WO2017102648A1 - Traitement combiné avec un inhibiteur de hbsag et un analogue de nucléos(t)ide - Google Patents

Traitement combiné avec un inhibiteur de hbsag et un analogue de nucléos(t)ide Download PDF

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WO2017102648A1
WO2017102648A1 PCT/EP2016/080638 EP2016080638W WO2017102648A1 WO 2017102648 A1 WO2017102648 A1 WO 2017102648A1 EP 2016080638 W EP2016080638 W EP 2016080638W WO 2017102648 A1 WO2017102648 A1 WO 2017102648A1
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Prior art keywords
methoxy
methoxypropoxy
oxo
quinolizine
dihydrobenzo
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PCT/EP2016/080638
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English (en)
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Hassan JAVANBAKHT
Isabel Najera
Steffen Wildum
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2017102648A1 publication Critical patent/WO2017102648A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems

Definitions

  • the present invention is directed to compositions and methods for treating hepatitis B virus infection.
  • the present invention is directed to a combination therapy comprising administration of an HBsAg inhibitor and a nucleos(t)ide analogue for use in the treatment or prophylaxis of hepatitis B virus infections.
  • HBV Hepatitis B virus
  • HBV belongs to the Hepadnaviridae family of viruses. Following entry into hepatocyte, its viral genome is delivered into nucleus where a covalently closed circular DNA (cccDNA) is formed through DNA repair of partially double- stranded viral genome. cccDNA serves as the template for transcription of viral RNAs. Viral pre-genomic RNA interacts with other two viral components, capsid protein and polymerase to form capsid particles where viral DNA replication occurs. HBV has an icosahedral core comprising of 240 copies of the capsid (or core) protein.
  • capsid protein The predominant biological function of capsid protein is to act as a structural protein to encapsidate pre-genomic RNA and form immature capsid particles in the cytoplasm. This step is prerequisite for viral DNA replication. When a near full-length relaxed circular DNA is formed through reverse-transcription of viral pregenomic RNA, an immature capsid becomes a mature capsid. Most copies of the encapsidated genome efficiently associate with cellular lipids and viral envelope proteins (S, M, and L) for virion assembly and secretion. However, non-infectious particles are also produced that greatly outnumber the infectious virions. These empty, enveloped particles are referred to as subviral particles (SVPs).
  • SVPs subviral particles
  • the S, M, and L envelope proteins are expressed from a single ORF (open reading frame) that contains three different start codons. All three proteins share a 226aa sequence, the S -domain, at their C-termini. S-domain contains the HBsAg epitope (Lambert, C. & R. Prange. Virol J, 2007, 4, 45).
  • HBV empty subviral particles may participate to the maintenance of the immunological tolerant state observed in chronically infected patients (CHB).
  • CHB chronically infected patients
  • the persistent exposure to HBsAg and other viral antigens can lead to HBV-specific T-cell deletion or to progressive functional impairment (Kondo et al. Journal of Immunology 1993, 150, 4659-4671; Kondo et al. Journal of Medical Virology 2004, 74, 425-433; Fisicaro et al. Gastroenterology , 2010, 138, 682-93;).
  • HBsAg has been reported to suppress the function of immune cells such as monocytes, dendritic cells (DCs) and natural killer (NK) cells by direct interaction (Op den Brouw et al. Immunology, 2009b, 126, 280-9; Woltman et al. PLoS One, 2011, 6, el5324; Shi et al. J Viral Hepat. 2012, 19, e26-33; Kondo et al. ISRN Gasteroenterology, 2013, Article ID 935295).
  • Viral proteins expressed from the HBV genome include HBsAg, HBV polymerase, HBV
  • HBsAg exists in at least three forms and it is involved in the viral-recognition of hepatocytes and is also a component of non-infectious particles. HBsAg, as well as other HBV antigens, may also play a role in suppressing host innate immune responses. Unlike current therapies, HBsAg inhibitors inhibit HBV DNA and expression of viral proteins (including HBsAg) by specifically reducing HBV mRNAs. Thus, HBsAg inhibitors potentially obstruct both virion production and evasion of host immune responses, and may offer a functional cure (sustained HBsAg loss) for CHB.
  • nucleos(t)ide analogues e.g. Lamivudine, Adefovir, Tenofovir, Telbivudine and Entecavir
  • nucleos(t)ide analogues have demonstrated very low rates of HBsAg clearance comparable to those observed naturally (Janssen et al. Lancet, 2005, 365, 123-9; Marcellin et al. N. Engl. J. Med., 2004, 351, 1206-17; Buster et al. Hepatology, 2007, 46, 388- 94).
