JP2015517528A - イミダゾール−ビフェニル−イミダゾールコアを有する抗ウイルス性化合物 - Google Patents
イミダゾール−ビフェニル−イミダゾールコアを有する抗ウイルス性化合物 Download PDFInfo
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- JP2015517528A JP2015517528A JP2015512798A JP2015512798A JP2015517528A JP 2015517528 A JP2015517528 A JP 2015517528A JP 2015512798 A JP2015512798 A JP 2015512798A JP 2015512798 A JP2015512798 A JP 2015512798A JP 2015517528 A JP2015517528 A JP 2015517528A
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- 125000003107 substituted aryl group Chemical group 0.000 description 1
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本出願は、2013年3月14日に出願された米国仮特許出願第13/828,104号、2012年3月16日に出願された米国仮特許出願第61/647,979号、2012年3月17日に出願された米国仮特許出願第61/648,414号の優先権を主張し、これら全ての米国仮特許出願は、その全体が参考として援用される。
C型肝炎は、肝疾患によって特徴付けられる肝臓の慢性ウイルス性疾患として認識されている。肝臓を標的とする薬物は広範に使用されており、有効性を示してきたが、毒性および他の副作用によってこれらの有用性は限定されている。C型肝炎ウイルス(HCV)の阻害剤は、HCVによる感染の確立および進行を制限するのに、ならびにHCVについての診断アッセイにおいて、有用である。
一実施形態において、
ここで本開示のある特定の実施形態について詳細に言及するが、これらの例は添付の構造および式において例示されている。本開示は列挙された実施形態と結びつけて記載されるが、それらは本開示をこれらの実施形態に限定することを意図していないことが理解される。これに反して、本開示は、全ての変更、改変および均等物をカバーすることが意図され、これらは実施形態によって定義されるような本開示の範囲内に含まれ得る。
本開示の化合物は、今までに公知である化合物を除外する。しかし、抗ウイルスの目的で抗ウイルス特性を有する(例えば、動物において抗ウイルス効果を生じさせる)ことが従前公知でなかった化合物を使用することは本開示の範囲内である。米国に関して、本明細書における化合物または組成物は、米国特許法§102のもとで先行した化合物、または米国特許法§103のもとで自明な化合物を除外する。
「プロドラッグ」という用語は、本明細書において使用する場合、生物系に投与されると、HCV活性を阻害する本開示の化合物(「活性阻害性化合物」)を生じさせる任意の化合物を指す。化合物は、(i)自発性化学反応(複数可)、(ii)酵素触媒化学反応(複数可)、(iii)光分解、および/または(iv)代謝性化学反応(複数可)の結果としてプロドラッグから形成され得る。
本開示の文脈において、保護基は、プロドラッグ部分および化学的保護基を含む。
本開示の化合物は、キラル中心、例えば、キラル炭素またはリン原子を有し得る。このように、本開示の化合物は、エナンチオマー、ジアステレオマーおよびアトロプ異性体を含めた全ての立体異性体を含む。さらに、本開示の化合物は、任意または全ての非対称キラル原子において富化または分割された光学異性体を含む。言い換えると、描写から明らかなキラル中心は、非ラセミまたはラセミ混合物として提供される。ラセミおよびジアステレオマー混合物の両方、ならびに単離または合成されて、それらの鏡像異性またはジアステレオマーパートナーを実質的に含まない個々の光学異性体は全て、本開示の範囲内である。ラセミ混合物は、周知の技術、例えば、光学活性な補助剤、例えば酸または塩基によって形成されるジアステレオマー塩の分離、それに続く光学活性な物質へ変換し戻すことなどによって、これらの個々の実質的に光学的に純粋な異性体に分離される。殆どの場合、所望の光学異性体は、所望の出発材料の適当な立体異性体から開始する立体特異的反応によって、またはエナンチオ選択的反応によって合成される。
本開示の化合物の生理学的または薬学的に許容される塩の例には、適当な塩基、例えば、アルカリ金属(例えば、ナトリウム)、アルカリ土類金属(例えば、マグネシウム)、アンモニウムおよびNX4 +(式中、Xは、C1〜C4アルキルである)などに由来する塩が含まれる。水素原子またはアミノ基の生理学的に許容される塩は、有機カルボン酸、例えば、酢酸、安息香酸、乳酸、フマル酸、酒石酸、マレイン酸、マロン酸、リンゴ酸、イセチオン酸、ラクトビオン酸およびコハク酸など;有機スルホン酸、例えば、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸およびp−トルエンスルホン酸など;ならびに無機酸、例えば、塩酸、硫酸、リン酸およびスルファミン酸などの塩を含む。ヒドロキシ基の化合物の生理学的に許容される塩は、適切なカチオン、例えば、Na+およびNX4 +(式中、Xは、HまたはC1〜C4アルキル基から独立に選択される)などと組み合わせた前記化合物のアニオンを含む。
