WO2017114812A1 - Traitement combiné avec un inhibiteur de hbsag et un interféron - Google Patents

Traitement combiné avec un inhibiteur de hbsag et un interféron Download PDF

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WO2017114812A1
WO2017114812A1 PCT/EP2016/082678 EP2016082678W WO2017114812A1 WO 2017114812 A1 WO2017114812 A1 WO 2017114812A1 EP 2016082678 W EP2016082678 W EP 2016082678W WO 2017114812 A1 WO2017114812 A1 WO 2017114812A1
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Prior art keywords
methoxy
oxo
methoxypropoxy
dihydrobenzo
carboxylic acid
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PCT/EP2016/082678
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English (en)
Inventor
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 WO2017114812A1 publication Critical patent/WO2017114812A1/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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention is directed to composit ions and methods for treating hepatitis B virus infect ion.
  • the present invention is directed to a combination therapy comprising admin istration of an HBsAg inhibitor and an interferon for use in the treatment or prophylaxis of chronic Hepat itis B v irus infections.
  • HBV Hepat itis B vims
  • HBV belongs to the Hepadnav iriclac family of viruses. Following entry into hepatocytc, its v iral genome is delivered into nucleus where a covalcnt!y closed circular DNA (cccD A) is formed through DNA repair of partially double-stranded v iral genome.
  • cccDNA serves as the template for transcript ion of viral R As.
  • Viral pre-genomic RNA interacts with other two viral components, capsid protein and polymerase to form capsid particles where viral DNA replicat ion occurs.
  • HBV has an icosahedral core comprising of 240 copies of the capsid (or core) protein.
  • capsid protein The predominant biological funct ion of capsid protein is to act as a structural protein to cncapsidate pre-genomic R A and form immature capsid particles in the cytoplasm. This step is prerequisite for v iral DNA replication.
  • a near full-length relaxed circular DNA is formed through reverse- 1 ranscr ipt io n 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 secret ion. How ever, non-infect ious particles are also produced that greatly outnumber the infectious virions.
  • SVPs subviral part icles
  • the S, M, and L env elope proteins are expressed from a single ORF (open reading frame) that contains three different start co dons. All three proteins share a 226aa sequence, the S-domain, at their C-tcrmini. S-domain contains the HBsAg epitope (Lambert, C. & R. Prange. Virol J, 2007, 4, 45 ).
  • Viral proteins expressed from the H B V genome include HBsAg, HBV polymerase, HBV
  • HBV empty subviral particles may participate to the maintenance of the immunological tolerant state observed in chronically infected patients (CUB).
  • HBsAg. as well as other HBV antigens, may also play a role in suppressing host innate immune responses. The persistent exposure to HBsAg and other viral antigens can lead to HBV -specific T-celi 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.
  • HBsAg has been reported to suppress the function of immune ceils such as monocytes, dendritic cells (DCs) and natural killer (NK) cells by direct interaction (Op den Brouvv et al. Immunology, 2009b, 126, 280-9; Wo It man et al. PLoS One, 2011, 6, el 5324; Shi et al. J Viral Hepat.2012, 19, e26-33; Kondo et al. ISRN
  • IFN-a interferon alpha
  • ISGs inter fe r o n - s t i m u 1 a t ed genes
  • IFN-a has an i m m u no mod u I ato ry effect that can indirectly inhibit HBV replication by affecting cell-mediated immunity in vivo (Micco L, et a!., J. Hepatol, 2013, 58, 225-233).
  • IFN- administration has shown to inhibit HBV replication in vitro and in vivo (Christen V., et al., J. Virol.2007, 81:159 165; Guan S.H., et al., J. Gastroenterol, 2007, 13:228 235: Wicland S.F., et al., .1.
  • HBV infection is generally characterized by dysfunct ional innate and adapt ive immune responses (Boni ( ' ., .1. Virol., 2007, 81, 4215 4225).
  • Bioni ' ., .1. Virol., 2007, 81, 4215 4225.
  • IFN-a was not induced (Wieiand S., et al., Proc. Natl. Acad. Sci. USA, 2004.101, 6669 6674).
  • 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.
  • PEG- I F -a and nucleos(t)ide are available to HBV pat ients, the ma jority (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 an interferon, in a pharmaceutically acceptable carrier for the treatment or prophylaxis of HBV infect ion.
  • the "HBsAg inhibitor” is a compound of formula (I), ( I I ) or any one of the compounds disclosed in patent application WO 2015 1 13990, particularly the "HBsAg inhibitor " herein is (+)-10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid.
