JP6816106B2 - 6−ピリジル−1,3,5−トリアジン−2,4−ジオール及び6−ピリジル−1,3,5−トリアジン−2,4−ジアミンを調製する方法 - Google Patents
6−ピリジル−1,3,5−トリアジン−2,4−ジオール及び6−ピリジル−1,3,5−トリアジン−2,4−ジアミンを調製する方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 92
- MTSVIHVYYVZVLK-UHFFFAOYSA-N 6-pyridin-2-yl-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(C=2N=CC=CC=2)=N1 MTSVIHVYYVZVLK-UHFFFAOYSA-N 0.000 title 1
- UZEMPDYVCUWBGP-UHFFFAOYSA-N 6-pyridin-2-yl-1h-1,3,5-triazine-2,4-dione Chemical compound N1C(=O)NC(=O)N=C1C1=CC=CC=N1 UZEMPDYVCUWBGP-UHFFFAOYSA-N 0.000 title 1
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- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 18
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 18
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
IDH2(イソクエン酸脱水素酵素2(NADP+)、ミトコンドリア型)は、IDH、IDP、IDHM、IDPM、ICD−M、またはmNADP−IDHとしても知られている。この遺伝子によってコードされるタンパク質は、ミトコンドリアに見られるNADP(+)依存性イソクエン酸脱水素酵素である。これは、中間代謝及びエネルギー産生に関与する。このタンパク質は、ピルビン酸脱水素酵素複合体と密接に結合するか、または相互作用することもある。ヒトIDH2遺伝子は、452のアミノ酸のタンパク質をコードする。IDH2に関するヌクレオチド配列及びアミノ酸配列は、それぞれGenBank登録NM_002168.2及びNP_002159.2として見出すことができる。ヒトIDH2に関するヌクレオチド配列及びアミノ酸配列は、例えば、HuhらがEMBL/GenBank/DDBJデータベースに提出したもの(NOV−1992);及びThe MGC Project Team、Genome Res. 14:2121−2127(2004)にも記載されている。
イソクエン酸+NAD+(NADP+)→α−KG+CO2+NADH(NADPH)+H+。
環Aは任意に置換された5〜6員単環式アリールまたは単環式ヘテロアリールであり;
環Bは、任意に置換された5〜6員単環式アリールまたは単環式ヘテロアリールであり;
R1及びR3はそれぞれ、水素、C1〜C4アルキル、C1〜C4ハロアルキル、−O−C1〜C4アルキル、及びCNから独立して選択され、R1の任意のアルキル部分は、−OH、NH2、NH(C1〜C4アルキル)、またはN(C1〜C4アルキル)2により任意に置換され;
R2は、−(C1〜C6アルキル)、−(C2〜C6アルケニルもしくはアルキニル)、−(C1〜C6アルキレン)−N(R6)−(C1〜C6アルキレン)−O−(C1〜C6アルキル)、−(C1〜C6アルキレン)−N(R6)−(C0〜C6アルキレン)−Q、−(C1〜C6アルキレン)−N(R6)(R6)、−(C1〜C6アルキレン)−N(R6)−S(O)1〜2−(C1〜C6アルキル)、−(C1〜C6アルキレン)−N(R6)−S(O)1〜2−(C0〜C6アルキル)−Q、−(C1〜C6アルキレン)−S(O)1〜2−N(R6)(R6)、−(C1〜C4アルキレン)−S(O)1〜2−N(R6)−(C1〜C6アルキレン)−Q、−C(O)N(R6)−(C1〜C6アルキレン)−C(O)−(C0〜C6アルキレン)−O−(C1〜C6アルキル)、−C(O)N(R6)−(C1〜C6アルキレン)−C(O)−(C0〜C6アルキレン)−O−(C0〜C6アルキレン)−Q、−(C1〜C6アルキレン)−O−C(O)−(C1〜C6アルキル)、−(C1〜C6アルキレン)−O−C(O)−(C0〜C6アルキル)−Q、−(C1〜C6アルキレン)−O−(C1〜C6アルキル)、−(C1〜C6アルキレン)−O−(C1〜C6アルキレン)−Q、−(C0〜C6アルキレン)−C(O)−(C0〜C6アルキレン)−O−(C1〜C6アルキル)、−(C0〜