本開示の別の態様は、HCVを含有することが疑われる試料を本開示の化合物または組成物で処置するステップを含む、HCVの活性を阻害する方法に関する。
本開示の化合物は、通常の実施を踏まえて選択される慣例的な担体および添加剤と共に製剤化される。錠剤は、添加剤、流動促進剤、充填剤、および結合剤などを含有する。水性製剤は、無菌の形態で調製され、経口投与以外による送達を意図するとき、一般に等張性である。全ての製剤は、添加剤、例えば、Handbook of Pharmaceutical Excipients(1986年)において記載されるものなどを任意選択で含有する。添加剤には、アスコルビン酸および他の抗酸化剤、キレート剤、例えば、EDTAなど、炭水化物、例えば、デキストリン、ヒドロキシアルキルセルロース、ヒドロキシアルキルメチルセルロース、およびステアリン酸などが含まれる。製剤のpHは、約3〜約11の範囲であるが、通常約7〜10である。典型的には、化合物は、0.01ミリグラム〜2グラムの用量で投与される。一実施形態において、用量は、約10ミリグラム〜450ミリグラムである。化合物は、1日1回、2回または3回投与され得ることが企図されている。
1種または複数種の本開示の化合物(本明細書で活性成分と称する)は、処置される状態に対して適当な任意の経路によって投与される。適切な経路には、経口、直腸、経鼻、局所(口腔内頬側および舌下を含めた)、ならびに膣および非経口(皮下、筋内、静脈内、皮内、くも膜下腔内および硬膜外を含めた)などが含まれる。好ましい経路は、例えば、レシピエントの状態によって異なり得ることを理解されたい。本開示の化合物の利点は、これらが、経口的に生物が利用可能であり、経口的に投薬することができることである。
別の実施形態において、適切な組合せの非限定的例には、式(I)および(A1〜A4)の1種または複数種の化合物と、1種または複数種のインターフェロン、リバビリンまたはその類似体、HCV NS3プロテアーゼ阻害剤、アルファ−グルコシダーゼ1阻害剤、肝臓保護剤、HCV NS5Bポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤、HCV NS5Bポリメラーゼの非ヌクレオシド阻害剤、HCV NS5A阻害剤、TLR−7アゴニスト、シクロフィリン(cyclophillin)阻害剤、HCV IRES阻害剤、薬物動態増強剤、およびHCVを処置するための他の薬物または治療剤との組合せを含む。
1)インターフェロン、例えば、ペグ化rIFN−アルファ2b(PEG−Intron(登録商標))、ペグ化rIFN−アルファ2a(Pegasys(登録商標))、rIFN−アルファ2b(Intron(登録商標)A)、rIFN−アルファ2a(Roferon(登録商標)−A)、インターフェロンアルファ(MOR−22、OPC−18、Alfaferone(登録商標)、Alfanative(登録商標)、Multiferon(登録商標)、スバリン(subalin))、インターフェロンアルファコン−1(Infergen(登録商標))、インターフェロンアルファ−n1(Wellferon)、インターフェロンアルファ−n3(Alferon(登録商標))、インターフェロン−ベータ(Avonex(登録商標)、DL−8234)、インターフェロン−オメガ(omega DUROS(登録商標)、Biomed(登録商標)510)、アルブインターフェロンアルファ−2b(Albuferon(登録商標))、IFNアルファ−2b XL、BLX−883(Locteron(登録商標))、DA−3021、グリコシル化インターフェロンアルファ−2b(AVI−005)、PEG−Infergen、ペグ化インターフェロンラムダ−1(ペグ化IL−29)、およびbelerofon(登録商標);
2)リバビリンおよびその類似体、例えば、リバビリン(Rebetol(登録商標)、Copegus(登録商標))、およびタリバビリン(Viramidine(登録商標));
3)HCV NS3プロテアーゼ阻害剤、例えば、ボセプレビル(SCH−503034、SCH−7)、テラプレビル(VX−950)、TMC435350、BI−1335、BI−1230、MK−7009、VBY−376、VX−500、GS−9256、GS−9451、BMS−605339、PHX−1766、AS−101、YH−5258、YH5530、YH5531、ABT−450、ACH−1625、ITMN−191、AT26893、MK5172、MK6325、およびMK2748;
4)アルファ−グルコシダーゼ1阻害剤、例えば、セルゴシビル(MX−3253)、ミグリトール、およびUT−231B;
5)肝臓保護剤、例えば、エムリカサン(emericasan)(IDN−6556)、ME−3738、GS−9450(LB−84451)、シリビニン(silibilin)、およびMitoQ;
6)HCV NS5Bポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤、例えば、R1626、R7128(R4048)、IDX184、IDX−102、BCX−4678、バロピシタビン(NM−283)、MK−0608、ソホスブビル(GS−7977(以前はPSI−7977))、VLX−135(以前はALS−2200)、およびINX−189(現在BMS986094);