  • the "interferon” herein is selected from the group consisting of interferon alpha, peg i n t erfero n -a 1 p ha 2a, recombinant interferon alpha-2a, interferon aipha-2a, peginterferon alpha-2b, recombinant interferon alpha-2b, interferon alpha-2b, glycosylated interferon aipha-2b, interferon alpha-2b XL, recombinant interferon aipha-2c, interferon alpha- 2c, interferon beta, peginterferon beta- l a, interferon beta- l a, interferon delta, peginterferon lambda- 1 , interferon lambda, interferon omega, interferon tau, gamma interferon, interferon alfacon- 1 , interferon alpha-nl, interferon a 1 p h a
  • the interferon is a y-branched pegylated recombinant human interferon alpha-2b in ject ion Pai Ge Bin (Amoytop Biotech ).
  • the interferon is a non-conjugated interferon alfa or a pegylated alfa-type interferon; particularly the interferon is Roferon A* ( Hoffmann-La Roche, Inc. ). Intron A* (Schering-Plough Corp. ). Pegasys ® (Hoffmann-La Roche, Inc.) or Peglntron* (Schering Corp.); more particularly the interferon is Roferon A ® . BRIEF DESCRIPTION OF THE FIGURE(S)
  • Figure 1 Iso hologram of FIC for the pair-wise checkerboard combination of Compound 1 A and Compound 7 (at the 50% effect level).
  • Data points below this lane show synergism, data points above show antagonism. Shown are mean v alues from 3 independent experiments.
  • C h alky refers to a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms.
  • C i ⁇ ,alkyl has 1 to 6 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms.
  • Examples of C i ⁇ ,alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or ferf-butyl.
  • C u.alkoxy refers to a group of Ci ⁇ ,alkyl-0-, wherein the "Ci_ 6 alkyi” is as defined above; for example methoxy, ethoxy, propoxy, / ' w-propoxy, «-butoxy, iso- butoxy, 2-butoxy, /tvt-butoxy and the like.
  • Particular "Cu.alkoxy” groups are methoxy and ethoxy and more particularly methoxy.
  • C ; -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, cyclopcntyl, cyclohexyl, cycloheptyl and the like.
  • Part icular "C; -cycloalkyl” groups arc cyclopropyl, cyclopcntyl and cyclohexyl.
  • C ⁇ alkenyr refers to an unsaturated, linear or branched chain alkenyl group containing 2 to 6, particularly 2 to 4 carbon atoms, for example vinyl, propenyl. ally 1- butenyl and the like. Particular “ .alkenyl " group is allyl.
  • ('. ⁇ ( .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, propargyi, butynyl and the like.
  • Particular "('.-> .(.alkyny ' groups are ethynyl, 1 - propynyl and propargyi.
  • C H ?X alone or in combinat ion signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms.
  • the term "monocyclic heteroaryl” denotes a monovalent aromat ic heterocyclic mono- ring system of 5 to 8 ring atoms, comprising 1 , 2. 3 or 4 heteroatoms selected from , O and S, the remaining ring atoms being carbon.
  • Examples of monocyclic heteroaryl moiet ies include pyrrolyl, furanyl, thienyl, imidazoiyi, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazcpinyl, isoxazolyl, isothiazolyl and the like.
  • N-containing monocycl ic heteroaryl refers to a monocyclic heteroaryl wherein at least one of the heteroatoms is N.
  • a ' -containing monocyclic heteroaryl are pyrrolyi, imidazolyl, o azolyl, thiazolyl, triazolyl, oxadiazolyl. thiadiazo!yl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepiny!, diazepinyl, isoxazolyl, isothiazolyl and the like.
  • A'-containing monocyclic heteroaryl groups are imidazolyl, pyrazolyl and triazolyl, and more particularly imidazol-l-yl, pyrazol-l-yl and 1 ,2,4-triazol-l-yl.
  • monocyclic heterocycioalkyi 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 , O and S, the remaining ring atoms being carbon.
  • Examples for monocyclic heterocycioalkyi are aziridinyl, oxiranyl, azet idinyl, oxetanyl, pyrrol id inyl, 2 -o xo - pyrro 1 i d i n y 1 , tetrahydrofuranyl, tetrahydro-thienyi, pyrazolidinyi, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyi, t et a h yd ro thiop yra n y 1 , piperazinyl, morpholinyi, thio morpholinyi, 1 .
  • 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. melt ing points, boil ing points, spectral properties, act iv it ies and reactivities.
  • enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the term “pharmaceutically acceptable salts” refers to salts which are not biologically o otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addit ion salts.
