JP2021500400A - 広域スペクトルの抗ウイルス治療のための組成物及び方法 - Google Patents
広域スペクトルの抗ウイルス治療のための組成物及び方法 Download PDFInfo
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Abstract
Description
本発明の主題は、−−−である装置、システム及び方法を提供するものである。
ヒト胚腎臓(HEK293T)細胞、ヒト肺癌(A549)細胞、ヒト肝臓癌(Huh7)細胞、ヒト横紋筋肉腫(RD)細胞、ヒト上皮2型(HEp−2)細胞、ヒト肺腺癌(Calu−3)細胞、ヒト白血病(THP−1)単球、マジンダービーイヌ腎臓(MDCK)細胞、アフリカミドリザル腎臓(Vero)細胞及びVero−E6細胞をATCCから得て、供給業者/製造業者によって示唆されるように培養培地中で維持した。香港大学の施設内倫理委員会によって承認されたプロトコルに従ってHong Kong Red Cross Blood Transfusion Serviceから回収された成人健常者血液試料からヒト末梢血単球由来マクロファージ(MDM)を単離した。本発明者らが以前に記載したように[45]充分に確立されたプロトコルに従って単球の調製及び分化を行った。全ての細胞系を5%のCO2中において37℃で培養した。前記試験で用いられた全ての細胞系は、Plasmo Test(InvivoGen)によって決定されるようにマイコプラズマの混入がないことが確認された。ウイルス感染の際、化合物を有する又は有さないFBS不含培地中で前記感染細胞を維持した。インフルエンザA型ウイルス株A/香港/415742/2009(H1N1)pdm09をMDCK細胞内で培養した。MERS−CoV(HCoV−EMC/2012)及びSARS−CoV(GZ50)をVero−E6細胞内で増殖させた。ZIKV(Puerto Rico株PRVABC59)の臨床分離株をVero細胞内で増幅した。エンテロウイルスA71(SZ/HK08−5)をRD細胞内で培養した。ヒトアデノウイルス5型(AdV5)の臨床分離株をA549細胞内で増殖させた。インビボ抗ウイルス試験のために、二種のマウス適合ウイルス株、すなわちA/Anhui/1/2013(H7N9)及びMERS−CoV(HCoV−EMC/2012)を用いた。本発明者らがわずかな修飾と共に以前に記載したように[46]プラーク形成単位アッセイ(プラークアッセイ)及び/又は50%組織培養感染用量(TCID50)アッセイによって、全ての培養ウイルスを滴定した。全てのウイルスストックを、アリコートで、−80℃で保持した。本発明者らが以前に記載したように[47]生物学的安全性レベル2又は3の施設を用いて生ウイルスによる全ての実験を行った。
特に明記しない限り、Cayman Chemical(米国ミシガン州)からAM580を購入し、Sigma−Aldrich(米国ミズーリ州)から他の化学阻害剤を得た。本発明者らが以前に記載したように[48]、モルモット抗MERS−CoV NP血清によってMERS−CoV NPを検出した。ヒトRAR−α(Abcam)、SREBP1(Santa Cruz)、SREBP2(Santa Cruz)、n−SREBP1(Novus Biological)、n−SREBP−2(Novus Biological)、Flag−タグ(Sigma)に対する一次抗体を購入し、関連した実験で用いた。免疫蛍光染色のための二次抗体としてAlexa Fluor488ヤギ抗pg IgG(H+L)抗体(Invitrogen)を利用した。核及び細胞膜の染色のために、それぞれ4’,6−ジアミジノ−2−フェニルインドール(DAPI、Sigma)及びPhalloidin−Atto 647N(Sigma)を用いた。Life TechnologiesからSilencer SelectヒトSREBP1 siRNA、Silencer SelectヒトSREBP2 siRNA及びSilencer Select siRNA陰性対照を得た。脂質滴(LD)を染色するために蛍光中性脂質染料4,4−ジフルオロ−1,3,5,7,8−ペンタメチル−4−ボラ−3a,4a−ジアザ−s−インダセン(BODIPY493/503、Invitrogen)を使用し、細胞内コレステロールの視覚化のためにFilipin III(Cayman chemical)を用いた。アジド標識分子、すなわちAzido−AM580の特異的標識化及び検出のために、ホスフィン活性蛍光染料DyLight(商標)488−Phosphine(Invitrogen)を利用した。
