JP7017523B2 - 代謝性疾患および癌の治療のための新規のミトコンドリア脱共役剤 - Google Patents
代謝性疾患および癌の治療のための新規のミトコンドリア脱共役剤 Download PDFInfo
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- JP7017523B2 JP7017523B2 JP2018560569A JP2018560569A JP7017523B2 JP 7017523 B2 JP7017523 B2 JP 7017523B2 JP 2018560569 A JP2018560569 A JP 2018560569A JP 2018560569 A JP2018560569 A JP 2018560569A JP 7017523 B2 JP7017523 B2 JP 7017523B2
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Classifications
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Description
本出願は、2016年5月18日に出願された「NOVEL MITOCHONDRIAL UNCOUPLERS FOR TREATMENT OF METABOLIC DISEASES AND CANCER」という名称の米国仮特許出願第62/338,190号の利益および優先権を主張するものであり、その内容は全体として参照により本明細書に組み込まれる。
この出願の発明に関連する先行技術文献情報としては、以下のものがある(国際出願日以降国際段階で引用された文献及び他国に国内移行した際に引用された文献を含む)。
(先行技術文献)
(特許文献)
(特許文献1) 国際公開第2016/004513号
(特許文献2) 米国特許出願公開第2013/0324555号明細書
(特許文献3) 米国特許出願公開第2016/0046560号明細書
(特許文献4) 国際公開第2015/154169号
(特許文献5) 米国特許出願公開第2010/0113770号明細書
(特許文献6) 米国特許出願公開第2006/0089395号明細書
(特許文献7) 国際公開第2012/025638号
(特許文献8) 米国特許出願公開第2008/0039629号明細書
(特許文献9) 米国特許出願公開第2014/0221411号明細書
式中、
R1aは、水素、選択的に置換されたC1~C6アルキル、選択的に置換されたC2~C6アルケニル、選択的に置換されたC2~C6アルキニル、選択的に置換されたC3~C10シクロアルキル、((C1~C6アルキルスルホニル)アミノ)C1~C6アルキル、選択的に置換されたC3~C10ヘテロシクリル、選択的に置換されたC3~C10アリール、選択的に置換されたC3~C10ヘテロアリール、C1~C6ペルフルオロアルキル、ハロ、シアノ、ニトロ、選択的に置換されたアミノ、-C(O)NHR5、-C(O)NR5R6、-C(O)H、-C(O)R7、-C(O)OH、および-C(O)OR5から成る群から選択され、
R1b、R1c、およびR1dの各々は、独立して、水素、C1~C6ペルフルオロアルキル、C1~C6アルキル、C2~C6アルケニル、C1~C6アルキニル、C3~C10シクロアルキル、シアノ、およびハロから成る群から選択され、
R2は、水素、単糖類、二糖類、C(O)NR5R6、C(O)R7、-P(O)(OH)2、および-P(O)(ONa)2から成る群から選択され、単糖類および二糖類は、アノマー中心のフェノール性酸素に結合してグリコシド結合を形成し、
R3は、水素であるか、あるいはR2とR3が一緒になったカルボニル基であり、それらが結合している原子と一緒になって6員複素環カルバメートを形成し、
R4a、R4b、R4c、およびR4dの各々は、独立して、水素、C1~C6ペルフルオロアルキル、シアノ、ニトロ、-CHF2、C1~C6アルキル、-OC1~C6アルキル、-OCF3、C3~C10シクロアルキル、CF3、-SO2CH3、およびハロから成る群から選択され、
R5およびR6の各々は、独立して、選択的に置換されたC1~C6アルキル、およびC1~C6アルキルスルホニルから成る群から選択され、あるいは、R5およびR6は、それらが結合している窒素と一緒になって、選択的に置換されたC3~C6ヘテロシクリルを形成し、