C6アルキレン)−C(O)−(C0〜C6アルキレン)−O−(C1〜C6アルキレン)−Q、−(C1〜C6アルキレン)−O−C(O)−(C1〜C6アルキル)、−(C1〜C6アルキレン)−O−C(O)−(C0〜C6アルキレン)−Q、−(C0〜C6アルキレン)−C(O)N(R6)−(C1〜C6アルキル)、−(C0〜C6アルキレン)−C(O)N(R6)−(C0〜C6アルキレン)−Q、−(C1〜C6アルキレン)−N(R6)C(O)−(C1〜C6アルキル)、−(C1〜C6アルキレン)−N(R6)C(O)−(C0〜C6アルキレン)−Q、−(C0〜C6アルキレン)−S(O)0〜2−(C1〜C6アルキル)、−(C0〜C6アルキレン)−S(O)0〜2−(C0〜C6アルキレン)−Q、−(C1〜C6アルキレン)−N(R6)−C(O)−N(R6)−(C1〜C6アルキル)、−(C0〜C6アルキレン)−Q、−(C0〜C6アルキレン)−C(O)−(C1〜C6アルキル)、−(C0〜C6アルキレン)−C(O)−(C0〜C6アルキレン)−Qから選択され、
R2に存在する任意のアルキルまたはアルキレン部分は、1つ以上の−OH、−O(C1〜C4アルキル)またはハロにより任意に置換され;
R2に存在する任意の末端メチル部分は、−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、C(O)CF3、CN、またはCO2Hにより任意に置き換えられ;
各R6は、水素及びC1〜C6アルキルから独立して選択され;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され、そのいずれも任意に置換され;
R1及びR3は、任意にそれらが結合する炭素原子と一緒になって、C(=O)を形成し、
R1及びR2は、任意に一緒になって、置換カルボシクリル、任意に置換されたヘテロシクリルまたは任意に置換されたヘテロアリールを形成する。
Xは、脱離基、例えば、ハロゲン化物またはトリフルオロメタンスルホナートであり、例えば、Xはハロゲン化物であり、例えば、Xはクロロである。
酢酸イソプロピル(i−PrOAc)、酢酸エチル(EtOAc)及びメチルtert−ブチルエーテル(MTBE)から成る群から選択される溶媒中のメタンスルホン酸の第1の溶液を準備すること;
メチルエチルケトン(MEK)から選択される溶媒中の式(VIII)の化合物の第2の溶液を準備すること;及び
第1の溶液と第2の溶液を混合して、式(VIII)の化合物のメタンスルホン酸塩を得ること。ある実施形態において、式(VIII)の化合物のメタンスルホン酸塩は、スラリーである。
をベンジルトリエチルアンモニウムクロリド及びPOCl3と反応させて、化合物(IVb)
b)化合物(IVb)を2(トリフルオロメチル)ピリジン−4−アミンと反応させて、化合物(VIb)
ならびにc)化合物(VIb)を1−アミノ−2−メチルプロパン−2−オールと反応させて、式(VIIIa)の化合物を得ることを含む。ある実施形態において、ステップa)は、約90℃に約100℃に、または約95℃から約98℃に加熱することを含む。一実施形態において、ステップa)の加熱することは、約18時間行われる。ある実施形態において、ステップa)は、約18時間約95〜98℃に加熱することを含む。ある実施形態において、ステップb)は、約20℃で約3時間置き、その後、約15.5時間約60〜65℃に加熱することを含む。ある実施形態において、ステップb)は、メチルテトラヒドロフラン中で行われる。ある実施形態において、ステップc)は、約20〜30℃で行われる。ある実施形態において、ステップc)は、ジイソプロピルエチルアミンの存在下において行われる。ある実施形態において、化合物(Ia)は、化合物(IIa)
本明細書に記載される方法によって調製される化合物は、対象へ投与される前に薬学的に許容される担体またはアジュバントとともに薬学的に許容される組成物に製剤化されてもよい。別の実施形態において、そのような薬学的に許容される組成物は、付加的な治療薬を、本明細書に記載されているものを含む疾患または疾患症状の調節を達成するのに有効な量でさらに含む。
本明細書に記載される方法によって調製される化合物の阻害活性は、米国特許出願第13/735,467号、公開第US/2013/0190287号、及び国際出願第PCT/US2014/049469号に記載されている方法によってIDH2変異体(例えば、IDH2 R140Q及びIDH2 R172K)に対して試験することができ、これらの文献のそれぞれは参照によってその全体を本明細書に援用する。
一部の実施形態において、本明細書に記載される方法によって調製される化合物は、それを必要とする対象に第2の療法、例えば、追加の癌治療薬または追加の癌処置と同時に投与されてもよい。
