JP7426967B2 - ヒストンデアセチラーゼのヘテロハロ阻害剤 - Google Patents
ヒストンデアセチラーゼのヘテロハロ阻害剤 Download PDFInfo
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Description
本出願は、2015年7月6日に出願の米国特許仮出願第62/188,857号の優先権を主張する。この仮出願の全内容は、参照により本明細書に組み込まれる。
27:6128;Bredy,2008,Learn Mem 15:460-467;Guan et al.,2009,Nature 459:55-60;Malvaez et al.,2010,Biol.Psychiatry 67:36-43;Roozendaal et al.,2010,J.Neurosci.30:5037-5046)。例えば、HDAC阻害は、長期記憶につながらない学習事象を顕著な長期記憶をもたらす学習事象に変換できる(Stefanko et al.,2009,Proc.Natl.Acad.Sci.USA 106:9447-9452)。さらに、HDAC阻害は、通常の記憶がなくなる時点を超えて持続する長期記憶の形をも生じ得る。HDAC阻害剤は、アルツハイマー病の遺伝モデルにおいて、認知障害を改善することが明らかにされている(Fischer et al.,2007,Nature 447:178-182、Kilgore et al.,2010,Neuropsychopharmacology 35:870-880)。これらの実証は、HDAC阻害によって、記憶を調節することが、多くの記憶および認知障害のために多くの治療的可能性を有することを示唆している。
本発明はHDAC2の阻害剤である化合物を提供する。したがって、化合物は、神経障害、記憶または認知機能障害または欠陥、消去学習障害、真菌疾患もしくは感染症、炎症疾患、血液疾患、または新生物疾患などの対象の病状を処置、軽減、もしくは予防するために、または記憶の改善のために、または記憶喪失もしくは記憶障害の処置、軽減もしくは予防のために、有用である
環Aは、
R1は、任意に置換されてもよい単環式または二環式非芳香族ヘテロシクリルであり、
R2は、任意に置換されてもよいC2-C6アルケニル、任意に置換されてもよいヘテロアリール、任意に置換されてもよい部分不飽和ヘテロシクリル、任意に置換されてもよい部分不飽和カルボシクリル、およびパラ置換フェニルから選択され、前記フェニルは、必要に応じてさらに置換でき、環Aが2個の窒素原子を含む場合、R2は非置換フェニルからさらに選択され、
R2における隣接する環原子上の任意の2個の置換基は、必要に応じて隣接する環原子と共に、アリール、カルボシクリル、ヘテロアリール、またはヘテロシクリル環である環を形成し、
R3は、存在する場合、クロロ、フルオロ、-CF3および-CHF2から選択され、
nは0または1であり;
「1」は、環Aと-NH-C(O)-R1との間の結合点を表し、
「2」は、環AとR2との間の結合点を表し、
「3」は、環Aと-NH2との間の結合点を表す。
ルケニル、任意に置換されてもよいヘテロアリール、任意に置換されてもよい部分不飽和ヘテロシクリル、任意に置換されてもよい部分不飽和カルボシクリル、およびパラ置換フェニルから選択され、環Aが2個の窒素原子を含む場合、R2は非置換フェニルからさらに選択され、
R2における隣接する環原子上の任意の2個の置換基は、必要に応じて隣接する環原子と共に、アリール、カルボシクリル、ヘテロアリール、またはヘテロシクリル環である環を形成する。
環A’B’は、少なくとも2個の窒素原子を含む縮合二環式系であり、環A’は6員ヘテロシクリルで、環B’は5員ヘテロアリールであり、
X1は炭素または窒素であり、
R3’およびR4は、それぞれ独立に、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、またはハロ(C1-C4)アルコキシであり、
R5はハロ、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、単環式ヘテロシクリル、または単環式ヘテロシクリルで任意に置換されてもよい(C1-C4)アルキルであり、それぞれの前記ヘテロシクリルは、ハロ、(C1-C4)アルキル、およびハロ(C1-C4)アルキルから選択される1~2個の基で任意におよび独立に置換されてもよく、
n’は0または1であり、
pおよびtはそれぞれ独立に、0、1、または2である。
本発明の化合物は、式IおよびIIとして上記で一般的に記載されたものを含み、本明細書で開示のクラス、サブクラス、および種によってさらに例示される。本明細書のそれぞれの変数に対し記載された好ましいサブセットは、任意の構造的サブセットに対しても同様に使用できることは理解されよう。本明細書で使用される場合、別に定める場合を除き、下記の定義が本明細書で適用されるものとする。
