JP6661643B2 - 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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- JP6661643B2 JP6661643B2 JP2017535955A JP2017535955A JP6661643B2 JP 6661643 B2 JP6661643 B2 JP 6661643B2 JP 2017535955 A JP2017535955 A JP 2017535955A JP 2017535955 A JP2017535955 A JP 2017535955A JP 6661643 B2 JP6661643 B2 JP 6661643B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- 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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Description
OH、OAc(Ac=COCH3、アセテート)、OBz(Bz=COPh、ベンゾイル)、OBn(Bn=ベンジル)、OTs(Ts=トシル、p-トルエンスルホニル)、OMs(Ms=メタンスルホニル)、OSiR3、OTf(Tf=トリフルオロメタンスルホニル)、OTHP(THP、テトラヒドロピラン)、OCOR、OR、NH2、NHBoc(Boc=tert-ブチルオキシカルボニル)、NHAc(Ac=COCH3、アセテート)、NHBz(Bz=COPh、ベンゾイル)、NHTs (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(-OSO 2 OH)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;
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。
「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。
上記用語(例えば、「アルキル」、「ヘテロアルキル」、「アリール」及び「ヘテロアリール」)はそれぞれ、指定された遊離基の置換及び非置換の形式の両方を含むことを意味する。それぞれの遊離基の好ましい置換基は下記のとおり。
HBV及びHDV感染測定。感染前にHepG2NTCP 細胞をPMMにて12〜24時間培養し、その後、200マルチゲノム当量(mge)のHBV、又は500mgeのHDVで接種し、5%のPEG8000のPMMの存在下で、37℃で約24時間培養する。具体的な測定法で指定されているように、前記細胞に試験される化学品を加える。感染後、接種物にPMMを再度補充する。感染後5日目(dpi)に、感染が検出された。
10mLの一口丸底フラスコの中で、(4R)-4-((3R,7S,9S,10S,13R,14S,17R)-3-アミノ-7-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)ペンタン酸メチルエステル(120.0mg、0.3mmol、1.0当量)を室温で、DMF(2.0mL)に溶解する。 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。
100mLの一口丸底フラスコの中で、(4R)-4-((3R,7S,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) ペンタン酸(10.0g、25.5mmol、1.0当量)を室温で、MeOH(100mL)に溶解する。それからPTSA(触媒)を添加する。添加完了後、混合物を80℃で14時間撹拌する。混合物を濃縮し、濃いNaHCO3でpH>8まで塩基化し、それからEAで抽出し、減圧下で濃縮し、目標物(9.3g)を得る。これはNMRで確認される。
25mLの一口丸底フラスコの中で、(4R)-4-((3S,7S,9S,10S,13R,14S,17R)-7-ヒドロキシ-10,13-ジメチル-3-((メチルスルホニル)オキシ)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)ペンタン酸メチルエステル(1.2g、2.5mmol、1.0当量)を室温で、DMF(10mL)に溶解する。それからNaN3(325mg、5.0mmol、2.0当量)を添加する。添加完了後、混合物を80℃で1.5時間撹拌する。混合物を水で洗浄し、EAで抽出し、濃縮し、カラムクロマトグラフィー(PE:EA=5:1)で純化し、黄色固体としての目標物(700mg)を得る。これはNMRで確認される。
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。
表 T の実例は表 Sに類推して得られる。
Claims (5)
- 下記より選択されるUDCAの胆汁酸誘導体。
- HBV又は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)を阻害するのに用いられる請求項1に記載の胆汁酸誘導体を含む組成物。
- 異なる第二種のHBV又はHDV 薬と同時に処方された又は同時に包装された又は同時に投与された請求項1に記載の胆汁酸誘導体又はその塩を含む組成物。
- 前記薬はラミブジン(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、又はブロムスルフサレインである請求項3に記載の組成物。
- HBV又は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)を阻害するの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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CN104662036B (zh) * | 2012-04-25 | 2018-11-09 | 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 |
EP2917231B1 (en) | 2012-11-12 | 2019-03-06 | Ruprecht-Karls-Universität Heidelberg | Lipopeptides for use in treating liver diseases and cardiovascular diseases |
PL3043865T3 (pl) * | 2013-09-11 | 2021-07-05 | Institut National De La Santé Et De La Recherche Médicale (Inserm) | SPOSOBY I KOMPOZYCjE FARMACEUTYCZNE W LECZENIU ZAKAŻENIA WIRUSEM ZAPALENIA WĄTROBY TYPU B |
CN106794188B (zh) * | 2014-09-28 | 2022-12-02 | 华辉安健(北京)生物科技有限公司 | 聚合胆汁酸衍生物抑制乙型肝炎病毒和丁型肝炎病毒和ntcp运输 |
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EP3197459A4 (en) | 2018-06-20 |
US11701369B2 (en) | 2023-07-18 |
CN106794188A (zh) | 2017-05-31 |
JP6802862B2 (ja) | 2020-12-23 |
CN115990171A (zh) | 2023-04-21 |
US20170266206A1 (en) | 2017-09-21 |
CN106794188B (zh) | 2022-12-02 |
EP3197459A1 (en) | 2017-08-02 |
JP2017530194A (ja) | 2017-10-12 |
JP2019077710A (ja) | 2019-05-23 |
WO2016045642A1 (en) | 2016-03-31 |
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