CL2013000069A1 - Compuestos derivados de heterociclos fusionados, moduladores s1p; composicion farmaceutica; y uso en enfermedades neurodegenerativas. - Google Patents

Compuestos derivados de heterociclos fusionados, moduladores s1p; composicion farmaceutica; y uso en enfermedades neurodegenerativas.

Info

Publication number
CL2013000069A1
CL2013000069A1 CL2013000069A CL2013000069A CL2013000069A1 CL 2013000069 A1 CL2013000069 A1 CL 2013000069A1 CL 2013000069 A CL2013000069 A CL 2013000069A CL 2013000069 A CL2013000069 A CL 2013000069A CL 2013000069 A1 CL2013000069 A1 CL 2013000069A1
Authority
CL
Chile
Prior art keywords
modulators
pharmaceutical composition
neurodegenerative diseases
compounds derived
fused heterocycles
Prior art date
Application number
CL2013000069A
Other languages
English (en)
Inventor
Pieter Smid
Bakker Wouter I Iwema
Hein K A C Coolen
Leonardus A J M Sliedregt
Dongen Maria J P Van
Hartog Jacobus A J Den
Original Assignee
Abbvie Bv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44358260&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CL2013000069(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbvie Bv filed Critical Abbvie Bv
Publication of CL2013000069A1 publication Critical patent/CL2013000069A1/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Compuestos derivados de heterociclos fusionados, moduladores S1P; composición farmacéutica; y uso en enfermedades neurodegenerativas.
CL2013000069A 2010-07-09 2013-01-08 Compuestos derivados de heterociclos fusionados, moduladores s1p; composicion farmaceutica; y uso en enfermedades neurodegenerativas. CL2013000069A1 (es)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US36278410P 2010-07-09 2010-07-09
EP10169107 2010-07-09
US201161446541P 2011-02-25 2011-02-25
EP11156007 2011-02-25

Publications (1)

Publication Number Publication Date
CL2013000069A1 true CL2013000069A1 (es) 2013-06-07

Family

ID=44358260

Family Applications (1)

Application Number Title Priority Date Filing Date
CL2013000069A CL2013000069A1 (es) 2010-07-09 2013-01-08 Compuestos derivados de heterociclos fusionados, moduladores s1p; composicion farmaceutica; y uso en enfermedades neurodegenerativas.

Country Status (27)

Country Link
US (3) US8796262B2 (es)
EP (1) EP2590980B1 (es)
JP (1) JP5973429B2 (es)
KR (1) KR101889694B1 (es)
CN (1) CN103068827B (es)
AR (1) AR082136A1 (es)
AU (1) AU2011275755B2 (es)
BR (1) BR112013000627B1 (es)
CA (1) CA2804137C (es)
CL (1) CL2013000069A1 (es)
CO (1) CO6670577A2 (es)
CR (1) CR20130056A (es)
DO (1) DOP2013000009A (es)
EC (1) ECSP13012416A (es)
ES (1) ES2653682T3 (es)
IL (1) IL224054A (es)
MX (1) MX2013000360A (es)
MY (1) MY161229A (es)
NZ (1) NZ605491A (es)
PE (1) PE20130592A1 (es)
PH (1) PH12013500004A1 (es)
RU (1) RU2576660C2 (es)
SG (1) SG186952A1 (es)
TW (1) TWI522361B (es)
UY (1) UY33496A (es)
WO (1) WO2012004373A1 (es)
ZA (1) ZA201300157B (es)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI543984B (zh) 2010-07-09 2016-08-01 艾伯維公司 作為s1p調節劑的螺-哌啶衍生物
USRE48301E1 (en) 2010-07-09 2020-11-10 Abbvie B.V. Fused heterocyclic derivatives as S1P modulators
JP2016011257A (ja) * 2012-10-23 2016-01-21 大日本住友製薬株式会社 テトラヒドロオキサゾロピリジン誘導体
EP3341369A1 (en) * 2015-08-28 2018-07-04 AbbVie Inc. Fused heterocyclic compounds as s1p modulators
WO2018083171A1 (en) 2016-11-02 2018-05-11 AbbVie Deutschland GmbH & Co. KG Spiro-compounds as s1p modulators
MX2022005085A (es) * 2019-10-31 2022-05-26 Escape Bio Inc Procesos para preparar un modulador del receptor s1p.
CA3159378A1 (en) * 2019-10-31 2021-05-06 ESCAPE Bio, Inc. Solid forms of an s1p-receptor modulator
CN115279740B (zh) * 2020-03-04 2025-02-28 南昌弘益药业有限公司 苯并2-氮杂螺[4.4]壬烷类化合物及其应用
CN117362316A (zh) * 2023-10-07 2024-01-09 康龙化成手性医药技术(宁波)有限公司 一种四氢吡咯并噻唑类化合物的合成方法