置き換えられることを意味する。指定した原子に関連して使用される場合、用語の「置換可能な」は、水素ラジカルが原子に結合しており、その水素原子が好適な置換基のラジカルによって置き換えることができることを意味する。別段の指示がない限り、「任意に置換されていてもよい」基は、基のそれぞれの置換可能な位置に置換基を有してよく、任意の所与の構造における1つ以上の位置が、明記した基から選択される1個以上の置換基により置換され得る場合には、置換基は全ての位置で同じでも、または異なっていてもよい。本発明により想定される置換基の組み合わせは、安定なまたは化学的に実現可能な化合物を形成するものが好ましい。
ト基に結合でき、いずれの環原子も任意に置換され得る。このような飽和または部分不飽和複素環式ラジカルの例には、限定されないが、テトラヒドロフラニル、テトラヒドロチエニル、ピペリジニル、デカヒドロキノリニル、オキサゾリジニル、ピペラジニル、ジオキサニル、ジオキソラニル、ジアゼピニル、オキサゼピニル、チアゼピニル、モルホリニル、およびチアモルホリニル、が挙げられる。別段の指定がない限り、ヘテロシクリル基は、単環式、二環式、三環式、または多環式、好ましくは単環式、二環式、または三環式、より好ましくは単環式または二環式であってよい。さらに、ヘテロ環はまた、ヘテロ環が1個または複数のアリール、ヘテロアリールおよび/または炭素環に縮合した基も含む。
基はまた、-R+、-N(R+)2、-C(O)R+、-C(O)OR+、-C(O)C(O)R+、-C(O)CH2C(O)R+、-S(O)2R+、-S(O)2N(R+)2、-C(S)N(R+)2、-C(=NH)-N(R+)2、または-N(R+)S(O)2R+も含み、一般的にこれらから選択され、それぞれのR+は上記で定義されている。ヘテロアリールまたは非芳香族ヘテロ環の環窒素原子はまた、酸化されて対応するN-ヒドロキシまたはN-酸化物化合物を形成してもよい。このような酸化環窒素原子を有するヘテロアリールの非制限的例には、N-オキシドピリジルが挙げられる。
上記で一般的に記載したように、いくつかの実施形態では、本発明は、式I:
環Aは、
R1は、任意に置換されてもよい単環式または二環式ヘテロシクリルであり、
R2は、C2-C6アルケニル、ヘテロアリール、部分不飽和ヘテロシクリル、部分不飽和カルボシクリル、およびパラ置換フェニルから選択され、環Aが2個の窒素原子を含む場合、R2は非置換フェニルからさらに選択され、
R2は必要に応じてさらに置換され、R2における隣接する環原子上の任意の2個の置換基は、必要に応じて隣接する環原子と共に、アリール、カルボシクリル、ヘテロアリール、またはヘテロシクリル環である環を形成し、
R3は、存在する場合、クロロ、フルオロ、-CF3および-CHF2から選択され、
nは0または1であり;
「1」は、環Aと-NH-C(O)-R1との間の結合点を表し、
「2」は、環AとR2との間の結合点を表し、
「3」は、環Aと-NH2との間の結合点を表す。
環A’B’は、少なくとも2個の窒素原子を含む縮合二環式系であり、環A’は6員ヘテロシクリルで、環B’は5員ヘテロアリールであり、
X1は炭素または窒素であり、
R3’およびR4は、それぞれ独立に、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、またはハロ(C1-C4)アルコキシであり、
R5はハロ、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、単環式ヘテロシクリル、または単環式ヘテロシクリルで任意に置換されてもよい(C1-C4)アルキルであり、それぞれの前記ヘテロシクリルは、ハロ、(C1-C4)アルキル、およびハロ(C1-C4)アルキルから選択される1~2個の基で任意におよび独立に置換されてもよく、
n’は0または1であり、
pおよびtはそれぞれ独立に、0、1、または2である。
物を、それらを必要としている対象に投与することを含む。
a.アルツハイマー病、ハンチントン病、発作誘導性記憶喪失(seizure induced memory loss)、統合失調症、ルービンスタイン・テービ症候群、レット症候群、脆弱X、レヴィー小体認知症、血管性認知症、前頭側頭型認知症、ADHD、失読症、自閉症に関連する双極性障害ならびに社会、認知および学習障害、外傷性頭部損傷、注意欠陥障害、不安障害、条件性恐怖反応、パニック障害、強迫性障害、外傷後ストレス障害(PTSD)、恐怖症、社会不安障害、物質依存症回復、加齢関連性記憶障害(AAMI)、加齢性認知機能低下(ARCD)、運動失調、もしくはパーキンソン病;または
