WO2017061466A1 - 抗b型肝炎ウイルス剤 - Google Patents
抗b型肝炎ウイルス剤 Download PDFInfo
- Publication number
- WO2017061466A1 WO2017061466A1 PCT/JP2016/079614 JP2016079614W WO2017061466A1 WO 2017061466 A1 WO2017061466 A1 WO 2017061466A1 JP 2016079614 W JP2016079614 W JP 2016079614W WO 2017061466 A1 WO2017061466 A1 WO 2017061466A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- optionally substituted
- hepatitis
- groups
- virus agent
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to an anti-hepatitis B virus agent.
- Hepatitis B is one of viral hepatitis that develops by infection with hepatitis B virus (HBV), and about 350 million people worldwide are thought to be infected with hepatitis B. ing. Interferon and nucleic acid analogues are used for the treatment of hepatitis B, but the effect is not sufficient.
- pyridonecarboxylic acid derivatives having antibacterial activity are known (Patent Document 1). However, it is not known that the pyridonecarboxylic acid derivative described in Patent Document 1 has antiviral activity.
- An object of the present invention is to provide a novel anti-HBV agent.
- R 1 represents an optionally substituted aryl group or an optionally substituted heterocyclic group
- R 2 represents an optionally substituted C 3-8 cycloalkyl group, optionally substituted.
- R 3 represents a hydrogen atom or a carboxyl protecting group, ”or a salt thereof.
- ⁇ 4> The anti-hepatitis B virus agent according to ⁇ 1>, wherein R 1 is an optionally substituted heterocyclic group.
- R 1 is an optionally substituted bicyclic heterocyclic group.
- R 6> The anti-hepatitis B virus agent according to any one of ⁇ 1> to ⁇ 5>, wherein R 2 is an optionally substituted aryl group.
- R 7> The anti-hepatitis B virus agent according to any one of ⁇ 1> to ⁇ 5>, wherein R 2 is an optionally substituted phenyl group.
- the compound represented by the general formula [1] of the present invention or a salt thereof has excellent anti-HBV activity and is useful as an anti-hepatitis B virus agent.
- a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- C 1-3 alkyl group means a methyl, ethyl, propyl or isopropyl group.
- the C 1-6 alkyl group is a linear or branched C 1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups.
- An alkyl group is meant.
- C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
- An aryl group means a phenyl or naphthyl group.
- An ar C 1-6 alkyl group means an ar C 1-6 alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl groups.
- the C 1-3 alkoxy group means a methoxy, ethoxy, propoxy or isopropoxy group.
- the C 1-6 alkoxy group means a linear or branched C 1 -1 group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
- 6 means an alkoxy group.
- the C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkoxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl groups.
- An al C 1-6 alkoxy C 1-6 alkyl group means an al C 1-6 alkoxy C 1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl groups.
- the C 2-6 alkanoyl group means a linear or branched C 2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
- An aroyl group means a benzoyl or naphthoyl group.
- An acyl group means a formyl group, a C 2-6 alkanoyl group or an aroyl group.
- the C 1-6 alkoxycarbonyl group is a linear or branched C 1 -1 group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl groups. 6 means an alkoxycarbonyl group.
- the al C 1-6 alkoxycarbonyl group means an al C 1-6 alkoxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups
- the C 1-6 alkylsulfonyl group means a C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
- An arylsulfonyl group means a benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.
- the C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy groups.
- An arylsulfonyloxy group means a benzenesulfonyloxy, p-toluenesulfonyloxy or naphthalenesulfonyloxy group.
- the C 1-3 alkylamino group means a methylamino, ethylamino, propylamino or isopropylamino group.
- the C 1-6 alkylamino group is a linear or branched chain such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups.
- -Like C 1-6 alkylamino group is a linear or branched chain such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino and hexylamino groups.
- the di (C 1-3 alkyl) amino group is a linear or branched chain such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, (ethyl) (methyl) amino and (methyl) (propyl) amino groups
- a di (C 1-3 alkyl) amino group in the form of a ring is a linear or branched chain such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, (ethyl) (methyl) amino and (methyl) (propyl) amino groups
- Di (C 1-6 alkyl) amino group means dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino and A linear or branched di (C 1-6 alkyl) amino group such as a (methyl) (propyl) amino group is meant.
- the cyclic amino group includes one or more nitrogen atoms as a hetero atom forming the ring such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl and thiomorpholinyl, and further one or more oxygen atoms Or the cyclic amino group which may contain a sulfur atom is meant.
- Monocyclic nitrogen-containing heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, pyridyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazylyl It means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring, such as pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl groups.
- a monocyclic oxygen-containing heterocyclic group means a tetrahydrofuranyl, furanyl, tetrahydropyranyl, dihydropyranyl or pyranyl group.
- the monocyclic sulfur-containing heterocyclic group means a thienyl group.
- the monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic nitrogen-containing / oxygen heterocyclic ring containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups. Means a formula group.
- a monocyclic nitrogen-containing / sulfur heterocyclic group is a heterocycle that forms the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups.
- a monocyclic nitrogen-containing / sulfur heterocyclic group containing only nitrogen and sulfur atoms as atoms.
- the monocyclic heterocyclic group is a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, or a monocyclic nitrogen-containing / oxygen heterocyclic group. It means a group or a monocyclic nitrogen-containing / sulfur heterocyclic group.