式VIIIaの化合物の調製
6−(6−(トリフルオロメチル)ピリジン−2−イル)−1,3,5−トリアジン−2,4(1H,3H)−ジオンの調製
脱水剤としてTi(OEt)4を用いた6−(6−(トリフルオロメチル)ピリジン−2−イル)−1,3,5−トリアジン−2,4(1H,3H)−ジオンの調製
脱水剤としてHC(OMe)3及びTFAを用いた6−(6−(トリフルオロメチル)ピリジン−2−イル)−1,3,5−トリアジン−2,4(1H,3H)−ジオンの調製
2−メチル−1−((4−(6−(トリフルオロメチル)ピリジン−2−イル)−6−((2−(トリフルオロメチル)ピリジン−4−イル)アミノ)−1,3,5−トリアジン−2−イル)アミノ)プロパン−2−オール(VIIIa)の調製
窒素下でガラス反応器(2L)に化合物10(0.030kg、0.146mol、1当量)、エタノール(0.360kg、12当量)及びビウレット(0.018kg、0.175mol、1.2当量)を入れた。その反応混合物を30〜35℃に加熱し、10〜20分間撹拌した。Ti(OEt)4を(0.0168kg、0.56当量)を入れた。その反応混合物を30〜35℃に加熱し、30〜60分間撹拌した。EtOH中の19%のNaOEt溶液(0.2625kg、8.75当量)を2時間かけて入れた。その反応混合物を2時間かけて55〜65℃に加熱し、2〜4時間撹拌した。その反応混合物を真空下で(IT<60℃)0.2Lにまで濃縮した。その反応混合物を20〜30℃に冷ました。水(0.450kg、15当量)、HClの35%水溶液(0.135kg、4.5当量)、及びDCM(0.200kg、6.67当量)。粗生成物を20〜30℃で5〜6時間置き、その後、ろ過した。粗生成物を水(0.5〜1当量)で洗浄した。粗生成物を水(0.450kg、15当量)、NaOH(0.0215kg、0.712当量)に入れ、20〜30℃で2〜4時間撹拌した。粗生成物をセライト(0.009kg、0.3当量)を通してろ過し、水(0.040kg、1.333当量)で洗浄した。ろ過した生成物を、20〜30℃でHClの35%溶液(0.060kg、2当量)及び水(0.225kg、7.5当量)に少なくとも3時間かけて滴加した。その生成物を20〜30℃に加熱し、1〜2時間撹拌した。その生成物をろ過し、水(6当量)で洗浄し、真空下50〜70℃において20〜40時間乾燥した。単離収率:25.3gの化合物11(67%);HPLC純度100.0%a/a
窒素下でガラス反応器(15L)に化合物11(0.892kg、3.46mol、1当量)、BTEAC(1.970kg、8.65mol、2.5当量)、及びPOCl3(2.150kg、14.0mol、4.1当量)を入れた。その反応混合物を95〜98℃に18時間、反応が完了するまで加熱した。その反応混合物を真空下(IT 82〜90℃)で3.5Lにまで濃縮した後、EtOAc(8.5kg)で希釈した。そのバッチを減圧下において4Lにまで濃縮した後、EtOAc(2.0kg)で再び希釈した。2回のさらなるサイクル(希釈に続く濃縮)を実施した。最後に、2つの液相混合物が生じたとき、残留物をEtOAc(11.2kg)で希釈した。BTEAC、いくらかのPOCl3及び化合物12(120g、バッチの9%)を含む下層を分離し、廃棄した。
窒素下でガラス反応器(15L)に化合物12(774g、2.62mol、1当量)及びMeTHF(3.300kg)を入れた。得られた混合物を10分間撹拌した後、2−(トリフルオロメチル)ピリジン−4−アミン(875g、5.40mol、2.1当量)を一度にその反応器に入れた。その反応混合物を20℃で3時間置いた後、60〜65℃に15.5時間、反応が完了するまで加熱した。2−(トリフルオロメチル)ピリジン−4−アミンの塩酸塩をろ過除去し、Me−THF(2×1.060kg)で洗浄した。合わせたMe−THF溶液(ろ液+洗浄液)を0.5NのHCl(2×2L)で洗浄した。そのバッチをヘプタン(1.35kg)で希釈し、得られた黄色の溶液を水(2×2.1L)で洗浄した。最後に、有機層をブライン(0.6kg)で洗浄し、蒸留により脱水した。Me−THF/ヘプタン混合物をヘプタン(2.2kg)で31〜35℃において処理した。追加のヘプタン(3.69kg)を入れ、その混合物を真空下で7.4Lにまで濃縮した。その混合物をヘプタン(2.13kg)で希釈し、真空下で7.4Lにまで濃縮した後、ヘプタン(2.13kg)で希釈した。そのバッチを20〜22℃で2時間置いた。最後に、その生成物をろ過により単離し、ヘプタン(2×1.1L)で洗浄し、35℃で22時間乾燥した。単離収量:1.068kgの14(97%)、淡黄色の粉末として。HPLC純度98.5%a/a。
