JP2015510942A - 置換ピリドピリミジン化合物およびflt3阻害剤としてのこれらの使用 - Google Patents
置換ピリドピリミジン化合物およびflt3阻害剤としてのこれらの使用 Download PDFInfo
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Description
本願は、米国仮特許出願No. 61/614,274、出願日2012年3月22日、に対する利益および優先権を主張し、その内容をその全体で参照により本明細書に組み入れる。
FLT3(FMS様チロシンキナーゼ3、Flk2としても公知である)はタイプIII受容体チロシンキナーゼ(RTK)ファミリーのメンバーであり、造血幹細胞の増殖および分化において重要な役割を果たしている。この受容体の活性化突然変異(activating mutation)または過剰発現は、急性骨髄性白血病(AML)、急性リンパ性白血病(ALL)、マスト細胞症および消化管間質腫瘍(GIST)において所見される。活性化突然変異に加えて、過剰発現した野生型FLT3による自己分泌リガンド刺激および傍分泌リガンド刺激は、悪性表現型の原因となり得る。
本発明は、式Iで表される化合物、ならびにその個々の立体異性体、異性体の混合物、または薬学的に許容し得る塩
R1は、アリール、アリールアルキル、C5〜C6シクロアルキルまたはR3で任意に置換されていてもよいC5〜C6シクロアルキルメチルであり、
R3は独立して、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、またはCF3であり;
Yは、クロロ、ブロモ、ヨード、C1〜C3アルキルまたはフェニルであり;
R2は、C3〜C6シクロアルキルまたはC4〜C7ヘテロシクロアルキルであり、ここで該C3〜C6シクロアルキルは炭素原子において1つまたは2つのR4で任意に置換されていてもよく、およびここで該C4〜C7ヘテロシクロアルキルは窒素、酸素、硫黄、スルホン、またはスルホキシドからなる群から選択される1つまたは2つのヘテロ原子を有し、および炭素においてR4でまたは窒素においてR5で独立して置換されている;
R4は、ヒドロキシル、ヒドロキシル(C1〜C6)アルキル、アミノ、アミノ(C1〜C6)アルキル、NHC1〜C3アルキル、N(C1〜C3アルキル)2、C1〜C3アルキルまたはハロであり;
R5は、H、C1〜C3アルキルまたはC(O)C1〜C3アルキルであり、ここで該C1〜C3アルキル基は1〜3個のフッ素原子で任意に置換されていてもよい;
または、その薬学的に許容し得る塩を提供する。
本発明は、1つまたは2つ以上のタンパク質キナーゼを阻害するのに、およびタンパク質キナーゼにより媒介される疾患および障害、例えば細胞増殖性疾患を処置するのに有用な、一群の4−フェニルアミノ−ピリド[4,3,−d]ピリミジン−5−オン誘導体およびその薬学的に許容し得る塩を提供する。本発明はまた、該4−フェニルアミノ−ピリド[4,3,−d]ピリミジン−5−オン誘導体の合成方法および投与方法を提供する。本発明は、少なくとも1つの該化合物をそれに対する薬学的に許容し得る担体、希釈剤または賦形剤とともに含む医薬処方物を提供する。本発明はまた、4−フェニルアミノ−ピリド[4,3,−d]ピリミジン−5−オン誘導体化合物の合成の間に作り出される有用な中間体を提供する。
R1は、アリール、アリールアルキル、C5〜C6シクロアルキルまたはR3で任意に置換されていてもよいC5〜C6シクロアルキルメチルであり、
R3は独立して、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、またはCF3であり;
Xは、F、Cl、Br、I、CH3またはCF3であり;
Yは、クロロ、ブロモ、ヨード、C1〜C3アルキルまたはフェニルであり;
R2は、C3〜C6シクロアルキルまたはC4〜C7ヘテロシクロアルキルであり、ここで該C3〜C6シクロアルキルは炭素原子において1つまたは2つのR4で任意に置換されていてもよく、およびここで該C4〜C7ヘテロシクロアルキルは窒素、酸素、硫黄、スルホン、またはスルホキシドからなる群から選択される1つまたは2つのヘテロ原子を有し、および炭素においてR4でまたは窒素においてR5で独立して置換されている;
R4は、ヒドロキシル、ヒドロキシル(C1〜C6)アルキル、アミノ、アミノ(C1〜C6)アルキル、NHC1〜C3アルキル、N(C1〜C3アルキル)2、C1〜C3アルキルまたはハロであり;
R5は、H、C1〜C3アルキルまたはC(O)C1〜C3アルキルであり、ここで該C1〜C3アルキル基は1〜3個のフッ素原子で任意に置換されていてもよい;
あるいはその薬学的に許容し得る塩を開示する。
ある態様において、R3は、フッ素、塩素、CH3、またはイソプロピルを表す。
ある態様において、R3は、H、メチルまたはFを表す。