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1069387A1 (ru) * 1982-07-01 1985-11-30 Институт физико-органической химии и углехимии АН УССР Дигидрохлорид 5-/ @ -( @ -анизил)- @ -оксиэтил/ 2-(3,4-диметоксифенил)-1-метил-4,5,6,7-тетрагидроимидазо(4,5- @ )пиридина,обладающий спазмолитическим действием
GB2228432A (en) 1989-01-13 1990-08-29 Grayston Central Services Multi-role machine for heating and coating pipe welds.
JPH03206042A (ja) * 1990-01-06 1991-09-09 Takeda Chem Ind Ltd 降圧剤
JP2681589B2 (ja) 1992-12-28 1997-11-26 日揮株式会社 配管溶接継手の熱処理方法
JPH072848A (ja) 1993-04-23 1995-01-06 Sankyo Co Ltd モルホリンおよびチオモルホリン誘導体
GB9522845D0 (en) 1995-11-08 1996-01-10 Smithkline Beecham Plc Novel compounds
JP3822680B2 (ja) 1996-08-30 2006-09-20 新日本製鐵株式会社 誘導加熱された接合部の冷却方法および冷却装置
AU4691601A (en) 2000-04-21 2001-11-12 Shionogi & Co Oxadiazole derivatives having anticancer effects
FR2822727A1 (fr) 2001-04-03 2002-10-04 Gesal Ind Procede d'application d'un revetement resistant aux hautes temperatures, dispositif pour la mise en oeuvre de ce procede et objet pourvu dudit revetement
JP3649223B2 (ja) 2003-01-08 2005-05-18 株式会社日立製作所 配管系の熱処理方法および熱処理装置
JP4564952B2 (ja) * 2003-01-17 2010-10-20 メルク・シャープ・エンド・ドーム・コーポレイション 糖尿病の治療および予防のためのジペプチジルペプチダーゼ阻害薬としての３−アミノ−４−フェニルブタン酸誘導体
RU2006101055A (ru) 2003-06-12 2006-07-10 Би Ти Джи Интернэшнл Лимитед (Gb) Циклические гидроксиламины как психотропные соединения
US7550485B2 (en) 2003-10-14 2009-06-23 Wyeth Substituted N-heterocycle derivatives and methods of their use
GB0329498D0 (en) 2003-12-19 2004-01-28 Novartis Ag Organic compounds
GB0401332D0 (en) 2004-01-21 2004-02-25 Novartis Ag Organic compounds
GB0409744D0 (en) 2004-04-30 2004-06-09 Pfizer Ltd Novel compounds
AP2006003771A0 (en) 2004-04-30 2006-10-31 Warner Lambert Co Substituted morpholine compounds for the treatmentof central nervous system disorders
ES2398694T3 (es) * 2004-06-30 2013-03-21 Athersys, Inc. Derivados de azepina sustituidos como moduladores de receptores de serotonina
EP1804793A4 (en) 2004-10-22 2010-03-31 Merck Sharp & Dohme 2- (ARYL) AZACYCLYLMETHYL-CARBOXYLATE, SULPHONATE, PHOSPHONATE, PHOSPHINATE AND HETEROCYCLES AS S1P RECEPTOR AGONISTS
JP4491334B2 (ja) 2004-12-01 2010-06-30 日立Ｇｅニュークリア・エナジー株式会社 配管の熱処理方法および装置
