JP2017531688A - ブロモドメイン阻害剤 - Google Patents
ブロモドメイン阻害剤 Download PDFInfo
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- JP2017531688A JP2017531688A JP2017522518A JP2017522518A JP2017531688A JP 2017531688 A JP2017531688 A JP 2017531688A JP 2017522518 A JP2017522518 A JP 2017522518A JP 2017522518 A JP2017522518 A JP 2017522518A JP 2017531688 A JP2017531688 A JP 2017531688A
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- alkyl
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- cycloalkyl
- heterocycloalkyl
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Abstract
Description
Aは、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され、ここで部分Aは、1〜4つのR2基により任意選択で置換されており;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R2は、それぞれ現れるとき独立して、(C1〜C6)アルキル、(C2〜C6)アルケニル、ハロ(C1〜C6)アルコキシ、ハロ(C1〜C6)アルキル、ヒドロキシ(C1〜C6)アルキル、(C1〜C6)アルコキシ(C1〜C6)アルキル、(C3〜C12)シクロアルキル、−(C1〜C6)アルキレン−(C3〜C12)シクロアルキル、(C3〜C12)ヘテロシクロアルキル、−(C1〜C6)アルキレン−(C3〜C12)ヘテロシクロアルキル、(C1〜C6)アルコキシ、−C(O)(C1〜C6アルキル)、−C(O)O(C1〜C6アルキル)、−OC(O)(C1〜C6アルキル)、−C(O)NR7R8、−NR9C(=O)R10、−NR11R12、ハロゲン、オキソ、または−OHであり;
R3、R4、R5、R6、R7、R8、R9、R10、R11及びR12は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
各m、n及びpは、独立して、0、1、2、3、または4である。
「アルキル」は、特定の数の炭素原子を有する、任意選択で置換されている飽和脂肪族分岐鎖または直鎖一価炭化水素ラジカルを意味する。したがって、「(C1〜C6)アルキル」は、直鎖または分岐鎖の配置で1〜6個の炭素原子を有するラジカルを意味する。「(C1〜C6)アルキル」には、メチル、エチル、プロピル、イソ−プロピル(またはi−プロピル)、ブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシルなどが含まれる。用語「アルキル」、「アルコキシ」、「ヒドロキシアルキル」、「ハロアルキル」、「アラルキル」、「アルコキシアルキル」、「アルキルアミン」、「ジアルキルアミン」、「アルキルアミノ」、「ジアルキルアミノ」、「アルコキシカルボニル」などは、単独で、または大きな部分の一部として使用され、1〜12個の炭素原子を含有する直鎖状及び分岐鎖状飽和鎖の両方が含まれる。
本発明は、式(I〜III)により表される化合物またはその薬学的に許容される塩である。式(I〜III)、またはその鏡像異性体、ジアステレオマー、もしくは薬学的に許容される塩における及び本明細書に記載されているそれぞれの実施形態における変数の値及び代替値が、以下の段落に提示される。本発明は、本明細書に定義されている置換値(すなわち、R1、R2、R20など)の全ての組み合わせを包含することが理解される。
Aは、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され、ここで部分Aは、1〜4つのR2基により任意選択で置換されており;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R2は、それぞれ現れるとき独立して、(C1〜C6)アルキル、(C2〜C6)アルケニル、ハロ(C1〜C6)アルコキシ、ハロ(C1〜C6)アルキル、ヒドロキシ(C1〜C6)アルキル、(C1〜C6)アルコキシ(C1〜C6)アルキル、(C3〜C12)シクロアルキル、−(C1〜C6)アルキレン−(C3〜C12)シクロアルキル、(C3〜C12)ヘテロシクロアルキル、−(C1〜C6)アルキレン−(C3〜C12)ヘテロシクロアルキル、(C1〜C6)アルコキシ、−C(O)(C1〜C6アルキル)、−C(O)O(C1〜C6アルキル)、−OC(O)(C1〜C6アルキル)、−C(O)NR7R8、−NR9C(=O)R10、−NR11R12、ハロゲン、オキソ、または−OHであり;