  • HBsAg is a biomarker for prognosis and treatment response in CHB.
  • the standard of clinic cure of HBV infection is the loss and/or seroconversion of HBsAg.
  • nucleos(t)ide analogues are available to HBV patients, the majority (around or more than 90%) of treated patients fail to achieve this goal.
  • the Hepatitis B virus (HBV) infection remains a major health problem worldwide which concerns an estimated 240 million chronic carriers who have a higher risk of liver cirrhosis and hepatocellular carcinoma.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an HBsAg inhibitor and a nucleos(t)ide analogue, in a pharmaceutically acceptable carrier for the treatment or prophylaxis of HBV infection.
  • the "HBsAg inhibitor” is a compound of formula (I), (II) or any one of the compounds disclosed in patent application WO 2015113990, particularly the "HBsAg inhibitor” herein is (+)-10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid, (-)-10-methoxy-6-isopropyl-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid, (+)- 10-chloro-6- isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid, (-)- 10-chloro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a
  • the "nucleos(t)ide analogue” is any nucleoside and nucleotide analogue known to those skilled in the art.
  • the "nucleos(t)ide analogue” is Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, Clevudine, Tenofovir disoproxil and Tenofovir disoproxil fumarate.
  • the "nucleos(t)ide analogue” is Entecavir or
  • Figure 1 Isobologram of FIC for the pair-wise checkerboard combination of Compound 1A and Compound 12 (at the 50% effect level).
  • Data points below this lane show synergism, data points above show antagonism. Shown are mean values from 3 independent experiments.
  • Figure 2 Isobologram of FIC for the pair-wise checkerboard combination of Compound 1A and Compound 9 (at the 50% effect level).
  • Data points below this lane show synergism, data points above show antagonism. Shown are mean values from 3 independent experiments.
  • Ci_ 6 alkyl refers to a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms.
  • Ci_ 6 alkyl has 1 to 6 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms.
  • Examples of Ci_ 6 alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso -butyl, sec-butyl or tert-butyl.
  • halo or halogen
  • halogen are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo. Halogen is particularly fluorine, chlorine or bromine.
  • Ci_ 6 alkoxy refers to a group of Ci_ 6 alkyl-0-, wherein the "Ci_ 6alkyl” is as defined above; for example methoxy, ethoxy, propoxy, zsopropoxy, w-butoxy, iso- butoxy, 2-butoxy, ie/t-butoxy and the like.
  • Particular "Ci_ 6 alkoxy” groups are methoxy and ethoxy and more particularly methoxy.
  • C 3 _ 7 Cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Particular "C 3 _ 7 Cycloalkyl” groups are cyclopropyl, cyclopentyl and cyclohexyl.
  • C 2 - 6 alkenyl refers to an unsaturated, linear or branched chain alkenyl group containing 2 to 6, particularly 2 to 4 carbon atoms, for example vinyl, propenyl, allyl, butenyl and the like.
  • Particular "C 2 - 6 alkenyl” group is allyl.
  • C 2 - 6 alkynyl refers to an unsaturated, linear or branched chain alkynyl group containing 2 to 6, particularly 2 to 4 carbon atoms, for example ethynyl, 1- propynyl, propargyl, butynyl and the like.
  • Particular "C 2 - 6 alkynyl” groups are ethynyl, 1 - propynyl and propargyl.
  • C X H 2X alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms.
  • monocyclic heteroaryl denotes a monovalent aromatic heterocyclic mono- ring system of 5 to 8 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • Examples of monocyclic heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, isothiazolyl and the like.
  • the term 'W-containing monocyclic heteroaryl refers to a monocyclic heteroaryl wherein at least one of the heteroatoms is N.
  • N-containing monocyclic heteroaryl are pyrrolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, isothiazolyl and the like.
  • Particular 'W-containing monocyclic heteroaryl” groups are imidazolyl, pyrazolyl and triazolyl.
  • monocyclic heterocycloalkyl is a monovalent saturated or partly unsaturated monocyclic ring system of 3 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • Examples for monocyclic heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydro -thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, l, l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl.
  • Particular "monocyclic heterocycloalkyl” groups are morpholinyl, 2-oxo- pyrrolidinyl, pyrrolidinyl, tetrahydropyranyl.
  • diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, activities and reactivities.
  • the term “enantiomers” refers to two stereoisomers of a compound which are non-superimpo sable mirror images of one another.
  • the term “pharmaceutically acceptable salts” refers to salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.
  • the term “prodrug” refers to a form or derivative of a compound which is metabolized in vivo, e.g., by biological fluids or enzymes by a subject after administration, into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. Prodrugs are described e.g. in the Organic Chemistry of Drug Design and Drug Action by Richard B. Silverman, Academic Press, San Diego, 2004, Chapter 8 Prodrugs and Drug Delivery Systems, pp. 497-558.
  • pharmaceutically acceptable acid addition salt refers to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cyclo aliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethane sulfonic acid, p-tolu
  • pharmaceutically acceptable base addition salt refers to those pharmaceutically acceptable salts formed with an organic or inorganic base.
  • acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.
  • substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, trieth
  • hepatitis B virus or “HBV” refers to a member of the Hepadnaviridae family having a small double- stranded DNA genome of approximately 3,200 base pairs and a tropism for liver cells.
  • HBV includes hepatitis B virus that infects any of a variety of mammalian (e.g., human, non-human primate, etc.) and avian (duck, etc.) hosts.
  • HBV includes any known HBV genotype, e.g., serotype A, B, C, D, E, F, and G; any HBV serotype or HBV subtype; any HBV isolate; HBV variants, e.g., HBeAg-negative variants, drug-resistant HBV variants (e.g., lamivudine-resistant variants; adefovir-resistant mutants; tenofovir-resistant mutants; entecavir-resistant mutants; etc.); and the like.
  • HBV genotype e.g., serotype A, B, C, D, E, F, and G
  • HBV serotype or HBV subtype e.g., HBeAg-negative variants
  • drug-resistant HBV variants e.g., lamivudine-resistant variants; adefovir-resistant mutants; tenofovir-resistant mutants; entecavir-resistant mutants; etc.
  • HBV DNA refers to DNA material of HBV.
  • HBsAg refers to hepatitis B surface antigen
  • HBeAg refers to hepatitis B e antigen.
  • HBsAg inhibitor refers to a compound that inhibits expression of the hepatitis B virus surface antigen. Unless otherwise indicated, an HBsAg inhibitor can include the compound in any pharmaceutically acceptable form, including any isomer (e.g., diastereomer or enantiomer), salt, solvate, polymorph, and the like.
  • nucleos(t)ide analogue refers to nucleosides which contain a nucleobase analogue and a sugar and nucleotides which contain a nucleobase analogue, a sugar and one to three phosphate groups.
  • Nucleoside analogue drugs include but are not limited to deoxyadenosine analogues (Didanosine and Vidarabine), adenosine analogues (BCX4430), deoxycytidine analogues (Cytarabine, Emtricitabine, Lamivudine and Zalcitabine), guanosine and deoxyguanosine analogues (Abacavir, Aciclovir and Entecavir), thymidine and
  • Nucleotide analogue drugs include Adefovir dipivoxil (ADV) and Tenofovir disoproxil fumarate (TDF).
  • Nucleobase means any nitrogen-containing heterocyclic moiety capable of forming Watson-Crick-type hydrogen bonds and stacking interactions in pairing with a complementary nucleobase or nucleobase analogue (i.e., derivatives of nucleobases) when that nucleobase is incorporated into a polymeric structure.
  • Nucleobase means any nitrogen-containing heterocyclic moiety capable of forming Watson-Crick-type hydrogen bonds and stacking interactions in pairing with a complementary nucleobase or nucleobase analogue (i.e., derivatives of nucleobases) when that nucleobase is incorporated into a polymeric structure.
  • Heterocyclic refers to a molecule with a ring system in which one or more ring atom is a heteroatom, e.g., nitrogen, oxygen, or sulfur (i.e., not carbon).
  • terapéuticaally effective amount refers to an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • the present invention relates to a pharmaceutical composition comprising an HBsAg inhibitor and a nucleos(t)ide analogue, in a pharmaceutically acceptable carrier.
  • Compounds of the general formula (I) and (II) which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers. The racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphor sulfonic acid.
  • an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphor sulfonic acid.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an HBsAg inhibitor and a nucleos(t)ide analogue, in a pharmaceutically acceptable carrier.