FASプロモータルシフェラーゼは、Bruce Spiegelman博士からの寄贈であり(Addgeneプラスミド#8890)、HMG−CoA合成酵素プロモータを含むpSynSRE−T−Luc(Addgeneプラスミド#60444)、pcDNA3.1−2×FLAG−SREBP−2(Addgeneプラスミド#26807)、pcDNA3.1−2×FLAG−SREBP−1c(Addgeneプラスミド#26802)は、Timothy Osborne博士からの寄贈であった。ルシフェラーゼ構築物IFNβ−Luc及びISRE−Lucは、Dong−yan JIN博士(香港大学)によって提供された。
スクリーニングのために189の生体活性脂質を含む化合物ライブラリ(Cayman Chemical、米国ミシガン州)を購入した。ライブラリ回収は、プロスタグランジン、受容体作動薬及び拮抗剤並びにセラミド誘導体を含んだが、それは、Gタンパク質共役型受容体スクリーニング及び通常の薬理学的スクリーニングのために理想的である。本発明者らがわずかな修飾と共に以前に記載したように[49]、MTT系CPE阻害アッセイを行った。抗MERS−CoV阻害剤を同定するために、三つの組における96ウェル培養平板におけるコンフルエントHuh7細胞(4×l04細胞/ウェル)を、感染多重度(MOI)が0.1でMERS−CoVに感染させた。ウイルス吸収の1時間後、接種物を除去し、その後薬物含有培地(10μM)を加えた。24時間後、前記ウェルに10μLの5mg/mL MTT溶液(Sigma)を加えた。単層を、4時間、上記のようにインキュベートした。最後に、0.01MのHClを有する100μLの10%SDSを加え、さらに5%CO2により37℃で一晩インキュベートした。640nmにおける参照波長で570nmにおいて活性を読み取った。抗インフルエンザウイルス阻害剤をスクリーニングするため、0.01MOIにおいてインフルエンザウイルスA型(H1N1)pdm09ウイルスにMDCK細胞を感染させたが、細胞生存率のスコアリングのための時点は感染の48時間後(hpi)であった。他の手順は上記と同じであった。次に、プラーク低減アッセイ(PRA)を用いた用量反応分析[50]を行い、一次ヒットのインビトロ抗ウイルス有効性を評価したが、ここで個別の化合物を連続的に希釈し(10μM、5μM、2.5μM、1.25μM及び0.625μM)、MERS−CoV又はインフルエンザA型(H1N1)ウイルス阻害について試験した。
各化合物の選択指数(SI)を、50%阻害濃度(IC50)に対する50%の細胞の細胞毒性濃度(CC50)の比として算出した。CC50値を、製造業者のプロトコルに従ってMTTアッセイ(Invitrogen)及びCellTiter−Gloアッセイ(Promega)によって決定したが、一方でプラーク低減アッセイ又は示される通りのウイルス負荷低減アッセイ[51]によってIC50データを得た。GraphPad Prism6を用いて、CC50及びIC50の両方を算出した。
細胞内染色のために、細胞を、PBS中における10mMのEDTAによって剥離し、4%パラホルムアルデヒド中で固定し、PBS中における0.1%Triton X−100で透過処理した。本発明者らが以前に記載したように[52]標準的手法に従ってフローサイトメトリーのためのイムノ染色を行った。BD FACSCanto IIフローサイトメータ(BD Biosciences)を用いて前記フローサイトメトリーを行い、Flow Jo vX(Tree Star)を用いてデータを分析した。
ヒトジペプチジルペプチダーゼ4トランスジェニック(DPP4)C57BL/6マウス及びBALB/c雌性マウスを生物学的安全性レベル3のハウジング内に保持し、随時に標準ペレット飼料及び水にアクセスさせた。全ての実験プロトコルは、香港大学におけるAnimal Ethics Committeeによって承認され、生物学的安全性レベル3の動物施設の標準操作手順を遵守して行われた。MERS−CoV及びインフルエンザウイルスA型(H7N9)を、本発明者らが以前に記載したように、それぞれDDP4マウスモデル[23]及びBALB/cマウスモデル[47]において試験した。AM580の抗MERS−CoV活性を検討するために、合計36匹のマウス(18匹/群)を評価した。