R3、R4、R5、R6、R7、R8、R9、R10、R11及びR12は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
各m、n及びpは、独立して、0、1、2、3、または4である。
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R3、R4、R5及びR6は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R30は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
各m、n及びpは、独立して、0、1、2、3、または4である。
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R3、R4、R5及びR6は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R40は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
各q、m、n及びpは、独立して、0、1、2、3、または4である。
本発明に使用される組成物には、眼内用、経口用、経鼻用、経皮用、閉塞を伴う、または伴わない局所用、静脈内(ボーラスと注入の両方)、吸入用及び注射用(腹腔内、皮下、筋肉内、腫瘍内、または非経口)製剤が含まれる。特定の実施形態において、組成物は、静脈内または経口投与用である。組成物は、眼内、経口、鼻腔内、舌下、非経口、もしくは直腸内投与用の、または吸入もしくは吹送用の、錠剤、丸剤、カプセル剤、粉末剤、顆粒剤、リポソーム、イオン交換樹脂、滅菌眼球液剤もしくは眼球送達装置(例えば、即時放出、時限放出、もしくは持続放出を促進するコンタクトレンズなど)、非経口液剤もしくは懸濁剤、定量エアゾールもしくは液体噴霧剤、滴下剤、アンプル剤、自動注入装置、または坐剤などの投与単位であってもよい。
特定の実施形態において、本発明の方法は、本発明の化合物またはその薬学的に許容される塩を単独で、または1つ以上の治療剤と組み合わせて使用して、BETファミリーポリペプチドの調節に応答する障害を治療することも含む。1つ以上の治療剤は、例えば、BETファミリーポリペプチドの調節に応答しうる本明細書に記載されている障害のいずれかを治療することができる任意の作用物質でありうる。BETファミリーポリペプチドの調節に応答する障害を治療し、かつ本発明の化合物と組み合わせて使用することに適している当該技術に既知の治療剤の例には、ダウノルビシン、Ara−C、ポマリドミド、レナリドミド、ベルケイド、デキサメタゾン、リツキシマブ、フルベストラント、イブルチニブ及びポナチニブが含まれるが、これらに限定されない。
以下の略語が明細書全体にわたって使用される。
Ac アセチル
AcOH 酢酸
AIBN 2,2’−アゾビス(2−メチルプロピオニトリル)
aq 水性
Asp アスパラギン酸
BET ブロモドメイン及び末端外ドメイン
BRDT ブロモドメイン精巣特異的タンパク質
BRD2 ブロモドメイン含有タンパク質2
BRD3 ブロモドメイン含有タンパク質3
BRD4 ブロモドメイン含有タンパク質4
Bn ベンジル
Boc tert−ブトキシカルボニル
BOP (ベンゾトリアゾール−1−イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェート
BSA ウシ血清アルブミン
Bu ブチル
DIPEA N,N−ジイソプロピルエチルアミン
DMEM ダルベッコー修飾イーグル培地
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDC N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド
ESI エレクトロスプレーイオン化
Et エチル
EtOAc 酢酸エチル
EtOH エタノール
Fmoc フルオレニルメチルオキシカルボニル
HCTU (2−(6−クロロ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルアミニウムヘキサフルオロホスフェート
His ヒスチジン