  • the term “prodrug” refers to a form or derivative of a compound which is metabolized in v iv o, e.g., by biological fluids or enzymes by a subject after admin istration, 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. Silv erman, 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 aliphat ic, cycloaliphatic, aromat ic, araliphat ic, heterocyclic, earboxylic, 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, malcic acid, maloneic acid, succin ic acid, fu marie acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranil ic acid, benzoic acid, cinnamic acid, mandel ic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulf
  • salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, subst ituted amines including naturally occurring subst ituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine.
  • hepatit is B virus or "HBV” refers to a member of the Hepadnaviridae family hav ing a small double-stranded DNA genome of approximately 3,200 base pairs and a trap ism 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 H B V genotype, e.g., serotype A, B, C, D, E, F.
  • HBV v ariants e.g., HBeAg-negat ive v ariants, drug-resistant HBV v ariants (e.g., la m i v u d i n e- res i st a n t variants; adefovir-resistant mutants; t c no fo v i r- res i s t a n t mutants; entecavir-resistant mutants; etc. ); and the like.
  • H BV DNA refers to DNA material of HBV.
  • HBsAg refers to hepatitis B surface ant igen.
  • 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 pharmaceut ically acceptable form, including any isomer (e.g., diastercomer or cnant iomer), salt, solvate, polymorph, and the like.
  • interferon o "I F " as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response.
  • Human interferons are grouped into two classes; Type I. including alpha and bet a- interferon, and Type I I, which is represented by gamma-interferon only. Recombinant forms of each group have been developed and are commercially available. Subtypes in each group are based on antigeiiic/structural characteristics.
  • interferon further includes conjugates, for instance interferon alfa (IFN-a) conjugates that can be prepared by coupling an interferon alfa to a water-soluble polymer.
  • IFN-a interferon alfa
  • a non-limiting list of such polymers includes other polyalkylene oxide homopolymers such as polyethylene glycol (PEG), polypropylene glycols, polyoxyethylenated polyols,
  • copolymers thereof thereof and block copolymers thereof.
  • effectively non-antigetiic materials such as dextran, poiyvinylpyirolidones,
  • polyacryl amides polyvinyl, alcohols, carbohydrate-based polymers and the like can be used.
  • interferon alfa-polymer conjugates are described in U.S. Pat. No. 4,766, 106, U.S. Pat. No. 4,917,888, European. Patent Application No. 0 236 987, European Patent Application Nos. 0510 356, 0 593 868 and 0 809 996 (pegylated interferon alfa-2a) and international Publication No. WO 95/13090.
  • pegylated means covalent conjugates of one or more
  • PEG polyethylene glycol
  • Preferred conjugates for use in the formulations of the invent ion have one to four PEG molecules per interferon molecule, and more preferably, the conjugates are between a single PEG molecule and a single interferon molecule.
  • the pegylated interferon may comprise a single posit ional isomer or a mixture of conjugate positional isomers, e.g, the PEG molecules are covalently attached to different amino acid residues on the indiv idual interferon molecules.
  • 5,95 1 ,974 describes the preparation of mixtures of PEG-interferon alpha conjugate posit ional isomers in which some of the isomers are conjugates between PEG and a histidine residue of the interferon molecule, other isomers in the mixture are conjugates between PEG and an interferon lysine residue and st ill other isomers are conjugates between PEG and the amino terminus of the interferon molecule.
  • 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 an interferon, 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 camphorsuifonic acid.
  • the present invention relates to a pharmaceutical composition comprising an HBsAg inhibitor and an interferon, in a pharmaceutically acceptable carrier.
  • the "HBsAg inhibitor” is a compound of formula (I):
  • R ! is hydrogen, halogen, C ' u.alkyl. C ' u.alkylamino or C ' u.alkoxy;
  • R is hydrogen; halogen; ( ⁇ ⁇ >alkyl, which is unsubstituted or once, twice or three times
  • R is hydrogen; C i ⁇ ,alkyl, which is unsubstituted or substituted with one to three substituents independently selected from fluoro, hydroxy and (Y ⁇ ,alkcnyl; CY
  • R 4 is hydrogen, halogen, C, ⁇ ,alkyl, cyano or C i ⁇ ,alkoxy;
  • R 5 is hydrogen or C i ⁇ ,alkyl
  • R 6 is hydrogen; CY ⁇ alkyl, which is unsubstituted or once, twice or three times substituted by fluoro; CY-cycloalkyl, which is unsubst ituted or once, twice or three times subst ituted by fluoro or C i ⁇ ,alkyl; or phenyl-C x H 2x -;
  • x is 1 -6;
  • Compounds of formula (I), Compounds 1 A to 3A and Compounds IB to 3B can be obtained according to the synthetic procedures disclosed in WO 201 5 1 13990. Particularly. the "HBsAg inhibitor " ' of the present invention relates to
  • the "HBsAg inhibitor” is a compound of formula ( I I ):
  • R 8 , R 9 , R 10 and R 1 1 arc independently selected from hydrogen, halogen.