一態様において、Yは、クロロ、ブロモ、ヨード、メチル、またはフェニルを表す。さらなる態様において、Yは、クロロまたはブロモを表す。
ある態様において、R5は、メチルを表す。ある態様において、R2は、ピロリジニル、またはピペリジニルを表す。ある態様において、R2は、N−メチルピロリジニルまたはN−メチルピペリジニルを表す。
ある態様において、R6は、ヒドロキシル、ヒドロキシル(C1〜C6)アルキル、アミノ、アミノ(C1〜C6)アルキル、NHC1〜C3アルキル、N(C1〜C3アルキル)2、C1〜C3アルキルまたはハロを表す。ある態様において、R6は、ヒドロキシル、アミノ、またはN−メチルアミノを表す。
本明細書で用いられる、用語「アルコキシ」は、酸素を介して結合する上のアルキル基を指し、その例はメトキシ、エトキシ、iso−プロポキシ、tert−ブトキシなどを含む。加えて、アルコキシはまた、ポリエーテル、例えば−O−(CH2)2−O−CH3などを指す。アルコキシは、非置換であるか、あるいは1つまたは2つ以上の好適な置換基で置換されていることができる。
用語「アリール」はまた、非芳香族炭素環式のまたはヘテロ環式の基へと縮合したフェニル環を含む。用語「アリール」は、「アリール環」、「芳香族基」、および「芳香環」と互換的に用いられ得る。ヘテロアリール基は4〜14個の原子を有し、このうちの1〜9個は酸素、硫黄および窒素からなる群から独立して選択される。ヘテロアリール基は、5〜8員の芳香族基に1〜3個のヘテロ原子を有する。アリールまたはヘテロアリールは、単環式のまたは多環式の芳香族基であることができる。典型的なアリールおよびヘテロアリール基は、例えば、フェニル、キノリニル、インダゾイル、インドリル、ジヒドロベンゾジオキシニル、3−クロロフェニル、2,6−ジブロモフェニル、ピリジル、ピリミジニル、3−メチルピリジル、ベンゾチエニル、2,4,6−トリブロモフェニル、4−エチルベンゾチエニル、フラニル、3,4−ジエチルフラニル、ナフチル、4,7−ジクロロナフチル、ピロール、ピラゾール、イミダゾール、チアゾールなどであることができる。アリールまたはヘテロアリールは、非置換であるかあるいは1つまたは2つ以上の好適な置換基で置換されていることができる。
本明細書で用いられる、用語「ヒドロキシル」または「ヒドロキシ」は、−OHを指す。
本明細書で用いられる、用語「アミノ」は、−NH2を指す。
本明細書で用いられる、用語「ヒドロキシアルキル」は、アルキルラジカルの任意のヒドロキシル派生物を指す。用語「ヒドロキシアルキル」は、水酸基で置き換えられた1つまたは2つ以上の水素原子を有する任意のアルキルラジカルを含む。
本明細書で用いられる、用語「薬学的に許容し得る塩」は、それが投与される生命体に著しい刺激を引き起こさず、かつ本明細書中に記載の化合物の生物学的活性および特性を無効にしない化合物の処方物を指す。
本明細書で用いられる、用語「医薬組成物」は、本明細書で記載される化合物の、他の化学成分、例えば担体、安定化剤、希釈剤、分散剤、懸濁化剤、増粘剤、および/または賦形剤などとの組み合わせを指す。
本明細書で用いられる、用語「プロドラッグ」は、in vivoで活性薬物または「親」薬物へと変換される薬剤を指す。
本明細書で用いられる、用語「担体」は、本明細書に記載される化合物の細胞または組織への取り込みを促進する化学化合物または薬剤を指す。
本明細書で用いられる、用語「希釈剤」は、送達前に本明細書に記載される化合物を希釈するために用いられる化学化合物を指す。希釈剤はまた、本明細書に記載される化合物を安定化させるために用いることができる。
タンパク質キナーゼは、広汎な種類の細胞プロセスの調節および細胞機能に対する制御の維持において中心的役割を果たす。タンパク質キナーゼはリン酸化のプロセスを触媒および調節し、それによってキナーゼはさまざまな細胞外シグナルに応答してタンパク質または脂質標的に向かってリン酸基に共有結合する。かかる刺激の例は、ホルモン、神経伝達物質、成長因子および分化因子、細胞周期事象、環境ストレスおよび栄養ストレスを含む。細胞外刺激は、細胞成長、遊走、分化、ホルモンの分泌、転写因子の活性化、筋肉収縮、グルコース代謝、タンパク質合成の制御、および細胞周期の調節に関連する1つまたは2つ以上の細胞応答に影響を及ぼし得る。
式(I)で表される化合物、またはその薬学的に許容し得る塩、溶媒和物、N−オキシド、プロドラッグおよび異性体など、本明細書において提供される化合物の治療的使用のために、かかる化合物は治療的有効量で、単独でまたは医薬組成物の一部分として投与される。従って、本明細書において、式(I)で表される化合物、その薬学的に許容し得る塩および/または溶媒和物などの、本明細書において提供される少なくとも1種の化合物、ならびに1種または2種以上の薬学的に許容し得る塩、希釈剤、アジュバントまたは賦形剤を含む、医薬組成物が提供される。加えて、かかる化合物および組成物は、単独で、あるいは1種または2種以上の追加の治療剤と組み合わせて投与される。
