特徴とする形態X(クエン酸塩)を提供する。
本開示のいくつかの治療方法では、第2の治療薬をTG02多形形態と組み合わせてがん患者に投与する。
を有するかまたはその薬学的に許容される塩であり、ここで、化合物は、PD-1シグナル伝達経路を阻害することができる治療薬として有用な少なくとも5個のアミノ酸を含む。
本明細書で提供される治療方法では、TG02多形形態および任意の治療薬、例えば抗がん剤は、以下の1つまたは複数の条件下でがん患者に投与され得る:異なる周期性、異なる期間、異なる濃度、異なる投与経路等。
(b)約20重量%〜約83重量%の充填剤;
(c)約1重量%〜約10重量%の崩壊剤;
(d)約1重量%〜約10重量%の結合剤;および
(e)約0.1重量%〜約1重量%の潤滑剤
を含む、薬学的組成物。
本明細書で使用される「バイオマーカー」という用語は、インビボでがん患者においてまたはがん患者から得られた生物学的試料中で検出および/または定量化され得る遺伝子、タンパク質、タンパク質の断片、ペプチド、ポリペプチド、核酸等のような任意の生物学的化合物を指す。バイオマーカーは、無傷の分子全体であり得るか、またはその一部もしくは断片であり得る。一態様では、バイオマーカーの発現レベルを測定する。バイオマーカーの発現レベルは、例えばタンパク質またはRNA、例えばmRNA、バイオマーカーのレベルを検出することによって測定することができる。いくつかの態様では、例えば抗体または他の特異的結合剤によって、バイオマーカーの一部または断片を検出または測定することができる。いくつかの態様では、バイオマーカーの測定可能な局面は、がんの特定の病期などの、患者の所与の状態に関連する。タンパク質レベルまたはRNAレベルで検出されるバイオマーカーについて、そのような測定可能な局面には、例えば、がん患者またはがん患者から得られた生物学的試料におけるバイオマーカーの存在、不在または濃度、すなわち発現レベルが含まれ得る。核酸レベルで検出されるバイオマーカーについて、そのような測定可能な局面には、例えば、バイオマーカーの対立遺伝子バージョン、またはバイオマーカーの突然変異の種類、率および/もしくは、本明細書では突然変異状態とも称する、突然変異度が含まれ得る。
(a)患者からの生物学的試料中のMCL-1、MYC、またはMCL-1およびMYCの発現レベルを決定すること、ならびに発現レベルが、対照試料、例えば正常な非疾患患者またはMCL-1、MYC、もしくはMCL-1およびMYCの過剰発現がないがんを有する患者からの試料の発現レベルよりも高いと決定された場合、
(b)治療有効量のTG02多形形態を患者に投与すること
を含む方法。
(a)患者から生物学的試料を得ること;
(b)生物学的試料がMCL-1とMYCとを同時過剰発現するかどうかを決定すること;および
(c)生物学的試料がMCL-1とMYCとの同時過剰発現を示す場合、治療有効量のTG02多形形態を患者に投与すること
を含む方法。
(a)TG02多形形態を対象に投与する前に、患者から得られた生物学的試料中のMCL-1発現レベルを測定すること;
(b)MCL-1発現レベルが所定の閾値基準よりも高いかどうかを決定すること;ならびに
(c)MCL-1発現レベルが所定の閾値標準よりも高い場合、治療有効量のTG02多形形態および、任意で、MCL-1阻害剤を患者に投与すること
を含む方法。
(a)TG02多形形態を対象に投与する前に、患者から得られた生物学的試料中のMYC発現レベルを測定すること;
(b)MYC発現レベルが所定の閾値基準よりも高いかどうかを決定すること;ならびに
(c)MYC発現レベルが所定の閾値標準よりも高い場合、治療有効量のTG02多形形態および、任意で、MYC阻害剤を患者に投与すること
を含む方法。
15.2、15.5、21.7、22.1、23.0、26.2、および29.9度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態X(クエン酸塩);
6.077、17.675、17.994、18.475、19.135、および19.727度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態I(FB);
8.238、11.607、16.683、17.153、および19.073度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態II(FB);
6.236、17.674、17.769、19.056、19.082、21.631、および25.596度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態III(FB);
8.484、17.409、18.807、19.299、および22.616度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態IV(FB);