b.急性骨髄性白血病、急性前骨髄球性白血病、急性リンパ性白血病、慢性骨髄性白血病、骨髄異形成症候群、および鎌状赤血球貧血から選択される血液疾患;または
c.新生物疾患;または
d.恐怖消去障害および外傷後ストレス障害から選択される消去学習障害である。
a.有効量の薬学的に有効成分を対象に投与すること;および/または
b.対象を認知行動療法(CBT)、精神療法、行動曝露処置(behavioral
exposure treatment)、仮想現実曝露(VRE)および/または認知機能改善療法に曝露することをさらに含む。
。
本発明の化合物は、当業者に既知の方法により、および/または以下に示すスキームおよびそれに続く合成実施例を参照することにより調製できる。代表的合成ルートは下記スキーム、および実施例で示される。
代表的使用
本発明の化合物はクラスIヒストンデアセチラーゼ(HDAC)および特にHDAC2の阻害剤であり、認知機能を促進し、学習および記憶形成を増強するために有用である。その結果、これらの化合物は、例えば、ヒトおよび動物における神経障害、記憶および認知機能障害/欠陥、消去学習障害、真菌疾患、炎症疾患、血液疾患、ならびに新生物疾患を含む、種々の病状を処置、軽減、および/または予防するのに有用である。
本発明の化合物は、ヒトおよび動物の健康のための様々な用途に有用である。本発明の化合物はヒストンデアセチラーゼ(HDAC)阻害剤である。本明細書で用いられるヒストンデアセチラーゼ阻害剤は、ヒストンデアセチラーゼの活性を阻害、低減、または別の方法で調節する化合物である。HDACは、ヒストンを含むタンパク質上のリジン残基からのアセチル基の除去を触媒する。HDAC阻害剤は、遺伝子発現、細胞分化、細胞周期進行、増殖停止、および/またはアポトーシスをもたらすことを含む、多様な生物学的機能も示す。(J.Med.Chem.2003,46:5097およびCurr.Med.Chem.2003,10:2343)。種々の実施形態では、本発明の化合物は、HDAC活性を少なくとも約50%、少なくとも約75%、または少なくとも約90%またはそれ以上低減させる。さらなる実施形態では、HDAC活性を少なくとも約95%または少なくとも約99%またはそれ以上低減させる。
では、細胞を接触させるステップをインビトロで行う。
例えば、式I、IIの化合物、または化合物100~128のいずれかまたは表2もしくは3のいずれかの化合物)は、特定細胞内でHDAC2の活性を部分的に阻害する。理論に制限されるものではないが、HDAC2が細胞中の複数のタンパク質複合体内に存在する場合、この部分的阻害は、HDAC2に対する差次的効力の結果であると仮定される。HDAC2を含む複数のタンパク質複合体は、細胞間で異なり、特定の細胞型内には特定の複合体がある。したがって、本明細書で記載の化合物(例えば、式I、IIの化合物、または化合物100~128のいずれかまたは表2もしくは3のいずれかの化合物)は、いくつかの複合体では、不完全にHDAC2活性を阻害し、HDAC2の十分な機能を残しておき、向上した安全性を与え、同時に、十分な阻害効力を維持し、所望の効果をもたらすということが提唱されている。
一態様では、本発明は、神経障害を処置、軽減、および/または予防するための方法および組成物を提供する。
一態様では、本発明は、正常対象ならびに記憶喪失および認知機能障害/欠陥を患っている対象の両方における認知機能を促進し、学習および記憶形成を増強するための方法および組成物を提供する。本明細書で使用される場合、正常対象は、認知機能障害に関連する障害と診断されていない対象である。「認知機能」とは、情報収集および/または処理、情報および/または概念の理解、推論、および/または適用;概念および/または情報の抽象化または特異化;創造性、問題解決、およびおそらくは直感の行為;ならびに概念および/または情報の学習、知覚、および/または自覚などの精神プロセスに関連する、対象の精神プロセスを意味する。精神プロセスは信念、欲求などのプロセスとは異なる。
転写は長期記憶プロセスのための鍵となるステップと考えられる(Alberini,2009,Physiol.Rev.89,121-145)。転写は、ヒストン-DNA相互作用を調節するヒストンアセチル化などの、特定のクロマチン修飾により促進される(Kouzarides,2007,Cell,128:693-705)。ヒストンアセチルトランスフェラーゼ(HAT)およびヒストンデアセチラーゼ(HDAC)などの修飾酵素は、ヒストン尾部のアセチル化の状態を制御する。一般に、ヒストンアセチル化は遺伝子発現を促進するが、ヒストン脱アセチル化は遺伝子サイレンシングを引き起こす。多くの調査は、強力なHATであるcAMP応答配列結合タンパク質(CREB)-結合タンパク質(CBP)がシナプス可塑性の長期持続型および長期記憶のために必須であることを示している(総説については、Barrett,2008,Learn Mem 15:460-467参照)。