本発明の化合物の保護化誘導体は、当業者に公知の手段により作製され得る。保護基の創出および除去に利用可能な技術の詳細な記載は、T. W. Greene, “Protecting Groups in Organic Chemistry,” 3rd edition, John Wiley and Sons, Inc., 1999において見ることができ、その全体の教示を参照により本明細書に組み入れる。
本発明はさらに、本発明による式(I)で表される化合物の製造を説明する以下の実施例により例証される。実施例は説明の目的のみのためのものであり、本発明をいかなる様式においても限定することを意図しないし、またそのように解釈されるべきではない。当業者は、変形および修飾形が本発明の範囲を変更することなく、なされることができると考えるであろう。
1.試料を、室温で流速1.5mL/分で実行するZorbax Eclipse XDB-C18(3.5μ)逆相カラム(4.6×50mm)を有するAgilent Technologies 6120 MSDシステム上に流す。
2,移動相は、溶媒A(水/0.1%ギ酸)および溶媒B(アセトニトリル/0.1%ギ酸):95%/5%〜0%/100%(A/B)を5分間用いる。
3.質量分析(m/z)をエレクトロスプレーイオン化(ESI)を用いて記録した。
4.イオン化データを最も近い整数へと丸めた。
1.キナーゼ阻害アッセイ
本発明の化合物をアッセイして、FLT3およびJAK2を限定せずに含むキナーゼを阻害するそれらの能力を測定した。
FLT3は、タイプIII受容体チロシンキナーゼ(RTK)ファミリーのメンバーである。FLT3に対するリガンドは骨髄間質細胞および他の細胞により発現され、他の成長因子とともに相乗効果を与え、幹細胞、前駆細胞、樹状細胞、およびナチュラルキラー細胞の増殖を刺激する。FLT3は、前悪性障害である造血障害、例えば骨髄増殖性障害、例えばAMLおよびALLなどにおいて関与してきた。
酵素的FLT3およびJAK2キナーゼ活性の阻害
本発明の化合物を最初に、貯蔵のために100%DMSO(CALBIOCHEM(登録商標))に希釈し、キナーゼバッファーとし、1uM〜10uMの範囲の化合物濃度を作り出した。本発明の化合物の連続希釈物を96ウェルプレート(GREINER BIOSCIENCES(登録商標))中にそれぞれ6μLで分注した。切断ヒトFLT3野生型、変異D835Y、およびJAK2(CARNA BIOSCIENCES(登録商標))をキナーゼバッファー中に希釈し、化合物溶液に添加し、30分間室温で前培養した。次に、ATP(TEKNOVA(登録商標))および基質溶液(PerkinElmer(登録商標)の提唱する製造基質、例えばFLT野生型および変異型D835Yに対してUlight(登録商標)-TKペプチドおよびJAK2に対してUlight(登録商標)-JAK1(PERKINELMER(登録商標))を、化合物溶液および酵素を含有するウェルへと添加した(それぞれ12uL)。
式(I)で表される化合物は、有用な薬理学的特性を呈した。本明細書で用いられる、阻害活性の能力(nM)を記載する方法は、表2に示される、50%の阻害活性の値(IC50)である。参照化合物、AC220(Quizartinib, Ambit)、PKC412(Midostaurin, Novartis)およびスタウロスポリン(汎キナーゼ阻害剤)をFLT3に対して用いて、式(I)で表される化合物の阻害活性を判断した。参照化合物、スタウロスポリン、汎キナーゼ阻害剤をJAK2に対して独立して用いて、式(I)で表される化合物の選択性および阻害性を判断した。
本発明の化合物を、ヒト急性白血病細胞株(MV4−11)におけるFLT3−ITD(内部タンデム複写(Internal Tandem Duplication))の阻害に対するそれらの効果に関して試験する。FLT3は主に、未成熟造血前駆細胞においてならびに成熟骨髄細胞において発現する。それは、KIT、FMS、およびPDGFRを含む、タイプIII受容体チロシンキナーゼ(RTK)ファミリーに属する。それはFLに結合することにより活性化され、増加したキナーゼ活性ならびにSTAT5、Ras、およびPI3キナーゼを含む下流シグナリング経路の活性化を誘導する。
本発明の化合物を、MV4−11細胞に対する細胞生存効果に関して試験した。細胞生存能アッセイのために、ヒトFLT3−ITDを発現するMV4−11細胞をAmerican Type Culture Collection(ATCC, Manassas, VA)から獲得した。この細胞株を、鉄添加10ウシ胎児血清(BCS; Hyclone(登録商標))含有Roswell Park Memorial Institute(RPMI)培地(HyClone(登録商標))で維持した。MV4−11細胞を96ウェル培養プレート中に2×104細胞で播種し、そして連続希釈した化合物を添加した。37℃での72時間培養期間後に、細胞生存能を、生存細胞からのATPの定量化に基づくATPLite1ステップアッセイ(Perkin-Elmer(登録商標))を用いて測定した。CellTiter Aqueousアッセイ(Promega(登録商標))もまた、直交アッセイとして平行して実行した。IC50値は、非線形回帰を用いて計算し、処置細胞対非処置対照細胞の発光または吸光における50%低減のために必要な濃度として定義した(Prism(登録商標)Software)。