  • R 14 is hydrogen; C ⁇ ⁇ ,alkyl; or C ,alkyl. w hich is subst ituted once or more times by fluoro, C; -cycloalkyl, phenyl, hydroxyl. amino, C i ⁇ ,alkoxy, Ci ⁇ alkylsulfanyl, Ci ⁇ a!kylsulfonyl, diCi ⁇ ,alkylamino, C i ⁇ alkoxycarbonylam ino. monocyclic heterocycloalkyl, pyrazoyl or imidazolyl; R 12 is hydrogen or C ' u.alky;
  • R 13 is hydrogen, G ⁇ ,alkyl, phenyl-C x H 2x -, C .alkylcarbonyl. Cu.alkylsulfbnyl. 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 15 and R 16 are independently selected from hydrogen, fluoro, hydroxy and C
  • z is 0-6;
  • X is a bond; O; S; S(0) 2 ; or NR 17 , wherein R 1 is hydrogen, G ⁇ aikyl;
  • H BsAg inhibitor of the present invent ion relates to
  • an HBsAg inhibitor can include any one of the compounds in any pharmaceutically acceptable form, including any isomer (e.g., diastereomer or enant iomer), salt, solvate, polymorph, and the like.
  • Suitable interferons in accordance with the present invention may be any naturally- occurring or recombinant interferon alfa, beta or gamma known to those skilled in the art. Natural and recombinant alfa-interferons that may be used include interferon alfa-n l (e.g...
  • interferon alfa-n3 interferon alfa-2a
  • Roferon A ® interferon alfa-2a
  • interferon alfa-2b Intron A*
  • interferon aifa-2c Berofor " , Boehringer Ingelheim, Inc.
  • consensus interferon I nfergen " , InterMune, Inc.
  • Preferred interferons are interferon aifa-2a and interferon alfa-2b.
  • suitable interferons in accordance with the present invent ion include, but are not limited to, recombinant interferon a 1 fa -2b such as Intron A ® ; recombinant interferon alfa-2a such as Roferon A*; recombinant interferon beta- lb such as Betaferon ® ( Bayer AG ); recombinant interferon beta- 1 a such as Avonex ® ( Bio gen Canada Inc. ) and Rebif ® (Merck KGaA); and recombinant interferon gamma- l b such as Imukin* ( Boehringer Ingelheim).
  • recombinant interferon a 1 fa -2b such as Intron A ®
  • recombinant interferon alfa-2a such as Roferon A*
  • recombinant interferon beta- lb such as Betaferon ® ( Bayer AG )
  • interferon alfa-2a is recombinant interferon a 1 fa -2 a or alfa-2b.
  • interferon alfa-2a is further intended to include “pegylated” analogs meaning polyethylene glycol modified conjugates of interferon alfa-2a such as Pegasys*, interferon a 1 fa -2b such as Peglntron* and Pai Ge Bin, and interferon beta- l a such as Plegridy ® ( Bio gen Canada Inc. ).
  • pegylated recombinant interferon alfa-2a or alfa 2b is preferred.
  • the "interferon” is a non-conjugated interferon alfa or a pegylated con jugate thereof.
  • interferon alfa- 2a such as Roferon A ®
  • interferon alfa-2b such as Intron A* '
  • pegylated interferon alfa-2a such as Pegasys ®
  • pegylated interferon alfa-2b such as Peglntron ® and Pai Ge Bin respect ively.
  • interferon is a non-conjugated interferon alfa-2a (for instance Roferon A*) or a pegylated alfa-type interferon (for instance Pegasys ® ):
  • the above pegylated alfa-type interferon is an alfa-2a interferon.
  • the pharmaceut ical composit ion comprises an
  • H BsAg viral expression inh ibitor and an interferon wherein the H BsAg inhibitor and the interferon are independently selected from Table 1.
  • Table 1 List of HBsAg inhibitors and interferons Compound
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an HBsAg inhibitor and an interferon which is selected from any one of the following combinations:
  • the present invention relates to a pharmaceut ical composit ion
  • the pharmaceutical composition consists of an
  • HBsAg inhibitor and an interferon in a pharmaceutically acceptable carrier. More particularly, the composit ion consists of: ( + )- 10-methoxy-6-isopropy -9-( 3-methoxypropoxy )-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid and Roferon A ® in a pharmaceutically acceptable carrier.