R7は、選択的に置換された(アルキルアミノ)C1~C6アルキル、および選択的に置換されたC3~C6ヘテロシクリルから成る群から選択される。
式中、
R8は、C(O)NR9R10およびC(O)R11から成る群から選択され、
R9およびR10の各々は、独立して、選択的に置換されたC1~C6アルキル、およびC1~C6アルキルスルホニルから成る群から選択され、あるいは、R9およびR10は、それらが結合している窒素と一緒になって、選択的に置換されたC3~C6ヘテロシクリルを形成し、
R11は、選択的に置換された(アルキルアミノ)C1~C6アルキル、および選択的に置換されたC3~C6ヘテロシクリルから成る群から選択され、
R12は、C1~6ペルフルオロアルキル、ハロ、シアノ、およびニトロから成る群から選択される。
式中、
R13およびR14の各々は、独立して、選択的に置換されたC1~C6アルキル、およびC1~C6アルキルスルホニルから成る群から選択され、あるいは、R13およびR14は、それらが結合している窒素と一緒になって、選択的に置換されたC3~C6ヘテロシクリルを形成し、
R15は、C1~C6ペルフルオロアルキル、ニトロ、ハロ、およびシアノから成る群から選択される。
R1aは、水素、メチル、エチル、イソプロピル、シクロプロピル、シアノ、ヒドロキシメチル、ハロ、-CH2N(CH3)2、-CH2CH2N(CH3)2、および-CH2CH2CH2N(CH3)2、-CH2CH2CH2NHS(O)2CH3から成る群から選択され、
R1b、R1c、およびR1dの各々は、独立して、水素およびハロから選択される群から選択され、
R2は、水素、-P(O)(OH)2、-P(O)(ONa)2から成る群から選択され、
R4a、R4b、R4c、およびR4dの各々は、独立して、水素、フルオロ、OCF3、
-SO2CH3、およびトリフルオロメチルから選択される。
一実施形態において、式(IV)の化合物は:
いくつかの実施形態において、対象において、インスリン抵抗性または組織における脂質の異常な蓄積を特徴とする代謝性疾患または障害、または組織におけるインスリン抵抗性または脂質の異常な蓄積が症状である疾患または障害を治療する方法、または癌または過形成を治療する方法は、治療有効量の本明細書に記載の実施形態による化合物または医薬組成物を対象に投与することを含む。いくつかの実施形態において、代謝性疾患または障害は、2型糖尿病、またはインスリン抵抗性または高血糖症を特徴とする疾患である。
この出願で使用される場合、分子用語は、特に明記しない限り、それらの共通の意味を有する。
[実施例]
室温で硫酸(10ml)およびTFA(20ml)中の5-クロロ-2-メトキシ安息香酸(5.58g、30mmol)の撹拌溶液に、NBS(5.88g、33mmol)を添加した。淡色溶液を室温で3時間撹拌した。得られた淡色懸濁液を砕氷500g上に慎重に注いだ。混合物をEAで抽出した。EA層を硫酸ナトリウムで乾燥させ、減圧下で濃縮した。薄黄色の残渣を最小限のDCMに懸濁させた。固体を収集し、冷DCMで洗浄し、減圧下で一晩乾燥して、3-ブロモ-5-クロロ-2-メトキシ安息香酸(7g、89%)を白色固体として得た。1H NMR(300MHz、アセトン)δ7.86(d、1H、J=3.0Hz)、7.78(d、1H、J=3.0Hz)、3.91(s、3H)。
DMF(30ml)中の3-ブロモ-5-クロロ-2-メトキシ安息香酸(6g、22.6mmol)の撹拌溶液に、炭酸カリウム(31g、226mmol)、続いてCH3I(1.4ml、22.6mmol)を添加した。混合物を室温で24時間撹拌した。水を添加し、EAで2回抽出した。合わせた有機層を水およびブラインで洗浄し、硫酸ナトリウムで乾燥させた。有機層を濾過し、溶媒を真空で除去して、淡黄色油状物を得た(6.18g、97%)。
N2下、トリエチルアミン(15ml)中のメチル3-ブロモ-5-クロロ-2-メトキシベンゾエート(1.02g、3.65mmol)、N,N-ジメチルプロプ-2-イン-1-アミン(1.19ml、10.94mmol)、PdCl2(PPh3)2(51mg、0.073mmol)、CuI(14mg、0.073mmol)の混合物を60℃で一晩加熱した。水を添加し、EAで2回抽出した。合わせた有機層を水およびブラインで洗浄し、硫酸ナトリウムで乾燥し、真空で濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製して、表題化合物を黄色油状物として得た(1.02g、100%)。1H NMR(300MHz、CHCl3)δ7.67(d、1H、J=3.0Hz)、7.50(d、1H、J=3.0Hz)、3.96(s、3H)、3.90(s、3H)、3.54(s、2H)、2.38(s、6H)。MS(ESI)[M+H]+は、m/z282.09を必要とし、実測値m/z282.05。