式(I)で表される代表的な化合物のIC50阻害データを、表3に示す。式(I)で表される化合物は、IC50濃度における10nMよりも少ない阻害を呈した。具体的には、化合物237、8−ブロモ−4−(4−(シクロペンチルオキシ)フェニルアミノ)−2−(1−メチルピペリジン−4−イルアミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩は、FLT3 ITD誘発性MV4−11癌細胞株において参照PKC−412により呈されるものよりも大きな阻害レベルを呈した。かかる強力な抗腫瘍活性により、本発明の化合物は、参照化合物および先行技術(PCTファイル番号:PCT/US2010/056583)に記載されるアスタリスクにより表示される化合物203よりもよい治療的価値がある。
本発明の化合物が十分なin vivo有効性を示すかどうかを試験するために、それらをMV4−11癌細胞株を用いる異種移植マウスモデルにおいて試験した。
本発明の化合物を、FLT3−ITDのMV4−11細胞株を用いる異種移植マウスモデルにおいて試験した。6週齢のBalb/Cヌードマウスの全てのオス動物をコーンコブ含有プラスチックケージ(4〜6マウス/ケージ)に収容し、病原体フリー施設(20〜25℃、30〜70%湿度)中に12時間明:暗周期で維持した。MV4−11細胞懸濁液での皮下注射により、腫瘍モデルを確立した。平均腫瘍容積がおよそ400mm3に達したとき(〜5週腫瘍移植後)、担癌マウスを2群に割り当てた(それぞれ9マウス)。30mg/kg毎日の化合物238処置を開始し、28日間継続する。ビヒクル20%ヒドロキシ−β−シクロデキストリンを用いた。腫瘍容積を週あたり2回で測定した。適用できる場合には、それぞれの群に対する%腫瘍退縮(percent tumor regression(PTR))を以下の式により計算するであろう:
PTR=100×(腫瘍容積初期−腫瘍容積最終)/(腫瘍容積初期)
式(I)で表される代表的な化合物238は、表4において、たった4日処置後に74.6%腫瘍退縮を、および結果的には化合物処置の11日後に完全な腫瘍退縮を示す。この結果により、代表的な化合物は異種移植マウスモデルにおいて非常に強力な抗腫瘍活性であることを示唆し、本発明の化合物はdys調節および/または過剰活性FLT3誘発性疾患、例えばAMLおよびALLなどに対する大いなる治療オプションであることが示唆されている。
Claims (18)
- 式(I)
R1は、任意にR3で置換されていてもよい、アリール、アリールアルキル、C5〜C6シクロアルキル、またはC5〜C6シクロアルキルメチルであり;
R3は独立して、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、またはCF3であり;
Xは、F、Cl、Br、I、CH3、またはCF3であり;
Yは、クロロ、ブロモ、ヨード、−C1〜C3アルキルまたはフェニルであり;
R2は、C3〜C6シクロアルキルまたはC4〜C7ヘテロシクロアルキルであり、ここで該C3〜C6シクロアルキルは炭素原子において1つまたは2つのR4で任意に置換されていてもよく、およびここで該C4〜C7ヘテロシクロアルキルは窒素、酸素、硫黄、スルホン、およびスルホキシドからなる群から選択される1つまたは2つのヘテロ原子を有しており、かつ炭素においてR4でまたは窒素においてR5で独立して置換されており;
R4は、ヒドロキシル、ヒドロキシル(C1〜C6)アルキル、アミノ、アミノ(C1〜C6)アルキル、NHC1〜C3アルキル、N(C1〜C3アルキル)2、C1〜C3アルキルまたはハロであり;
R5は、H、C1〜C3アルキルまたはC(O)C1〜C3アルキルであり、ここで該C1〜C3アルキル基は1〜3個のフッ素原子で任意に置換されていてもよい
で表される化合物、またはその薬学的に許容し得る塩。 - R1が、R2により任意に置換されていてもよい、フェニル、ベンジル、シクロヘキシル、シクロペンチル、シクロヘキシルメチル、またはシクロペンチルメチルを表す、請求項1に記載の化合物。
- R2が、窒素においてR5で置換されているピペリジンまたはピロリジンを表す、請求項1または2に記載の化合物。
- R5が、メチル、エチル、トリフルオロエチル、またはイソプロピルである、請求項1〜3のいずれか一項に記載の化合物。
- R3が、HまたはFを表す、請求項1〜4のいずれか一項に記載の化合物。