7)HCV NS5Bポリメラーゼの非ヌクレオシド阻害剤、例えば、PF−868554、VCH−759、VCH−916、JTK−652、MK−3281、GS−9190、VBY−708、VCH−222、A848837、ANA−598、GL60667、GL59728、A−63890、A−48773、A−48547、BC−2329、VCH−796(ネスブビル)、GSK625433、BILN−1941、XTL−2125、ABT−072、ABT−333、GS−9669、PSI−7792、およびGS−9190;
8)HCV NS5A阻害剤、例えば、AZD−2836(A−831)、BMS−790052、ACH−3102、ACH−2928、MK8325、MK4882、MK8742、PSI−461、IDX719、GS−5885、およびA−689;
9)TLR−7アゴニスト、例えば、イミキモド、852A、GS−9524、ANA−773、ANA−975(イサトリビン)、AZD−8848(DSP−3025)、およびSM−360320;
10)シクロフィリン阻害剤、例えば、DEBIO−025、SCY−635、およびNIM811;
11)HCV IRES阻害剤、例えば、MCI−067;
12)薬物動態増強剤、例えば、BAS−100、SPI−452、PF−4194477、TMC−41629、GS−9350(コビシスタット)、GS−9585、およびロキシスロマイシン(roxythromycin);ならびに
13)HCVを処置するための他の薬物、例えば、サイモシンアルファ1(Zadaxin)、ニタゾキサニド(Alinea、NTZ)、BIVN−401(ビロスタット(virostat))、PYN−17(アルチレックス(altirex))、KPE02003002、アクチロン(CPG−10101)、GS−9525、KRN−7000、civacir、GI−5005、XTL−6865、BIT225、PTX−111、ITX2865、TT−033i、ANA971、NOV−205、タルバシン、EHC−18、VGX−410C、EMZ−702、AVI4065、BMS−650032、BMS−791325、バビツキシマブ、MDX−1106(ONO−4538)、オグルファニド、およびVX−497(メリメポジブ)
からなる群から選択される1種または複数種の化合物と組み合わせられ得る。
また、本開示の範囲内に入るのは、本明細書に記載されている化合物のin vivoでの代謝産物である。このような生成物は、例えば、主に酵素的プロセスに起因して、投与した化合物の酸化、還元、加水分解、アミド化、およびエステル化などの結果生じ得る。したがって、本開示は、その代謝産物を生じさせるのに十分な期間、本開示の化合物と哺乳動物とを接触させることを含むプロセスによって生成される化合物を含む。このような生成物は典型的には、放射標識された(例えば、C14またはH3)本開示の化合物を調製し、これを検出可能な用量(例えば、約0.5mg/kg超)で動物、例えば、ラット、マウス、モルモット、サルなどに、またはヒトに非経口的に投与し、代謝が起こるのに十分な時間(典型的には、約30秒〜30時間)を置き、その変換生成物を尿、血液または他の生体試料から単離することによって同定される。これらの生成物は、標識されているので容易に単離される(他は代謝物中の残存するエピトープに結合することができる抗体を使用することによって単離される)。代謝物の構造は、慣例的な方式で、例えば、MSまたはNMR分析によって決定される。一般に、代謝物の分析は、当業者には周知の慣例的薬物代謝研究と同様の方法で行われる。変換生成物は、これらがin vivoで別の方法で見出されない限り、たとえそれらが、それら自体でHCV阻害活性を所有しなくても、本開示の化合物の治療的投薬についての診断アッセイにおいて有用である。
本開示はまた、本開示の組成物を作製する方法に関する。組成物は、適用可能な有機合成の技術のいずれかによって調製される。多くのこのような技術は、当技術分野で周知である。しかし、公知の技術の多くは、Compendium of Organic Synthetic Methods(John Wiley & Sons、New York)、第1巻、Ian T. HarrisonおよびShuyen Harrison、1971年;第2巻、Ian T. HarrisonおよびShuyen Harrison、1974年;第3巻、Louis S. HegedusおよびLeroy Wade、1977年;第4巻、Leroy G. Wade, Jr.、1980年;第5巻、Leroy G. Wade, Jr.、1984年;および第6巻、Michael B. Smith;ならびにMarch, J.、Advanced Organic Chemistry、第3版、(John Wiley & Sons、New York、1985年)、Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry.、第9巻、Barry M. Trost、編集長(Pergamon Press、New York、1993年、印刷)において詳述されている。本開示の化合物を調製するのに適した他の方法は、国際特許出願公開番号WO2006/020276に記載されている。
これらの例示的な方法の一般態様を、以下および実施例において記載する。下記のプロセスの生成物のそれぞれは、それに続くプロセスにおけるその使用の前に任意選択で分離、単離および/または精製される。
E−V−C(=O)−P−W−P−C(=O)−V−E(I)
(式中、
各Eは、独立に、