本発明は、認知機能障害/欠陥を処置、軽減、および/または予防する方法に関する。
gStateコンピューター認知試験が含まれる(Dehaene et al.”Reward-dependent learning in neuronal networks for planning and decision making.”Brain Res.2000;126:21729、Iverson et al.”Interpreting change on the WAIS-III/WMS-III in clinical samples.”Arch Clin Neuropsychol.2001;16(2):183-91、およびWeaver et al.”Mild memory impairment in healthy older adults is distinct from normal aging.”Cogn.2006;60(2):146-55も参照されたい)。本発明の方法を用いて、正常対象の認知機能を促進してもよく、または対象の認知障害を処置、軽減および/もしくは予防してもよい。本明細書で使用される場合、正常対象は、認知機能障害に関連する障害と診断されていない対象である。
一態様では、本発明は、消去学習障害、例えば、恐怖消去障害を処置、軽減、および/または予防する方法に関する。
まれるが、これらに限定されない。
を可能にする上で特に有用である。本明細書で使用される場合、「バイオフィードバック」という用語は、対象を自身の生理的反応を制御するために自身の体からのシグナルを用いることによって、その健康を改善するよう訓練する技術を意味する。
いくつかの態様では、本発明は、真菌疾患または感染症を処置、軽減、および/または予防する方法に関し、該方法は、対象に本発明の化合物を投与することを含む。本発明は、HIVおよび癌患者を含む免疫無防備状態の患者を攻撃する院内感染真菌感染症を処置、軽減、および/または予防する方法を提供する。一実施形態では、本発明は、癌を患っていない対象の真菌疾患を処置、軽減、および/または予防する方法を提供する。
いくつかの態様では、本発明は、限定されないが、卒中、関節リウマチ、紅斑性狼蒼、潰瘍性結腸炎および外傷性脳損傷を含む、炎症疾患を処置、軽減、および/または予防する方法に関する(Leoni et al.,PNAS,99(5);2995-3000(2002)、Suuronen et al.J.Neurochem.87;407-416(2003)およびDrug Discovery Today,10:197-204(2005)。
いくつかの態様では、本発明は、新生物細胞の終末分化、ならびに細胞成長停止および/またはアポトーシスを選択的に誘導し、それによりそのような細胞の増殖を阻害する方法に関する。本発明の化合物は、対象の癌を処置、軽減、および/または予防する上で有用である。
いくつかの態様では、本発明は、血液疾患を処置、軽減、または予防する方法に関する。血液疾患には、血液細胞の異形成変化を引き起こし得る血液細胞の異常な成長および様々な白血病などの血液系腫瘍が含まれる。血液疾患の例には、急性骨髄性白血病、急性前骨髄球性白血病、急性リンパ芽球性白血病、慢性骨髄性白血病、骨髄異形成症候群、および鎌状赤血球貧血が含まれるが、これらに限定されない。
Lは、染色体9および22の転座を伴う特異的染色体異常を特徴とし、フィラデルフィア染色体を生じる。電離放射線が、CMLの発症に関連している。
したがって、本発明の別の態様では、医薬組成物が提供され、これらの組成物は、本明細書に記載のいずれかの化合物、および必要に応じ、薬学的に許容可能なキャリア、アジュバントまたはビークルを含む。特定の実施形態では、これらの組成物は必要に応じて、1つまたは複数の追加の治療薬をさらに含む。
水和物、溶媒和物、もしくはプロドラッグを投与することを含む。一態様では、消去学習障害は恐怖消去障害である。一態様では、消去学習障害は外傷後ストレス障害である。一態様では、方法は、消去学習障害の処置を必要としている対象にその処置をするための併用療法であって、該併用療法は、(1)有効量の本発明の化合物またはその薬学的に許容される塩、水和物、溶媒和物、もしくはプロドラッグを対象に投与すること、および(2)認知行動療法(CBT)、精神療法、行動曝露処置、仮想現実曝露(VRE)または認知機能改善療法に対象を曝露することを含む。
スポットをUV光(254および365nm)で可視化した。シリカゲル(200~300メッシュ)を使って、カラムおよびフラッシュクロマトグラフィーによる精製を実施した。溶媒系は、溶媒の比率として報告されている。