- 8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((3−フェノキシフェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩または8−ブロモ−4−((3−(3−フルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩である、請求項5に記載の化合物。
- Yがブロモを表す、請求項1〜3のいずれか一項に記載の化合物。
- Xが、フッ素またはメチルを表す、請求項1に記載の化合物。
- 8−ブロモ−4−((3−フルオロ−4−フェノキシフェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩である、請求項8に記載の化合物。
- 請求項1の異性化合物。
- 請求項1〜10のいずれか一項に記載の化合物またはその薬学的に許容し得る塩を、薬学的に許容し得る担体、希釈剤または賦形剤と組み合わせて含む、医薬処方物。
- 請求項1に定義される化合物またはその薬学的に許容し得る塩の、FLT3、MER、VEGFR3またはAurora−B酵素の阻害により処置できる疾患の処置のための医薬の製造のための使用。
- 血液学的悪性疾患、例えば白血病、リンパ腫(非ホジキンリンパ腫)、ホジキン病(ホジキンリンパ腫とも呼ばれる)、または骨髄腫、例えば、急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)、急性前骨髄球性白血病(APL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、慢性好中球性白血病(CNL)、急性未分化白血病(AUL)、未分化大細胞リンパ腫(ALCL)、前リンパ球性白血病(PML)、若年性骨髄単球性白血病(JMML)、成人T細胞ALL、3系統骨髄異形成を伴うAML(AML/TMDS)、混合系統白血病(MLL)、骨髄異形成症候群(MDSs)、骨髄増殖性疾患(MPD)、多発性骨髄腫(MM)および骨髄性肉腫。異常発現FLT3が、急性骨髄性白血病(AML)、3系統骨髄異形成を伴うAML(AML/TMDS)、急性リンパ芽球性白血病(ALL)、または骨髄異形成症候群(MDS)を含む、成人性または小児性白血病の処置における使用のための、請求項1に記載の化合物またはその薬学的に許容し得る塩。
- 自己免疫性疾患、例えば自己免疫性脳脊髄炎、多発性硬化症、ランゲルハンス細胞組織球または全身性エリテマトーデスの処置における使用のための、請求項1に記載の化合物またはその薬学的に許容し得る塩。
- 悪性固形腫瘍、例えば胃癌、乳癌、非小細胞肺癌、頸癌、結腸直腸癌、前立腺癌、カポジ肉腫、頭頸部扁平上皮癌腫、子宮内膜癌腫または中皮腫の処置における使用のための、請求項1に記載の化合物またはその薬学的に許容し得る塩。
- FLT3、MER、VEGRF3またはAurora−Bにより媒介される疾患または状態の処置方法であって、請求項1〜10のいずれか一項に記載の有効量の化合物またはその薬学的に許容し得る塩を、それを必要とする対象に投与することを含む、前記方法。
- 化合物が単独でまたは1つまたは2つ以上の追加の治療剤と併用で投与される、請求項16に記載の方法。
- 化合物が、静脈内投与、皮下投与、吸入、経口投与、直腸投与、非経口、硝子体内投与、筋肉内投与、鼻腔内投与、経皮投与、局所投与、眼投与、点眼投与、口腔内投与、気管内投与、気管支投与、または舌下投与により投与される、請求項16または17に記載の方法。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021528383A (ja) * | 2018-06-27 | 2021-10-21 | オスコテック インコーポレイテッド | Axl阻害剤として使用するためのピリドピリミジノン誘導体 |
JP2021535088A (ja) * | 2018-08-23 | 2021-12-16 | オスコテック インコーポレイテッド | 8−ブロモ−2−(1−メチルピペリジン−4−イルアミノ)−4−(4−フェノキシフェニルアミノ)ピリド[4,3−d]ピリミジン−5(6h)−オン塩酸塩の結晶多形及びその調製方法 |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2014340249B2 (en) * | 2013-10-21 | 2017-05-25 | Genosco | Substituted pyrimidine compounds and their use as SYK inhibitors |
KR102485100B1 (ko) * | 2014-07-17 | 2023-01-04 | 선샤인 레이크 파르마 컴퍼니 리미티드 | 치환된 우레아 유도체 및 이의 약제학적 용도 |
KR20160035411A (ko) * | 2014-09-23 | 2016-03-31 | 주식회사 오스코텍 | LRRK2 (Leucine Rich Repeat Kinase 2) 키나제 억제제로서의 피리도피리미딘 유도체 화합물 |