- Bicyclic nitrogen-containing heterocyclic groups include indolinyl, indolyl, isoindolinyl, isoindolyl, pyrrolopyridinyl, indazolyl, benzimidazolyl, benzotriazolyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolinyl, dihydroquinolinyl, tetrahydro Heteromorphs forming the ring such as isoquinolinyl, decahydroisoquinolinyl, isoquinolinyl, dihydroquinazolinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups
- Bicyclic oxygen-containing heterocyclic groups are 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodi It means a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as oxanyl and 1,4-benzodioxanyl group.
- the bicyclic sulfur-containing heterocyclic group is a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups. means.
- Bicyclic nitrogen-containing / oxygen heterocyclic groups include dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxino It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as a pyridyl and dihydropyridoxazinyl group.
- Bicyclic nitrogen-containing / sulfur heterocyclic group means nitrogen atom and sulfur atom as hetero atoms forming the ring such as dihydrobenzothiazolyl, benzothiazolyl, benzoisothiazolyl and benzothiadiazolyl group. This means a bicyclic nitrogen-containing / sulfur heterocyclic group.
- Bicyclic heterocyclic groups are bicyclic nitrogen-containing heterocyclic groups, bicyclic oxygen-containing heterocyclic groups, bicyclic sulfur-containing heterocyclic groups, bicyclic nitrogen-containing An oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group is meant.
- the heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.
- Substituent group A halogen atom, nitro group, cyano group, hydroxyl group which may be protected, C 1-6 alkyl group which may be substituted with one or more groups selected from substituent group B, substituent An aryl group which may be substituted with one or more groups selected from group B, a C 1-6 alkoxy group which may be substituted with one or more groups selected from substituent group B, C 1-6 An alkylamino group, a di (C 1-6 alkyl) amino group, a heterocyclic group optionally substituted with one or more groups selected from substituent group B, and an oxo group.
- Substituent group A1 Halogen atom, optionally protected hydroxyl group, C 1-3 alkyl group, C 1-3 alkoxy group.
- Substituent group A2 a halogen atom, a phenyl group which may be substituted with one or more groups selected from substituent group B1, a C 1-3 alkylamino group, a di (C 1-3 alkyl) amino group, a cyclic group Amino group, monocyclic heterocyclic group.
- Substituent group B halogen atom, nitro group, cyano group, C 1-6 alkyl group, aryl group, C 1-6 alkoxy group, C 1-6 alkylamino group, di (C 1-6 alkyl) amino group, Heterocyclic group, oxo group.
- Substituent group B1 halogen atom, nitro group, cyano group.
- the carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups.
- Greene's Protective Groups in Organic Synthesis 5th edition, No. 686-836, 2014, John Wiley & Sons, INC.
- Specific examples include a C 1-6 alkyl group, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, and an al C 1-6 alkoxy C 1-6 alkyl group. These groups may be substituted with one or more groups selected from the substituent group A.
- the hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary hydroxyl groups.
- Greene's Protective Groups in Organic Synthesis 5th edition, No. Pp. 17-471, 2014, John Wiley & Sons, INC.
- a C 1-6 alkyl group an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an al C 1-6
- examples thereof include an alkoxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group.
- These groups may be substituted with one or more groups selected from the substituent group A.
- Examples of the leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group, or an arylsulfonyloxy group.
- the C 1-6 alkylsulfonyloxy group and arylsulfonyloxy group may be substituted with one or more groups selected from the substituent group A.
- preferable compounds include the following compounds.
- R 1 is an optionally substituted aryl group or an optionally substituted heterocyclic group.
- the aryl group and heterocyclic group of R 1 may be substituted with one or more groups selected from the substituent group A.
- a compound in which R 1 is an aryl group which may be substituted is preferable, a compound in which a phenyl group may be substituted is more preferable, and a phenyl which may be substituted with one or more groups selected from substituent group A1 More preferred are compounds that are groups.
- a compound in which R 1 is an optionally substituted heterocyclic group is preferable, and a compound in which R 1 is an optionally substituted bicyclic heterocyclic group is more preferable, which is selected from substituent group A1. More preferred are compounds that are bicyclic heterocyclic groups that may be substituted with one or more groups.
- R 2 is an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.
- the C 3-8 cycloalkyl group, aryl group and heterocyclic group of R 2 may be substituted with one or more groups selected from the substituent group A.
- R 2 is preferably an aryl group that may be substituted, more preferably a phenyl group that may be substituted, and phenyl that may be substituted with one or more groups selected from substituent group A2. More preferred are compounds that are groups.
- a compound in which R 2 is an optionally substituted heterocyclic group is preferable, and a compound in which R 2 is an optionally substituted monocyclic heterocyclic group is more preferable, which is selected from the substituent group A2. More preferred are compounds that are monocyclic heterocyclic groups optionally substituted with one or more groups.
- R 3 is a hydrogen atom or a carboxyl protecting group.
- a compound in which R 3 is a hydrogen atom is preferable.
- Examples of the salt of the compound represented by the general formula [1] include salts that are generally known in basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups.
- salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
- formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
- Salts with organic carboxylic acids
- Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, 4-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
- alkali metals such as sodium and potassium
- alkaline earth metals such as calcium and magnesium
- ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, 4-methylmorpholine, diethylamine
- preferred salts include pharmacologically acceptable salts.