化合物114。120mg、50%、白色固体。
化合物116。160mg、54%、白色固体。
化合物119。14mg、8%、白色固体。
として得た。
ン(30mLx3)で洗浄し、Na2SO4上で乾燥後、減圧下で濃縮し、158-2を粗生成物として得て、これをさらに精製することなく次のステップに直接使用した。
化合物103。10mg、7%、白色固体。
氷浴下で滴加した。反応混合物を室温で2時間撹拌した。溶媒を減圧下で除去した。残渣をEtOAc(200mL)に溶解し、得られた溶液を水(30mLx5)で洗浄した。有機層をNa2SO4上で乾燥後、濃縮し、224-1(20.0g、70%)を黄色固体として得た。
化合物108。15mg、24%、白色固体。
を黄色固体として得た。
化合物111。20mg、28%、白色固体。
化合物120。14mg、38%、黄色固体。
のMeOH(5mL)中混合物を、H2雰囲気下、室温で2時間撹拌した。Pd/Cをセライトを使った濾過により除去した。濾液を濃縮し、残渣をMTBEで再結晶化して110(40mg、73%)を黄色固体として得た。
化合物121。24mg、43%、黄色固体。
化合物113。130mg、45%、白色固体。
化合物117。70mg、86%、白色固体。
を、シリカゲルによるカラムクロマトグラフィー(PE:EtOAc=10:1~5:1)で精製し、732-1(360mg、83%)を黄色固体として得た。
化合物118。72mg、52%、白色固体。
中溶液に、LiOH・H2O(893mg、21mmol)の水(11mL)中溶液を氷浴下で滴加した。その後、MeOH(11mL)を添加した。混合物を室温で3時間撹拌した。揮発性溶媒を減圧下で除去し、水層を2NのHCl溶液でpH=4に調節した。得られたものをEtOAc(30mLx3)で抽出した。合わせた有機層を無水Na2SO4上で乾燥させて、減圧下で濃縮した。残渣を、シリカゲルによるカラムクロマトグラフィー(DCM:MeOH=50:1~15:1)で精製し、156-4(780mg、48%)を褐色固体として得た。
冷却した。混合物を水(15mL)で希釈し、DCM(10mLx3)で抽出した。合わせた有機層をブライン(10mLx3)で洗浄し、無水Na2SO4上で乾燥させた後、減圧下で濃縮した。残渣を、シリカゲルによるカラムクロマトグラフィー(DCM:MeOH=100:1~20:1)で精製し、143-E(80mg、48%)を黄色固体として得た。
化合物172。100mg、60%、白色固体。
化合物179。60mg、43%、白色固体。
化合物181。18mg、19%、白色固体。
化合物188。40mg、41%、白色固体。
化合物237。8mg、45%、淡黄色固体。
化合物248。30mg、54%、淡黄色固体。
化合物189。27mg、19%、黄色固体。
化合物191。80mg、67%、黄色固体。
0.1mmol)のMeOH(160mL)中溶液に、SOCl2(11.92g、100.2mmol)を氷浴下で滴加した。次に、溶液を室温で一晩攪拌した。溶液を減圧下で濃縮し、123-A(8.70g、84%)を白色固体として得た。
6%)を白色固体として得た。
化合物124。85mg、49%、黄色固体。
化合物125。53mg、32%、白色固体。
化合物130。45mg、23%、黄色固体。
化合物131。18mg、10%、黄色固体。
化合物132。40mg、22%、黄色固体。
化合物133。70mg、33%、白色固体。
化合物134。70mg、38%、白色固体。
化合物136。50mg、31%、黄色固体。
化合物137。35mg、25%、灰色固体。
化合物140。60mg、37%、灰色固体。
化合物128。56mg、50%、白色固体。
化合物129。62mg、52%、白色固体。
化合物142。48mg、23%、白色固体。
化合物139。11mg、9%、灰色固体。
化合物126。54mg、45%、白色固体。
化合物141。47mg、17%、黄色固体。
をセライトを使った濾過により除去した。濾液を減圧下で濃縮し、残渣を分取TLC(DCM:MeOH=8:1)により精製して、138(15mg、32%)を淡黄色固体として得た。
合物を65℃で16時間攪拌した後、減圧下で濃縮した。残渣をDCM(50mL)で溶解し、溶液をブライン(20mLx3)で洗浄した。有機層を無水Na2SO4上で乾燥させた後、減圧下で濃縮した。残渣を、シリカゲルによるカラムクロマトグラフィー(DCM:MeOH=100:1~20:1)で精製し、146-C(200mg、20%)を黄色固体として得た。
化合物150。50mg、67%、黄色固体。
化合物157。15mg、16%、黄色固体。
化合物158。12mg、13%、黄色固体。