CN113230257A (zh) | 2014-11-17 | 2021-08-10 | 罗得岛医院 | 纳米材料组合物、合成、与组装 |
KR102230721B1 (ko) | 2019-02-01 | 2021-03-22 | 주식회사 오스코텍 | 피리도피리미딘계 염산염을 포함하는 경구용 고형제제 및 이의 제조방법 |
AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
CN110327347B (zh) * | 2019-08-16 | 2021-06-01 | 陕西科技大学 | G-749在制备抗真菌药物中的应用 |
TWI759829B (zh) * | 2019-08-23 | 2022-04-01 | 財團法人生物技術開發中心 | 作為第iii型受體酪胺酸激酶抑制劑之雜環吡唑衍生物 |
US20220401436A1 (en) | 2019-11-08 | 2022-12-22 | INSERM (Institute National de la Santé et de la Recherche Médicale) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2023027966A1 (en) | 2021-08-24 | 2023-03-02 | Biomea Fusion, Inc. | Pyrazine compounds as irreversible inhibitors of flt3 |
US11945785B2 (en) | 2021-12-30 | 2024-04-02 | Biomea Fusion, Inc. | Pyrazine compounds as inhibitors of FLT3 |
WO2023225005A1 (en) | 2022-05-17 | 2023-11-23 | Biomea Fusion, Inc. | Flt3 combination therapy for cancer and compositions therefor |
KR102440707B1 (ko) | 2022-07-10 | 2022-09-05 | 이우미 | 공장 추천 시스템 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009023978A1 (en) * | 2007-08-17 | 2009-02-26 | Oncalis Ag | Pyrazolo [3,4 -d] pyrimidine compounds and their use as modulators of protein kinase |
JP2011510990A (ja) * | 2008-02-01 | 2011-04-07 | アイアールエム・リミテッド・ライアビリティ・カンパニー | キナーゼ阻害剤としての化合物および組成物 |
WO2011053861A1 (en) * | 2009-10-29 | 2011-05-05 | Genosco | Kinase inhibitors |
JP2012500204A (ja) * | 2008-08-12 | 2012-01-05 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | 化学化合物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR0017075A (pt) * | 2000-01-27 | 2002-11-05 | Warner Lambert Co | Derivados de piridopirimidinona para tratamento de doença neurodegenerativa |
BR0113628A (pt) * | 2000-08-31 | 2003-07-01 | Hoffmann La Roche | 7-oxo-piridopirimidinas como inibidores de uma proliferação celular |
JP4146721B2 (ja) * | 2000-08-31 | 2008-09-10 | エフ.ホフマン−ラ ロシュ アーゲー | 7−オキソ−ピリドピリミジン類 |
US8338481B2 (en) * | 2009-01-28 | 2012-12-25 | Ramot At Tel-Aviv University Ltd. | Alkoxyalkyl S-prenylthiosalicylates for treatment of cancer |