7.151、14.299、19.114、19.185、および21.495度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態V(FB);
8.055、12.695、15.868、16.664、18.460、19.392、22.103、24.552、25.604度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態VI(HCl);
6.601、12.691、13.364、21.785、23.554、および27.007度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態VII(HCl);ならびに
12.994、16.147、22.211、23.305、および24.586度2θにピークを有する粉末X線回折パターンを有することを特徴とする形態VIII(HCl)。
(a)エタノール中のクエン酸の溶液とDMSO/エタノール中のTG02遊離塩基の溶液とを組み合わせること;
(b)(a)の溶液を約70℃で少なくとも約15分間加熱して、TG02クエン酸塩を含む溶液を得ること;
(c)TG02クエン酸塩を含む(b)の溶液を約5℃に冷却して、結晶性固体を得ること;および
(d)(c)の結晶性固体を単離して、TG02形態X(クエン酸塩)を得ること
を含む方法。
本明細書で使用される「TG02」という用語は、(16E)-14-メチル-20-オキサ-5,7,14,26-テトラアザテトラシクロ[19.3.1.1(2,6).1(8,12)]ヘプタコサ-1(25),2(26),3,5,8(27),9,11,16,21,23-デカエンを指す。
X線粉末回折
X線粉末回折(XRPDまたはPXRD)の回折図を、Cu Kα放射線を使用してBruker AXS C2 GADDS、Bruker AXS DB Advance、PANalytical Empyrean、または同様の回折計で収集した。
XRPD回折図を、Cu Kα放射線(40kV、40mA)、自動XYZステージ、自動試料ポジショニングのためのレーザービデオ顕微鏡およびVantec-500二次元面積検出器を使用して、Bruker AXS C2 GADDS回折計で収集した。X線光学系は、0.3 mmのピンホールコリメータに接続された単一のGobel多層鏡からなる。
XRPD回折図を、Cu Kα放射線(40kV、40mA)およびGeモノクロメータを取り付けた8-28ゴニオメータを使用して、Bruker D8回折計で収集した。入射ビームは、2.0mmの発散スリットを通過し、続いて0.2 mmの散乱防止スリットとナイフエッジを通過する。回折されたビームは、2.5°ソーラースリットと8.0mmの受光スリットを通過した後、Lynxeye検出器を通る。データの収集および分析に使用したソフトウェアは、それぞれDiffrac Plus XRD CommanderおよびDiffrac Plus EVAであった。
XRPD回折図を、透過ジオメトリでCu Kα放射線(45kV、40mA)を使用して、PANalytical Empyrean回折計で収集した。0.5°スリット、4mmマスクおよび0.04ラドのソーラースリットを集束鏡と共に入射ビームに使用した。回折ビーム上に配置されたPIXcel3D検出器に受光スリットと0.04ラドのソーラースリットを取り付けた。データ収集に使用したソフトウェアは、X’Pert Operator Interfaceを使用するX’Pert Data Collectorであった。Diffrac Plus EVAまたはHighScore Plusを使用してデータを分析し、提示した。
1H NMRスペクトルを、オートサンプラーを備え、DRX400コンソールによって制御されるBruker 400MHz機器で収集した。特に明記しない限り、試料はDMSO-d6溶媒中で調製した。自動化実験は、標準Bruker負荷実験(1H、13C{1H}、DEPT135)を用いて、Topspinソフトウェア内のICON-NMRコンフィギュレーションを使用して取得した。ACD Spectrus Processorを使用してオフライン分析を実施した。
DSCデータを、50ポジションのオートサンプラーを装備したTA Instruments Q2000で収集した。典型的には、ピンホール付きアルミニウムパンで、0.5〜1.5mgの各試料を2℃/分または10℃/分で25℃から250℃に加熱した。50ml/分の乾燥窒素のパージを試料上で維持した。機器制御ソフトウェアは、Q SeriesのAdvantageおよびThermal Advantageであり、Universal AnalysisまたはTRIOSを使用してデータを分析した。
TGAデータを、16ポジションのオートサンプラーを装備したTA Instruments Q500 TGAで収集した。典型的には、3〜6mgの各試料を、予め風袋重量を計量したアルミニウムDSCパンに充填し、10℃/分で周囲温度から350℃に加熱した。60ml/分の窒素パージを試料上で維持した。