  • the "HBsAg inhibitor” is a compound of formula (I):
  • R 1 is hydrogen, halogen, C 1-6 alkyl, Ci_ 6 alkylamino or
  • R is hydrogen; halogen; C 1-6 alkyl, which is unsubstituted or once, twice or three times
  • Ci- 6 alkoxy which is unsubstituted or once, twice or three times substituted by fluoro; cyano; C 3 _ 7 cycloalkyl; hydroxy or phenyl- C x H2 X -0-;
  • R is hydrogen
  • Ci_ 6 alkyl which is unsubstituted or once, twice or three times substituted by fluoro;
  • R is hydrogen; C 1-6 alkyl, which is unsubstituted or substituted with one to three substituents independently selected from fluoro, hydroxy and C 2-6 alkenyl; Ci_
  • R 4 is hydrogen, halogen, C 1-6 alkyl, cyano or C 1-6 alkoxy
  • R 5 is hydrogen or C 1-6 alkyl
  • R 6 is hydrogen; C 1-6 alkyl, which is unsubstituted or once, twice or three times substituted by fluoro; C 3-7 cycloalkyl, which is unsubstituted or once, twice or three times substituted by fluoro or C 1-6 alkyl; or phenyl-C x H 2x -;
  • x is 1-6;
  • Compounds of formula (I), Compounds 1A to 3A and Compounds IB to 3B can be obtained according to the synthetic procedures disclosed in WO 2015/113990.
  • the "HBsAg inhibitor" of the present invention relates to
  • the "HBsAg inhibitor” is a compound of formula (II):
  • R 8 , R 9 , R 10 and R 11 are independently selected from hydrogen, halogen, Ci- 6 alkyl, diCi_
  • R 14 is hydrogen; C 1-6 alkyl; or Ci- 6 alkyl which is substituted once or more times by fluoro, C3_ 7 cycloalkyl, phenyl, hydroxyl, amino, Ci_ 6 alkoxy, Ci- 6 alkylsulfanyl, Ci_ 6 alkylsulfonyl, diCi_ 6 alkylamino, Ci_ 6 alkoxycarbonylamino, monocyclic heterocycloalkyl, pyrazoyl or imidazolyl;
  • R is hydrogen or C h alky
  • Ci-6alkyl is hydrogen, Ci-6alkyl, phenyl-C x H2 X -, Ci_6alkylcarbonyl, Ci_6alkylsulfonyl, benzoyl or monocyclic heterocycloalkyl, wherein
  • x is 1-6;
  • W is a bond, C y H 2y C(R 15 )(R 16 )C z H 2z or C y H 2y CH(R 15 )CH(R 16 )C z H 2z , wherein
  • R and R are independently selected from hydrogen, fluoro, hydroxy and C 1-6 alkyl, y is 0-6;
  • z is 0-6;
  • X is a bond; O; S; S(0) 2 ; or NR , wherein R is hydrogen, C 1-6 alkyl;
  • the "HBsAg inhibitor" of the present invention relates to
  • an HBsAg inhibitor can include any one of the compounds of formula (I) and (II), in any pharmaceutically acceptable form, including any isomer (e.g., diastereomer or enantiomer), salt, solvate, polymorph, and the like.
  • suitable nucleos(t)ide analogues of the present invention include nucleoside analogue drugs and nucleotide analogue drugs.
  • Nucleoside analogue drugs include but are not limited to deoxyadenosine analogues (Didanosine and Vidarabine), adenosine analogues (BCX4430), deoxycytidine analogues (Cytarabine, Emtricitabine, Lamivudine and Zalcitabine), guanosine and deoxyguanosine analogues
  • Nucleotide analogue drugs include but are not limited to Adefovir dipivoxil (ADV), Tenofovir disoproxil and Tenofovir disoproxil fumarate (TDF).
  • the "nucleos(t)ide analogue” is Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, Clevudine, Tenofovir disoproxil or Tenofovir disoproxil fumarate. More particularly, the "nucleos(t)ide analogue” is Entecavir or Tenofovir disoproxil.
  • the pharmaceutical composition comprises an HBsAg inhibitor and a nucleos(t)ide analogue, wherein the HBsAg inhibitor and the
  • nucleos(t)ide analogue are independently selected from Table 1.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an HBsAg inhibitor and a nucleos(t)ide analogue which is selected from any the following combinations:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an HBsAg inhibitor and a nucleos(t)ide analogue which is selected from any one of the following combinations:
  • the pharmaceutical composition consists of an HBsAg inhibitor and a nucleos(t)ide analogue, in a pharmaceutically acceptable carrier. More particularly, the composition consists of:
  • HBsAg inhibitors or nucleos(t)ide analogues can also be used in the pharmaceutical composition including small molecules or large molecules.