窒素パージした15Lのガラス反応器に化合物14(1.038kg、2.47mol、1当量)を入れた後、Me−THF(6.176kg)及びDIEA(0.384kg、2.97mol、1.2当量)を入れた。得られた混合物を室温で撹拌した後、20〜30℃に維持しながら、Me−THF(2.647kg)中の1−アミノ−2−メチルプロパン−2−オール(0.265kg、2.97mol、1.2当量)をゆっくりと入れた。反応の完了後、水(2.6L)及びn−ヘプタン(2.076kg)を添加した。その混合物を20分間撹拌し、水層を除去し、水(2.6L)を添加し、0.1NのHClを使用して水相のpHを7に調節した。水層を除去し、有機層を水(2×2.6L)、4%NaHCO3(1.1L)、及び水(1.15L)で洗浄した。有機層を真空下で3.4Lにまで濃縮した。Me−THF(4.950kg)を添加し、その混合物を3.4Lまで濃縮した。残留物をMe−THF(4.931kg)で希釈した。その溶液を1.2μインラインフィルターを通して浄化した。浄化した溶液を2.6Lにまで濃縮した。残留物を45℃に加熱した後、45℃に維持しながら、n−ヘプタン(2.599kg)をゆっくりと添加した。そのバッチに2−メチル−1−((4−(6−(トリフルオロメチル)ピリジン−2−イル)−6−((2−(トリフルオロメチル)ピリジン−4−イル)アミノ)−1,3,5−トリアジン−2−イル)アミノ)プロパン−2−オール(10g)を入れた。45℃に維持しながらn−ヘプタン(2.599kg)をゆっくりと添加した。1時間後、そのバッチを20℃まで冷ました。その混合物を20Cで1時間撹拌した。そのバッチをろ過した。その固体をn−ヘプタン(2×1L)で洗浄した後、オーブン中において35℃で20時間真空乾燥した。単離収量:1.124kgの2−メチル−1−((4−(6−(トリフルオロメチル)ピリジン−2−イル)−6−((2−(トリフルオロメチル)ピリジン−4−イル)アミノ)−1,3,5−トリアジン−2−イル)アミノ)プロパン−2−オール(96%)、淡黄色の粉末として。
本件出願は、以下の構成の発明を提供する。
(構成1)
環Aが任意に置換された5〜6員単環式アリールまたは単環式ヘテロアリールである式(I):
(化1)
を有する化合物を調製する方法であって、前記方法は、Rがアルキル、アルケニルまたはアルキニルである式(II):
(化2)
の化合物を、脱水剤の存在下において
(化3)
(ビウレット)と反応させることを含む、前記方法。
(構成2)
式(Ia):
(化4)
の化合物を調製する方法であって、前記方法は、式(IIa):
(化5)
の化合物を、脱水試薬の存在下において
(化6)
(ビウレット)と反応させて、前記式(Ia)の化合物を得ることを含む、前記方法。
(構成3)
前記脱水試薬は、オルトギ酸トリメチル(HC(OMe) 3 )及び触媒量のトリフルオロ酢酸(TFA)を含む、構成2に記載の方法。
(構成4)
前記脱水試薬は、チタン(IV)エトキシドを含む、構成2に記載の方法。
(構成5)
前記反応は、塩基の存在下におけるものである、構成2に記載の方法。
(構成6)
前記塩基は、ナトリウムエトキシドである、構成5に記載の方法。
(構成7)
前記式(II)の化合物は、式(III)
(化7)
の化合物を酸ハロゲン化物及びアルコールと反応させることによって調製される、構成1に記載の方法。
(構成8)
前記式(IIa)化合物は、式(IIIa):
(化8)
の化合物を塩化水素及びメタノールと反応させることによって調製される、構成2に記載の方法。
(構成9)
前記式(I)の化合物をハロゲン化して、Xがハロゲンである式(IV)
(化9)
の化合物を得ることをさらに含む、構成1または7のいずれか1項に記載の方法。
(構成10)
前記式(Ia)の化合物をベンジルトリエチルアンモニウムクロリド及びPOCl 3 と反応させて、式(IVb)
(化10)
の化合物を得ることをさらに含む、構成2〜6または8のいずれか1項に記載の方法。
(構成11)
式(IV)の化合物を、環Bが任意に置換された5〜6員単環式アリールまたは単環式ヘテロアリールである式(V)
(化11)
の化合物と反応させて、式(VI)
(化12)
の化合物を得ることをさらに含む、構成9に記載の方法。
(構成12)
前記式(IVb)の化合物を式(Va)
(化13)
の化合物と反応させて、式(VIa)
(化14)
の化合物を得ることをさらに含む、構成10に記載の方法。
(構成13)
式(VI)の化合物を式(VII)
(化15)
の化合物と反応させて、式(VIII)
(化16)
の化合物を得ることをさらに含む、構成11に記載の方法。
(構成14)
式(VIa)の化合物を式(VIIa)
(化17)
