JP6802862B2 - 重合胆汁酸誘導体によるb型肝炎ウイルス及びd型肝炎ウイルスとntcp輸送の阻害 - Google Patents
重合胆汁酸誘導体によるb型肝炎ウイルス及びd型肝炎ウイルスとntcp輸送の阻害 Download PDFInfo
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Classifications
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- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
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Description
Iの構造を独立して有する:
ヘテロアルキニル、アルコキシル、又はヘテロアルコキシル、それぞれの環状及び置換の形式を含み、アリール及びヘテロアリール、中で、ヘテロ形式がN、O、P及びSのような1〜4個のヘテロ原子を含み;又は置換もしくは非置換の(C1-C4)アルキル、(C2-C4)アルケニル、(C6-C8)アルケニル、(C2-C4)アルキニル、(C6-C8)アルキニル、(C1-C4)アルコキシル、(C6-C8)アルコキシル、3-オキセタルニルオキシ、3-テトラヒドロフラニルオキシ、Cl、F、フッ素置換された(C1-C2)アルキル、(C1-C4)アルキル-SO2-、(C3-C6)シクロアルキル、又はN、O、P、Si又はSからそれぞれ独立して選択された1又は2個のヘテロ原子を有する(C5-C6)ヘテロ環、又はヒドロキシル、ハロホルミル、カルボニル、アルデヒド、カルボキシル、エステル、アセタール、 カルボキサミド、ヒドロペルオキシル、エポキシド、過酸化物、オキシム、アミン(第一級アミン、第二級アミン及び第三級アミンを含む)、アミド、イミン、イミド、第四級アンモニウム塩、アミンオキシド、アジ化物、アゾ、アルジミン、イソシアニド、イソシアネート、イソチオシアネート、ジアゾ、アジド、アジリジン、ジアジリジン、ヒドラジン、ヒドラゾン、シアネート、硝酸エステル、ニトリル、亜硝酸エステル、ニトリド、ニトロ、ニトロソ、シラン、アルキルシラン、シロキサン、ハロシラン、ホスフィン、フォスフォライト、フォスフェート、チオホスホン酸エステル、第四ホスホニウム塩、ホスホノ、リン化物、硫化物、亜硫酸エステル、スルホン酸エステル、チオシアネート、チオ硫酸エステル、スルホキシド、スルフィミド、スルホン、スルホキシイミン、スルホニウム、及びスルフヒドリルのような官能基。
(Ts=トシル、p-トルエンスルホニル)、NHTf(Tf=トリフルオロメタンスルホニル)、NHMs(Ms=メタンスルホニル)、NHSiR3、NHR;NBn2(Bn=ベンジル)、NTf2(Tf=トリフルオロメタンスルホニル)、NHCOR及びNR1R2、-N2、-N3;リン酸(-OP(O)(OH)2)、硫酸(-OSO2OH)又はカルボン酸 (-OCOH)、カルボン酸エステル(-OCOR);フォスフォライト(-OP(O)mO-)又はフォスフェート(-OP(OR)mO-)、スルホン酸エステル、硫酸エステル(-OS(O)mO-)、亜硫酸エステル(-OS(OR)mO-)、二亜硫酸エステル又はピロ硫酸エステル、中で、mは0、1及び2に等しく、R、R1及びR2のそれぞれは独立してH、最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル遊離基、非置換の又はハロゲン、(C1-C4)-アルキル又は(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミン、エチレンオキシドでモノ、ビス又はトリ置換された3〜15個の炭素原子を有するシクロ-(アルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル)遊離基又はフェニル又はベンジル遊離基;
ベンジル遊離基である。
ベンジル遊離基、又は
本出願は、慢性的なHBV及びHDV感染を治療することを含み、垂直伝播及び事故的被曝による新HBV感染を防ぎ、肝細胞が有毒な胆汁酸又は他のNTCP輸送物を取り込まないように肝臓移植後のHBVの再発及び指定されたNTCP阻害の病状を予防する。特定の実施形態と実施例の説明は例として提供されるものであり、限定することを目的とするものではない。本質的に類似の結果がもたらされるように、重要でない様々なパラメータは変更又は修正されてもよいと当業者は容易に理解できる。
プロピオニル、ブチリル、デカノイル、ピバロイル、
ベンゾイル等を含むことを意味する。
2-ナフチル、
4-ビフェニル及び
1,2,3,4-テトラヒドロナフタレンが含まれる。「ヘテロアリール」という用語は、N、O、及びSより選択される0〜6個のヘテロ原子を含むアリール基(又は環)を指し、前記窒素原子及び硫黄原子は任意に酸化され、かつ前記窒素ヘテロ原子は任意に四級化される。ヘテロアリール基は、ヘテロ原子を介して、分子の残りの部分に結合することができる。ヘテロアリール基の非限定的な例には、1-ピロリル、2-ピロリル、3-ピロリル、3-ピラゾリル、2-イミダゾリル、4-イミダゾリル、ピラジニル、2-オキサゾリル、4-オキサゾリル、2-フェニル-4-オキサゾリル、5-オキサゾリル、3-イソオキサゾリル、4-イソオキサゾリル、5-イソオキサゾリル、2-チアゾリル、4-チアゾリル、5-チアゾリル、2-フリル、3-フリル、2-チエニル、3-チエニル、2-ピリジル、3-ピリジル、4-ピリジル、2-ピリミジル、4-ピリミジル、5-ベンゾチアゾリル、プリニル、2-ベンゾイミダゾリル、5-インドリル、1-イソキノリル、5-イソキノリル、2-キノキサリニル、5-キノキサリニル、3-キノリル及び6-キノリルが含まれる。