麻酔後、マウスに対して、50PFUのMERS−CoVを含む20μLのウイルス懸濁剤を鼻腔内に(i.n.)接種した。ウイルス攻撃の6時間後、治療的処置を腹腔内(i.p.)接種によって開始した。一方の群のマウスに200μLのAM580をi.p.で3日間接種した(12.5mg/kg/日)。第二の群のマウスに未処置対照としてPBS中における200μLの0.1%DMSOをi.p.で投与した。動物の生存及び病気のシグナルを14日間又は死亡までモニタした。各群における四匹のマウスを、それぞれ攻撃後の2日及び4日にランダムに安楽死させた。本発明者らが以前に記載したように[47]、ウイルス滴定及びH&E組織病理学的分析のためにマウスの肺及び脳を回収した。AM580の抗インフルエンザ効力をインビボで評価するために、BALB/cマウス(18匹/群)に対して、20μLのウイルス懸濁剤、すなわち100PFUのインフルエンザA型(H7N9)ウイルスを鼻腔内に(i.n.)接種した。ウイルス攻撃の6時間後、治療的処置をi.n.鼻腔内投与によって開始した。一方の群のマウスに20μLのi.n.によるAM580(1mg/kg/日)を接種した。第二の群のマウスを陽性対照として20μLのi.n.によるザナミビル(2mg/kg/日)で処置した。第三の群に、未処置対照として、i.n.でPBS中における0.1%DMSOを与えた。AM580、ザナミビル又はPBSの一日当たり二回のi.n.による投与を三日間行った(合計六回投与/匹)。動物の生存及び病気のシグナルを14日間又は死亡までモニタした。ウイルス滴定及びH&E組織病理学的分析のために、それぞれ攻撃後の3日及び6日に肺組織(四匹/群)を回収した。
香港大学/Hospital Authority Hong Kong West Clusterの施設内倫理委員会によって承認されたプロトコルの下で、外科的切除を受けた患者から正常小腸を得た。次いで、腸管オルガノイドを、本発明者らが他で記載したように[23]、MERS−CoV感染のために培養し、分化させた。105PFUのMERS−CoVの接種物を用いて、一滴のインテスチノイド(50〜100のインテスチノイドを含む)に0.1の推定MOIを感染させた。前記接種物を除去した後、ウイルス接種された前記インテスチノイドをPBSで濯ぎ、次いで、マトリゲル内に再包埋し、AM580(20μM)を含有するか又は含有しない培養培地を有する48ウェル平板内で培養した。示された時点で、細胞内ウイルス負荷の定量のために前記インテスチノイドを採取したが、一方で細胞外上清のウイルス滴定のために無細胞マトリゲル及び培養培地を併用した。
エクスビボ肺組織培養及びウイルス感染実験は、香港大学/Hospital Authority Hong Kong West Clusterの施設内倫理委員会によって承認された。肺外科的切除を受けている患者から新鮮な正常肺組織を得た。本発明者らが以前に記載したように[45]、ウイルス感染及びその後の免疫蛍光染色のための実験条件を行った。簡潔に言えば、肺組織を2mm3の立方体に切断し、続いて、37℃で1時間、2×108PFU/mLのMERS−CoV接種物によって感染させるか、又は擬感染させた。接種後、組織立方体を、固定及び凍結切片化の前に、10%ヒト血清及びペニシリン/ストレプトマイシンを補充したDMEM/F12培地中で維持した。
Calu−3細胞を擬感染させるか、又はMOIが2のMERS−CoVに感染させ、AM580(20μM)を含有する(又は含有しない)DMEM培地中でインキュベートした。24hpiにおいて、個別の群のトータルRNA(n=3)を回収した。RNA−Seq技術[53]を用いて、MERS−CoV感染及びAM580処置の後の改変された遺伝子発現を分析した。Beijing Genomics Institute(BGI)によって配列決定ライブラリを構築し、配列決定したが、それによって、低い質の濾過後に平均して23,977,722の清浄な読み取りを生成した。HISAT[54]/Bowtie2[55]を用いて、清浄な読み取りを参照にマップした。AM580処置を行った又は行っていないMERS感染試料における差次的に発現した遺伝子を、経路強化分析及びクラスタ分析を行うためにDAVIDサーバに提出した。