  • other interferons or HBsAg inhibitors can also be used in the pharmaceutical composition including small molecules or large molecules.
  • interferons examples include, but not limited to, Surniferon, Sumitomo, Berofor, Infergen, Multiferon, Rebif, Avonex, Cinnovex, Betaseron / Betaferon, Imukin, Plegridy, Act immune, Reifercm Retard and Pegetron.
  • Typical dosages of an HBsAg inhibitor and/or an interferon can be in the ranges recommended by the manufacturer, 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. Thus, the actual dosage will depend upon the judgment of the physician, the condit ion of the patient, and the effect iveness of the therapeutic method based on the in v/tro responsiveness of the appropriate animal models.
  • Another embodiment of the present invent ion relates to a method for manufacturing a medicament for treatment or prophylaxis of hepat it is B virus infect ion, characterized in that an HBsAg inhibitor and an interferon are used in the medicament.
  • a further embodiment of the present invent ion relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatit is B virus infection, characterized in that the HBsAg inhibitor and the interferon are co-administered in the same formulation or different formulation.
  • co -administer refers to any administration of the HBsAg inhibitor and interferon 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 pharmaceutical compositions.
  • the two active agents can be administered either at the same time, or sequentially.
  • the pharmaceutical composition of the HBsAg inhibitor and interferon can be any pharmaceutical composition of the HBsAg inhibitor and interferon.
  • 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 the HBsAg inhibitor and interferon 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 the HBsAg inhibitor and interferon thereof 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 the HBsAg inhibitor and interferon thereof 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 admin istration of agents separately or sequent ially can be in any order.
  • HBsAg inhibitor thereof is a compound of formula (I), or formula ( I I ), or pharmaceut ically acceptable salt, enantiomer or diastereomer thereof
  • the HBsAg inhibitor thereof is a compound of formula (I), or formula ( I I ), or pharmaceut ically acceptable salt, enantiomer or diastereomer thereof
  • the HBsAg inhibitor thereof is a compound of formula (I), or formula ( I I ), or pharmaceut ically acceptable salt, enantiomer or diastereomer thereof
  • the HBsAg inhibitor thereof is
  • Another embodiment of the present invent ion relates to the method for manufacturing a medicament for treatment or prophylaxis of hepatitis B virus infection, characterized in that the interferon thereof is a non-conjugated interferon a I fa, a pegylated a 1 fa-type interferon or a y- branched pegylated recombinant human interferon alpha-2b; particularly the interferon is oferon A ® , Intion A*, Pegasys ® , Peglntron ® or Pai Ge Bin; more particularly the interferon is Roferon A ® ,
  • 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 and the interferon used in the medicament are (+)-10-methoxy-6-isopropyl-9- (3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinoiizine-3-carboxylic acid and Roferon ⁇ :; in a pharmaceut ically acceptable carrier.
  • kits comprising a container comprising an HBsAg inhibitor and an interferon, 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 an interferon as a method for treatment or prophylaxis of hepatitis B virus infect ion.
  • Another embodiment of the present inv ent ion relates to the said kit, wherein the HBsAg inhibitor is
  • Another embodiment of the present invent ion relates to the said kit, characterized in that the interferon thereof is a non-conjugated interferon alfa, a pegylated alfa-type interferon or a y- branched pegylated recombinant human interferon alpha-2b; particularly the interferon is
  • Roferon A* Intro n. A*, Pegasys*, Peglntron* or Pai Ge Bin; more particularly the interferon is Roferon A*.
  • kits characterized in that the HBsAg inhibitor and the interferon used in the container are (+)-10-methoxy-6-isopropyi-9- (3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinoiizine-3-carboxyiic acid and Roferon A 3 ⁇ 4 ; or pharmaceut ically acceptable salt, or enantiomer, or diastereomer thereof.
  • Another embodiment of the present invent ion relates to a method for the treatment or prophylaxis of hepatitis B virus infection, comprising administration to a subject with an effect ive first amount of an HBsAg inhibitor, or pharmaceut ically acceptable salt, enant iomer or diastereomer thereof; and a second amount of an interferon; or vice versa; wherein the HBsAg inhibitor thereof is
  • Another embodiment of the present invention relates to a method for the treatment or prophylaxis of hepatitis B virus infection, comprising administration to a subject with an effect ive first amount of an HBsAg inhibitor, or pharmaceut ically acceptable salt, enantiomer or diastereomer thereof; and a second amount of an interferon; or vice versa; wherein the interferon thereof is a non-conjugated interferon alfa, a pegylated al fa-type interferon or a y-branched pegylated recombinant human interferon alpha-2b; particularly the interferon is Roferon A*, Intro n. A*, Pegasys*, Peglntron* or Pai Ge Bin; more part icularly the interferon is Roferon A*.