- the present invention when isomers (for example, optical isomers, geometric isomers, tautomers and the like) exist, the present invention includes those isomers, It includes solvates, hydrates and crystals of various shapes. Furthermore, this invention also includes the prodrug of the compound represented by General formula [1].
- formulation adjuvants such as excipients, carriers, and diluents that are usually used for formulation may be appropriately mixed.
- excipients such as excipients, carriers, and diluents that are usually used for formulation
- these are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches, ointments , And can be administered orally or parenterally in the form of a lotion, cream or injection.
- the administration method, the dose, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg daily may be divided into 1 to several doses. Good.
- the compound represented by the general formula [1] is produced by a combination of methods known per se, and can be produced, for example, according to the production method shown below.
- the compound represented by the general formula [S2] is represented by the general formula R 1 NH 2 after reacting the compound represented by the general formula [S1] with an acetal such as N, N-dimethylformamide dimethyl acetal. It can manufacture by making the compound which reacts. This reaction may be performed according to the method described in Patent Document 1.
- the compound represented by the general formula [S3] can be produced by subjecting the compound represented by the general formula [S2] to a ring-closing reaction. This reaction may be performed according to the method described in Patent Document 1.
- the compound represented by the general formula [1a] can be produced by subjecting the compound represented by the general formula [S3] to a dehydrogenation reaction. This reaction may be performed according to the method described in Patent Document 1.
- the compound represented by the general formula [1b] can be produced by subjecting the compound represented by the general formula [1a] to a deprotection reaction. This reaction may be performed according to the method described in Patent Document 1.
- Test Example 1 Anti-HBV Assay HepG2.2.15 cells (Proc. Natl. Acad. Sci. USA, 84), which is a virus-producing cell in which the HBV genome has been introduced into the hepatoblastoma cell line HepG2. , 1005-1009, 1987), the anti-HBV activity of compounds 1 to 16 was evaluated by the following procedure. The following was used as the medium.
- DMEM / F-12 GlutaMAX (Invitrogen) + 5 ⁇ g / mL insulin (Wako) + 1% penicillin / streptomycin (Sigma) + 10 mmol / L HEPES (Sigma) + 50 ⁇ mol / L hydrocortisone (Sigma) + 10 % FBS
- DMSO dimethyl sulfoxide
- HepG2.2.15 cells were suspended in the above medium to prepare a 1.5 ⁇ 10 5 cells / mL HepG2.2.15 cell suspension. This suspension was used to inoculate a 96-well microtiter plate (100 ⁇ L / well) and incubated at 37 ° C. for 1 day in a 5% CO 2 incubator. (2) The culture supernatant was removed, and the cells were washed twice with PBS ( ⁇ ) (100 ⁇ L / well) and then once with the above medium (100 ⁇ L / well). (3) The test solution was added to the plate of (2) (100 ⁇ L / well) and incubated at 37 ° C. for 3 days in a 5% CO 2 incubator.
- Compounds 1 to 16 showed excellent anti-HBV activity.
- Test Example 2 Anti-HBV assay with PXB-cells Using fresh hepatocytes (PXB-cells, manufactured by Phoenix Bio) collected from PXB mice (human hepatocyte chimeric mice), the anti-HBV activity of compound 8 was as follows. It was evaluated with. The following was used as the medium.
- PXB-cells seeded in a 48-well microtiter plate at a seeding density of 2.1 ⁇ 10 5 cells / cm 2 were incubated at 37 ° C. for 5 days in a 5% CO 2 incubator.
- PXB mouse serum-derived HBV (genotype AeUS) was suspended in the above medium containing 4% PEG-8000, and added to the plate of (1) so as to be about 10 copies / cell, and infected (250 ⁇ L / well). Incubation was performed at 37 ° C. for 1 day in a 5% CO 2 incubator.
- the above medium was added to the plate (250 ⁇ L / well) and incubated at 37 ° C. for 5 days in a 5% CO 2 incubator.
- the above medium was added to the plate (250 ⁇ L / well) and incubated at 37 ° C.
- the culture supernatant on the 32nd day after infection was collected.
- the collected culture supernatant on the 32nd day after infection was purified with QIAamp DNA Blood Mini Kit (manufactured by QIAGEN).
- the amount of HBV DNA in the obtained solution was quantified by a real-time PCR method.
- the amount of HBsAg (hepatitis B surface antigen) in the culture supernatant was quantified by chemiluminescence enzyme immunoassay using Lumipulse HBsAg-HQ (Fujirebio). For each, the relative viral load (%) relative to the control with no compound added was calculated.
- the relative viral load was 16% for HBV DNA and 29% for HBsAg.
- Compound 8 showed excellent anti-HBV activity.