化合物159。80mg、57%、黄色固体。
化合物160。60mg、43%、黄色固体。
化合物249。20mg、25%、白色固体。
化合物254。53mg、57%、黄色固体。
化合物149。30mg、40%、白色固体。
化合物240。14mg、29%、白色固体。
化合物250。28mg、29%、黄色固体。
化合物251。43mg、31%、黄色固体。
化合物252。130mg、76%、黄色固体。
化合物253。40mg、43%、黄色固体。
化合物255。10mg、32%、白色固体。
後、Pd/Cをセライトを使った濾過により除去した。濾液を濃縮し、残渣を分取TLC(DCM:MeOH=10:1)により精製し、151(103mg、69%)を白色固体として得た。
化合物165。80mg、57%、黄色固体。
化合物163。35mg、38%、白色固体。
化合物164。10mg、14%、黄色固体。
。
化合物144。80mg、60%、黄色固体。
化合物173。6mg、7%、黄色固体。
化合物187。85mg、71%、黄色固体。
化合物186。35mg、37%、白色固体。
化合物224。40mg、26%、黄色固体。
化合物225。25mg、13%、白色固体。
化合物229。12mg、43%、白色固体。
化合物238。70mg、50%、黄色固体。
化合物259。20mg、20%、赤色固体。
化合物260。50mg、54%、黄色固体。
化合物197。16mg、43%、黄色固体。
化合物212。80mg、87%、白色固体。
化合物171。15mg、25%、黄色固体。
化合物214。7mg、10%、黄色固体。
化合物216。30mg、41%、黄色固体。
化合物217。25mg、22%、黄色固体。
化合物218。30mg、33%、黄色固体。
化合物220。20mg、16%、黄色固体。
化合物221。165mg、66%、白色固体。
化合物228。25mg、21%、黄色固体。
化合物230。20mg、71%、白色固体。
化合物232。70mg、51%、白色固体。
化合物231。35mg、28%、黄色固体。
化合物177。75mg、65%、黄色固体。
化合物184。20mg、11%、黄色固体。
化合物185。30mg、33%、白色固体。
化合物190。20mg、36%、黄色固体。
化合物154。60mg、64%、黄色固体。
化合物155。110mg、65%、黄色固体。
化合物162。18mg、50%、黄色固体。
化合物178。125mg、61%、白色固体。
化合物144。80mg、60%、黄色固体。
化合物145。50mg、15%、黄色固体。
化合物161。30mg、32%、黄色固体。
化合物261。46mg、55%、黄色固体。
の後、Pd/Cをセライトを使った濾過により除去した。濾液を濃縮し、残渣を分取TLC(DCM:MeOH=10:1)により精製し、169(150mg、70%)を白色固体として得た。
化合物152。50mg、36%、淡黄色固体。
化合物182。70mg、38%、赤色固体。
化合物199。50mg、54%、淡黄色固体。
化合物201。30mg、42%、黄色固体。
化合物202。30mg、42%、黄色固体。
化合物203。30mg、18%、黄色固体。
化合物235。170mg、87%、白色固体。
化合物236。70mg、50%、白色固体。
化合物256。20mg、8%、淡黄色固体。
化合物210。160mg、96%、黄褐色固体。
化合物211。70mg、40%、白色固体。
化合物215。70mg、75%、白色固体。
化合物222。30mg、42%、黄色固体。
化合物223。35mg、31%、白色固体。
化合物242。50mg、34%、白色固体。
化合物262。38mg、43%、白色固体。
化合物166。12mg、28%、白色固体。
化合物176。35mg、41%、白色固体。
化合物174。65mg、50%、黄色固体。
化合物175。20mg、11%、黄色固体。
化合物193。80mg、41%、白色固体。
化合物195。60mg、43%、灰色固体。
化合物194。16mg、43%、黄色固体。
.45mmol)およびギ酸アンモニウム(183mg、2.90mmol)のMeOH(3mL)中混合物を、室温で1時間撹拌した。その後、亜鉛粉末をセライトを使った濾過により除去した。濾液を濃縮し、残渣を分取TLC(DCM:MeOH=15:1)により精製し、198(20mg、20%)を黄色固体として得た。
化合物204。60mg、73%、白色固体。
化合物239。60mg、62%、白色固体。
化合物241。69mg、58%、白色固体。
化合物263。83mg、64%、白色固体。
化合物264。50mg、79%、白色固体。
化合物205。20mg、43%、白色固体。
