RU2018145459A - Способ лечения фиброза печени - Google Patents
Способ лечения фиброза печени Download PDFInfo
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- RU2018145459A RU2018145459A RU2018145459A RU2018145459A RU2018145459A RU 2018145459 A RU2018145459 A RU 2018145459A RU 2018145459 A RU2018145459 A RU 2018145459A RU 2018145459 A RU2018145459 A RU 2018145459A RU 2018145459 A RU2018145459 A RU 2018145459A
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- inhibitor
- agonist
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Claims (48)
1. Способ лечения фиброза печени у пациента, включающий назначение пациенту, который в этом нуждается, эффективного количества соединения Формулы I:
Формула I
или фармацевтически приемлемой его соли, где
R1 – галоген или алкил C1-6;
R2 – водород, галоген, C1-6 алкил, C1-6 алкокси, C1-6 галоалкил, C1-6 галоoалкокси или
- CN;
R3 – водород, галоген или C1-6 алкил;
R4 – водород, галоген или С1-6 алкил;
каждый R5 - независимо C1-6 алкил, - О, или-NH2;
n – это 0, 1, 2, или 3; и
каждый из A1, A2 и A3- это -CH- или -N-, где, по меньшей мере, один из A1, A2 или A3 – это -N-.
2. Способ по п. 1, в котором
R1 – галоген или метил;
R2 – галоген или C1-6 галоалкил;
R3 – галоген или C1-6 алкил;
R4 - водород;
N –это 0;
A2 – это -CH-; и
A3- это -N-.
3. Способ по п. 1, в котором соединение выбирают из группы, состоящей из :
или фармацевтически приемлемой их соли.
4. Способ по п. 1, в котором соединение это
или фармацевтически приемлемая его соль.
5. Способ по п. 1, в котором фиброз печени связан с неалкогольным стеатогепатитом (NASH).
6. Способ по п. 1, в котором фиброз печени связан с неалкогольной жировой болезнью печени (NAFLD).
7. Способ по п. 1, в котором фиброз печени связан с одним или более развивающимся циррозом, первичным желчным холангитом, первичным склерозирующим холангитом, желчной атрезией, холестатическим заболеванием печени, хроническим заболеванием печени, инфекцией гепатита С, алкогольной болезнью печени, холистеринемией и гиперлипидемией.
8. Способ по п. 1, в котором фиброз печени - это нецирротический печеночный фиброз.
9. Способ по п. 1, в котором NASH связан с сахарным диабетом 2 типа (T2DM).
10. Способ по п. 1, в котором NASH связан с метаболическим синдромом (MS).
11. Способ по п. 1, дополнительно включающий назначение пациенту одного или более дополнительного терапевтического соединения.
12. Способ по п. 11, в котором одно или более дополнительных терапевтических соединений выбраны из одного или более ингибитора транспортера 2 глюкозы натрия, агониста глюкагон - подобного пептида 1, ингибитора галектина-3, стимулятора трансаминазы, агониста IL-10, сенсибилизатора инсулина, агониста PPAR гамма, агониста бета рецептора тироидного гормона, ингибитора каспазы, ингибитора дипептидил пептидазы IV, агониста PPAR альфа; агониста PPAR дельта, агониста PPAR, агониста фарнезоидного X рецептора, ингибитора гомолога лизил оксидазы 2, ингибитора протеинкиназы MEKK-5, модулятора метил CpG 2 связывающего белка, ингибитора трансглутаминазы, стимулятора миелин основного белка, стимулятора канала хлорида, антагониста хемокина CCR3, антагониста хемокина CCR5, антагониста ангиотензин В-1 рецептора, ингибитора транскрипционного фактора SREBP 1, модулятора бета рецептора PDGF, лиганда FGF-21, антагониста IL-17, ингибитора rho связаной протеинкиназы 2, ингибитора котранспортера желчных кислот натрия, ингибитора стеароил CoA десатуразы-1, агониста рецептора FGF1, стимулятора клото бета, ингибитора лиганда фактора роста соединительной ткани, липопротеинового ингибитора липазы; ингибитора транскрипционного фактора SREBP, лиганда FGF-19, антагониста CD3, ингибитора кавеолина 1, агониста амилинового рецептора; агониста кальцитонина, стимулятора NAD-зависимой деацетилазы сиртуина, ингибитора PDE 5, ингибитора NADPH 1 оксидазы, ингибитора NADPH 4 оксидазы, ингибитора NADPH оксидазы, агониста фактора роста гепатоцита, антагониста интегрин альфа -V/бета-6, антагониста TGF бета, стимулятора NAD-зависимой деацетилазы сиртуина, агониста рецептора никотиновой кислоты 1, стимулятора гидроксилазы фенилаланина, ингибитора мембранной медный амин оксидазы, ингибитора рибосомного белка киназы S6 1, ингибитора высоко мобильной группы белка B1, антагониста TLR 4, ингибитора катепсина B, лиганда фактора роста гепатоцита, лиганда гамма интерферона, ингибитора АСЕ, ингибитора HMG CoA редуктазы или фармацевтически приемлемой их соли.