MX2012001974A (es) * | 2009-08-19 | 2012-04-11 | Ambit Biosciences Corp | Compuestos de biarilo y metodos de uso de los mismos. |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009023978A1 (en) * | 2007-08-17 | 2009-02-26 | Oncalis Ag | Pyrazolo [3,4 -d] pyrimidine compounds and their use as modulators of protein kinase |
JP2011510990A (ja) * | 2008-02-01 | 2011-04-07 | アイアールエム・リミテッド・ライアビリティ・カンパニー | キナーゼ阻害剤としての化合物および組成物 |
JP2012500204A (ja) * | 2008-08-12 | 2012-01-05 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | 化学化合物 |
WO2011053861A1 (en) * | 2009-10-29 | 2011-05-05 | Genosco | Kinase inhibitors |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021528383A (ja) * | 2018-06-27 | 2021-10-21 | オスコテック インコーポレイテッド | Axl阻害剤として使用するためのピリドピリミジノン誘導体 |
JP7200453B2 (ja) | 2018-06-27 | 2023-01-10 | オスコテック インコーポレイテッド | Axl阻害剤として使用するためのピリドピリミジノン誘導体 |
JP2021535088A (ja) * | 2018-08-23 | 2021-12-16 | オスコテック インコーポレイテッド | 8−ブロモ−2−(1−メチルピペリジン−4−イルアミノ)−4−(4−フェノキシフェニルアミノ)ピリド[4,3−d]ピリミジン−5(6h)−オン塩酸塩の結晶多形及びその調製方法 |
JP2023071814A (ja) * | 2018-08-23 | 2023-05-23 | オスコテック インコーポレイテッド | 8-ブロモ-2-(1-メチルピペリジン-4-イルアミノ)-4-(4-フェノキシフェニルアミノ)ピリド[4,3-d]ピリミジン-5(6h)-オン塩酸塩の結晶多形及びその調製方法 |
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MX360912B (es) | 2018-11-22 |
KR20140144709A (ko) | 2014-12-19 |
NZ700283A (en) | 2016-08-26 |
MX2014011354A (es) | 2014-12-05 |
CA2868156A1 (en) | 2013-09-26 |
BR112014023460B1 (pt) | 2020-09-01 |
EP2828259A4 (en) | 2015-08-19 |
AU2013235344B2 (en) | 2017-03-16 |
AU2013235344A1 (en) | 2014-10-09 |
KR102011770B1 (ko) | 2019-08-19 |
CN104428298B (zh) | 2017-03-01 |
WO2013142382A1 (en) | 2013-09-26 |
CA2868156C (en) | 2020-07-28 |
US8877763B2 (en) | 2014-11-04 |
CN104428298A (zh) | 2015-03-18 |
EA201491747A1 (ru) | 2015-10-30 |
IL234802B (en) | 2018-10-31 |
EP2828259B1 (en) | 2018-08-08 |
MY184858A (en) | 2021-04-27 |
EP2828259A1 (en) | 2015-01-28 |
CL2014002505A1 (es) | 2015-10-02 |
US20130274274A1 (en) | 2013-10-17 |
JP6101341B2 (ja) | 2017-03-22 |
ES2694223T3 (es) | 2018-12-19 |
HK1208453A1 (en) | 2016-03-04 |
IN2014MN02082A (ja) | 2015-08-21 |
TR201816480T4 (tr) | 2018-11-21 |
EA031267B1 (ru) | 2018-12-28 |
PL2828259T3 (pl) | 2019-02-28 |
ZA201407588B (en) | 2015-11-25 |
SG11201405942RA (en) | 2014-10-30 |
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