JP2021519334A - ジヒドロオロト酸デヒドロゲナーゼを阻害するための組成物および方法 - Google Patents
ジヒドロオロト酸デヒドロゲナーゼを阻害するための組成物および方法 Download PDFInfo
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
- C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
Abstract
Description
本願は、それぞれの内容が参照により本明細書に組み込まれる、2018年3月26日出願の米国仮出願番号第62/648,320号、2018年4月10日出願の米国仮出願番号第62/655,407号、および2018年6月8日出願の米国仮出願番号第62/682,440号の利益および優先権を主張するものである。
本発明は、一般に、治療組成物および方法に関する。
増殖がん細胞は、それらの高い増殖速度を裏付けるように追加の栄養を必要とするので、正常な分化細胞と比較して実質的に異なる代謝的必要性を示す。がん細胞代謝の標的化の成功は、細胞が生合成に必須の経路への栄養素をどのように制御し、消費するかについての正確な理解の改善から具体化される。すべてのがん細胞がこの代謝変化に頼るので、これらの変化した経路は、強力な治療標的となる。しかし、正常増殖細胞とがん細胞との間の治療域の発見は、これらの細胞の代謝要件が類似しているため、未だ大きな困難である。したがって、代謝経路を標的にするわずかな分子しか、がん処置の形態として確立されていない。
本発明は、ブレキナルが、最適な酵素阻害を達成するように投与されてこなかったためにこれまで成功しなかったと認識している。本発明は、ターゲットエンゲージメントの高感度マーカーである代謝産物を使用して患者の用量を調節して、閾値を超える最適時間(治療域)を得ることによって、その問題を解決する。従来の手法とは異なり、特許請求される本発明は、薬物代謝の代わりにターゲットエンゲージメントの測定に基づく。その方式では、ブレキナルの適切な投与を達成して、患者への有害な毒性副作用を引き起こすことなくがん細胞を死滅させる。
[式中、
R1、R2、R3、およびR4は、独立に、H、F、Cl、Br、I、CH3、CF3、SCH3またはCH2CH3であり、R1、R2、R3、およびR4の少なくとも2つは、Hであり、
R5は、H、1〜3個の炭素原子を有するアルコキシ、または1〜2個の炭素原子を有するアルキルであり、
R6およびR7は、独立に、H、F、Cl、Br、1〜5個の炭素原子を有するアルキル、NO2、OH、CF3またはOCH3であり、
Xは、ハロゲンである]、
インキュベートするステップは、
約5:1〜約8:1のモル比の塩基と式(II)の化合物を含有する混合物を、約60℃〜約70℃の温度でインキュベートすること、および
混合物を約15時間〜約30時間インキュベートすること
の少なくとも1つを含む。
本発明は、患者におけるジヒドロオロト酸デヒドロゲナーゼ(DHODH)の持続的な阻害を促進する組成物および方法を提供する。DHODH阻害剤は、がんおよび自己免疫疾患の処置に潜在的に有用な薬物である。しかし、治療利益を達成するための一部のDHODH阻害剤の投与は、健康な細胞にとって毒性となる用量を回避する必要があるので困難を伴う。患者に治療利益を提供するためには、DHODHの持続的な阻害が必要とされるが、過度の阻害は、正常組織にとって有害であり、重篤な副作用をもたらす。本発明は、所与の患者におけるDHODH阻害剤の投与量が患者の体内のターゲットエンゲージメントに基づいて決定される組成物および方法を提供することによって、この問題を克服する。ターゲットエンゲージメントは、患者から得られた試料におけるDHODHのための基質であるジヒドロオロト酸(DHO)の測定されたレベルからアセスメントされる。DHODH阻害剤の投与をDHOレベルと結びつけることによって、本発明の組成物および方法は、投与の精度をより高くすることができる。結果的に、健康な細胞および組織に過度の害を引き起こすことなく、DHODHの阻害を長引かせることができる。