13. Способ по п. 12, в котором одно или более дополнительное терапевтическое соединение выбрано из одного или более агониста фарнезоидного X рецептора (FXR), двойного агониста TGR5/FXR, агониста PPAR альфа, агониста PPAR гамма, агониста PPAR дельта или фармацевтически приемлемой их соли.
14. Способ по п. 12, в котором одно или более дополнительное терапевтическое соединение выбрано из одного или более дапаглифлозина пропандиола, дапаглифлозина, лираглютида, GR-MD-02, семаглютида, сенекривирока, F-351, пег-илодецикина, ипраглифлозина, урсодезоксихолевой кислоты, целесвелама, пиоглитазона, VK-2809, эмрикасана, линаглиптина, элафибранора, DS-102, Px 102, Px 103, GS-4997, симтузумаба, DUR-928, меркаптамина, олезокцима, кобипростона, бертидимумаба, MDV-4463, ирбесартана, GS-9674, BOT-191, MGL-3196, BMS-986171, PEG-FGF21, LJN-452, CF-102, KD-025, воликсибата, калия этанолата гидрата воликсибата, арамхола, типелукаста, NGM-313, FG-3019, CAT-2003, NGM-282, TRX-318, IONIS-DGAT2Rx, IMM-124-E, RG-125, норурсодеоксихолиевой кислоты, KBP 042, лейцина, метформина, силденафила, A-4250, GKT-831, BB-3, сароглитазара, BG-00011, алипоген типарвовека, MB-12066, безводного бетаина, ARI-3037MO, ГепаСтема, PXS-4728A, CIGB-500, олтипраза, омега 3 карбоновых кислот, дапаглифлозина, ремоглифлозин этабоната, ремоглифлозина, LC-280126, JKB-121, DWP-10292, VBY-376, VBY-825, изосапент этилового эфира, капсулы Фучжен Хиайю, интерферона, ацетилсалициловой кислоты, гидрохлоротиазида, эналаприла, аторвастатина, NC-101, TCM-606F, обетихолиновой кислоты, INT 767, GNF-5120, криптохинона-D, фексарамина, каприлового триглицерида, эвоглиптина, GM-CT-01, витамина Е высокой дозировки (> 400 iU/d) или фармацевтически приемлемой их соли.
15. Способ по п. 1, в котором соединение улучшает чувствительность к инсулину.
16. Способ по п. 1, в котором соединение улучшает переносимость глюкозы.
17. Способ по п. 1, в котором соединение понижает печеночное накопление триглицерида.
18. Способ по п. 1, в котором соединение понижает концентрацию аланин аминотрансферазы (АLT).
19. Способ по п. 1, в котором соединение понижает концентрацию аспарт аминотрансферазы (AST).
20. Способ по п. 1, в котором соединение понижает содержание коллагена печени.
21. Способ по п. 1, в котором соединение понижает содержание макрофагов печени.
22. Способ по п. 1, в котором соединение понижает содержание макрофагов жировой ткани.
23. Способ по п. 1, в котором соединение понижает сальниковое содержание жировой ткани.
24. Способ по п. 1, в котором соединение понижает уровни холестерина печени.
25. Способ по п. 1, в котором соединение понижает уровни билирубина.
26. Способ по п. 1, в котором соединение уменьшает фиброз печени.
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| BR112018075734A2 (pt) | 2016-06-13 | 2019-04-02 | Gilead Sciences, Inc. | composto, composição farmacêutica, método para tratar um paciente com uma doença ou condição mediada pelo menos em parte por fxr, e, uso de um composto. |
| CA2968836C (en) | 2016-06-13 | 2025-09-02 | Gilead Sciences, Inc. | FXR MODULATING COMPOUNDS (NR1H4) |
| US11197870B2 (en) | 2016-11-10 | 2021-12-14 | Galmed Research And Development Ltd | Treatment for hepatic fibrosis |
| IL311409A (en) * | 2016-11-10 | 2024-05-01 | Galmed Res And Development Ltd | Aramchol for use in fibrosis treatment |
| ES2927019T3 (es) | 2017-03-28 | 2022-11-02 | Gilead Sciences Inc | Combinaciones terapéuticas para el tratamiento de enfermedades hepáticas |
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| US20210322324A1 (en) * | 2018-08-14 | 2021-10-21 | Avolynt | Method for treating primary sclerosing cholangitis |
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