試料を、画像取得用のデジタルビデオカメラを備えたLeica LM/DM偏光顕微鏡で分析した。少量の各試料を、浸漬油を用いてまたは浸漬油なしで、スライドガラス上に置き、スリップガラスで覆った。試料を、適切な倍率で、λ偽色フィルタに接続した部分偏光で観察した。StudioCaptureまたはImage ProPlusソフトウェアを使用して画像を取得した。
DVS Intrinsic Controlソフトウェアによって制御されるSMS DVS Intrinsic水分収着分析器を使用して、収着等温線を得た。機器の制御によって試料の温度を25℃に維持した。湿度を、200ml/分の合計流量で、乾燥窒素流と湿った窒素流とを混合することによって制御した。相対湿度は、試料の近くにある較正済みのRotronicプローブ(1.0〜100%RHのダイナミックレンジ)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)を、微量天秤(精度±0.005mg)によって常に監視した。
各試料の含水量を、Hydranal Coulomat AGオーブン試薬と窒素パージを使用して、851 Titrano Coulometerを備える150℃のMetrohm 874 Oven Sample Processorで測定した。計量された固体試料を、密封された試料バイアルに入れた。滴定ごとに約10mgの試料を使用し、二重の測定を行った。特に明記しない限り、これらの結果の平均を提示する。データの収集および分析は、Tiamoソフトウェアを使用して実施した。
十分な化合物を適切な媒質に懸濁して、化合物の親遊離形態の10mg/ml以上の最大最終濃度を得ることによって水溶解度を決定した。懸濁液を、750rpmに設定したHeidolphプレートシェーカーで、25℃で24時間平衡化した。次に、飽和溶液のpHを測定し、懸濁液をガラス繊維Cフィルタ(粒子保持1.2μm)で濾過し、適切に希釈した。DMSO中約0.15mg/mlの標準溶液を参照して、HPLCによる定量を行った。様々な容量の標準希釈および未希釈の試料溶液を注入した。標準注入の主要ピークと同じ保持時間で認められたピークの積分によって決定されたピーク面積を使用して、溶解度を計算した。
Atlas CPS+ライトボックスを使用して、固体および液体試料を加速ストレス条件に曝露した。試料を、液体試料の場合は蓋を閉じた透明なガラスバイアル、固体試料の場合は開放バイアルで、分析用に2つ組で調製した。バイアルのうちの2つを光条件に曝露し、その他のバイアルを、参照物質として機能するようにアルミ箔で包んだ。固体試料の試料厚さは約3mm以下であった。
TG02遊離塩基多形形態の調製
形態I(FB)
調製:NaHCO3(水溶液)をTG02・2HClとDCMを含む混合物に添加し、pHを8に調整した。分離した有機層をほぼ乾燥するまで濃縮して、TG02形態I(FB)を得た。
調製:K2CO3(水溶液)をTG02・HClとMeOHを含む溶液に40〜60℃で添加し、pHを8〜9に調整した。生成物を濾過し、乾燥させてTG02形態II(FB)を得た。
調製:DCM中のTG02遊離塩基の溶液をトルエンと交換した。20〜30℃に冷却した後、生成物を濾過し、乾燥させてTG02形態III(FB)を得た。
調製:TG02遊離塩基とDMFを含む温溶液を20〜30℃に冷却した。生成物を濾過し、乾燥させてTG02形態IV(FB)を得た。
調製:TG02遊離塩基とDMSO/アセトンまたはNMP/アセトンまたはDMF/EtOAcを含む温溶液を20〜30℃に冷却した。生成物を濾過し、乾燥させてTG02形態V(FB)を得た。
TG02 HCl多形形態の調製
形態VI(HCl)
調製:TG02・HCl(10g)、EtOH(184mL)および水(16mL)を含む溶液を1時間加熱還流した。混合物を0〜5℃に冷却し、1時間撹拌した。混合物を濾過し、フィルタケーキを90%EtOH(水溶液)で洗浄し、乾燥させてTG02形態VI(HCl)を得た。
調製方法A:TG02・2HCl(20g)、ピリジン(60mL)およびH2O(120mL)を含む溶液を80℃で1〜3時間加熱した。混合物を20〜30℃に冷却し、2時間撹拌した。混合物を濾過し、フィルタケーキをH2Oで洗浄し、乾燥させてTG02形態VII(HCl)を得た。
調製:TG02・HCl(77.1g)、EtOH(2340mL)およびH2O(185mL)を含む溶液を0.5時間加熱還流した。混合物を0〜5℃に冷却し、2時間撹拌した。混合物を濾過し、フィルタケーキをEtOHで洗浄し、乾燥させてTG02形態VIII(HCl)を得た。TG02形態VIII(HCl)は、経時的に徐々にTG02形態VI(HCl)に変換された。
TG02形態X(クエン酸塩)の調製