の化合物と反応させて式(VIIIa)
(化18)
の化合物を得ることをさらに含む、構成12に記載の方法。
(構成15)
式(VIIIa)
(化19)
の化合物を調製する方法であって、前記方法は、
a)化合物(Ia)
(化20)
をベンジルトリエチルアンモニウムクロリド及びPOCl 3 と反応させて化合物(IVb)
(化21)
を得ること、
b)化合物(IVb)を2−(トリフルオロメチル)ピリジン−4−アミンと反応させて、化合物(VIb)
(化22)
を得ること
ならびに
c)化合物(VIb)を1−アミノ−2−メチルプロパン−2−オールと反応させて、前記式(VIIIa)の化合物を得ることを含む、前記方法。
(構成16)
ステップa)は、約18時間約95〜98℃に加熱することを含む、構成15に記載の方法。
(構成17)
ステップb)は、約20℃で約3時間置いた後、約15.5時間約60〜65℃に加熱することを含む、構成15に記載の方法。
(構成18)
ステップb)は、メチルテトラヒドロフラン中で行われる、構成15に記載の方法。
(構成19)
ステップc)は、約20〜30℃で行われる、構成15に記載の方法。
(構成20)
ステップc)は、ジイソプロピルエチルアミンの存在下において行われる、構成15に記載の方法。
(構成21)
化合物(Ia)は、
(化23)
を、脱水試薬の存在下において
(化24)
と反応させることによって調製される、構成15に記載の方法。
(構成22)
前記脱水剤は、オルトギ酸トリメチル及びトリフルオロ酢酸を含む、構成21に記載の方法。
(構成23)
前記脱水剤は、チタン(IV)エトキシドを含む、構成21に記載の方法。
(構成24)
前記反応は、塩基の存在下において行われる、構成21に記載の方法。
(構成25)
前記塩基は、ナトリウムエトキシドである、構成21に記載の方法。
Claims (19)
- 前記脱水剤は、オルトギ酸トリメチル(HC(OMe)3)及びトリフルオロ酢酸(TFA)を含む、請求項1に記載の方法。
- 前記脱水剤は、チタン(IV)エトキシドを含む、請求項1に記載の方法。
- 前記反応は、塩基の存在下におけるものである、請求項1に記載の方法。
- 前記塩基は、ナトリウムエトキシドである、請求項4に記載の方法。
- 式(VIIIa)
a)化合物(Ia)
b)化合物(IVb)を2−(トリフルオロメチル)ピリジン−4−アミンと反応させて、化合物(VIb)
ならびに
c)化合物(VIb)を1−アミノ−2−メチルプロパン−2−オールと反応させて、前記式(VIIIa)の化合物を得ることを含み、化合物(Ia)は、
- ステップa)は、約18時間約95〜98℃に加熱することを含む、請求項10に記載の方法。
- ステップb)は、約20℃で約3時間置いた後、約15.5時間約60〜65℃に加熱することを含む、請求項10に記載の方法。
- ステップb)は、メチルテトラヒドロフラン中で行われる、請求項10に記載の方法。
- ステップc)は、約20〜30℃で行われる、請求項10に記載の方法。
- ステップc)は、ジイソプロピルエチルアミンの存在下において行われる、請求項10に記載の方法。
- 前記脱水剤は、オルトギ酸トリメチル及びトリフルオロ酢酸を含む、請求項10に記載の方法。
- 前記脱水剤は、チタン(IV)エトキシドを含む、請求項10に記載の方法。
- 前記反応は、塩基の存在下において行われる、請求項10に記載の方法。
- 前記塩基は、ナトリウムエトキシドである、請求項10に記載の方法。
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US201562201546P | 2015-08-05 | 2015-08-05 | |
US62/201,546 | 2015-08-05 | ||
PCT/US2016/045553 WO2017024134A1 (en) | 2015-08-05 | 2016-08-04 | Methods of preparing 6-(aryl or heteroaryl)-1,3,5-triazine-2,4-diols and 6-(aryl or heteroaryl)-1,3,5-triazine-2,4-diamines |
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JP2020213670A Pending JP2021063097A (ja) | 2015-08-05 | 2020-12-23 | 6−(アリールまたはヘテロアリール)−1,3,5−トリアジン−2,4−ジオール及び6−(アリールまたはヘテロアリール)−1,3,5−トリアジン−2,4−ジアミンを調製する方法 |