HPLC 高速液体クロマトグラフィー
HRMS 高分解能質量分析
i イソ
IC50 最大半量増殖阻害濃度
i−Pr2NEt N,N−ジイソプロピルエチルアミン
K2EDTA エチレンジアミン四酢酸二カリウム
KOt−Bu カリウムtert−ブトキシド
MTBE メチルtert−ブチルエーテル
MEG モノエチレングリコール
MeOH メタノール
Me メチル
MgSO4 硫酸マグネシウム
MS 質量分析
MW 分子量
Na2EDTA エチレンジアミン四酢酸二ナトリウム
NMR 核磁気共鳴分析
Papp 見掛透過率
PBS リン酸緩衝食塩水
Ph フェニル
PEG ポリエチレングリコール
PO(OEt)2Cl クロロリン酸ジエチル
Pr プロピル
p−TSA パラトルエンスルホン酸
PyBOP (ベンゾトリアゾール−1−イルオキシル)トリピロリジノホスホニウム
RT 逆転写
s 二次
S 硫黄
t 第三級
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
本発明の化合物を、本明細書に記載されている方法により、及び/または本明細書の記載を考慮しながら当業者に既知の方法に従って合成することができる。
プロトン及び炭素13核磁気共鳴(1H NMR及び13C NMR)スペクトルを、Varianインバースプローブ600 INOVA分光計により記録した。化学シフトは、百万分の一のδスケールで記録され、NMR溶媒中の残留プロチウム、1H NMRにより(CHCl3:δ7.24)及び溶媒の炭素共鳴、13C NMRにより(CDCl3:δ77.2)がそれぞれ参照される。データは以下のように報告される。化学シフト多重度(s=一重項、d=二重項、t=三重項、q=四重項、m=多重項、br=広帯域)及び結合定数(複数可)ヘルツ、積分。高分解能質量スペクトル(HRMS)を、エレクトロスプレーイオン源(ESI)を使用してBruker APEX 4.7 Tesler FTMS分光計により記録した。中間体及び最終生成物をCombiFlash RFシステム(Teledyne Isco)により精製した。有機溶媒を、Buechi R−205ロータリーエバポレーターにより濃縮した。鏡像異性体の純度を、Berger Supercritical Fluid Chromatography(SFC)及びAS−Hカラムにより検査した。鏡像異性体予備精製は、Agilent High Pressure Liquid Chromatography及びOD−Hカラムによって実施した。
S8から出発して、所望のエステルを下記の一般スキーム1に示されているように調製することができる。
実施例3:ラットのインスリノーマ細胞アッセイ
Cell Titer−Gloアッセイを利用して、4つのラットインスリノーマ(RIN)細胞株のRIN−14B、RIN−m5F、RIN−m及びRIN−5の、化合物1及び化合物2に対する感受性を検査した。
全ての細胞株は、40nM未満のIC50値で化合物1及び80nM未満のIC50値で化合物2に感受性があった。これらの結果は、BETブロモドメイン阻害剤が、インスリノーマ細胞株の繁殖を減少するのに極めて有効であることを示している。結果を下記の表Bに示す。
BROMOscan結合アッセイを利用して、BRD4の第1及び第2のブロモドメイン(BRD4(1)及びBRD4(2))それぞれに対する(S)−化合物1、2、3、4、5及び7のインビトロ結合活性を検査した。(S)−JQ1(S8)を陽性対照として使用した。
(S)−JQ1及び化合物1、2、3、4、5及び7は、BRD4(1)及びBRD4(2)の両方によるBROMOscanスクリーン結合アッセイにおいて、低いKd値を生じた。これらの結果は、全ての化合物が、BRD4(1)及びBRD4(2)の両方に対して優れたインビトロ結合活性を示し、Kd値が、既知のブロモドメイン阻害剤である(S)−JQ1に匹敵する、または(S)−JQ1より良好であることを示している。
Caco−2アッセイを利用して、化合物1〜7の腸管輸送を達成し、吸収率及び経口生物学的利用能を予測した。(S)−JQ1(S8)を陽性対照として使用した。ラニチジン、ワルファリンを対照化合物として使用した。
表Dの結果は、化合物1〜7がインビトロにおいて優れた細胞透過性を有し、強く予測された経口生物学的利用能を有することを示している。
化合物1〜2及び4〜5が良好な経口生物学的利用能を有するかを確立するため、化合物1〜2及び4〜5の薬物動態特性を、雄Sprague−Dawleyラットへの化合物の静脈内(IV)及び経口(PO)投与を介して得た。
結果は、化合物1、2、4及び5の暴露がIV投与後に検出されること、ならびに化合物1、2及び4がF>23%の経口生物学的利用能を有することを実証している。