JP4599250B2 (ja) 2005-08-10 2010-12-15 株式会社東芝 高周波誘導加熱時外面温度制御方法および当該制御装置
JP2007063642A (ja) 2005-09-01 2007-03-15 Hitachi Ltd 残留応力改善方法と高周波誘導加熱用コイル
GB0520164D0 (en) * 2005-10-04 2005-11-09 Novartis Ag Organic compounds
US20090088368A1 (en) * 2006-01-30 2009-04-02 Irm Llc Compositions comprising them as ppar modulators
AU2007221021B2 (en) 2006-02-28 2013-01-17 Dart Neuroscience (Cayman) Ltd Therapeutic piperazines as PDE4 inhibitors
EP2049548A1 (en) * 2006-07-27 2009-04-22 UCB Pharma, S.A. Fused oxazoles & thiazoles as histamine h3- receptor ligands
JP2010502675A (ja) 2006-09-08 2010-01-28 ノバルティス アクチエンゲゼルシャフト リンパ球相互作用が介在する疾患または障害を処置するために有用なｎ−ビアリール（ヘテロ）アリールスルホンアミド誘導体
AR064650A1 (es) 2006-12-21 2009-04-15 Abbott Lab Compuestos agonistas y antagonistas del receptor de esfingosina-1-fosfato
CA2674946A1 (en) * 2007-01-11 2008-07-24 Allergan, Inc. 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity
JP5191497B2 (ja) 2007-03-21 2013-05-08 エピックス ファーマシューティカルズ，インコーポレイテッド Ｓ１ｐ受容体調節化合物およびその使用
BRPI0810123A2 (pt) 2007-04-23 2014-10-29 Novartis Ag Derivados de ftalazina e isoquinolina com atividades moduladoras do receptor de s1p
WO2009084501A1 (ja) * 2007-12-27 2009-07-09 Asahi Kasei Pharma Corporation スルタム誘導体
NZ586399A (en) * 2008-01-24 2011-12-22 Ucb Pharma Sa Compounds comprising a cyclobutoxy group
WO2009097567A1 (en) 2008-01-30 2009-08-06 Cephalon, Inc. Substituted spirocyclic piperidine derivatives as histamine-3 (h3) receptor ligands
MX2010008382A (es) 2008-01-30 2010-11-25 Cephalon Inc Derivados de piperidina espirociclicos substituidos, como ligandos de receptores de histamina-3 (h3).
US20090321144A1 (en) 2008-06-30 2009-12-31 Wyble Kevin J Protecting an element from excessive surface wear by localized hardening
UY32858A (es) 2009-08-31 2011-03-31 Abbott Healthcare Products Bv Derivados de (tio)morfolina como moduladores de sip
SG10201500832PA (en) 2010-02-04 2015-04-29 Esteve Labor Dr 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates
CN101812058B (zh) 2010-04-13 2012-03-21 湖南大学 吲哚美辛2-芳基吗啉乙酯及其制备方法与应用
TW201206893A (en) * 2010-07-09 2012-02-16 Abbott Healthcare Products Bv Bisaryl (thio) morpholine derivatives as S1P modulators