本発明の方法は、対象から得られた試料中の測定されたDHOレベルに基づいて、DHODH阻害剤を含有する薬物の投与量を決定するステップを含む。DHOは、ピリミジン合成経路における中間体である。ピリミジン生合成は、以下に示される通り、グルタミンをウリジン一リン酸に変換する一連の段階的酵素反応を伴う。
本発明の方法は、試料中の測定されたDHOレベルの分析を含む。その方法は、DHOの測定を含むことができる。
本発明の方法は、DHODH阻害剤の投与レジメンを対象に合わせて決定するステップを含む。投与レジメンは、用量、すなわち投与されるべき薬剤の量を含むことができる。投与レジメンは、対象にある用量のDHODH阻害剤を投与するための時点を含むことができる。投与レジメンは、対象から得られた試料中の1つまたは複数の測定されたDHOレベルに基づいて決まるので、個々の対象、例えば患者に合わせて調整される。結果的に、本発明の方法は、薬物動態特性、すなわち対象によるAPIの代謝、および薬力学的特性、APIのその標的に対する効果の個体間の変動性を考慮に入れる、カスタマイズされた投与レジメンを提供する。
本発明の方法は、障害を処置または防止するためにDHODHの活性を変える薬物(drugs that affect that alter)の投与量を決定するのに有用である。障害は、DHODH阻害が治療利益をもたらす任意の疾患、障害、または状態であってよい。
本発明の方法は、前述の通り決定された投与レジメンまたは投与量に従って、対象にDHODH阻害剤を提供するステップを含むことができる。対象へのDHODH阻害剤の提供は、DHODH阻害剤を対象に投与することを含むことができる。用量は、単一単位として、または複数単位で投与することができる。DHODH阻害剤は、任意の適切な手段によって投与することができる。例えばそれに限定されるものではないが、DHODH阻害剤は、経口で、静脈内に、経腸で、非経口で、皮膚に、頬側に、局所に、経皮で、注射により、静脈内に、皮下に、鼻に、肺に、または埋込式医療デバイス(例えば、ステントまたは薬物溶出ステントまたはバルーン等価物)を用いてもしくはその上に投与することができる。
本発明の組成物は、DHODH阻害剤を含む。いくつかのDHODH阻害剤は、当技術分野で公知である。例えば、DHODHの阻害剤には、ブレキナル、レフルノミド、およびテリフルノミドが含まれる。ブレキナルは、系統名6−フルオロ−2−(2’−フルオロ−1,1’ビフェニル−4−イル)−3−メチル−4−キノリンカルボン酸を有し、以下の構造
ブレキナルおよび関連化合物は、例えば、その内容が参照により本明細書に組み込まれる米国特許第4,680,299号および同第5,523,408号に記載されている。白血病を処置するためのブレキナルの使用は、例えば、その内容が参照により本明細書に組み込まれる米国特許第5,032,597号および国際公開第2017/037022号に記載されている。レフルノミド、N−(4’−トリフルオロメチルフェニル)−5−メチルイソオキサゾール−4−カルボキサミド(I)は、例えば、その内容が参照により本明細書に組み込まれる米国特許第4,284,786号に記載されている。テリフルノミド、2−シアノ−3−ヒドロキシ−N−[4−(トリフルオロメチル)フェニル]−2−ブテナミドは、例えば、その内容が参照により本明細書に組み込まれる米国特許第5,679,709号に記載されている。
本発明は、2−(2’−ハロ−1−1’−ビフェニル−4−イル)−キノリンカルボン酸、例えばブレキナルを作製する方法を提供する。その方法は、以下の反応:
[式中、
R1、R2、R3、およびR4は、独立に、H、F、Cl、Br、I、CH3、CF3、SCH3またはCH2CH3であり、R1、R2、R3、およびR4の少なくとも2つは、Hであり、
R5は、H、1〜3個の炭素原子を有するアルコキシ、または1〜2個の炭素原子を有するアルキルであり、
R6およびR7は、独立に、H、F、Cl、Br、1〜5個の炭素原子を有するアルキル、NO2、OH、CF3またはOCH3であり、
Xは、ハロゲンである]、
インキュベートするステップは、