Calu−3細胞を擬感染させたか、又はMOIが2のMERS−CoVに感染させ、AM580(20μM)を含有する(又は含有しない)DMEM培地中でインキュベートした。8hpi及び24hpiにおいて、それぞれ細胞を回収し、細胞脂質抽出に供した。プラークアッセイによってウイルス感染性の不活性化を確認した。公開された論文[56]に従って、少しの修飾と共に試料調製を行った。簡潔に言えば、150mM重炭酸アンモニウムの氷冷急冷緩衝液を加えて細胞を解離し、次いで前記細胞を抗クロロホルムチューブにトランスファーした。2ミリリットルのクロロホルム/メタノール(v/v2:1)を前記チューブに加えた後、4℃で10分間、4500rpmでボルテックス及び遠心分離を行った。底相をガラスバイアルに回収し、−80℃における貯蔵のために真空濃縮器によって乾燥した。LC−MS分析の際、前記乾燥試料を300μLのクロロホルム/メタノール(v/v2:1)中において再構成し、Synapt G2−HDMS質量分光計システム(Waters Corp.、米国マサチューセッツ州)に結合されたAcquity UPLCシステムを用いて分析した。Waters ACQUITY BEH C18カラム(1.7μm、2.1×100mm、I.D.、1.7mm、Waters、Milford、米国マサチューセッツ州)でクロマトグラフィを行った。移動相は、(A)水中における0.1%酢酸及び(B)アセトニトリルから成った。以下の通りの勾配プログラムの下で0.4mL/分の流速で分離を行った:0.5%B(0〜1.5分間)、0.5〜8%B(1.5〜2分間)、8〜35%B(2〜7分間)、35〜70%B(7〜13分間)、70〜99.5%B(13〜29分間)、99.5%B(29〜36分間)。陽性モード及び陰性モードで質量スペクトルデータを取得した。全ての実験のためのロック塊としてロイシンエンケファリンを用いた。重大な代謝産物の推定上の同定及び構造的解明を可能にするため、フラグメンテーションのために衝突エネルギーを20〜40eVの範囲で用いた。
MERS−CoV感染によって誘導された二重膜ビヒクル(DMV)を観察するために電子顕微観察を利用した。Vero細胞を6ウェル平板で増殖させた。MOIが3のMERS−CoVによる1時間の感染(又は擬感染)の後、細胞培養培地を20μΜのAM580又は対照としての0.1%DMSOを含む新鮮な培地に置き換えた。12時間後、前記細胞培養培地を除去した。前記細胞をPBSで洗浄し、トリプシン処理し、さらなる処理及び対比染色のために4%ホルムアルデヒドで固定した[57]。香港大学のElectron Microscope Unit内で画像を取得した。
Protein Data BankデータベースからSREBP1(PDBコード:1AM9)及びSREBP2(PDBコード:1UKL)の結晶構造を検索した。PymolによってSREBP1ダイマー及びSREBP2ダイマーを抽出した。I−TASSERサーバを用いて、SREBP2において失われた残基をモデル化した[58]。MaestroにおけるProtein Preparation Wizardモジュールでタンパク質モデルを調製した[59]。AM580の3D配座異性体をPubChemデータベースからダウンロードした[60]。Leadfinder v1.81を用いて、超精密方法によりドッキングシミュレーションを行った[61]。
AM580の細胞内視覚化のためにアジド−AM580を用いたが、一方でAM580結合標的のプルダウン試験のためにAM580dpを設計し、合成した。
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Claims (75)
- 前記RNAウイルスが、コロナウイルス科、ピコルナウイルス科、フラビウイルス科及びオルソミクソウイルス科から成る群から選択されるウイルス科から選択される、請求項1に記載の方法。
- 前記RNAウイルスが、MERS−CoV、SARS−CoV、ZIKAV、インフルエンザ及びエンテロウイルスから成る群から選択される、請求項1に記載の方法。
- 前記DNAウイルスがアデノウイルスである、請求項1〜3の何れか一項に記載の方法。
- 前記DNAウイルスがヒトアデノウイルスである、請求項4に記載の方法。
- 前記抗ウイルス化合物がレチノイド誘導体である、請求項1〜5の何れか一項に記載の方法。
- 前記R1がテトラリン基を含み、前記R2が安息香酸を含む、請求項1〜6の何れか一項に記載の方法。
- 前記架橋基(BG)がアミド又はエチレン基を含む、請求項1〜7の何れか一項に記載の方法。