- the compound represented by the general formula [1] or a salt thereof exhibits excellent anti-HBV activity and is useful as an anti-hepatitis B virus agent.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
B型肝炎の治療には、インターフェロンおよび核酸アナログなどが使用されているが、その効果は十分ではない。
一方、抗菌活性を有するピリドンカルボン酸誘導体が知られている(特許文献1)。しかし、特許文献1に記載されているピリドンカルボン酸誘導体が、抗ウイルス活性を有することは知られていない。
<1>
一般式[1]
「式中、R1は、置換されてもよいアリール基または置換されてもよい複素環式基を示し;R2は、置換されてもよいC3-8シクロアルキル基、置換されてもよいアリール基または置換されてもよい複素環式基を示し;R3は、水素原子またはカルボキシル保護基を示す。」で表される化合物またはその塩を含有する、抗B型肝炎ウイルス剤。
<2>
R1が、置換されてもよいアリール基である、<1>に記載の、抗B型肝炎ウイルス剤。
<3>
R1が、置換されてもよいフェニル基である、<1>に記載の、抗B型肝炎ウイルス剤。
<4>
R1が、置換されてもよい複素環式基である、<1>に記載の、抗B型肝炎ウイルス剤。
<5>
R1が、置換されてもよい二環式複素環式基である、<1>に記載の、抗B型肝炎ウイルス剤。
<6>
R2が、置換されてもよいアリール基である、<1>から<5>のいずれか一に記載の、抗B型肝炎ウイルス剤。
<7>
R2が、置換されてもよいフェニル基である、<1>から<5>のいずれか一に記載の、抗B型肝炎ウイルス剤。
<8>
R2が、置換されてもよい複素環式基である、<1>から<5>のいずれか一に記載の、抗B型肝炎ウイルス剤。
<9>
R2が、置換されてもよい単環の複素環式基である、<1>から<5>のいずれか一に記載の、抗B型肝炎ウイルス剤。
本発明において、特に断らない限り、%は質量%である。
本発明において、特に断らない限り、各用語は、次の意味を有する。
C1-3アルキル基とは、メチル、エチル、プロピルまたはイソプロピル基を意味する。
C1-6アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、sec-ブチル、イソブチル、tert-ブチル、ペンチル、イソペンチルおよびヘキシル基などの直鎖状または分枝鎖状のC1-6アルキル基を意味する。
C3-8シクロアルキル基とは、シクロプロピル、シクロブチル、シクロペンチルおよびシクロヘキシル基などのC3-8シクロアルキル基を意味する。
アリール基とは、フェニルまたはナフチル基を意味する。
アルC1-6アルキル基とは、ベンジル、ジフェニルメチル、トリチル、フェネチルおよびナフチルメチル基などのアルC1-6アルキル基を意味する。
C1-6アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、ペンチルオキシおよびヘキシルオキシ基などの直鎖状または分枝鎖状のC1-6アルコキシ基を意味する。
C1-6アルコキシC1-6アルキル基とは、メトキシメチルおよび1-エトキシエチル基などのC1-6アルコキシC1-6アルキル基を意味する。
アルC1-6アルコキシC1-6アルキル基とは、ベンジルオキシメチルおよびフェネチルオキシメチル基などのアルC1-6アルコキシC1-6アルキル基を意味する。
アロイル基とは、ベンゾイルまたはナフトイル基を意味する。
アシル基とは、ホルミル基、C2-6アルカノイル基またはアロイル基を意味する。
C1-6アルコキシカルボニル基とは、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、tert-ブトキシカルボニルおよび1,1-ジメチルプロポキシカルボニル基などの直鎖状または分枝鎖状のC1-6アルコキシカルボニル基を意味する。
アルC1-6アルコキシカルボニル基とは、ベンジルオキシカルボニルおよびフェネチルオキシカルボニル基などのアルC1-6アルコキシカルボニル基を意味する。
アリールスルホニル基とは、ベンゼンスルホニル、p-トルエンスルホニルまたはナフタレンスルホニル基を意味する。
C1-6アルキルスルホニルオキシ基とは、メチルスルホニルオキシ、エチルスルホニルオキシおよびプロピルスルホニルオキシ基などのC1-6アルキルスルホニルオキシ基を意味する。
アリールスルホニルオキシ基とは、ベンゼンスルホニルオキシ、p-トルエンスルホニルオキシまたはナフタレンスルホニルオキシ基を意味する。
C1-6アルキルアミノ基とは、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ブチルアミノ、sec-ブチルアミノ、tert-ブチルアミノ、ペンチルアミノおよびヘキシルアミノ基などの直鎖状または分枝鎖状のC1-6アルキルアミノ基を意味する。
ジ(C1-3アルキル)アミノ基とは、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ、(エチル)(メチル)アミノおよび(メチル)(プロピル)アミノ基などの直鎖状または分枝鎖状のジ(C1-3アルキル)アミノ基を意味する。
ジ(C1-6アルキル)アミノ基とは、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ、ジブチルアミノ、ジ(tert-ブチル)アミノ、ジペンチルアミノ、ジヘキシルアミノ、(エチル)(メチル)アミノおよび(メチル)(プロピル)アミノ基などの直鎖状または分枝鎖状のジ(C1-6アルキル)アミノ基を意味する。
単環の含酸素複素環式基とは、テトラヒドロフラニル、フラニル、テトラヒドロピラニル、ジヒドロピラニルまたはピラニル基を意味する。
単環の含硫黄複素環式基とは、チエニル基を意味する。
単環の含窒素・酸素複素環式基とは、オキサゾリル、イソオキサゾリル、オキサジアゾリルおよびモルホリニル基などの該環を形成する異項原子として窒素原子および酸素原子のみを含む単環の含窒素・酸素複素環式基を意味する。
単環の含窒素・硫黄複素環式基とは、チアゾリル、イソチアゾリル、チアジアゾリル、チオモルホリニル、1-オキシドチオモルホリニルおよび1,1-ジオキシドチオモルホリニル基などの該環を形成する異項原子として窒素原子および硫黄原子のみを含む単環の含窒素・硫黄複素環式基を意味する。
単環の複素環式基とは、単環の含窒素複素環式基、単環の含酸素複素環式基、単環の含硫黄複素環式基、単環の含窒素・酸素複素環式基または単環の含窒素・硫黄複素環式基を意味する。
二環式の含酸素複素環式基とは、2,3-ジヒドロベンゾフラニル、ベンゾフラニル、イソベンゾフラニル、クロマニル、クロメニル、イソクロマニル、1,3-ベンゾジオキソリル、1,3-ベンゾジオキサニルおよび1,4-ベンゾジオキサニル基などの該環を形成する異項原子として酸素原子のみを含む二環式の含酸素複素環基を意味する。
二環式の含硫黄複素環基とは、2,3-ジヒドロベンゾチエニルおよびベンゾチエニル基などの該環を形成する異項原子として硫黄原子のみを含む二環式の含硫黄複素環式基を意味する。
二環式の含窒素・酸素複素環式基とは、ジヒドロベンゾオキサゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾオキサジアゾリル、ベンゾモルホリニル、ジヒドロピラノピリジル、ジヒドロジオキシノピリジルおよびジヒドロピリドオキサジニル基などの該環を形成する異項原子として窒素原子および酸素原子のみを含む二環式の含窒素・酸素複素環式基を意味する。
二環式の含窒素・硫黄複素環式基とは、ジヒドロベンゾチアゾリル、ベンゾチアゾリル、ベンゾイソチアゾリルおよびベンゾチアジアゾリル基などの該環を形成する異項原子として窒素原子および硫黄原子を含む二環式の含窒素・硫黄複素環式基を意味する。
二環式複素環式基とは、二環式の含窒素複素環式基、二環式の含酸素複素環式基、二環式の含硫黄複素環式基、二環式の含窒素・酸素複素環式基または二環式の含窒素・硫黄複素環式基を意味する。