約5:1〜約8:1のモル比の塩基と式(II)の化合物を含有する混合物を、約60℃〜約70℃の温度でインキュベートすること、および
混合物を約15時間〜約30時間インキュベートすること
の少なくとも1つを含む。
本発明はまた、腫瘍に対するDHODH阻害剤の効果をin vivoによりリアルタイムでアセスメントするための方法を提供する。このようなin vivo分析から得られた情報は、投与レジメンを決定または調整するために使用することができる。
本発明はまた、目的の代謝産物、例えばDHOのレベルを迅速に測定するためのデバイスまたはアッセイを含む。患者からの血漿は、血漿中の代謝産物レベルを決定する目的でアッセイされる。記載されるアッセイでは、公知の活性を有する規定レベルの標的酵素が添加される。アッセイでは、比色変化、競合アッセイ、または本分野で公知の他の技術によって血漿中に存在する代謝産物の量を定量する。一実施形態では、その目的は、ブレキナルの投与後のDHOの量を定量することである。患者の血漿検体が収集される。血漿は、規定量のDHODHを含有するアッセイで実施される。患者のDHOは、アッセイにおいて着色DHOと競合し、血漿中のDHOレベルの尺度として読み取ることができる色の変化を引き起こすことができる。別の実施形態では、基質およびDHODHは、採血管内で凍結乾燥させることができる。チューブに引き入れた血液は、DHOが特定の閾値未満であるか、その閾値であるか、またはその閾値を超えるかを決定するために、目に見える色の変化をもたらすことができる。これにより、必要に応じて用量の迅速な調整のために代謝産物レベルの診療現場でのモニタリングが可能になるはずである。
本発明はまた、投与レジメン、例えばDHODH阻害剤の投与量、用量を投与するためのタイミング、用量調整を決定するために代謝産物を収集するためのタイミングもしくはそれらの任意の組合せ、または投与レジメンの調整に関して対象に通知するためのデバイスを含む。そのデバイスは、メモリユニットに接続されたプロセッサを含む。メモリユニットは、プロセッサに、DHODH阻害剤の用量に関するデータを受け取らせ、試験した代謝産物の実験室または診療現場での分析からデータを収集させ、投与レジメンに関する通知または投与レジメンの変更を生成させ、対象にリマインダを出力させる。
本発明の方法は、ある代謝経路に特異的に依存している腫瘍における、その代謝経路の活性を変える薬剤を提供することを含む投与レジメンを決定するステップを含む。例えば、第1の経路の活性に影響を及ぼす変異を担持している腫瘍細胞は、第1の経路の変えられた活性を相殺するまたはそれに対抗する第2の経路の活性により大きく依存し得る。したがって、第2の経路の活性の変化は、正常細胞にとってではなく腫瘍細胞にとって致命的となり得、この現象は合成致死性と呼ばれる。DHODH阻害剤、例えばブレキナルが合成致死性となり得る、経路が変えられた腫瘍の例として、低ホスファターゼおよびテンシンホモログ(PTEN)、Mycタンパク質ファミリーメンバー増幅、Notchタンパク質ファミリーメンバー変異、およびRasタンパク質ファミリーメンバーの活性化変異を有する腫瘍が挙げられる。
本発明の方法は、前述の通りのDHODH阻害剤を、1つまたは複数の他の治療剤と組み合わせて提供することを含む投与レジメンを決定するステップを含む。その方法はまた、両方の治療剤を、このような組合せの投与レジメンで提供するステップを含むことができる。
サイトカイン関連毒性は、サイトカイン放出症候群(CRS)またはサイトカインストームとも呼ばれ、高レベルの免疫活性化の結果として生じる非抗原特異的毒性である。IOを使用して臨床利益を得るのに必要な免疫活性化の度合いは、典型的に、自然免疫活性化中に生じる免疫活性化レベルを上回る。IO治療が効力および有効性を増加させてきたため、CRSは、解決を必要とする問題としてますます認識されている。
本開示は特に、免疫腫瘍学(IO)処置の安全性を改善すると同時に、有効性を維持する方法に関する。がんまたは自己免疫疾患は、正常な免疫系の機能不全の結果とみなすことができる。IOの目的は、障害の処置をもたらす、患者自身の免疫系を利用することである。IO処置には、造血幹細胞移植(HSCT)、がんワクチン、モノクローナル抗体(mAbs)、および養子T細胞免疫療法が含まれ得る。