Claims (36)
- 構造式I:
Aは、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され、ここで部分Aは、1〜4つのR2基により任意選択で置換されており;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R2は、それぞれ現れるとき独立して、(C1〜C6)アルキル、(C2〜C6)アルケニル、ハロ(C1〜C6)アルコキシ、ハロ(C1〜C6)アルキル、ヒドロキシ(C1〜C6)アルキル、(C1〜C6)アルコキシ(C1〜C6)アルキル、(C3〜C12)シクロアルキル、−(C1〜C6)アルキレン−(C3〜C12)シクロアルキル、(C3〜C12)ヘテロシクロアルキル、−(C1〜C6)アルキレン−(C3〜C12)ヘテロシクロアルキル、(C1〜C6)アルコキシ、−C(O)(C1〜C6アルキル)、−C(O)O(C1〜C6アルキル)、−OC(O)(C1〜C6アルキル)、−C(O)NR7R8、−NR9C(=O)R10、−NR11R12、ハロゲン、オキソ、または−OHであり;
R3、R4、R5、R6、R7、R8、R9、R10、R11及びR12は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
各m、n及びpは、独立して、0、1、2、3、または4である]。 - Aが、(C1〜C6)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルである、請求項1に記載の化合物。
- Aが、エチルまたはシクロヘキシルである、請求項1または2に記載の化合物。
- R2が、それぞれ現れるとき独立して、−OHまたは(C1〜C6)アルキルである、請求項1〜3のいずれか一項に記載の化合物。
- R2が、それぞれ現れるとき独立して、−OHまたはメチルである、請求項1〜4のいずれか一項に記載の化合物。
- R1が、−F、−Cl、−Br、または−Iである、請求項1〜5のいずれか一項に記載の化合物。
- R20が、それぞれ現れるとき独立して、Hまたは(C1〜C3)アルキルである、請求項1〜6のいずれか一項に記載の化合物。
- pが0である、請求項1〜7のいずれか一項に記載の化合物。
- mが1である、請求項1〜8のいずれか一項に記載の化合物。
- nが1である、請求項1〜9のいずれか一項に記載の化合物。
- 構造式II:
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R3、R4、R5及びR6は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R30は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
各m、n及びpは、独立して、0、1、2、3、または4である]。 - R1が、−F、−Cl、−Br及び−Iからなる群から選択される、請求項11に記載の化合物。
- R20が、それぞれ現れるとき独立して、Hまたは(C1〜C3)アルキルである、請求項11または12に記載の化合物。
- R30が、それぞれ現れるとき独立して、Hまたは(C1〜C3)アルキルである、請求項11〜13のいずれか一項に記載の化合物。
- pが1である、請求項11〜14のいずれか一項に記載の化合物。
- mが1である、請求項11〜15のいずれか一項に記載の化合物。
- nが1である、請求項11〜16のいずれか一項に記載の化合物。
- 構造式III:
R1は、それぞれ現れるとき独立して、−OH、ハロゲン、−CN、(C1〜C4)アルコキシ、−C(O)(C1〜C4)アルキル、−C(O)O(C1〜C4)アルキル、−OC(O)(C1〜C4アルキル)、−C(O)NR3R4、−NR5C(=O)R6、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C3〜C12)シクロアルキル及び(C5〜C7)ヘテロシクロアルキルからなる群から選択され;
R3、R4、R5及びR6は、それぞれ独立して、Hまたは(C1〜C4)アルキルであり;
R20は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
R40は、それぞれ現れるとき独立して、−H、−OH、(C1〜C3)アルキル、(C3〜C12)シクロアルキル、または(C5〜C7)ヘテロシクロアルキルであり;
各q、m、n及びpは、独立して、0、1、2、3、または4である]。 - R1が、−F、−Cl、−Br及、またはIからなる群から選択される、請求項18に記載の化合物。
- R20が、それぞれ現れるとき独立して、Hまたは(C1〜C3)アルキルである、請求項18または19に記載の化合物。