R1のアリール基および複素環式基は、置換基群Aから選ばれる一つ以上の基で置換されてもよい。
R1が、置換されてもよいアリール基である化合物が好ましく、置換されてもよいフェニル基である化合物がより好ましく、置換基群A1から選ばれる一つ以上の基で置換されてもよいフェニル基である化合物がさらに好ましい。
別の態様として、R1が、置換されてもよい複素環式基である化合物が好ましく、置換されてもよい二環式複素環式基である化合物がより好ましく、置換基群A1から選ばれる一つ以上の基で置換されてもよい二環式複素環式基である化合物がさらに好ましい。
R2のC3-8シクロアルキル基、アリール基および複素環式基は、置換基群Aから選ばれる一つ以上の基で置換されてもよい。
R2が、置換されてもよいアリール基である化合物が好ましく、置換されてもよいフェニル基である化合物がより好ましく、置換基群A2から選ばれる一つ以上の基で置換されてもよいフェニル基である化合物がさらに好ましい。
別の態様として、R2が、置換されてもよい複素環式基である化合物が好ましく、置換されてもよい単環の複素環式基である化合物がより好ましく、置換基群A2から選ばれる一つ以上の基で置換されてもよい単環の複素環式基である化合物がさらに好ましい。
R3が、水素原子である化合物が好ましい。
一般式[1]で表される化合物において、異性体(たとえば、光学異性体、幾何異性体および互変異性体など)が存在する場合、本発明は、それらの異性体を包含し、また、溶媒和物、水和物および種々の形状の結晶を包含するものである。
さらに、本発明は、一般式[1]で表される化合物のプロドラッグも包含する。
これらは、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、粉体製剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤、ローション剤、クリーム剤または注射剤などの形態で経口または非経口で投与することができる。また、投与方法、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択することができる。通常、成人に対しては、経口または非経口(たとえば、注射、点滴および直腸部位への投与など)投与により、1日、0.01~1000mg/kgを1回から数回に分割して投与すればよい。
一般式[1]で表される化合物は、自体公知の方法を組み合わせることにより製造されるが、たとえば、次に示す製造法にしたがって製造することができる。
一般式[S2]で表される化合物は、一般式[S1]で表される化合物にN,N-ジメチルホルムアミドジメチルアセタールなどのアセタール類を反応させたのち、一般式R1NH2で表される化合物を反応させることにより、製造することができる。
この反応は、特許文献1に記載の方法に従って行えばよい。
一般式[S3]で表される化合物は、一般式[S2]で表される化合物を閉環反応に付すことにより、製造することができる。
この反応は、特許文献1に記載の方法に従って行えばよい。
一般式[1a]で表される化合物は、一般式[S3]で表される化合物を脱水素反応に付すことにより、製造することができる。
この反応は、特許文献1に記載の方法に従って行えばよい。
一般式[1b]で表される化合物は、一般式[1a]で表される化合物を脱保護反応に付すことにより、製造することができる。
この反応は、特許文献1に記載の方法に従って行えばよい。
試験化合物として、化合物1~16を使用した。
肝芽細胞腫(hepatoblastoma)細胞株HepG2にHBVゲノムが導入された、持続的にウイルスを産生する細胞であるHepG2.2.15細胞(Proc. Natl. Acad. Sci. USA, 84, 1005-1009, 1987)を用いて、化合物1~16の抗HBV活性を以下の手順で評価した。
培地として、以下を用いた。
DMEM/F-12,GlutaMAX(Invitrogen社製)+5μg/mLインスリン(Wako社製)+1%ペニシリン/ストレプトマイシン(Sigma社製)+10mmol/L HEPES(Sigma社製)+50μmol/Lヒドロコルチゾン(Sigma社製)+10%FBS
さらに上記培地に、試験化合物のジメチルスルホキシド(DMSO)混合物をDMSOの終濃度が1%(v/v)となるようを加え、各化合物の種々濃度の試験液を調製した。また、薬物非添加の対照として上記培地にDMSOのみを終濃度1%(v/v)となるよう加えた試験液を調製した。
(2)培養上清を除き、細胞をPBS(-)(100μL/ウェル)で2回洗浄した後、上記培地(100μL/ウェル)で1回洗浄した。
(3)試験液を(2)のプレートに加え(100μL/ウェル)、5%CO2インキュベーターにて37℃で3日間インキュベートした。
(4)培養上清を除き、再度試験液をプレートに加え(100μL/ウェル)、5%CO2インキュベーターにて37℃で3日間インキュベートした。
(5)培養上清を回収し、Buffer AL(QIAGEN社製)およびProteinase K(Invitrogen社製)の混合物で処理した。得られた溶液中のHBV DNA量を、リアルタイムPCR法にて定量した。また培養上清中のHBsAg(hepatitis B surface antigen)を、ルミパルスHBsAg-HQ(富士レビオ社製)を用いた化学発光酵素免疫測定法にて定量した。それぞれについて、化合物非添加ウェルに対する化合物添加ウェルの相対ウイルス量(%)を算出した。濃度を対数、相対ウイルス量を実数でプロットし、Microsoft Office Excel 2007のFORECAST関数(1次回帰法)を用いて化合物のIC50を算出した。
結果を表1に示す。
PXBマウス(ヒト肝細胞キメラマウス)から採取した新鮮肝細胞(PXB-cells, フェニックスバイオ社製)を用いて、化合物8の抗HBV活性を以下の手順で評価した。
培地として、以下を用いた。
500mL DMEM(Sigma社製)+0.25μg/mLインスリン(Wako社製)+1%ペニシリン/ストレプトマイシン(Sigma社製)+20mmol/L HEPES(Sigma社製)+15μg/mL L-プロリン(Sigma社製)+50nmol/Lデキサメタゾン(Sigma社製)+5ng/mL EGF(Peprotech社製)+0.1mmol/L アスコルビン酸2リン酸(wako社製)+10%FBS+2%DMSO
さらに上記培地に化合物8を加え、10μmol/L濃度の試験液を調製した。
(2)PXBマウス血清由来HBV(genotype AeUS)を、4%PEG-8000含上記培地に懸濁し、約10 copies/cellとなるよう(1)のプレートに加えて感染させ(250μL/ウェル)、5%CO2インキュベーターにて37℃で1日間インキュベートした。
(3)培養上清を除き、細胞を10%FBS 1%ペニシリン/ストレプトマイシン含DMEMで3回洗浄した後、上記培地を加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で1日間インキュベートした。
(4)培養上清を除き、細胞を10%FBS 1%ペニシリン/ストレプトマイシンDMEMで3回洗浄した後、上記培地を加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。
(5)培養上清を除き、上記培地をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。
(6)感染後12日目の培養上清を除き、上記培地をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。
(7)感染後17日目の培養上清を除き、試験液をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。薬物非添加の対照には、上記培地をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。
(8)感染後22日目の培養上清を除き、試験液をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。薬物非添加の対照には、上記培地をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。