  • a further embodiment of the present invention relates to a method for the treatment or prophylaxis of hepat it is B virus infection, wherein the HBsAg inhibitor and the interferon used in the subject are (+)-10-methoxy-6-isopropyi-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid and Roferon A*; in a pharmaceutically acceptable carrier.
  • Another embodiment of the present invent ion relates to use of pharmaceut ical composit ion herein ment ioned above as an ant iviral medicament, in particular as the medicament for treatment or prophylaxis of hepat itis B v irus infection.
  • Another embodiment of the present invent ion relates to the use of an I IBsAg inhibitor and an interferon for the manufacture of pharmaceutical composition herein mentioned above as an ant iviral medicament, in particular the medicament for treatment or prophylaxis of hepat itis B virus infect ion.
  • Step 1 Preparation of 4-hydroxy-3 -dimethyI-butan-2-one
  • Step 3 Preparation of 4-methoxy-l-
  • Step 5 Preparation of N-[3-methoxy-l-[[ -methoxy-3-(3-methoxypropoxy)phenyl]methyl]-
  • 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-d!methyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-l ,6 7,l l b-tetrahydrobenzo
  • Step 8 Preparation of ethyl 10-methoxy-6-(2-methoxy-l ,l -dimethyI-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo
  • Step 9 Preparation of 10-methoxy-6-(2-methoxy-l ,l -dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo
  • Step 10 preparation of (+)-10-methoxy-6-(2-methoxy-l ,l -dimethyl-ethyl)-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo
  • Step 3 Preparation of 4-benzyloxy-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3- dimethyl-biitan-2-amine
  • Step 5 Preparation of 3-(2-benzyloxy-l,l-dimethyl-ethyl)-7-methoxy-6-(3- methoxypropoxy)-3,4-dih droisoquinoline
  • Step 6 Preparation of ethyl 6-(2-benzyloxy- 1 , 1 -dimethyl-ethyl)- 10-methoxy-9-(3- methoxypropoxy)-2-oxo- 1 ,6,7,1 l b-tetrahydrobenzo
  • Step 7 Preparation of ethyl 6-(2-bfelloxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypn)poxy)-2-oxo-6,7-dihydrobenzo
  • Step 8 Preparation of 6-(2-benzyloxy-l,l-dimethyl-ethyl)-10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzo
  • Step 9 Preparation of 6-(2-hydroxy- 1 ,1 -dimethyl-ethyl)- 10-methoxy-9-(3- inethoxypropoxy)-2-oxo-6,7-dihydrobenzo
  • Step 10 Preparation of (+)-6-(2-hydroxy- 1 , 1 -dimethyl-ethyl)- 10-methoxy-9-(3- methoxypropoxy)-2-oxo-6,7-dihydrobenzoia
  • Step 1 Preparation of 4-chloro-l -
  • Step 2 Preparation of 4-chloro-l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3-dimethyl- biitan-2-amine
  • Step 3 Preparation of V-
  • Step 4 Preparation of 7-chloro-3-(2-methoxy-l,l-dimethyl-ethyl)-6-(3-methox propox )- 3,4-dihydroisoquinoline
  • Step 5 Preparation of ethyl 10-chloro-6-(2-methoxy-l ,l -dimethyi-ethyl)-9-(3- methoxypropoxy)-2-oxo- 1 , 6,7,1 l b-tetrahydrobenzo
  • Step 7 Preparation of 10-chloro-6-(2-methoxy- l ,l-dimethyl-ethyI)-9-(3-metlioxypropoxy)- 2-oxo-6,7-dihydrobenzo [a] qiiino!izine-3-earboxylic acid
  • Step 8 Preparation of (+)-10-chloro-6-(2-methoxy-l ,l -dimethyl-ethyI)-9-(3- inetlioxypropoxy)-2-oxo-6,7-dihydrobenzo
  • HBsAg Assay to test capacity of HBsAg inhibitor to inhibit HBsAg
  • HepG2.2.15 cells (Acs et al. Proc Natl Acad Sci USA, 84, (1987), 4641-4), a
  • constitutively HBV-expressing cell line were cultured in DMEM+Glutamax-I medium
  • HepG2.2 1 5 cells were seeded in duplicate into white, 96-well plates at 1.5 x 10 4 ceils/well. The cells were treated with a three-fold serial dilution series of the compounds in DM SO. The final D SO concentration in all wells was 1% and DM SO was used as no d ug control.