- 前記レチノイド誘導体が、医薬的に許容し得る担体と共に投与される、請求項1〜7の何れか一項に記載の方法。
- 前記レチノイド誘導体が、医薬的に活性な化合物と併用して投与される、請求項1〜9の何れか一項に記載の方法。
- 前記医薬的に活性な化合物が、抗ウイルス化合物、抗炎症化合物、鎮痛性化合物、制吐剤及び抗生剤から成る群から選択される、請求項10に記載の方法。
- 前記炎症プロセスが間質性炎症又は肺胞障害を含む、請求項12に記載の方法。
- 前記炎症プロセスが、炎症誘発性サイトカインのウイルス誘導活性化の抑制を含む、請求項12又は13に記載の方法。
- 前記炎症誘発性サイトカインが、TNF−α、IL−1β及びIL−8から成る群から選択される、請求項14に記載の方法。
- 前記RNAウイルスが、コロナウイルス科、ピコルナウイルス科、フラビウイルス科及びオルソミクソウイルス科から成る群から選択されるウイルス科から選択される、請求項12〜15の何れか一項に記載の方法。
- 前記RNAウイルスが、MERS−CoV、SARS−CoV、ZIKAV、インフルエンザ及びエンテロウイルスから成る群から選択される、請求項12〜16の何れか一項に記載の方法。
- 前記DNAウイルスがアデノウイルスである、請求項12〜17の何れか一項に記載の方法。
- 前記DNAウイルスがヒトアデノウイルスである、請求項18に記載の方法。
- 前記化合物がレチノイド誘導体である、請求項12〜19に記載の方法。
- 前記R1がテトラリン基を含み、前記R2が安息香酸を含む、請求項12〜20の何れか一項に記載の方法。
- 前記架橋基(BG)がアミド又はエチレン基を含む、請求項12〜21の何れか一項に記載の方法。
- 前記化合物が医薬的に許容し得る担体と共に投与される、請求項12〜22の何れか一項に記載の方法。
- 前記化合物が、医薬的に活性な化合物と併用して投与される、請求項12〜23の何れか一項に記載の方法。
- 前記医薬的に活性な化合物が、抗ウイルス化合物、抗炎症化合物、鎮痛性化合物、制吐剤及び抗生剤から成る群から選択される、請求項24に記載の方法。
- 前記化合物が、AM580、タミバロテン及びベキサロテンから成る群から選択される、請求項12〜25の何れか一項に記載の方法。
- 前記脂質生成プロセスの調節が、RAR−αシグナル伝達及び宿主自然免疫応答の活性化から独立している、請求項27に記載の方法。
- 前記脂質生成プロセスの調節が、前記細胞のウイルス感染から生じる脂質代謝の調節不全を修正する、請求項27又は28に記載の方法。
- 前記脂質生成プロセスの調節が、リゾホスホリピド生成のダウンレギュレーションを阻害することと、リン脂質生成のアップレギュレーションを阻害することと、から成る群から選択される活性を含む、請求項27に記載の方法。
- 前記脂質生成プロセスの調節が、遺伝子の発現の調節を含む、請求項27に記載の方法。
- 前記遺伝子が、脂肪酸代謝又はコレステロール合成に関連する、請求項31に記載の方法。
- 前記脂質生成プロセスの調節が、SREBP依存性脂質生合成の低減を含む、請求項27に記載の方法。
- 前記脂質生成プロセスの調節が、(1)第一標的核酸配列へのn−SREPB1の結合の阻害、及び(2)第二核酸配列へのnSREBP2の結合の阻害、の内の少なくとも一つの阻害を含む、請求項33に記載の方法。
- 前記脂質生成プロセスの調節が、nSREBP1又はnSREBP2のSRE認識ドメインのTyr335における、又は、の近くにおける前記化合物の結合を含む、請求項34に記載の方法。
- 前記脂質生成プロセスの調節が、遺伝子のSREBP依存性転写活性化の阻害を含む、請求項34又は35に記載の方法。
- 前記遺伝子が、HMGCSプロモータ又はFASプロモータを含む、請求項36に記載の方法。
- 前記RNAウイルスが、コロナウイルス科、ピコルナウイルス科、フラビウイルス科及びオルソミクソウイルス科から成る群から選択されるウイルス科から選択される、請求項27〜37の何れか一項に記載の方法。
- 前記RNAウイルスが、MERS−CoV、SARS−CoV、ZIKAV、インフルエンザ及びエンテロウイルスから成る群から選択される、請求項27〜38の何れか一項に記載の方法。
- 前記DNAウイルスであって、前記DNAウイルスがアデノウイルスである、請求項27〜41の何れか一項に記載の方法。
- 前記DNAウイルスがヒトアデノウイルスである、請求項40に記載の方法。