of Sciences)のものを使用する。これらを10%のウシ胎児血清(FBS、Gibco)が補充されたダルベッコ改良イーグル培地(DMEM;Invitrogen)を用いて 37℃で培養し、2日毎に継代する。HepG2NTCP安定細胞株はHepG2細胞から生成され、10%のFBS及び500μg/ml G418が補充されたDMEMにおいて維持される。HepG2-NTCP安定細胞株をコラーゲン(BD)がコートされたプレート又は皿において培養する。これらの細胞をPTH維持培地(PMM)において24 時間培養し、それからウイルス感染、ペプチド結合、基質取り込み、及び他のNTCPに関係する実験を行う。
登録番号 EU554535.1)のpre-S1ドメイン由来であり、それは前59個の残基を含み、アミノ末端ミリストイル化修飾及びカルボキシル末端共役フルオレセインイソチオシアネート(FITC)を有する;myr(+)47ペプチドは、HBVのpre-S1ドメインの2〜47位の残基を含み、N-末端ミリストイル化を有する。これらペプチドは全てSunLight peptides Inc.(Beijing、China)より合成される。1C10はHBVコアタンパク質を識別するマウスモノクローナル抗体(mAb)である。4G5は特異的にHDVデルタ抗原を標的としたマウスmAbであり、#36抗体は特異的にNTCPを標的としたマウスmAbである。mAbは全て実験室で通常のハイブリドーマ技術で開発されたものである。ほとんどの天然胆汁酸はSigma Aldrichから購入した。活性が15.3 Ci/mmol(0.185 TBq/mmol)である[3H]標識タウロコール酸塩と、液体シンチレーションカクテル(Ultima GOLDTMXR)はPerkin Elmerから購入した。
[3H]タウロコール酸塩取り込み測定は前に説明されたプロトコルに照らして実行される(60)。概して言えば、HepG2-NTCP細胞をPMMにて12〜24時間培養し、取り込み測定の前に指定された化学品を使用し又は使用せずに処理する。基質取り込み測定について、通常、細胞と0.5μl (0.5μCi)のNa+ Ringer’s溶液に溶解した[3H]-タウロコール酸塩を、化学品の存在下又は非存在下で、37℃で10分間インキュベートする。その後、 細胞をPBSで1回洗浄し、1%のTritonX-100を含むH2O 100μlを用いて室温で5分間分解する。分解物を液体シンチレーション管に移し、液体シンチレーションカクテル(Ultima GOLDTM XR)(Perkin Elmer、USA)900μlと混合する。Perkin Elmer 1450 LSC液体シンチレーションカウンター及びルミネッセンスカウンターで液体シンチレーションカウントを行う。
その後、細胞を室温で0.5%のTrition X-100/PBSで10分間透過処理し、37℃で3%のBSAで1時間ブロックし、それから5μg/mlのHBcAgを識別するマウスmAb1C10とインキュベートし、それからFITC共役第二抗体で染色する。核はDAPIで青色に染色される。染色された細胞を蛍光顕微鏡(Nikon)で画像形成する。HDV感染について、5 dpiにて、HDV感染した細胞を室温で100%のメタノールで10分間固定し、それから5μg/mlのFITC共役4G5で細胞内デルタ抗原を染色し、DAPIで核を青色に染色する。Eclipse
Ti蛍光顕微鏡(Nikon)で画像を収集し、代表的な画像を示す。
それから2-((4R)-4-((3R,7S,8R,9S,10S,13R,14S,17R)-3,7-ジヒドロキシ-10,13-ジメチルヘキサデカヒドロ-1H-シクロペンタ[α]フェナントレン-17-イル)ペンタンアミド)エタンスルホン酸(TUDCA)(20mg、0.04mmol、1.0当量)、N,N-ジイソプロピルエチルアミン(DIEA)(15.5mg、0.12mmol、3.0当量)、4-ジメチルアミノピリジン(DMAP)(5mg、0.04mmol、1.0当量)及びN,N'-ジシクロヘキシルカルボジイミド(DCC)(16.5mg、0.08mmol、2.0当量)を添加する。添加完了後、混合物を室温で14時間撹拌する。混合物を濃縮し、分取HPLCにより純化し、白色固体としての目標物(5.0mg)を得る。
(EDC)(23.0mg、0.12mmol、2.4当量)を添加する。添加完了後、混合物を室温で14時間撹拌する。混合物を濃縮し、直接使用する。
それから2-グルタル酸(39.6mg、0.3mmol、1.0当量)、DIEA(116.0mg、0.9mmol、3.0当量)、 DMAP(36mg、0.3mmol、1.0当量)及びEDC(173mg、0.9mmol、3.0当量)を添加する。添加完了後、混合物を室温で24 時間撹拌する。混合物をUPLCで確認し、濃縮し、カラムクロマトグラフィー(DCM:MeOH=20:1)で純化し、目標物(52mg)を得る。