  • the HBsAg chemiiuminescence immunoassay (CLIA) kit (Autobio Diagnostics Co., Zhengzhou, China, Catalog number: CL03 10-2 ) was used to measure the levels of secreted HBV antigens semi-quantitative iy.
  • CLIA HBsAg chemiiuminescence immunoassay
  • 50 .uL/well culture supernatant was used and HBsAg was quantified using HBsAg chemiiuminescence immunoassay (CLIA) kit (Autobio Diagnostics Co., Zhengzhou, China, Catalog number: CL0310-2), 50 ⁇ L of the supernatant was transferred to the CLIA assay plate and 50 ⁇ 1, of enzyme conjugate reagent was added into each well. The plates were sealed and gently agitated for 1 hour at room temperature.
  • the HBsAg chemiiuminescence immunoassay (CLIA) kit Autobio Diagnostics Co., Zhengzhou, China, Catalog number
  • Luminance was measured using a hi mi no meter (Mithras LB 940 Mult imodc Microplatc Reader) after 1 0 minutes incubat ion. Dose-response curves were generated and the IC 50 value was extrapolated by using the E- Work Book Suite (ID Business Solutions Ltd., Guildford, UK). The IC 50 was defined as the compound concentration (or condit ioned media log dilut ion) at which HBsAg secretion was reduced by 50% compared to the no drug control.
  • Virus and cells HepG2.2.15 cells were cultured in DMEM+Glutamax I (Gibco, #21885) supplemented w ith 10% FBS, 1% Pen/Strep (Gibco, #15140) and G-418 (250 iig ml. ) and used for production of infect ious HBV (genotype D). 90% confluent cells from three T 1 75 flasks were trypsinized and transferred into one collagen coated hypcrflask (550 ml. ). Once the cells are confluent, medium was changed to DMEM+Glutamax I with 1% DM SO and 2.5% FBS.
  • HepaRG cells Biopredie Internat ional, Saint-Gregoire. France were cultured in working growth medium (500 ml , Willams E Medium w ith 50 ml, HepaRG Growth supplement from Biopredie, 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% D SO (500 ml, Willams E Medium with 50 ml, HepaRG Growth supplement from Biopredie, 5 ml, Pen/Strep, 5 ml .
  • working growth medium 500 ml , Willams E Medium w ith 50 ml, HepaRG Growth supplement from Biopredie, 5 mL Glutamax-I (Gibco, #35050) and 5 ml, Pen/Strep
  • D SO 500 ml, Willams E Medium with 50 ml, HepaRG Growth supplement from Biopredie,
  • new differentiation medium 120 ⁇ , well containing 4% PEG-8000 and virus stock (20 to 30 GE/cell) was added.
  • Cells were cultured at 37°C for 1 6 to 20 h before medium was removed. ceils were washed 4 times with PBS and new differentiation medium (120 ⁇ ) was added.
  • new differentiation medium 120 ⁇ was added to each well.
  • the concentration ranges tested were 50 nM to 0.62 nM for Compound 1 , and 30 IU/mL to 0.04 lU/mL for Compound 7.
  • Medium was replaced by new medium with compound at day 6 and day 8 post infect ion and at day 11 post infect ion cell supernatants were harvested and directly used for I I B V DNA ext action or stored at -20 C.
  • Cell viabil ity of the cells was determined using the cell viability assay described below.
  • a 1 f 137 example of combinat ion of drug A and B at different ratios DNA extraction
  • H BV DNA from HepaRG cel l supematants was extracted using the MagNA Pure 96
  • Forward core primer ( F3 core): CTG TGC CTT GGG TGG CTT T
  • Reverse primer A AG GAA AG A AGT GAG A AG GCA AAA
  • Taqman probe P3 core: 56-FAM/AGC TGC AAA /ZEN/TTC TTT ATA AGG GTC
  • Cell viability assay Cell viability of the HBV infected and treated HepaRG cells was determined at day 1 1 post infection using the CeUTiter-Gio ® (CTG) Luminescent Cell Viabil ity Assay (Promega, Cat. no. G7572). 100 uL of CTG reagent were added to each well of the cells, incubated for 1 0 min and 80 uL of each well were transferred to a new white 96 well plate. Luminescence (0.2 sec) was measured using an Envision reader ( Perkin Elmer).
  • FIC ratio [EC50 combination ⁇ EC50 alone]
  • a CI ⁇ 1 means synergism
  • a C! 1 means addit ivity
  • a CI > 1 means antagonism.