メタノール(20ml)中の5-クロロ-3-(3-(ジメチルアミノ)プロプ-1-イン-1-イル)-2-メトキシベンゾエート(1.02g、3.65mmol)およびPd-C(200mg)の混合物をH2下の室温で一晩撹拌した。反応の完了後、触媒を濾別し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を黄色油状物として得た(556mg、55%)。1H NMR(300MHz、CHCl3)δ7.64(d、1H、J=3.0Hz)、7.34(d、1H、J=3.0Hz)、3.93(s、3H)、3.83(s、3H)、2.68(t、2H、J=6.0Hz)、2.37(t、2H、J=6.0Hz)、2.28(s、6H)、1.85-1.75(m、2H)。MS(ESI)[M+H]+は、m/z286.1を必要とし、実測値m/z285.7。
MeOH(5ml)中のメチル5-クロロ-3-(3-(ジメチルアミノ)プロピル)-2-メトキシベンゾエート(90mg、0.32mmol)の撹拌溶液に、1.5mlの1N KOH溶液を添加した。得られた混合物を室温で終夜撹拌した。溶媒を蒸発させ、ジオキサン(1ml)中の4N HClを残渣に添加した。混合物をさらに10分間撹拌した後、濃縮し、減圧下で乾燥させた。この残渣にHBTU(144mg、0.38mmol)、DMF(3ml)、およびDIPEA(275μl、1.58mmol)を添加した。混合物を10分間撹拌し、次いで、6(トリフルオロメチル)ベンゾ[d]チアゾール-2-アミン(69mg、0.32mmol)を添加した。得られた反応物を80℃で24時間加熱した。室温に冷却した後、混合物をEAと水との間で分離した。有機層をブラインで洗浄し、Na2SO4で乾燥し、真空で濃縮した。カラムクロマトグラフィーにより精製して、表題化合物を淡黄色固体として得た(50mg、34%)。MS(ESI)[M+H]+は、m/z472.1を必要とし、実測値m/z471.6。
5-クロロ-3-(3-(ジメチルアミノ)プロピル)-2-メトキシ-N-(6-(トリフルオロメチル)ベンゾ[d]チアゾール-2-イル)ベンズアミド(50mg、0.11mmol)を塩化ピリジニウム(1.0g)と混合した。混合物を210℃に加熱し、15分間撹拌し、室温に冷却した。得られた固体を水に溶解し、酢酸エチルで抽出した。有機層を真空で濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製して、表題化合物MB5-3を淡黄色粉末として得た(15.0mg、収率30%)。1H NMR(300MHz、メタノール)δ8.21(s、1H)、7.82-7.78(m、2H)、7.68(d、1H、J=3.0Hz)、7.25(d、1H、J=3.0Hz)、2.94(t、2H、J=6.0Hz)、2.89(s、6H)、2.80(t、2H、J=6.0Hz)、2.12-2.03(m、2H)。MS(ESI)[M+H]+は、m/z458.1を必要とし、実測値m/z458.2。
ミトコンドリア脱共役活性アッセイ
定義上、ミトコンドリア脱共役は、ミトコンドリアATPシンターゼによるATP合成からのミトコンドリア電子輸送鎖活性(ミトコンドリア酸化)の脱結合である。技術的には、ミトコンドリア脱共役活性は、オリゴマイシンなどのミトコンドリアATP合成酵素阻害剤の存在下で細胞または単離ミトコンドリアの酸素消費を誘導する化学化合物の能力によって定義される。したがって、本発明者らは、10%ウシ胎仔血清を含有する培地中で成長するマウス筋芽細胞C2C12細胞を使用して、ベンダーの指示に従ってSeahorse XF96またはSeahorse XF24器具を用いて、酸素消費速度(OCR)アッセイによるミトコンドリア脱共役活性を決定した。OCRは、正常な成長条件下で最初に測定され、次いで、オリゴマイシン(最終濃度2.5μM)処理後にOCRを測定し、次いで、様々な濃度のオリゴマイシンおよび合成化合物の両方を添加した後にOCRを測定した。図1は、ミトコンドリア脱共役剤を用いたSeahorse OCRアッセイの典型的なプロファイルを示す。オリゴマーの存在下でOCRが誘導される各化合物の最小濃度(Cmin)を決定した。以下の表(表1)は、化合物のミトコンドリア活性をまとめたものである。