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US (1) | US9751863B2 (ja) |
EP (1) | EP3331866B1 (ja) |
JP (2) | JP6816106B2 (ja) |
CN (1) | CN108349933A (ja) |
AU (2) | AU2016303614A1 (ja) |
CA (1) | CA2993615A1 (ja) |
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JP2021063097A (ja) * | 2015-08-05 | 2021-04-22 | アジオス ファーマシューティカルズ, インコーポレイテッド | 6−(アリールまたはヘテロアリール)−1,3,5−トリアジン−2,4−ジオール及び6−(アリールまたはヘテロアリール)−1,3,5−トリアジン−2,4−ジアミンを調製する方法 |
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KR20180063125A (ko) | 2015-10-15 | 2018-06-11 | 아지오스 파마슈티컬스 아이엔씨. | 악성종양을 치료하기 위한 복합 요법 |
JP6895956B2 (ja) | 2015-10-15 | 2021-06-30 | セルジーン コーポレイション | 悪性腫瘍を治療するための併用療法 |
JP6892448B2 (ja) | 2015-12-04 | 2021-06-23 | アジオス ファーマシューティカルズ, インコーポレイテッド | 悪性腫瘍の処置の方法 |
JP6856657B2 (ja) | 2016-02-26 | 2021-04-07 | アジオス ファーマシューティカルズ, インコーポレイテッド | 血液学的悪性疾患および固形腫瘍の処置のためのidh1阻害剤 |
WO2018048847A1 (en) | 2016-09-07 | 2018-03-15 | Celgene Corporation | Tablet compositions |
WO2018204787A1 (en) | 2017-05-05 | 2018-11-08 | Memorial Sloan Kettering Cancer Center | Methods of treatment of myeloproliferative neoplasm |
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US20220017490A1 (en) | 2018-11-02 | 2022-01-20 | Celgene Corporation | Co-crystals of 2-methyl-1 -[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl) pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol, compositions and methods of use thereof |
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JP2021063097A (ja) * | 2015-08-05 | 2021-04-22 | アジオス ファーマシューティカルズ, インコーポレイテッド | 6−(アリールまたはヘテロアリール)−1,3,5−トリアジン−2,4−ジオール及び6−(アリールまたはヘテロアリール)−1,3,5−トリアジン−2,4−ジアミンを調製する方法 |
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EP3331866A1 (en) | 2018-06-13 |
CA2993615A1 (en) | 2017-02-09 |
MX2018001424A (es) | 2018-08-01 |
JP2021063097A (ja) | 2021-04-22 |
US20170037031A1 (en) | 2017-02-09 |
MX365590B (es) | 2019-06-07 |
AU2016303614A1 (en) | 2018-02-15 |
US9751863B2 (en) | 2017-09-05 |
EP3331866B1 (en) | 2023-07-26 |
AU2021200494A1 (en) | 2021-03-11 |
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