  • Typical dosages of an HBsAg inhibitor and/or a nucleos(t)ide analogue can be in various ranges, and where indicated by in vitro responses in an animal model, can be reduced by up to about one order of magnitude concentration or amount.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in v tro responsiveness of the appropriate animal models.
  • Another embodiment of the present invention relates to a method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that an HBsAg inhibitor and a nucleos(t)ide analogue are used in the medicament.
  • a further embodiment of the present invention relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that an HBsAg inhibitor and a nucleos(t)ide analogue are co- administered in the same formulation or different formulation.
  • co -administer refers to any administration of an HBsAg inhibitor and a nucleos(t)ide analogue as the two active agents, either separately or together, where the two active agents are administered as part of an appropriate dose regimen designed to obtain the benefit of the combination therapy.
  • the two active agents can be administered either as part of the same pharmaceutical composition or in separate
  • the two active agents can be administered either at the same time, or sequentially.
  • the pharmaceutical composition of an HBsAg inhibitor and a nucleos(t)ide analogue can be administered with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozengens, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Administration of such dosage forms can be carried out in single or multiple doses. Carries include solid diluents of fillers, sterile aqueous media and various non-toxic organic solvents. Administration of such dosage forms can be carried out through, but not limited to, oral administration, parenteral administration, veterinary administration.
  • a further embodiment of the present invention relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that an HBsAg inhibitor and a nucleos(t)ide analogue are intended for administration to a subject by the same route or different routes.
  • a further embodiment of the present invention relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that an HBsAg inhibitor and a nucleos(t)ide analogue are intended for administration to a subject by parenteral or oral administration.
  • a further embodiment of the present invention relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that the administration of an HBsAg inhibitor and a nucleos(t)ide analogue to a subject is simultaneous or sequential.
  • the administration of agents simultaneously can be performed by separately or sequentially administering agents at the same time, or together as a fixed combination.
  • the administration of agents separately or sequentially can be in any order.
  • Another embodiment of the present invention relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that the HBsAg inhibitor is a compound of formula (I) or formula (II), or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • the HBsAg inhibitor is a compound of formula (I) or formula (II), or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • the HBsAg inhibitor is a compound of formula (I) or formula (II), or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • the HBsAg inhibitor is a compound of formula (I) or formula (II), or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • the HBsAg inhibitor is
  • nucleos(t)ide analogue is Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, Clevudine, Tenofovir disoproxil or Tenofovir disoproxil fumarate.
  • nucleos(t)ide analogue is Entecavir or Tenofovir disoproxil.
  • Another embodiment of present invention relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that the HBsAg inhibitor and the nucleos(t)ide analogue used in the medicament are (+)-10-methoxy-6- isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid and Entecavir; or (+)-10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid and Tenofovir disoproxil.
  • kits comprising a container comprising an HBsAg inhibitor and a nucleos(t)ide analogue, said kit can further comprise a sterile diluent.
  • kits can further comprise a package insert comprising printed instructions directing the use of a combined treatment of an HBsAg inhibitor and a nucleos(t)ide analogue as a method for treatment or prophylaxis of hepatitis B virus infection.
  • a package insert comprising printed instructions directing the use of a combined treatment of an HBsAg inhibitor and a nucleos(t)ide analogue as a method for treatment or prophylaxis of hepatitis B virus infection.
  • the HBsAg inhibitor is
  • nucleos(t)ide analogue is Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, Clevudine, Tenofovir disoproxil or Tenofovir disoproxil fumarate.
  • nucleos(t)ide analogue is Entecavir or Tenofovir disoproxil.
  • kits characterized in that the HBsAg inhibitor and the nucleos(t)ide analogue used in the container are (+)-10-methoxy-6- isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid and Entecavir; or (+)-10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid and Tenofovir disoproxil.