下で濃縮した。残渣を、シリカゲルによるカラムクロマトグラフィー(DCM:MeOH=100:1~30:1)で精製し、206-C(500mg、58%)を黄色固体として得た。
化合物208。28mg、38%、淡黄色固体。
化合物219。10mg、8%、黄色固体。
化合物226。60mg、44%、黄色固体。
黄色固体として得た。
化合物246。20mg、54%、黄色固体。
化合物247。6mg、43%、黄色固体。
。
化合物352。20mg、28%、灰色がかった白色の固体。
化合物353。17mg、20%、灰色がかった白色の固体。
化合物360。31mg、34%、茶色がかった固体。
化合物361。35mg、37%、白色固体。
化合物382。15mg、14%、灰色がかった白色の固体。
化合物383。12mg、13%、灰色がかった白色の固体。
化合物384。25mg、21%、灰色がかった白色の固体。
化合物362。15mg、18%、灰色がかった白色の固体。
化合物363。68mg、34%、灰色がかった白色の固体。
化合物365。30mg、54%、灰色がかった白色の固体。
化合物367。52mg、55%、灰色がかった白色の固体。
化合物371。47mg、45%、灰色がかった白色の固体。
化合物372。45mg、38%、灰色がかった白色の固体。
化合物373。42mg、38%、灰色がかった白色の固体。
化合物374。48mg、34%、灰色がかった白色の固体。
化合物385。80mg、44%、灰色がかった白色の固体。
化合物386。130mg、76%、灰色がかった白色の固体。
化合物387。15mg、19%、灰色がかった白色の固体。
化合物388。60mg、33%、灰色がかった白色の固体。
化合物389。168mg、73%、灰色がかった白色の固体。
化合物390。80mg、43%、灰色がかった白色の固体。
化合物392。70mg、38%、灰色がかった白色の固体。
化合物396。85mg、56%、淡黄色固体。
化合物397。27mg、27%、淡黄色固体。
化合物398。110mg、46%、黄色がかった固体。
化合物399。100mg、46%、灰色がかった白色の固体。
化合物400。32mg、34%、灰色がかった白色の固体。
化合物401。8mg、06%、灰色がかった白色の固体。
化合物403。145mg、78%、灰色がかった白色の固体。
化合物404。165mg、91%、灰色がかった白色の固体。
化合物405。64mg、46%、灰色がかった白色の固体。
化合物408。45mg、43%、灰色がかった白色の固体。
化合物409。15mg、18%、灰色がかった白色の固体。
化合物410。33mg、30%、灰色がかった白色の固体。
化合物411。100mg、63%、灰色がかった白色の固体。
化合物368。35mg、47%、灰色がかった白色の固体。
化合物377。45mg、35%、灰色がかった白色の固体。
化合物378。75mg、20%、灰色がかった白色の固体。
化合物379。75mg、53%、灰色がかった白色の固体。
366の合成。366-AのTHF(5mL)中の冷却した(0℃)溶液に、窒素下でTHF中のLAH溶液を加え、混合物を10℃までゆっくり温めながら2時間撹拌した。反応混合物をNa2SO4の飽和水溶液でクエンチした。固形物を濾過し、DCM(20mL)で洗浄した。合わせた濾液を無水Na2SO4上で乾燥させて、減圧下で濃縮した。残渣を分取HPLCにより精製し、366(10mg、11%)を灰色がかった白色の固体として得た。
化合物350。13mg、14%、灰色がかった白色の固体。
化合物395。10mg、11%、緑色を帯びた固体。
化合物AM353。210mg、87%、灰色の固体。
化合物AM355。300mg、93%、薄紅色の固体。
化合物AM363。300mg、94%、灰色がかった白色の固体。
化合物AM386。300mg、92%、灰色がかった白色の固体。
化合物AM408。210mg、84%、灰色の固体。
化合物AM410。210mg、89%、灰色の固体。
C末端Hisタグ(Proteros)および蛍光標識抗His抗体を含むHDAC2を1つのバイアルのアッセイバッファー:50mMトリス、pH8.0、1mMのDTT、150mMのNaCl、および0.01%のツイーン20中に希釈する。成分を30分間、プレインキュベートした後、少量のレポータープローブ(Proteros)を高度濃縮ストックから添加し、インキュベーションをさらに30分間継続する。レポータープローブを添加後の最終濃度は、20nMのHDAC2、4nMの抗体、および180nMのプローブとなる。
HDAC酵素アッセイ