本発明の組成物は、DHODH阻害剤を、1つまたは複数の他の治療剤と組み合わせて含むことができる。組合せの投与レジメンに使用することができる治療剤の例を、以下に記載する。
第2の治療剤またはさらなる治療剤は、ピリミジン合成経路とは異なる代謝経路を標的にすることができる。例えば、第2の薬剤は、グルタミナーゼ、PI3K経路、またはオロチジン5’−一リン酸(OMP)デカルボキシラーゼを阻害することができる。
養子T細胞免疫療法は、天然T細胞または操作されたT細胞のいずれかを用いて実施することができる。操作されたT細胞には、それらの表面上にキメラ抗原受容体(CAR)を発現するように操作されているT細胞(CAR−T細胞)が含まれ得る。
一部の実施形態では、免疫腫瘍学治療は、がんワクチンである。がんワクチンは、抗腫瘍抗体を生成するように患者の免疫系を刺激し、それによって免疫系にがん性細胞を標的にし、破壊させることができる、免疫原性組成物である。一部の実施形態では、がんワクチンは、ペプチドワクチンである。一部の実施形態では、がんワクチンは、コンジュゲートワクチンである。
HSCTは、骨髄または免疫系が欠損した患者において造血機能を再確立するための幹細胞移植である。一部の実施形態では、幹細胞は自己由来である。一部の実施形態では、幹細胞は同種異系である。一部の実施形態では、移植は、静脈内注入によって実施される。
モノクローナル抗体は、様々ながんの処置において有用である。mAbがん処置は、がん性細胞を攻撃する自然免疫系機能を利用する。腫瘍抗原に特異的なmAbの投与は、免疫系によって破壊するための腫瘍細胞を標的にするのに有用となり得る。ある場合には、mAbは、がん細胞の溶解を引き起こし、がん細胞の成長/複製を遮断し、血管新生を防止し、チェックポイント阻害剤として作用し、ある場合には腫瘍抗原に結合するように作用すると同時に、特異的免疫細胞を活性化することもできる。一部の実施形態では、モノクローナル抗体は、単一特異性である。一部の実施形態では、モノクローナル抗体は、二重特異性である。一部の実施形態では、モノクローナル抗体は、チェックポイント阻害剤である。一部の実施形態では、mAbは、CAR−T治療と組み合わせて使用することができる。
血漿中のブレキナルレベルを決定する
図4は、毎週2回投与した場合の対象の血漿中のブレキナルの経時的な濃度を例示する散布図である。
ブレキナルを受けた対象において観察された有害事象
ブレキナルを、用量中央値1200mg/m2(範囲588〜3110)で、患者当たりの投与回数の中央値4(範囲1〜24)で対象209名に週1回静脈内投与した。対象の3%よりも多くに観察された有害事象を下記表4に報告する:
標準としてDHOを使用する血漿試料中のDHOレベルを決定する
分析前に、血漿試料を、50kD Amicon限外濾過膜による遠心分離によって除タンパクする。10μLの血漿試料を、5μLの(S)−4,5−ジヒドロオロト−4,5,6−カルボキシ−13C4酸(13C4−DHO)の標準溶液でスパイクし、次いで、35μLの0.1%(w/w)ギ酸で希釈する。試料を、逆相4μm C18カラム(Synergy Hydro RP−80A、3μm、150×3mm;Phenomenex、Australia)に注入する。クロマトグラフィーを、溶媒A(5mM酢酸アンモニウム水溶液、0.05%(w/v)ギ酸)および溶媒B(メタノール中の0.05%(w/v)ギ酸)を使用して、A:B 98:2(v/v)から85:15(v/v)まで11分間にわたって、40:60(v/v)まで1分間の線形勾配溶出で、全流速0.3mL/分で、30℃で実行し、その後、さらに6分間平衡化する初期条件に戻す。
標準としてオロチン酸を使用する血漿試料中のDHO酸レベルを決定する