  • this program converts the dose-effect curves for each drug or drug combination to median effect plots.
  • a combinat ion index (CI) for each experimental combinat ion was then calculated by the following equation: [(D) 1 /(Dx) 1 ]+[(D) 2 /(Dx) 2 ]+[(D) 1 (D) 2 /(Dx) 1 (Dx) 2 ] where (Dx)i and (Dx) 2 arc the doses of drug 1 and drug 2 that have x effect when each drug is used alone, and (D)i and (D) 2 arc the doses of drug 1 and drug 2 that have the same x effect when they are used in combinat ion, respectively.
  • the software calculates the CIs at 50%, 75% and 90% antiviral effect of combinations.
  • Combination effect assessment was based on overall CI values as follow s: 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). Theoret ical basis, experimental design, and computerized simulat ion of synergism and antagonism in drug combinat ion studies. Pharmacol. Rev., 58:621 -681). Drug combinat ions were analyzed at three different fixed drug ratios spanning and including the approximate rat io of their ECsoS.
  • Combinat ion of Compound 1 A with Compound 7 was tested for anti-HBV activ ity in HBV infected differentiated HepaRG cells.
  • Combination of Lamivudine with Lamivudine was set as the control combinat ion.
  • the single compound inhibitory activites (EC 50 ) obtained in the combination studies were determined (Table 4).
  • the concentration ranges chosen were also confirmed below the cytotoxic concentrations for each of the compounds (Table 5) and had no significant cytotoxic effect which could interfere with antiviral act iv ity.

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Abstract

L'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 interféron destinés à être utilisés dans le traitement ou la prophylaxie d'infections chroniques par le virus de l'hépatite B.
PCT/EP2016/082678 2015-12-29 2016-12-27 Traitement combiné avec un inhibiteur de hbsag et un interféron WO2017114812A1 (fr)

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Cited By (13)

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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
EP3492467A4 (fr) * 2016-07-29 2019-07-24 Ginkgo Pharma Co., Ltd. Composé isoquinolinone et son utilisation dans la préparation d'un médicament antiviral
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2020023710A1 (fr) 2018-07-27 2020-01-30 Arbutus Biopharma Corporation Tétrahydrocyclopenta[c]pyrroles substituées, dihydropyrrolizines substituées, analogues de celles-ci, et procédés les utilisant
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
US10966970B2 (en) * 2017-06-01 2021-04-06 Sunshine Lake Pharma Co., Ltd. Fused tricyclic compounds and uses thereof in medicine
US11234977B2 (en) 2017-12-20 2022-02-01 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals

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WO2015113990A1 (fr) * 2014-01-30 2015-08-06 F. Hoffmann-La Roche Ag Nouvelles dihydroquinolizinones pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
WO2016071215A1 (fr) * 2014-11-03 2016-05-12 F. Hoffmann-La Roche Ag Nouveaux dérivés de 6,7-dihydrobenzo[a]quinolizin-2-one pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b

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WO1998019670A2 (fr) * 1996-11-01 1998-05-14 Thomas Najarian Procedes et compositions de traitement des infections par le virus de l'hepatite c
WO2003028722A1 (fr) * 2001-10-04 2003-04-10 Xtl Biopharmaceuticals Ltd Traitement des infections par le virus de l'hepatite b avec des anticorps monoclonaux humains
WO2015113990A1 (fr) * 2014-01-30 2015-08-06 F. Hoffmann-La Roche Ag Nouvelles dihydroquinolizinones pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
WO2016071215A1 (fr) * 2014-11-03 2016-05-12 F. Hoffmann-La Roche Ag Nouveaux dérivés de 6,7-dihydrobenzo[a]quinolizin-2-one pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP3492467A4 (fr) * 2016-07-29 2019-07-24 Ginkgo Pharma Co., Ltd. Composé isoquinolinone et son utilisation dans la préparation d'un médicament antiviral
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
US10301312B2 (en) 2017-04-27 2019-05-28 Novartis Ag Fused indazole pyridone compounds as antivirals
US10975078B2 (en) 2017-04-27 2021-04-13 Novartis Ag Fused indazole pyridone compounds as antivirals
US10966970B2 (en) * 2017-06-01 2021-04-06 Sunshine Lake Pharma Co., Ltd. Fused tricyclic compounds and uses thereof in medicine
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
WO2020023710A1 (fr) 2018-07-27 2020-01-30 Arbutus Biopharma Corporation Tétrahydrocyclopenta[c]pyrroles substituées, dihydropyrrolizines substituées, analogues de celles-ci, et procédés les utilisant
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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