  • the HBsAg inhibitor and the nucleos(t)ide analogue used in the container are (+)-10-methoxy-6- isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid and Entecavir; or (+)-10-methoxy-6-isopropyl-9
  • Another embodiment of present invention relates to a method for the treatment or prophylaxis of hepatitis B virus infection, comprising administration to a subject with an effective first amount of an HBsAg inhibitor, or pharmaceutically acceptable salt, enantiomer or diastereomer thereof; and a second amount of a nucleos(t)ide analogue; or vice versa; wherein the HBsAg inhibitor is
  • Another embodiment of present invention relates to a method for the treatment or prophylaxis of hepatitis B virus infection, comprising administration to a subject with an effective first amount of an HBsAg inhibitor, or pharmaceutically acceptable salt, enantiomer or diastereomer thereof; and a second amount of an nucleos(t)ide analogue; or vice versa; wherein the nucleos(t)ide analogue is Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, Clevudine, Tenofovir disoproxil or Tenofovir disoproxil fumarate. Particularly the nucleos(t)ide analogue is Entecavir or Tenofovir disoproxil.
  • Another embodiment of present invention relates to a method for the treatment or prophylaxis of hepatitis B virus infection, characterized in that the HBsAg inhibitor and the nucleos(t)ide analogue used are (+)-10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid and Entecavir; or (+)-10-mefhoxy-6-isopropyl-9- (3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid and Tenofovir disoproxil;
  • Another embodiment of present invention relates to use of pharmaceutical composition herein mentioned above as an antiviral medicament, in particular as the medicament for treatment or prophylaxis of hepatitis B virus infection.
  • Another embodiment of present invention relates to the use of an HBsAg inhibitor and a nucleos(t)ide analogue for the manufacture of pharmaceutical composition herein mentioned above as an antiviral medicament, in particular the medicament for treatment or prophylaxis of hepatitis B virus infection.
  • Step 4 Preparation of 4-methoxy-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3- dimethyl-butan-2-amine
  • the combined organic layers were washed with water (200 mL) 2 times and brine, dried over anhydrous Na 2 S0 4 and concentrated to give 4-methoxy- l-[4-methoxy-3-(3- methoxypropoxy)phenyl]-3,3-dimethyl-butan-2-amine (120 g).
  • Step 5 Preparation of N-[3-methoxy-l-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]- 2,2-dimethyl-propyl] formamide
  • Step 6 Preparation of 7-methoxy-3-(2-methoxy-l,l-dimethyl-ethyl)-6-(3-methoxypropoxy)- 3,4-dihydroisoquinoline
  • Step 7 Preparation of ethyl 10-methoxy-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
  • Step 8 Preparation of ethyl 10-methoxy-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
  • Step 9 Preparation of 10-methoxy-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid
  • Step 10 preparation of (+)-10-methoxy-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid (Compound 4A) and ( )-10-methoxy-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid (Compound 4B)
  • Step 3 Preparation of 4-benzyloxy-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3- dimethyl-butan-2-amine
  • Step 4 Preparation of N-[3-benzyloxy-l-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl] -2,2-dimethyl-propyl]formamide
  • Step 5 Preparation of 3-(2-benzyloxy-l,l-dimethyl-ethyl)-7-methoxy-6-(3- methoxypropoxy)-3,4-dihydroisoquinoline
  • Step 6 Preparation of ethyl 6-(2-benzyloxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
  • Step 7 Preparation of ethyl 6-(2-benzyloxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
  • Step 8 Preparation of 6-(2-benzyloxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid
  • Step 9 Preparation of 6-(2-hydroxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid
  • Step 10 Preparation of (+)-6-(2-hydroxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid (Compound 5A) and (-)-6-(2-hydroxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2- dihydrobenzo[a]quinolizine-3-carboxylic acid (Compound 5B)
  • Step 1 Preparation of 4-chloro-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3-dimethyl- butan-2-one
  • Step 2 Preparation of 4-chloro-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3-dimethyl- butan-2-amine
  • Step 5 Preparation of ethyl 10-chloro-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-l,6,7,llb-tetrahydrobenzo[a]quinolizine-3-carboxylate
  • Step 6 Preparation of ethyl 10-chloro-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate
  • Step 7 Preparation of 10-chloro-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3-methoxypropoxy)- 2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid
  • Step 8 Preparation of (+)-10-chloro-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid (Compound 6A) and (-)-10-chloro-6-(2-methoxy-l,l-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid (Compound 6B)
  • HBsAg Assay to test capacity of HBsAg inhibitor to inhibit HBsAg
  • HepG2.2.15 cells (Acs et al. Proc Natl Acad Sci U S A, 84, (1987), 4641-4), a
  • constitutively HBV-expressing cell line were cultured in DMEM+Glutamax-I medium (Invitrogen, Carlsbad, CA, USA, Catalog number: 11320082), supplemented with 10% fetal bovine serum (Invitrogen, Catalog number: 10099141) and G418 (Invitrogen, Catalog number: 10131027) at a final concentration of 200 mg/L and maintained in 5% C0 2 at 37°C.