分析前に、血漿試料を、50kD Amicon限外濾過膜による遠心分離によって除タンパクする。10μLの血漿試料を、5μLの15N2−オロチン酸の標準溶液でスパイクし、次いで、35μLの0.1%(w/w)ギ酸で希釈する。試料を、逆相4μm C18カラム(Synergy Hydro RP−80A、3μm、150×3mm;Phenomenex、Australia)に注入する。クロマトグラフィーを、溶媒A(5mM酢酸アンモニウム水溶液、0.05%(w/v)ギ酸)および溶媒B(メタノール中の0.05%(w/v)ギ酸)を使用して、A:B 98:2(v/v)から85:15(v/v)まで11分間にわたって、40:60(v/v)まで1分間の線形勾配溶出で、全流速0.3mL/分で、30℃で実行し、その後、さらに6分間平衡化する初期条件に戻す。
健康な対象およびがん患者におけるDHOレベルの決定
ヒトK2EDTA血漿試料中のジヒドロオロト酸濃度を、タンデム質量分析検出(LC−MS/MS)を用いる逆相高速液体クロマトグラフィーによって決定した。血漿試料(50μL)を、内部標準(IS)として使用した水中5μLの(S)−4,5−ジヒドロオロト−4,5,6−カルボキシ−13C4酸(13C4−DHO)の1.0μg/mL溶液でスパイクし、次いでアセトニトリル(200μL)と5分間激しく混合した。遠心分離(12,000rpm、5分)後、150μLの上清をあらかじめ調整したWaters(Milford、MA)Oasis MAX固相抽出カートリッジ(1cc、30mg)に適用した。カートリッジを水およびメタノールで逐次洗浄した後、メタノール中50μLの1%(体積/体積)ギ酸(1mL)で分析物を溶出した。溶離液を窒素ストリーム下で蒸発させ、水中の1%(体積/体積)ギ酸中で再構成させた。溶液を、琥珀色のオートサンプラーバイアル内に置かれた円錐底インサート(conical bottom insert)に移し、密封した。溶液の10μLアリコートを、AQ C18ガードカートリッジ(4.0mm×3.0mm i.d.)が前にあるPhenomenex(Torrance、CA)Synergi 4μm Hydro−RP 80A HPLCカラム(250mm×3.0mm i.d.)に注入し、水中の0.05%(体積/体積)ギ酸で構成される均一濃度の移動相を流速0.5mL/分で使用して分離した。エレクトロスプレーイオン化インターフェースを用いるAgilent Technologies(Santa Clara、CA)モデルG6410B三連四重極質量分析計を検出に使用した。窒素を、噴霧ガス(30p.s.i.)および乾燥ガス(10L/分、350℃)として使用した。1,500Vの転送キャピラリー電位で、ジヒドロオロト酸(dihydroorotic acid)についてm/z 157→113転移およびISについてm/z 161→117転移からの負イオンを多重反応モニタリング(滞留時間、150ミリ秒;断片化電位、70V;衝突エネルギー、4V;衝突セル加速器電圧、4V)によって測定した。定量は、ピーク面積を提供する両方の転移について抽出されたイオンクロマトグラムを積分することと、各試料について分析物ピーク面積のISピーク面積に対する比を算出することとに基づいた。
難治性固形腫瘍を有する患者においてブレキナルについて以前に試験した臨床的投与レジメン
以前の臨床的投与レジメンは、患者の難治性固形腫瘍の処置における使用についてブレキナルをアセスメントした。例えば、Arteagaは、「毎日1回のi.v.ボーラスを28日間毎に5日間にわたって反復した」ブレキナルの投与について報告した。Arteaga, et al., "Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC368390)," Cancer Res., 49(16):4648-4653 (August 15, 1989)。具体的には、Arteagaは、難治性固形腫瘍を有する患者45名(男性31名および女性14名)に、「36〜300mg/m2/日×5回の範囲の投与量で107コースの処置」を投与した。これら患者の報告されている年齢の中央値は、58歳(範囲30〜74歳)であり;南西部腫瘍学グループパフォーマンスステイタスの中央値は1になる(範囲、0〜3)と報告された。Arteagaは、「毎日×5回のi.v.スケジュールの場合、第2相評価に対するブレキナルの推奨される用量が、危険性が低い患者で250mg/m2であり、危険性が高い患者で135mg/m2である」ことを見出した。