各Vは、独立に、
各Pは、独立に、
Wは、
Raは、水素またはクロロである)
の化合物、またはその薬学的に許容される塩もしくはプロドラッグを作製するための代表的な方法を提供する。
メチル{(2S,3R)−1−((2S,4S)−2−(4−クロロ−5−(4’−(4−クロロ−2−((2S,5S)−1−((2S,3R)−2−(メトキシカルボニルアミノ)−O−メチル−L−トレオニル)−5−メチルピロリジン−2−イル)−1H−イミダゾール−5−イル)ビフェニル−4−イル)−1H−イミダゾール−2−イル)−4−(メトキシメチル)ピロリジン−1−イル)−3−メトキシ−1−オキソブタン−2−イル}カルバメート(0.05g、39%)。LCMS−ESI+:C43H55Cl2N8O9についての計算値:896.34(M+);実測値:898.56(M+H+)。
細胞をベースとする抗HCV活性の評価:
抗ウイルス効力(EC50)を、ウミシイタケルシフェラーゼ(RLuc)をベースとするHCVレプリコンレポーターアッセイを使用して決定した。遺伝子型1および2a JFH−1についてのアッセイを行うために、安定なHCV 1a RLucレプリコン細胞(RLucレポーターをコードするジシストロニックな遺伝子型1a H77レプリコンを持つ)、安定なHCV 1b RLucレプリコン細胞(RLucレポーターをコードするジシストロニックな遺伝子型1b Con1レプリコンを持つ)、または安定なHCV2a JFH−1Rlucレプリコン細胞(RLucレポーターをコードするジシストロニックな遺伝子型2a JFH−1レプリコンを持つ;L31がNS5Aに存在する)を、EC50アッセイのために384ウェルプレート中に分注した。遺伝子型2a(M31がNS5Aに存在する)または2bについてのアッセイを行うために、RLuc−NeoレポーターをコードするNS5Aキメラ遺伝子型2a JFH−1レプリコン、および、遺伝子型2a J6株NS5A遺伝子または遺伝子型2b MD2b−1株NS5A遺伝子(両方ともM31が存在する)をそれぞれ、Huh−Lunet細胞中に一過的にトランスフェクト(t)するか、または安定して複製するレプリコン細胞(複数可)として確立した。EC50アッセイのためにどちらの細胞も384ウェルプレート中に分注した。遺伝子型3および4についてアッセイを行うために、Pi−RLucレポーターをコードするNS5Aキメラ遺伝子型1b Con1レプリコン、および、遺伝子型3a S52株NS5A遺伝子または遺伝子型4a ED43株NS5A遺伝子をそれぞれ、Huh−Lunet細胞中に一過的にトランスフェクト(t)し、これを続いて384ウェルプレート中に分注した。代わりに、安定なHCV 3a RLucレプリコン細胞(複数可)(RLucレポーターをコードするジシストロニックな遺伝子型3a S52レプリコンを持つ)、または安定なHCV4a RLucレプリコン細胞(複数可)(RLucレポーターをコードするジシストロニックな遺伝子型4a ED43レプリコンを持つ)を、Huh−7−由来細胞において確立し、EC50アッセイのために384ウェルプレート中に分注した。化合物を10mMの濃度でDMSOに溶解させ、手作業でまたは自動化したピペット機器を使用してDMSOで希釈した。3倍段階希釈した化合物を、細胞培養培地と手作業で混合し、播種した細胞に加えるか、または自動化した機器を使用して細胞に直接加えた。DMSOを陰性(溶媒;阻害なし)対照として使用し、プロテアーゼ阻害剤ITMN−191を陽性対照として>100×EC50の濃度で含んだ。72時間後、細胞を溶解させ、ウミシイタケルシフェラーゼ活性をメーカー(Promega−Madison、WI)によって推奨されるように定量化した。非線形回帰を行い、EC50値を計算した。
Claims (17)
- 請求項1もしくは請求項2に記載の化合物または薬学的に許容されるその塩、および少なくとも1種の薬学的に許容される担体を含む医薬組成物。
- 障害C型肝炎(HCV)の処置において使用するための、請求項3に記載の医薬組成物。
- HCVを処置するための少なくとも1種のさらなる治療剤をさらに含む、請求項3に記載の医薬組成物。
- 前記さらなる治療剤が、リバビリン、NS3プロテアーゼ阻害剤、HCV NS5Bポリメラーゼのヌクレオシドもしくはヌクレオチド阻害剤、アルファ−グルコシダーゼ1阻害剤、肝臓保護剤、HCVポリメラーゼの非ヌクレオシド阻害剤、またはこれらの組合せから選択される、請求項5に記載の医薬組成物。
- HCV NS5Bポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤をさらに含む、請求項3に記載の医薬組成物。
- 前記HCV NS5Bポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤が、リバビリン、ビラミジン、レボビリン、L−ヌクレオシドまたはイサトリビンから選択される、請求項7に記載の医薬組成物。
- 請求項1または2に記載の化合物、少なくとも1種のHCV NS5Bポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤、および少なくとも1種の薬学的に許容される担体を含む医薬組成物。
- インターフェロン、ペグ化インターフェロン、リバビリンまたはこれらの組合せをさらに含む、請求項9に記載の医薬組成物。
- 前記HCV NS5Bポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤が、ソホスブビルである、請求項9または10のいずれか一項に記載の医薬組成物。