  • DMEM+Glutamax-I medium Invitrogen, Carlsbad, CA, USA, Catalog number: 11320082
  • 10% fetal bovine serum Invitrogen, Catalog number: 10099141
  • G418 Invitrogen, Catalog number: 10131027
  • HepG2.2.15 cells were seeded in duplicate into white, 96-well plates at 1.5 x 10 4 cells/well. The cells were treated with a three-fold serial dilution series of the compounds in DMSO. The final DMSO concentration in all wells was 1% and DMSO was used as no drug control.
  • the HBsAg chemiluminescence immunoassay (CLIA) kit (Autobio Diagnostics Co., Zhengzhou, China, Catalog number: CL0310-2) was used to measure the levels of secreted HBV antigens semi-quantitatively.
  • CLIA HBsAg chemiluminescence immunoassay
  • 50 ⁇ ⁇ of the supernatant was transferred to the CLIA assay plate and 50 ⁇ ⁇ of enzyme conjugate reagent was added into each well. The plates were sealed and gently agitated for 1 hour at room temperature.
  • the HBsAg chemiluminescence immunoassay (CLIA) kit Autobio Diagnostics Co., Zhengzhou, China, Catalog number: CL0310-2
  • Luminance was measured using a lumino meter (Mithras LB 940 Multimode Microplate Reader) after 10 minutes incubation. Dose-response curves were generated and the IC 50 value was extrapolated by using the E- WorkBook Suite (ID Business Solutions Ltd., Guildford, UK). The IC 50 was defined as the compound concentration (or conditioned media log dilution) at which HBsAg secretion was reduced by 50% compared to the no drug control.
  • HepG2.2.15 cells were cultured in DMEM+Glutamax I (Gibco, #21885) supplemented with 10% FBS, 1% Pen/Strep (Gibco, #15140) and G-418 (250 ⁇ / ⁇ ) and used for production of infectious HBV (genotype D). 90% confluent cells from three T175 flasks were trypsinized and transferred into one collagen coated hyperflask (550 mL). Once the cells are confluent, medium was changed to DMEM+Glutamax I with 1% DMSO and 2.5% FBS.
  • HepaRG cells (Biopredic International, Saint-Gregoire, France) were cultured in working growth medium (500 mL Willams E Medium with 50 mL HepaRG Growth supplement from Biopredic, 5 mL Glutamax-I (Gibco, #35050) and 5 mL Pen/Strep) for 2 weeks. After 2 weeks medium was changed to differentiation medium containing 1.8% DMSO (500 mL Willams E Medium with 50 mL HepaRG Growth supplement from Biopredic, 5 mL Pen/Strep, 5 mL Glutamax-I and 9 mL DMSO). Medium was changed twice a week up to 2 weeks.
  • working growth medium 500 mL Willams E Medium with 50 mL HepaRG Growth supplement from Biopredic, 5 mL Glutamax-I (Gibco, #35050) and 5 mL Pen/Strep
  • DMSO 500 mL Willams E Medium with 50 mL HepaRG Growth supplement from
  • cells were trypsinized and seeded into collagenated 96 well plates (50,000 cells/well in 100 ⁇ ) in differentiation medium. Cells were cultured at least 5 days in the 96 well plates before they were infected with HBV. Infection and compound treatment of hepaRG cells
  • Compound 1A The concentration ranges tested were 1 nM to 0.01 nM for Compound 9, 1000 nM to 12.15 nM for Compound 12, and 100 nM to 0.14 nM for Compound 1A.
  • Medium was replaced by new medium with compound at day 7 post infection and at day 11 post infection cell supernatants were harvested and directly used for HBV DNA extraction or stored at -20°C. Cell viability of the cells was determined using the cell viability assay described below.
  • CC cell control (uninfected)
  • VC virus control
  • A1+B7 example of combination of drug A and B at different ratios
  • HBV DNA from HepaRG cell supernatants was extracted using the MagNA Pure 96 (Roche) robot. 100 ⁇ ⁇ of the supernatants were mixed in a processing cartridge with 200 ⁇ ⁇ MagNA Pure 96 external lysis buffer (Roche, Cat. No. 06374913001) and incubated for 10 minutes. DNA was then extracted using the "MagNA Pure 96 DNA and Viral Nucleic Acid
  • Quantification of extracted HBV DNA was performed using a Taqman qPCR machine (ViiA7, life technologies). Each DNA sample was tested in duplicate in the PCR. 5 ⁇ ⁇ of DNA sample were added to 15 ⁇ ⁇ of PCR mastermix containing 10 ⁇ ⁇ TaqMan Gene Expression Master Mix (Applied Biosystems, Cat. no.