- 前記化合物がレチノイド誘導体である、請求項27〜41に記載の方法。
- 前記R1がテトラリン基を含み、R2が安息香酸を含む、請求項27〜42の何れか一項に記載の方法。
- 前記架橋基(BG)がアミド又はエチレン基を含む、請求項27〜43の何れか一項に記載の方法。
- 前記化合物が医薬的に許容し得る担体と共に投与される、請求項27〜44の何れか一項に記載の方法。
- 前記化合物が、医薬的に活性な化合物と併用して投与される、請求項27〜445の何れか一項に記載の方法。
- 前記医薬的に活性な化合物が、抗ウイルス化合物、抗炎症化合物、鎮痛性化合物、制吐剤及び抗生剤から成る群から選択される、請求項46に記載の方法。
- 前記化合物が、AM580、タミバロテン及びベキサロテンから成る群から選択される、請求項27〜47の何れか一項に記載の方法。
- 前記ウイルス複製プロセスの阻害が、ウイルス感染によって誘導される二重膜小胞を減少させることを含む、請求項49に記載の方法。
- 前記ウイルス複製プロセスの阻害がパルミトイル化を低下させることを含む、請求項49又は50に記載の方法。
- 前記RNAウイルスが、コロナウイルス科、ピコルナウイルス科、フラビウイルス科及びオルソミクソウイルス科から成る群から選択されるウイルス科から選択される、請求項49〜51の何れか一項に記載の方法。
- 前記RNAウイルスが、MERS−CoV、SARS−CoV、ZIKAV、インフルエンザ及びエンテロウイルスから成る群から選択される、請求項49〜52の何れか一項に記載の方法。
- 前記DNAウイルスがアデノウイルスである、請求項49〜53の何れか一項に記載の方法。
- 前記DNAウイルスがヒトアデノウイルスである、請求項54に記載の方法。
- 前記化合物がレチノイド誘導体である、請求項49〜55に記載の方法。
- 前記R1がテトラリン基を含み、前記R2が安息香酸を含む、請求項49〜56の何れか一項に記載の方法。
- 前記架橋基(BG)がアミド又はエチレン基を含む、請求項49〜57の何れか一項に記載の方法。
- 前記化合物が医薬的に許容し得る担体と共に投与される、請求項49〜58の何れか一項に記載の方法。
- 前記化合物が、医薬的に活性な化合物と併用して投与される、請求項49〜59の何れか一項に記載の方法。
- 前記医薬的に活性な化合物が、抗ウイルス化合物、抗炎症化合物、鎮痛性化合物、制吐剤及び抗生剤から成る群から選択される、請求項60に記載の方法。
- 前記化合物が、AM580、タミバロテン及びベキサロテンから成る群から選択される、請求項49〜61の何れか一項に記載の方法。
- 前記R1が芳香環部分(R1b)及び非芳香環部分(R1a)を含む、請求項63に記載の化合物。
- 前記R1がテトラリン基を含み、前記R2が安息香酸を含む、請求項64に記載の化合物。
- 前記連結基(LG)が、長さが2個〜20個の炭素を含む、請求項63〜65の何れか一項に記載の化合物。
- 前記連結基(LG)が、さらなる環構造を含む、請求項63〜66の何れか一項に記載の化合物。
- 前記連結基(LG)が、カルボキシミド、アゾ−チオ結合、エステル、エーテル、チオエステル、チオエーテル及びヒドラジン結合から成る群から選択される一つ以上の非炭素−炭素結合を含む、請求項63〜66の何れか一項に記載の化合物。
- 前記連結基(LG)が、アミド及びエチレン基から成る群から選択される、請求項63〜66の何れか一項に記載の化合物。
- 前記R2が、窒素、酸素及び硫黄から成る群から選択される一つ以上の非炭素原子を含む、請求項63〜69の何れか一項に記載の化合物。
- 前記荷電基(CG)が、少なくとも部分的負電荷を含む、請求項63〜70の何れか一項に記載の化合物。
- 前記荷電基(CG)が、カルボキシレート、ホスフェート及びスルフェートから成る群から選択される部分を含む、請求項63〜71の何れか一項に記載の化合物。
- 前記縮合環部分(R1)及び前記環部分(R2)の内の少なくとも一つが、さらなる芳香環構造又は非芳香環構造を含む、請求項63〜72の何れか一項に記載の化合物。
- 前記縮合環部分(R1)及び前記環部分(R2)の内の少なくとも一つがハロゲン化物を含む、請求項63〜73の何れか一項に記載の化合物。
- 前記化合物が、AM580、タミバロテン及びベキサロテンから成る群から選択される、請求項63に記載の化合物。
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