本開示による例示的な臨床的投与
組み入れ基準
以下は、提案された臨床試験において対象に提案された組み入れ基準である:
・意欲的であり、試験のために書面によるインフォームドコンセントを提供できる。
・病理学的に確認された、再発したまたは難治性の急性骨髄性白血病を有する成人、年齢18歳およびそれよりも年上。
・インフォームドコンセントに署名する日に≧年齢18歳
・ECOGパフォーマンスステイタス0〜2。
・心駆出率≧40%
・適切な肝機能(基礎となる白血病と関係するとみなされない限り)
・直接ビリルビン≦2×ULN
・ALT≦3×ULN
・AST≦3×ULN
・コッククロフト−ゴールト方程式に基づいてクレアチニンクリアランス≧30mL/分により記録される適切な腎機能
以下は、研究において対象を除外するために提案された除外基準である。
・白血球数>25×109個/L(注:ヒドロキシウレアは、この基準を満たすことを容認される)。
・研究処置の容認できない危険性に参加者をさらす可能性があるあらゆる同時制御の効かない臨床的に重大な医学的状態、検査所見の異常、または精神病。
・Fridericiaの式(QTcF)を使用するQTc間隔が≧470ミリ秒。脚ブロックおよびQTc間隔の延長を有する参加者は、メディカルモニターとの議論後に適格になり得る。
・他の化学療法剤または抗白血病剤の使用は、以下の例外を除いて研究の間許可されない:
・予防的使用または制御されたCNS白血病の維持のための髄腔内化学療法。
・ヒドロキシウレアの使用は、参加者にとって最大の利益になる場合には療法の最初の2週間可能な場合があり、メディカルモニターによって承認される。
・幹細胞移植後6ヵ月未満のAMLの再発。
・等価用量のプレドニゾン≧0.5mg/kg/日または全身性コルチコステロイド以外の療法(例えば、シクロスポリンもしくは他のカルシニューリン阻害剤またはGVHDに使用される他の免疫抑制剤)を必要とする移植片対宿主病(GVHD)の存在。
・AMLの活動型脳脊髄障害。
・急性前骨髄球性白血病(APL)の診断
・臨床的に活動性のB型肝炎(HBV)またはC型肝炎(HCV)感染。
・経口研究薬の吸収を妨げる可能性がある重度の胃腸または代謝状態
・活動性でないまたは少なくとも5年間安定であり続ける場合を除き、過去の悪性腫瘍。処置済みの非黒色腫皮膚がん、in situ癌または頸部上皮内新生物を有する参加者は、状態に対する根治的処置が完了している場合、無疾患期間に関係なく適格である。再発性または進行性疾患の証拠がない臓器限局性前立腺がんを有する参加者は、ホルモン療法が開始されている、または悪性腫瘍が外科的に除去されているもしくは根治的放射線療法で処置されている場合には適格である。
・授乳中の女性または尿妊娠検査陽性であり妊娠可能な女性(WoCBP)。
提案された投与レベルを、以下に提供する:
患者は、3.5日間毎に投与される。事象のスケジュール例を表8に報告する。
DHOレベルに基づいて最適化された投与量
図8は、DHOのレベルに応じてDHODHを阻害するブレキナルなどの薬物の治療利益を示すグラフである。グラフの左側において、DHOのレベルは最小閾値未満であり、薬物のターゲットエンゲージメントは治療効果を有するには不十分である。グラフの灰色領域において、DHOのレベルは最小閾値を超えるが、最大閾値未満であり、したがって薬物はその標的に十分に関与して治療効果をもたらしたが、健康な細胞に有害な効果を引き起こさなかった。グラフの右側において、DHOのレベルは最大閾値を超え、薬物の効果は健康な細胞に害を引き起こす。治療利益と代謝産物レベルの関係に基づく投与レジメンの調整について表9に例示する。
AMLを有する患者に対するブレキナル含有組成物の効果
ブレキナルを含有する組成物による効果を、急性骨髄性白血病(AML)を有する第1の患者に対して分析した。用量の組成物の投与後、患者は、24時間未満に1,600ng/mLのDHO血漿レベル閾値を達成し、84時間その閾値を超えたままであった。この患者は、骨髄芽球数の減少、髄外造血の改善、および末梢芽球におけるより多くの分化への移行によって示されるように正の応答を示した。
AMLを有する患者に対するブレキナル含有組成物の効果