(9)感染後27日目の培養上清を除き、試験液をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。薬物非添加の対照には、上記培地をプレートに加え(250μL/ウェル)、5%CO2インキュベーターにて37℃で5日間インキュベートした。
(10)感染後32日目の培養上清を回収した。
(11)回収した感染後32日目の培養上清を、QIAamp DNA Blood Mini Kit(QIAGEN社製)で精製した。得られた溶液中のHBV DNA量を、リアルタイムPCR法にて定量した。また培養上清中のHBsAg(hepatitis B surface antigen)量を、ルミパルスHBsAg-HQ(富士レビオ社製)を用いた化学発光酵素免疫測定法にて定量した。それぞれについて化合物非添加の対照に対する相対ウイルス量(%)を算出した。
Claims (9)
- R1が、置換されてもよいアリール基である、請求項1に記載の、抗B型肝炎ウイルス剤。
- R1が、置換されてもよいフェニル基である、請求項1に記載の、抗B型肝炎ウイルス剤。
- R1が、置換されてもよい複素環式基である、請求項1に記載の、抗B型肝炎ウイルス剤。
- R1が、置換されてもよい二環式複素環式基である、請求項1に記載の、抗B型肝炎ウイルス剤。
- R2が、置換されてもよいアリール基である、請求項1~5のいずれか一項に記載の、抗B型肝炎ウイルス剤。
- R2が、置換されてもよいフェニル基である、請求項1~5のいずれか一項に記載の、抗B型肝炎ウイルス剤。
- R2が、置換されてもよい複素環式基である、請求項1~5のいずれか一項に記載の、抗B型肝炎ウイルス剤。
- R2が、置換されてもよい単環の複素環式基である、請求項1~5のいずれか一項に記載の、抗B型肝炎ウイルス剤。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/765,011 US10308642B2 (en) | 2015-10-05 | 2016-10-05 | Anti-hepatitis B virus agent |
EP16853620.9A EP3360554B1 (en) | 2015-10-05 | 2016-10-05 | Anti-hepatitis b virus agent |
JP2017544524A JP6723254B2 (ja) | 2015-10-05 | 2016-10-05 | 抗b型肝炎ウイルス剤 |
CN201680058238.7A CN108135891B (zh) | 2015-10-05 | 2016-10-05 | 抗乙型肝炎病毒药 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015197725 | 2015-10-05 | ||
JP2015-197725 | 2015-10-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017061466A1 true WO2017061466A1 (ja) | 2017-04-13 |
Family
ID=58487791
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2016/079614 WO2017061466A1 (ja) | 2015-10-05 | 2016-10-05 | 抗b型肝炎ウイルス剤 |
Country Status (5)
Country | Link |
---|---|
US (1) | US10308642B2 (ja) |
EP (1) | EP3360554B1 (ja) |
JP (1) | JP6723254B2 (ja) |
CN (1) | CN108135891B (ja) |
WO (1) | WO2017061466A1 (ja) |
Cited By (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018181883A1 (ja) * | 2017-03-31 | 2018-10-04 | 富士フイルム株式会社 | 4-ピリドン化合物またはその塩、それを含む医薬組成物および剤 |
WO2019165374A1 (en) | 2018-02-26 | 2019-08-29 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds as hbv replication inhibitors |
WO2019193533A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'2'-cyclic dinucleotides |
WO2019193543A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides |
WO2019193542A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides |
WO2019195181A1 (en) | 2018-04-05 | 2019-10-10 | Gilead Sciences, Inc. | Antibodies and fragments thereof that bind hepatitis b virus protein x |
WO2019200247A1 (en) | 2018-04-12 | 2019-10-17 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome |
WO2019211799A1 (en) | 2018-05-03 | 2019-11-07 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide |
WO2020028097A1 (en) | 2018-08-01 | 2020-02-06 | Gilead Sciences, Inc. | Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid |
WO2020061435A1 (en) | 2018-09-21 | 2020-03-26 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2020092621A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
WO2020092528A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
US10662416B2 (en) | 2016-10-14 | 2020-05-26 | Precision Biosciences, Inc. | Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome |
US10729688B2 (en) | 2018-03-29 | 2020-08-04 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US10738035B2 (en) | 2015-05-13 | 2020-08-11 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
WO2020178770A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides and prodrugs thereof |
WO2020178768A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
WO2020178769A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides and prodrugs thereof |