- 請求項1または2に記載の化合物、少なくとも1種のNS3プロテアーゼ阻害剤、および少なくとも1種の薬学的に許容される担体を含む医薬組成物。
- ソホスブビルをさらに含む、請求項12に記載の医薬組成物。
- ヒト患者に、治療有効量の請求項1もしくは2に記載の化合物またはその薬学的に許容される塩もしくはプロドラッグを含む、医薬組成物を投与することを含む、C型肝炎を処置する方法。
- 前記患者にインターフェロンまたはペグ化インターフェロンを投与することをさらに含む、請求項14に記載の方法。
- 前記患者にリバビリンを投与することをさらに含む、請求項14〜15のいずれか一項に記載の方法。
- 医学療法において使用するための、請求項1もしくは2のいずれか一項に記載の化合物またはその薬学的に許容される塩もしくはプロドラッグ。
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US13/828,104 | 2013-03-14 | ||
PCT/US2013/041205 WO2013173492A1 (en) | 2012-05-16 | 2013-05-15 | Antiviral compounds with an imidazole - biphenyl - imidazole core |
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AU (1) | AU2013262784B2 (ja) |
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KR20190140486A (ko) * | 2010-11-17 | 2019-12-19 | 길리애드 파마셋 엘엘씨 | 항바이러스 화합물 |
PT3431477T (pt) | 2011-11-16 | 2020-12-15 | Gilead Pharmasset Llc | Imidazolilimidazolos condensados como compostos antivirais |
US9717712B2 (en) | 2013-07-02 | 2017-08-01 | Bristol-Myers Squibb Company | Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus |
US20150023913A1 (en) | 2013-07-02 | 2015-01-22 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
JP2016527232A (ja) | 2013-07-17 | 2016-09-08 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Hcvの治療に使用するためのビフェニル誘導体を含む組み合わせ |
EP4005560A1 (en) | 2013-08-27 | 2022-06-01 | Gilead Pharmasset LLC | Combination formulation of two antiviral compounds |
US9738629B2 (en) | 2014-01-23 | 2017-08-22 | Sunshine Lake Pharma Co., Ltd. | Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof |
MX2016012799A (es) * | 2014-04-02 | 2016-12-12 | Abbvie Inc | Metodos para tratar el virus de la hepatitis c. |
TWI721947B (zh) | 2014-06-11 | 2021-03-21 | 美商基利法瑪席特有限責任公司 | 抗病毒化合物的固態形式 |
BR112017013858A2 (pt) | 2014-12-26 | 2018-02-27 | Univ Emory | n4-hidroxicitidina e derivados e usos antivirais relacionados aos mesmos |
US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP3454856A4 (en) | 2016-05-10 | 2019-12-25 | C4 Therapeutics, Inc. | HETEROCYCLIC DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3 CARBON-BASED GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
KR102626210B1 (ko) | 2017-12-07 | 2024-01-18 | 에모리 유니버시티 | N4-하이드록시사이티딘 및 유도체 및 이와 관련된 항-바이러스 용도 |
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US20130309195A1 (en) | 2013-11-21 |
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