- R40が、それぞれ現れるとき独立して、−OHまたは(C1〜C3)アルキルである、請求項18〜20のいずれか一項に記載の化合物。
- pが0である、請求項18〜21のいずれか一項に記載の化合物。
- mが1である、請求項18〜22のいずれか一項に記載の化合物。
- nが1である、請求項18〜23のいずれか一項に記載の化合物。
- 薬学的に許容される担体または希釈剤と、治療有効量の請求項1〜26のいずれか一項に記載の化合物とを含む、薬学的組成物。
- BETファミリーポリペプチドの調節に応答する障害を、その必要性のある対象において治療する方法であって、有効量の請求項1〜26のいずれか一項に記載の化合物を前記対象に投与することを含む、前記方法。
- 前記BETファミリーポリペプチドの調節に応答する障害が、新生物、炎症性疾患、代謝症候群、肥満症、脂肪肝、糖尿病、アテローム性動脈硬化症、動脈のステント梗塞、心不全、高インスリン血症に関連する状態、悪液質、移植片対宿主病、ブロモドメインに関連する感染性疾患、マラリア及びトリパノソーマ疾患から選択される、請求項28に記載の方法。
- 前記新生物が血液学的新生物である、請求項29に記載の方法。
- 前記血液学的新生物が、白血病、リンパ腫、または骨髄腫から選択される、請求項30に記載の方法。
- 前記白血病、リンパ腫、または骨髄腫が、急性骨髄性白血病(AML)、慢性リンパ性白血病(CLL)、急性リンパ性白血病(ALL)、慢性骨髄性白血病(CML)、慢性骨髄単球性白血病(CMML)、バーキット白血病、MLL誘導性白血病(MLL driven leukemia)、慢性リンパ性白血病、好酸球性白血病、毛様細胞白血病、ホジキンリンパ腫、多発性骨髄腫、非ホジキンリンパ腫から選択される、請求項31に記載の方法。
- 前記新生物が、肺癌、乳癌、結腸癌、前立腺癌、子宮頸癌、神経芽細胞腫、多形神経膠芽腫、髄芽細胞腫、悪性末梢神経鞘腫、黒色腫、NUT正中癌(NUT midline carcinoma)、扁平上皮癌、またはNUT再編成に関連する任意の他の癌腫から選択される、請求項29に記載の方法。
- 前記新生物がNUT正中癌である、請求項33に記載の方法。
- 前記高インスリン血症に関連する状態が、インスリノーマ、先天性高インスリン症、多嚢胞性卵巣症候群(PCOS)、ベックウィズ・ウィーデマン症候群及び胃バイパス術後の患者から選択される、請求項29に記載の方法。
- 対象において男性の妊孕性を低減する方法であって、有効量の請求項1〜26のいずれか一項に記載の化合物を前記対象に投与することを含む、前記方法。
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CR20170219A (es) | 2017-08-14 |
JP6715243B2 (ja) | 2020-07-01 |
IL251784A0 (en) | 2017-06-29 |
UA122130C2 (uk) | 2020-09-25 |
US20170333444A1 (en) | 2017-11-23 |
HK1243415A1 (zh) | 2018-07-13 |
MX2017005555A (es) | 2018-02-09 |
EP3212654B1 (en) | 2020-04-08 |
BR112017008714A2 (pt) | 2017-12-19 |
CN107635979A (zh) | 2018-01-26 |
EA201790922A1 (ru) | 2017-08-31 |
US10124009B2 (en) | 2018-11-13 |
SG11201703414VA (en) | 2017-05-30 |
PH12017500745A1 (en) | 2017-10-30 |
CO2017004898A2 (es) | 2017-10-31 |
KR20170068597A (ko) | 2017-06-19 |
EP3212654A1 (en) | 2017-09-06 |
PE20171042A1 (es) | 2017-07-19 |
AU2015339511B2 (en) | 2020-05-14 |
AU2015339511A1 (en) | 2017-05-18 |
CA2965330A1 (en) | 2016-05-06 |
WO2016069578A1 (en) | 2016-05-06 |
CL2017001046A1 (es) | 2018-01-26 |
EA033325B1 (ru) | 2019-09-30 |
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