WO2020214663A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020214652A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020237025A1 (en) | 2019-05-23 | 2020-11-26 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
WO2020263830A1 (en) | 2019-06-25 | 2020-12-30 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
US10934306B2 (en) | 2016-03-07 | 2021-03-02 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US10952978B2 (en) | 2017-08-28 | 2021-03-23 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US10966999B2 (en) | 2017-12-20 | 2021-04-06 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
WO2021067181A1 (en) | 2019-09-30 | 2021-04-08 | Gilead Sciences, Inc. | Hbv vaccines and methods treating hbv |
WO2021113765A1 (en) | 2019-12-06 | 2021-06-10 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome |
US11058678B2 (en) | 2018-01-22 | 2021-07-13 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
WO2021188959A1 (en) | 2020-03-20 | 2021-09-23 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
US11198693B2 (en) | 2018-11-21 | 2021-12-14 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
US11203610B2 (en) | 2017-12-20 | 2021-12-21 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
US11236108B2 (en) | 2019-09-17 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
US11236111B2 (en) | 2019-06-03 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
WO2022031894A1 (en) | 2020-08-07 | 2022-02-10 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
WO2022087149A2 (en) | 2020-10-22 | 2022-04-28 | Gilead Sciences, Inc. | Interleukin-2-fc fusion proteins and methods of use |
US11472808B2 (en) | 2019-06-04 | 2022-10-18 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents |
WO2022241134A1 (en) | 2021-05-13 | 2022-11-17 | Gilead Sciences, Inc. | COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS |
WO2022271684A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271650A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271659A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271677A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
US11760755B2 (en) | 2019-06-04 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11802125B2 (en) | 2020-03-16 | 2023-10-31 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022268154A1 (zh) * | 2021-06-24 | 2022-12-29 | 上海齐鲁制药研究中心有限公司 | 新型抗乙肝化合物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5980665A (ja) * | 1982-10-29 | 1984-05-10 | Toyama Chem Co Ltd | 4−オキソ−1,4−ジヒドロニコチン酸誘導体 |
JPS61246163A (ja) * | 1985-04-09 | 1986-11-01 | Fujisawa Pharmaceut Co Ltd | 新規複素環化合物およびその塩 |
CN1465567A (zh) * | 2002-06-21 | 2004-01-07 | 陈依军 | 二氢吡啶酮类衍生物及其用途 |
WO2010110231A1 (ja) * | 2009-03-26 | 2010-09-30 | 塩野義製薬株式会社 | 置換された3-ヒドロキシ-4-ピリドン誘導体 |
CN103992290A (zh) * | 2013-05-14 | 2014-08-20 | 中国医学科学院医药生物技术研究所 | 二芳基乙烯结构类似化合物及其制备方法和应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3338846A1 (de) * | 1982-10-29 | 1984-05-03 | Toyama Chemical Co. Ltd., Tokyo | Neue 4-oxo-1,4-dihydronicotinsaeurederivate und salze derselben, verfahren zu ihrer herstellung und antibakterielle mittel mit einem gehalt derselben |
-
2016
- 2016-10-05 JP JP2017544524A patent/JP6723254B2/ja active Active
- 2016-10-05 WO PCT/JP2016/079614 patent/WO2017061466A1/ja active Application Filing
- 2016-10-05 EP EP16853620.9A patent/EP3360554B1/en active Active
- 2016-10-05 CN CN201680058238.7A patent/CN108135891B/zh active Active
- 2016-10-05 US US15/765,011 patent/US10308642B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5980665A (ja) * | 1982-10-29 | 1984-05-10 | Toyama Chem Co Ltd | 4−オキソ−1,4−ジヒドロニコチン酸誘導体 |