ブレキナルを含有する組成物の効果を、AMLを有する第2の患者に対して分析した。用量の組成物の投与後、患者は、24時間未満に(in less 24 hours)2,900ng/mLのDHO血漿レベル閾値を達成し、84時間その閾値を超えたままであった。この患者は、末梢芽球のより多くの分化と共に、末梢芽球の低下および絶対好中球数の増加を伴う疾患に対して正の応答を示した。
AMLを有する患者に対するブレキナル含有組成物の効果
ブレキナルを含有する組成物の効果を、AMLを有する第2の患者に対して分析した。用量の組成物の投与後、患者は、2時間未満に133ng/mLのDHO血漿レベル閾値を達成し、84時間その閾値を超えたままであった。この患者は、末梢芽球の分化に向かう傾向によって示されるように正の応答を示した。
特許、特許出願、特許公報、学術誌、書籍、論文、ウェブコンテンツなどの他の文書の参照および引用が、本開示の全体を通じてなされている。そのような文書全ては、全ての目的のためにその全体において参照により本明細書に組み込まれる。
本発明の様々な修正および多くのさらなるその実施形態は、本明細書に示され、記載されるそれらに加えて、本明細書に引用されている科学および特許文献の参照を含めた本文書の完全な内容から当業者に明らかになる。本明細書中の主題は、その様々な実施形態およびその均等物における本発明の実践に適合され得る重要な情報、例証およびガイダンスを含有する。
Claims (8)
- 2−(2’−ハロ−1−1’−ビフェニル−4−イル)−キノリンカルボン酸を作製する方法であって、
式(I)の化合物を式(II)の化合物と共に、塩基を含む混合物中でインキュベートするステップと、
前記混合物に酸を添加し、それによって、以下の反応:
[R1、R2、R3、およびR4は、独立に、H、F、Cl、Br、I、CH3、CF3、SCH3またはCH2CH3であり、R1、R2、R3、およびR4の少なくとも2つは、Hであり、
R5は、H、1〜3個の炭素原子を有するアルコキシ、または1〜2個の炭素原子を有するアルキルであり、
R6およびR7は、独立に、H、F、Cl、Br、1〜5個の炭素原子を有するアルキル、NO2、OH、CF3またはOCH3であり、
Xは、ハロゲンである]
前記インキュベートするステップが、
約5:1〜約8:1のモル比の前記塩基と前記式(II)の化合物とを含む前記混合物を、約60℃〜約70℃の温度でインキュベートすること、および
前記混合物を約15時間〜約30時間インキュベートすること
の少なくとも1つを含む、方法。 - 前記インキュベートするステップが、前記混合物を約60℃〜約70℃の温度でインキュベートすることを含む、請求項1に記載の方法。
- 前記インキュベートするステップが、約5:1〜約8:1のモル比の前記塩基と前記式(II)の化合物とを含む前記混合物を含む、請求項1に記載の方法。
- 前記インキュベートするステップが、前記混合物を約15時間〜約30時間インキュベートすることを含む、請求項1に記載の方法。
- 前記式(III)の化合物の収率が、少なくとも80%である、請求項1に記載の方法。
- 前記塩基が、KOH、NaOH、およびNH4OHからなる群から選択される、請求項1に記載の方法。
- 前記酸が、HClまたは酢酸のいずれかから選択される、請求項1に記載の方法。
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US20220177435A1 (en) | 2022-06-09 |
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JP2024028988A (ja) | 2024-03-05 |
US11230528B2 (en) | 2022-01-25 |
US10889548B2 (en) | 2021-01-12 |
US20210087146A1 (en) | 2021-03-25 |
US20190292154A1 (en) | 2019-09-26 |
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