調製:方法A:TG02遊離塩基の12.2%w/v溶液を、DMSO/エタノール(94/6v/v)中で約70℃に加熱してTG02遊離塩基を溶解することによって調製した。TG02遊離塩基に対して2%モル過剰のクエン酸を含むエタノール(10%w/v)中のクエン酸の別の溶液を調製した。クエン酸/エタノール溶液の体積は、TG02遊離塩基溶液に対して約64%であった。クエン酸/エタノール溶液(約70℃)をTG02遊離塩基溶液に移してTG02クエン酸塩を形成し、溶液を少なくとも30分間撹拌した。温エタノール(先のクエン酸/TG02遊離塩基溶液の1.5体積当量)を添加し、溶液を約70℃で少なくとも1時間撹拌した。溶液を約5℃に冷却した。冷却するとTG02クエン酸塩が結晶化した。濾過によってTG02クエン酸塩を収集し、エタノールで洗浄し、乾燥させて、88〜93%の収率でTG02形態X(クエン酸塩)を得た。
米国特許第9,120,815号のTG02クエン酸塩パターン
米国特許第9,120,815号のTG02クエン酸塩パターン1(「パターン1」)は、TG02クエン酸塩の、溶媒和されていない、わずかに吸湿性の結晶形態であり、高温および高い相対湿度(40℃/75%RH、25℃/97%RHおよび60℃/周辺RH)での28日間の保存後にXRPDで変化がなかった。プロトンNMR分析は提案された構造と一致したが、クエン酸塩のメチレンプロトンとD6-DMSO基準ピークの重複があった。熱重量分析は、おそらくクエン酸塩の損失のために、180〜240℃で29.6%w/wの重量損失を示した。示差走査熱量測定は、196.6℃での単一の吸熱事象(327.7J/g)を明らかにした。2つの異なる加熱速度(2℃および10℃)での物質のDSCプロフィールの比較は、開始温度とエンタルピーの大きな差を示した。この観察は、吸熱が物質の融解(熱力学的)とクエン酸塩の損失(動力学的)の両方による可能性が高いことを示唆する。HPLC純度分析の結果は、純度97.7%の測定値となった。GVS分析は、物質がわずかに吸湿性であり、取り込みが0〜90%RHで1.0%、最大ヒステリシスが40〜50%RHで0.2%であることを示した。試料は、GVS分析後のXRPDで変化がなかった。熱力学的溶解度の測定で、水性媒質への溶解度0.33mg/mlの測定値を得た。熱力学的溶解度分析後のXRPDは、TG02クエン酸塩パターン1からTG02クエン酸塩パターン2(どちらも米国特許第9,120,815号)への形態変化を明らかにした。パターン1のXRPDを図1に示す。
光安定性
米国特許第9,120,815号のパターン1およびパターン2、ならびに形態X(クエン酸塩)の光安定性を検討して、光曝露が物質の変化をもたらすかどうかを決定した。
薬学的組成物
ゼラチンカプセルで使用するTG02形態X(クエン酸塩)の賦形剤を選択するために、適合性実験を実施した。賦形剤とTG02形態X(クエン酸塩)の2成分混合物(1:1)を調製し、混合し、開閉式容器内で40°/75%RHで4週間保存した。開いた形状と閉じた形状の両方で4週間保存した後に得られた混合物の外観およびHPLC試験結果(クロマトグラフィ純度とアッセイ)を初期結果と比較した(表13および表14)。試験期間中に有意な外観の変化は認められなかった。適合性の賦形剤および非適合性の賦形剤のリストを表15に示す。
Claims (20)
(b)約20重量%〜約83重量%の充填剤;
(c)約1重量%〜約10重量%の崩壊剤;
(d)約1重量%〜約10重量%の結合剤;および
(e)約0.1重量%〜約1重量%の潤滑剤
を含む、請求項4記載の薬学的組成物。
(a)エタノール中のクエン酸の溶液とDMSO/エタノール中のTG02遊離塩基の溶液とを組み合わせること;
(b)(a)の溶液を約70℃で少なくとも約15分間加熱して、TG02クエン酸塩を含む溶液を得ること;
(c)TG02クエン酸塩を含む(b)の溶液を約5℃に冷却して、結晶性固体を得ること;および
(d)(c)の結晶性固体を単離して、TG02形態X(クエン酸塩)を得ること
を含む、方法。
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RU2020111019A (ru) | 2021-09-20 |
EP3668876B1 (en) | 2024-01-24 |
US10544162B2 (en) | 2020-01-28 |
JP7250764B2 (ja) | 2023-04-03 |
EP3668876A4 (en) | 2021-04-28 |
SG11202001441WA (en) | 2020-03-30 |
MX2020001875A (es) | 2020-07-29 |
WO2019035985A1 (en) | 2019-02-21 |
IL272697B1 (en) | 2023-08-01 |
RU2020111019A3 (ja) | 2022-03-18 |
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