ミトコンドリア脱共役はまた、ミトコンドリア膜電位の低下をもたらす可能性がある。本発明者らは、培養した哺乳動物細胞、NIH-3T3細胞、またはHepG2細胞を用いたTMRE(テトラメチルローダミンエチルエステル)染色法を使用して、ミトコンドリア膜電位アッセイを行った。細胞を6ウェルプレートに播種し、10%ウシ胎仔血清および2mMのグルタミンを補充したDMEM培地で培養した。実験前に細胞を対数成長期まで成長させた。細胞を様々な濃度で個々の各化合物で2時間処理し、続いてTMREで最終濃度100nMで15分間染色した。次いで、細胞をPBSで1回洗浄し、蛍光顕微鏡下で検査した。様々な濃度のニクロサミドエタノールアミンで処理した細胞を陽性対照として使用した。ミトコンドリアTMRE染色の減少を、ミトコンドリア脱共役活性の定量として推定した。示された化合物のEC50は、細胞中のミトコンドリアTMRE染色の蛍光強度が約50%に低下する濃度として定義される。以下の表(表II)は、培養した哺乳動物細胞におけるミトコンドリア膜電位を低下させる際の個々の化合物の活性をまとめたものである。
ミトコンドリア脱共役は、細胞の生体エネルギー効率を低下させ、通常、ATPのわずかな減少およびAMPの増加をもたらす。細胞内AMPの上昇は、AMPKを活性化する。ACCが肝細胞のように発現される細胞では、AMPKは、ACCを順にリン酸化(阻害)することができる。ACCは、脂質代謝のマスターレギュレーターである。ACCの阻害は、脂質新規合成を阻害し、脂肪酸ベータ酸化を促進する。本発明者らは、それぞれp-AMPKおよびp-ACC(Phospho-AMPKα(Thr172)mAb(#2535)、ホスホ-アセチル-CoAカルボキシラーゼ(Ser79)抗体(#3661)は、Cell Signaling Technology製である)に対する抗体を用いたイムノブロットアッセイによって、それぞれ線維芽細胞NIH3T3細胞および肝臓HepG2細胞におけるAMPK活性化(リン酸化AMPKレベル)およびACC阻害(リン酸化ACCレベル)を測定した。細胞を様々な濃度の化合物で3~6時間処理した。次いで、細胞抽出物を得て、ドデシル硫酸ナトリウム-ポリアクリルアミドゲル電気泳動(SDS-PAGE)に供した。タンパク質をポリビニリデンジフルオリド(PVDF)膜(Millipore、IPVH00010)に移した。イムノブロッティングアッセイを抗体で行った。(図2)ミトコンドリア脱共役に有効な濃度で指示された例示化合物を処理すると、リン酸化AMPK(図2A、活性化)およびリン酸化ACC(活性の阻害、図2B)における増加を示す図である。
インビボでの2型糖尿病の治療における化合物の有効性を試験するために、本発明者らは、化合物28を例として使用し、臨床的に関連するマウスモデル、HFD誘発脂肪肝、および糖尿病モデルにおいて、血糖値低下、血中インスリン濃度の低下、インスリン感受性の改善、および脂肪肝の低下におけるその効果を決定した。C57B6/J雄マウスにHFD(脂肪から60%カロリー)を2ヶ月齢から4ヶ月間摂取させて、高血糖症、高血圧インスリン、および2型糖尿病のインスリン耐性症状、ならびに脂肪肝を誘発した。次いで、マウスをHFDまたは600ppmの化合物28を含有するHFDで継続した。血糖、血中インスリンレベルを測定し、インスリン感受性を測定するためにグルコース耐性アッセイを行った。マウスを屠殺し、化合物28の脂肪肝発達に対する効果を、肝臓重量を比較することによって評価した。図3A~Cは、化合物28での処理が血糖濃度、血中インスリン濃度を著しく低下させ、インスリン感受性を改善することを示す。図3Dは、化合物28が高脂肪食に起因する脂肪肝重量を減少させたことを示す。血漿化合物28の濃度を測定し、レベルは、ミトコンドリアを脱共役する有効濃度であった。