HClでpH<3まで酸性化し、EAで抽出し、濃縮し、直接使用する。前記粗生成物を室温で、DMF(1.5mL)に溶解する。それから2-アミノエタンスルホン酸(17.8mg、0.142mmol、6.0当量)、DIEA(24.7mg、0.192mmol、8.0当量)、DMAP(3mg、0.024mmol、1.0当量)及びEDC(13.6mg、0.71mmol、3.0当量)を添加する。添加完了後、混合物を室温で14時間撹拌する。混合物を濃縮し、pre-HPLCで純化し、白色固体としての目標物(4.4mg)を得る。これはNMRで確認される。表 Pの実例は表 Oに類推して得られる。
HClでpH<3まで酸性化し、EAで抽出し、濃縮し、カラムクロマトグラフィー(DCM:MeOH=20:1)で純化し、目標物(47mg)を得る。これはUPLC/MSで確認される。
Claims (5)
- 下記より選択される重合胆汁酸。
- HBV若しくはHDV感染を治療する、又はヒトナトリウムタウロコール酸共輸送ポリペプチド(hNTCP)を阻害するために用いられる請求項1に記載の重合胆汁酸を含む組成物。
- 異なる第二のHBV若しくはHDV薬と同時に処方され、又は同時に包装され、又は同時に投与される、請求項1に記載の重合胆汁酸又はその塩を含む組成物。
- 前記HBV若しくはHDV薬はラミブジン(Epivir)、アデホビル(Hepsera)、テノホビル(Viread)、テルビブジン(Tyzeka)、エンテカビル(Baraclude)、ボセンタン、オキシステロール、エゼチミブ、レセルピン、ロスバスタチン、及びブロムスルフサレインからなる群から選択される少なくとも1種である、請求項3に記載の組成物。
- HBV若しくはHDV感染を治療する、又はヒトナトリウムタウロコール酸共輸送ポリペプチド(hNTCP)を阻害するために用いられる、請求項3又は4のいずれかに記載の組成物。
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CA2632903C (en) | 2005-12-02 | 2015-11-24 | Vianova Labs, Inc. | Treatment of cancer and other diseases |
US8076303B2 (en) | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
CN101134769A (zh) * | 2006-08-28 | 2008-03-05 | 曾昭斌 | 熊去氧胆酸恩替卡韦酰胺及其制法和用途 |
CN101439187B (zh) | 2007-11-19 | 2011-11-30 | 中国人民解放军军事医学科学院毒物药物研究所 | 胆汁酸-抗肝炎病毒药物偶合物及其制药用途 |
CN101182331A (zh) | 2007-11-30 | 2008-05-21 | 中国药科大学 | 阿德福韦酯胆酸类衍生物及其制备方法和用途 |
CN102123716B (zh) | 2008-04-03 | 2013-09-18 | 春堤公司 | 用于治疗病毒感染的化合物和方法 |
CN101307076A (zh) | 2008-05-30 | 2008-11-19 | 秦引林 | 一种具有肝靶向抗乙肝病毒作用的前药 |
US8729058B2 (en) * | 2009-10-27 | 2014-05-20 | Michael Zasloff | Methods and compositions for treating and preventing viral infections |
WO2011066260A2 (en) * | 2009-11-25 | 2011-06-03 | Michael Zasloff | Formulations comprising aminosterols |
CN109354623B (zh) * | 2012-04-25 | 2022-06-24 | 华辉安健(北京)生物科技有限公司 | 乙肝肝炎病毒功能性受体的组成以及相关应用 |
DK2917231T3 (da) * | 2012-11-12 | 2019-06-11 | Univ Heidelberg Ruprecht Karls | Lipopeptider til anvendelse ved behandling af leversygdomme og hjerte-kar-sygdomme |
EA031003B1 (ru) * | 2013-09-11 | 2018-10-31 | Инсерм (Энститю Насьональ Де Ля Сантэ Э Де Ля Решерш Медикаль) | Способы и фармацевтические композиции для лечения вызванных вирусом гепатита в инфекций |
JP6661643B2 (ja) * | 2014-09-28 | 2020-03-11 | フアフイ ヘルス リミテッドHuahui Health Ltd. | 重合胆汁酸誘導体によるb型肝炎ウイルス及びd型肝炎ウイルスとntcp輸送の阻害 |
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