Also Published As

Publication number Publication date
KR101889694B1 (ko) 2018-08-21
US20140066433A1 (en) 2014-03-06
ES2653682T3 (es) 2018-02-08
CO6670577A2 (es) 2013-05-15
IL224054A (en) 2016-07-31
MY161229A (en) 2017-04-14
AU2011275755A1 (en) 2013-01-31
HK1179956A1 (zh) 2013-10-11
TWI522361B (zh) 2016-02-21
JP2013531002A (ja) 2013-08-01
MX2013000360A (es) 2013-06-28
CN103068827A (zh) 2013-04-24
AU2011275755B2 (en) 2015-04-09
PE20130592A1 (es) 2013-05-22
UY33496A (es) 2012-01-31
RU2013105444A (ru) 2014-08-20
RU2576660C2 (ru) 2016-03-10
US9096612B2 (en) 2015-08-04
JP5973429B2 (ja) 2016-08-23
BR112013000627B1 (pt) 2020-12-08
ZA201300157B (en) 2017-05-31
CN103068827B (zh) 2016-05-04
TW201206945A (en) 2012-02-16
KR20140005849A (ko) 2014-01-15
BR112013000627A2 (pt) 2016-05-24
DOP2013000009A (es) 2013-10-15
US9670220B2 (en) 2017-06-06
US8796262B2 (en) 2014-08-05
US20150284403A1 (en) 2015-10-08
AU2011275755A8 (en) 2013-02-14
WO2012004373A1 (en) 2012-01-12
CA2804137A1 (en) 2012-01-12
NZ605491A (en) 2014-08-29
AR082136A1 (es) 2012-11-14
US20130203737A1 (en) 2013-08-08
CR20130056A (es) 2013-06-12
ECSP13012416A (es) 2013-03-28
EP2590980A1 (en) 2013-05-15
CA2804137C (en) 2019-06-11
SG186952A1 (en) 2013-02-28
PH12013500004A1 (en) 2015-06-03
EP2590980B1 (en) 2017-09-20

Similar Documents

Publication Publication Date Title
CL2013000069A1 (es) Compuestos derivados de heterociclos fusionados, moduladores s1p; composicion farmaceutica; y uso en enfermedades neurodegenerativas.
UA109464C2 (uk) Спірооксіндольні антагоністи mdm2
GB201106750D0 (en) Novel compounds
SMT201600398B (it) Inibitori di proteina chinasi (varianti), uso di questi nel trattamento di malattie oncologiche e composizione farmaceutica basata su questi
EA201591474A1 (ru) Модуляторы метил-модифицирующих ферментов, композиции и их применение
IL230662A0 (en) Indazoles
NZ730763A (en) Methods of treating a tauopathy
BR112016000825A2 (pt) compostos moduladores de sulfonamidas dos canais de sódio, composição farmacêutica, e uso dos mesmos
BR112014029115A2 (pt) composto, composição farmacêutica, e, uso de um composto ou composição
PH12019500176A1 (en) Heterocyclic compounds and ther uses
BR112015000420A2 (pt) composto, composição farmacêutica, e, uso de um composto
AR090923A1 (es) Anticuerpos anti-il-23
BR112012031226A2 (pt) composto, uso do composto, composição farmacêutica, e uso de composição farmacêutica
BR112013031493A2 (pt) composto, composição farmacêutica, uso de um composto, combinação de um composto, dispositivo e processo de preparação de um composto.
CL2012003075A1 (es) Composicion farmaceutica en solucion de pazopanib, estable y para uso oftalmico; metodo para la preparacion de dicha solucion.
BR112012022879A2 (pt) composto, composição farmacêutica, uso do composto e método de tratamento
BR112015004936A2 (pt) composição farmacêutica revestida contendo regorafenib
BR112014025041B8 (pt) Composição farmacêutica
EP3059238A4 (en) Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
MX2015012416A (es) Compuestos heterociclicos y sus usos.
BR112015002824A2 (pt) composto, uso de um composto, composição farmacêutica, e, produto farmacêutico de combinação.
BR112014020992A2 (pt) Composto,uso de composto na fabricação de um medicamento e composição farmacêutica
SI3735962T1 (sl) Farmacevtska sestava, obsegajoča fosfatne vezivne delce
BR112015009462A2 (pt) composição farmacêutica estável do tnfr:fc proteína de fusão
EA201390955A1 (ru) Слитый белок robo1-fc для применения в лечении гепатокарциномы