  • Forward core primer (F3_core): CTG TGC CTT GGG TGG CTT T
  • Reverse primer AAG GAA AG A AGT CAG AAG GCA AAA
  • Taqman probe (P3_core): 56-FAM/AGC TCC AAA /ZEN/TTC TTT ATA AGG GTC GAT GTC CAT G/3IABkFQ
  • FIC ratio [EC50 combination : EC50 alone]
  • a CI ⁇ 1 means synergism, a CI 1 means additivity and a CI > 1 means antagonism.
  • Combination effect assessment was based on overall CI values as follows: CI value ⁇ 0.7 as synergy, 0.7 to 0.9 as slight to moderate synergy, 0.9 to 1.1 as additive, 1.1 to 1.5 as slight to moderate antagonism and >1.5 as antagonism (Chou TC (2006). Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 58:621-681). Drug combinations were analyzed at three different fixed drug ratios spanning and including the approximate ratio of their EC 5 os.

Abstract

La présente invention concerne des compositions et des procédés de traitement d'une infection par le virus de l'hépatite B. En particulier, la présente invention concerne un traitement combiné comprenant l'administration d'un inhibiteur de HBsAg et d'un analogue de nucléos(t)ide destinés à être utilisés dans le traitement ou la prophylaxie d'un patient atteint d'hépatite B chronique.
PCT/EP2016/080638 2015-12-15 2016-12-12 Traitement combiné avec un inhibiteur de hbsag et un analogue de nucléos(t)ide WO2017102648A1 (fr)

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US20170342068A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
WO2018087345A1 (fr) * 2016-11-14 2018-05-17 F. Hoffmann-La Roche Ag Polythérapie comprenant un inhibiteur d'un antigène de hbsag, un analogue nucléosidique ou nucléotidique et un interféron
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
US10093673B2 (en) 2016-02-19 2018-10-09 Novartis Ag Tetracyclic pyridone compounds as antivirals
US10301312B2 (en) 2017-04-27 2019-05-28 Novartis Ag Fused indazole pyridone compounds as antivirals
WO2019110352A1 (fr) * 2017-12-04 2019-06-13 Galapagos Nv 2-oxo-5h-chromeno[4,3-b]pyridines destinées à être utilisées dans le traitement de l'hépatite b
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci
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CN114105987A (zh) * 2020-08-26 2022-03-01 上海博志研新药物技术有限公司 恩替卡韦药用盐及其制备方法、药物组合物和应用

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US10093673B2 (en) 2016-02-19 2018-10-09 Novartis Ag Tetracyclic pyridone compounds as antivirals
US20170342068A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
WO2018087345A1 (fr) * 2016-11-14 2018-05-17 F. Hoffmann-La Roche Ag Polythérapie comprenant un inhibiteur d'un antigène de hbsag, un analogue nucléosidique ou nucléotidique et un interféron
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
US10975078B2 (en) 2017-04-27 2021-04-13 Novartis Ag Fused indazole pyridone compounds as antivirals
US10301312B2 (en) 2017-04-27 2019-05-28 Novartis Ag Fused indazole pyridone compounds as antivirals
WO2019110352A1 (fr) * 2017-12-04 2019-06-13 Galapagos Nv 2-oxo-5h-chromeno[4,3-b]pyridines destinées à être utilisées dans le traitement de l'hépatite b
CN111448197A (zh) * 2017-12-04 2020-07-24 加拉帕戈斯股份有限公司 用于治疗乙型肝炎的2-氧代-5H-苯并吡喃并[4,3-b]吡啶
US11234977B2 (en) 2017-12-20 2022-02-01 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci
CN114105987A (zh) * 2020-08-26 2022-03-01 上海博志研新药物技术有限公司 恩替卡韦药用盐及其制备方法、药物组合物和应用
CN114105987B (zh) * 2020-08-26 2022-12-27 上海博志研新药物技术有限公司 恩替卡韦药用盐及其制备方法、药物组合物和应用

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