全ての組換え型ヒトHDACをBPS Bioscienceから購入した。基質であるFAM-TSRHK(AC)KL-CONHは、NanoSynで合成した。最終的アッセイ反応物は次記を含んでいた:100mMヘペス(pH7.5)、50mMのKCl、0.1%BSA、0.01%トリトンX-100、1%DMSO、1uM基質および5nMのHDAC酵素。酵素および化合物を25℃で5時間プレインキュベートし、基質の添加により反応を開始した。10uLの反応物を25℃で17時間インキュベートし、100mMヘペス(pH7.5)、0.1%BSA、0.01%トリトンX-100および0.05%SDSを含む40uLの緩衝液の添加により終了させた。それぞれの試料中に存在する基質および生成物ペプチドを、LabChip3000キャピラリー電気泳動装置を使って、電気泳動により分離した。基質および生成物のピークの相対的蛍光強度の変化は酵素活性を反映している。反応の進行を積和比率(SPR):P/(S+P)として決定した。式中、Pは生成物ペプチドのピーク高さであり、Sは基質ペプチドのピーク高である。反応は、12種の濃度(30uMから始まる3X系列希釈)で2回繰り返して実施した。4パラメータロジスティックモデルを使って、IC50値を計算した。
SH-SY5Y細胞(Sigma)を10%ウシ胎仔血清およびpen/strepを補充したイーグルの修飾基本培地中で培養した。化合物の注入の24時間前に、ホワイト384ウエルプレートに1,500細胞/ウエルの密度で20uLの細胞を播種した。未希釈のDMSO中に化合物を系列希釈した後、FBSなしで培地中に1:100v/vに希釈し、混合した。培地を播種した細胞から除去し、無血清培地中に希釈した化合物(1%v/v最終DMSO)を加え、37℃で5時間インキュベートした。次に、0.1%のトリトンX-100を含む10uLのHDAC-Glo2試薬を加え、プレートを混合し、室温で100分間発光させた。その後、0.4秒の積分時間を採用したSpectramax LMaxルミノメーターを使ってプレートを読み取った。正規化データを用いて用量反応曲線を構築した。ここで、100uMのCI-994を100%阻害、DMSO単独を0%阻害と定義した。
0またはEC50値;および「D」は5.0μMより大きいIC50またはEC50値を示す。
本明細書で記載の化合物(例えば、式I、IIによる化合物、または化合物100~128のいずれかまたは表2もしくは3のいずれかの化合物)は、モデル行動パラダイムであるモリス水迷路試験におけるその効力に関し、後述の通り試験できる。
Claims (8)
- 下記のいずれかから選択される化合物または薬学的に許容可能なその塩
- 請求項1に記載の化合物または薬学的に許容可能なその塩および薬学的に許容可能なキャリアを含む医薬組成物。
- HDAC活性を阻害するための、有効量の請求項1に記載の化合物または薬学的に許容可能なその塩を含む、医薬組成物。
- 神経障害、記憶もしくは認知機能障害または欠陥、消去学習障害、真菌疾患または感染、炎症性疾患、血液疾患、および新生物疾患から選択される病状を処置するための、有効量の請求項1に記載の化合物または薬学的に許容可能なその塩を含む、医薬組成物。
- 記憶を改善するための、または記憶喪失もしくは障害を処置、軽減、もしくは予防するための、有効量の請求項1に記載の化合物または薬学的に許容可能なその塩を含む、医薬組成物。
- 前記病状が、
a.アルツハイマー病、ハンチントン病、発作誘導性記憶喪失(seizure induced memory loss)、統合失調症、ルービンスタイン・テービ症候群、レット症候群、脆弱X、レヴィー小体認知症、血管性認知症、前頭側頭型認知症、ADHD、失読症、双極性障害に関連する認知機能障害もしくは欠陥、ならびに、自閉症、外傷性頭部損傷、注意欠陥障害、不安障害、条件性恐怖反応、パニック障害、強迫性障害、外傷後ストレス障害(PTSD)、恐怖症、社会不安障害、物質依存症回復、加齢関連性記憶障害(AAMI)、加齢性認知機能低下(ARCD)、運動失調、もしくはパーキンソン病に関連する社会的認知および学習障害;または
b.急性骨髄性白血病、急性前骨髄球性白血病、急性リンパ性白血病、慢性骨髄性白血病、骨髄異形成症候群、および鎌状赤血球貧血から選択される血液疾患;または
c.新生物疾患;または
d.恐怖消去障害および外傷後ストレス障害から選択される消去学習障害である、請求項4に記載の医薬組成物。 - 前記病状が、アルツハイマー病、ハンチントン病、前頭側頭型認知症、フリードライヒ運動失調症、外傷後ストレス障害(PTSD)、パーキンソン病、または物質依存症回復である、請求項6に記載の医薬組成物。
- シナプス密度を増やすための、またはシナプス可塑性を増やすための、または樹状突起密度を増やすための、有効量の請求項1に記載の化合物または薬学的に許容可能なその塩を含む、医薬組成物。
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