癌細胞成長に対する例示化合物の効果を評価した。細胞成長阻害アッセイは、抗癌剤(https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm)を評価するためにNational Cancer Institute(NCI)によって標準化されたプロトコルを使用して行った。ヒト大腸癌HCT116細胞株およびヒト肺癌細胞株H1299をアッセイに使用した。ヒト腫瘍細胞を96ウェルマイクロタイタープレートに接種した。細胞接種後、化合物を添加する前に、マイクロタイタープレートを細胞成長のために24時間インキュベートした。24時間後、各細胞株の2つのプレートをTCAでその場で固定し、化合物添加時(Tz)の各細胞株の細胞集団の測定を表した。試験化合物をジメチルスルホキシドに可溶化した。試験化合物の添加時に、5つの10倍または1/2対数連続希釈を行い、合計5つの試験化合物濃度に加えて対照を提供した。100μlのこれらの異なる試験化合物希釈物のアリコートを、既に100μlの培地を含有する適切なマイクロタイターウェルに添加し、必要な最終試験化合物濃度をもたらした。試験化合物の添加後、プレートをさらに48時間インキュベートした。冷たいTCAの添加によってアッセイを終了させた。50μlの冷50%(w/v)TCA(最終濃度、10%TCA)50μlでその場で細胞を固定し、水道水で5回洗浄し、空気乾燥させた。0.4%(w/v)の1%酢酸中のスルホローダミンB(SRB)溶液(100μl)を各ウェルに添加し、プレートを室温で10分間インキュベートした。染色後、未結合の色素を1%酢酸で5回洗浄することにより除去し、プレートを風乾した。その後、結合した染色液を10mMトリズマ塩基で可溶化し、515nmの波長で自動プレートリーダーで吸光度を読み取った。7つの吸光度測定値[5つの濃度レベル(Ti)での化合物の存在下での時間ゼロ、(Tz)、対照成長、(C)、および試験成長]を使用して、各試験化合物濃度レベルで成長率を計算した。[(Ti-Tz)/(C-Tz))×100=50から、50%の成長阻害(GI50)を計算し、これは、化合物のインキュベーション中の対照細胞における正味タンパク質増加(SRB染色によって測定される)の50%の減少をもたらした。HCT116細胞およびH1299細胞の両方で一貫した結果が得られた。表IIIは、試験した例示化合物のGI50を示す。
例示化合物の細胞周期進行に対する効果を分析した。腫瘍細胞、マウス膵臓癌細胞Panc2細胞、またはヒト膵臓癌Panc1細胞を、ミトコンドリア脱共役に48時間有効な濃度で個々の化合物で処理したが、対照群は、ビヒクルDMSOで処理した。次いで、細胞を氷上で氷冷した70%エタノールで30分間固定した。その後、固定化した細胞にヨウ化プロピジウム(PI)(Sigma、P4170、1mg/ml)溶液5μlおよびRNAseA(Sigma、R-4875)溶液50μlを添加し、次いで、室温の暗所で30分間保持した。フローサイトメトリーにより細胞の細胞周期プロファイルを分析した。図4に示すように、例示化合物28は、G0/G1期で癌細胞を停止させた。以下の表IVは、G0/G1細胞周期停止を誘導する際の他の例示的化合物の活性をまとめたものである。
例示化合物である化合物28のインビボでの抗癌有効性を、十分に確立された膵臓癌マウスモデルの肝転移を使用して調べた。マウス膵臓癌細胞であるPanc2細胞(25万個の細胞)を免疫不全NOD-scidマウスの脾臓に注射した。マウスを2群(各群n=6)にランダム化し、一方の群には通常の飼料を与え、第2の群には750ppmの化合物28を含有する飼料を与えた。3週間後、マウスを屠殺し、対照および化合物28処置マウスにおいて、膵臓癌の肝転移を観察し(図5)、定量した(図6)。図5Aに示すように、未処置マウスは、大量の肝腫瘍転移を有した。対照的に、図5Bに示すように、化合物28で処置したマウスは、肝腫瘍転移をほとんどまたは全く示さなかった。抗腫瘍有効性を図6で定量したところ、化合物28での処置は、転移性腫瘍結節の数および転移性腫瘍体積の両方を劇的に減少させ、化合物28がインビボで優れた抗癌活性を有することを実証した。重要なことに、治療用投与レジメン下での化合物28の血漿中濃度を測定したところ、ミトコンドリアを脱共役するための有効濃度の範囲内にある。
ミトコンドリアは、宿主細胞との共生関係を形成する古細菌である。細菌の原形質膜は、ミトコンドリアのものと類似の電子輸送鎖およびATPシンターゼを含有する。例示化合物を抗生物質活性について試験した。最小阻害濃度(MIC)を決定するための試験を行った。試験化合物および基準化合物をDMSOに溶解してストック溶液(6.4または3.2mg/ml)を調製し、V底96ウェルプレート中の最終濃度の100倍で連続2倍化合物希釈物を調製すると、合計11の希釈物は、6.4または3.2mg/ml~0.0625mg/mlの範囲であった。2μlの100×ワーキング溶液のアリコートを、丸底96ウェルプレートのカラム1からカラム11に移し、2μlのDMSOをカラム12(模擬対照として)に移した。調製した微量希釈プレートをMIC試験に使用した。
Claims (15)
- 式(I)の化合物:
式中、
R1aは、水素、任意選択的に置換されたC1~C6アルキル、任意選択的に置換されたC2~C6アルケニル、任意選択的に置換されたC2~C6アルキニル、任意選択的に置換されたC3~C10シクロアルキル、任意選択的に置換されたC3~C10ヘテロシクリル、任意選択的に置換されたC3~C10アリール、任意選択的に置換されたC3~C10ヘテロアリール、C1~C6ペルフルオロアルキル、ハロ、シアノ、ニトロ、任意選択的に置換されたアミノ、-C(O)NHR5、-C(O)NR5R6、-C(O)H、-C(O)R7、-C(O)OH、および-C(O)OR5から成る群から選択され、
R1bおよびR1dの各々は、独立して、水素、C1~C6ペルフルオロアルキル、およびハロから成る群から選択され、
R1cは、クロロであり、
R2は、水素、単糖類、二糖類、C(O)NR5R6、およびC(O)R7から成る群から選択され、前記単糖類および二糖類は、アノマー中心でフェノール性酸素に結合してグリコシド結合を形成し、
R3は水素であり、あるいはR2とR3 が一緒にカルボニル基を形成し、それらが結合している原子と一緒になって、6員複素環カルバメートを形成し、
R4a、R4b、R4c、およびR4dの各々は、独立して、水素、C1~C6ペルフルオロアルキル、シアノ、ニトロ、およびハロから成る群から選択され、
R5およびR6の各々は、独立して、任意選択的に置換されたC1~C6アルキル、およびC1~C6アルキルスルホニルから成る群から選択され、あるいはR5およびR6は、それらが結合している窒素と一緒になって、任意選択的に置換されたC3~C6ヘテロシクリルを形成し、
R7は、任意選択的に置換されたC3~C6ヘテロシクリルであり、
但し、R2は水素である時、R1aは任意選択的に置換されたC1~C6アルキルである、式(I)の化合物またはその薬学的に許容される塩、または溶媒和物。 - 請求項1記載の化合物において、R1aは、水素、C1~C6アルキル、C3~C6シクロアルキル、(N,N-ジメチルアミノ)C1~C6アルキル、および((C1~C6アルキルスルホニル)アミノ)C1~C6アルキルからなる群から選択される化合物。
- 請求項1記載の化合物において、
R2は、水素、C(O)NR5R6およびC(O)R7から選択され、
あるいは、R2およびR3 が一緒にカルボニル基を形成し、それらが結合している原子と一緒になって、6員複素環カルバメートを形成し、
R5およびR6は、それらが結合している窒素と一緒になって、任意選択的に置換されたC3~C6ヘテロシクリルを形成し、
R7は、2-ピロリジニルである化合物。 - 請求項1記載の化合物において、それぞれの場合におけるR4bおよびR4dは、独立して、水素、トリフルオロメチル、シアノ、ニトロ、およびフルオロから成る群から選択される化合物。
- 請求項1記載の化合物、またはその薬学的に許容される塩と、薬学的に許容されるキャリアまたは希釈剤とを有する医薬組成物。
- 請求項2記載の化合物、またはその薬学的に許容される塩と、薬学的に許容されるキャリアまたは希釈剤と、を有する医薬組成物。
- 請求項6記載の化合物、またはその薬学的に許容される塩と、薬学的に許容されるキャリアまたは希釈剤と、を有する医薬組成物。
- 請求項11記載の化合物、またはその薬学的に許容される塩と、薬学的に許容されるキャリアまたは希釈剤と、を有する医薬組成物。
- 請求項12記載の化合物、またはその薬学的に許容される塩と、薬学的に許容されるキャリアまたは希釈剤と、を有する医薬組成物。
- 請求項7記載の化合物、またはその薬学的に許容される塩と、薬学的に許容されるキャリアまたは希釈剤と、を有する医薬組成物。
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CN109415363B (zh) | 2021-07-20 |
US20170334869A1 (en) | 2017-11-23 |
EP3458454A1 (en) | 2019-03-27 |
WO2017201313A1 (en) | 2017-11-23 |
EP3458454A4 (en) | 2019-12-18 |
US10227315B2 (en) | 2019-03-12 |
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