JPS61246163A (ja) * | 1985-04-09 | 1986-11-01 | Fujisawa Pharmaceut Co Ltd | 新規複素環化合物およびその塩 |
CN1465567A (zh) * | 2002-06-21 | 2004-01-07 | 陈依军 | 二氢吡啶酮类衍生物及其用途 |
WO2010110231A1 (ja) * | 2009-03-26 | 2010-09-30 | 塩野義製薬株式会社 | 置換された3-ヒドロキシ-4-ピリドン誘導体 |
CN103992290A (zh) * | 2013-05-14 | 2014-08-20 | 中国医学科学院医药生物技术研究所 | 二芳基乙烯结构类似化合物及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
LV ,Z. ET AL.: "Design, Synthesis, and Antihepatitis B Virus Activities of Novel 2- Pyridone Derivatives", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, 2010, pages 660 - 668, XP055371244 * |
Cited By (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10738035B2 (en) | 2015-05-13 | 2020-08-11 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US10934306B2 (en) | 2016-03-07 | 2021-03-02 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11274285B2 (en) | 2016-10-14 | 2022-03-15 | Precision Biosciences, Inc. | Engineered meganucleases specific for recognition sequences in the Hepatitis B virus genome |
US10662416B2 (en) | 2016-10-14 | 2020-05-26 | Precision Biosciences, Inc. | Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome |
JPWO2018181883A1 (ja) * | 2017-03-31 | 2020-01-16 | 富士フイルム株式会社 | 4−ピリドン化合物またはその塩、それを含む医薬組成物および剤 |
US11161830B2 (en) | 2017-03-31 | 2021-11-02 | Fujifilm Corporation | 4-pyridone compound or salt thereof, and pharmaceutical composition and formulation including same |
WO2018181883A1 (ja) * | 2017-03-31 | 2018-10-04 | 富士フイルム株式会社 | 4-ピリドン化合物またはその塩、それを含む医薬組成物および剤 |
CN110475775A (zh) * | 2017-03-31 | 2019-11-19 | 富士胶片株式会社 | 4-吡啶酮化合物或其盐、包含4-吡啶酮化合物的药物组合物及剂 |
EP3604301A4 (en) * | 2017-03-31 | 2020-02-05 | FUJIFILM Corporation | 4-PYRIDONE COMPOUND OR SALT THEREOF, PHARMACEUTICAL COMPOSITION AND FORMULATION COMPRISING SAME |
CN110475775B (zh) * | 2017-03-31 | 2023-05-09 | 富士胶片株式会社 | 4-吡啶酮化合物或其盐、包含4-吡啶酮化合物的药物组合物及剂 |
AU2018246563B2 (en) * | 2017-03-31 | 2020-07-30 | Fujifilm Corporation | 4-Pyridone compound or salt thereof, and pharmaceutical composition and formulation including same |
US10952978B2 (en) | 2017-08-28 | 2021-03-23 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11596611B2 (en) | 2017-08-28 | 2023-03-07 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US12011425B2 (en) | 2017-08-28 | 2024-06-18 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US10966999B2 (en) | 2017-12-20 | 2021-04-06 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
US11203610B2 (en) | 2017-12-20 | 2021-12-21 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
US11058678B2 (en) | 2018-01-22 | 2021-07-13 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
WO2019165374A1 (en) | 2018-02-26 | 2019-08-29 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds as hbv replication inhibitors |
US10729688B2 (en) | 2018-03-29 | 2020-08-04 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
WO2019195181A1 (en) | 2018-04-05 | 2019-10-10 | Gilead Sciences, Inc. | Antibodies and fragments thereof that bind hepatitis b virus protein x |
WO2019193533A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'2'-cyclic dinucleotides |
WO2019193542A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides |
US11149052B2 (en) | 2018-04-06 | 2021-10-19 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′-cyclic dinucleotides |
WO2019193543A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides |
US11292812B2 (en) | 2018-04-06 | 2022-04-05 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′-cyclic dinucleotides |
US11142750B2 (en) | 2018-04-12 | 2021-10-12 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome |
US11788077B2 (en) | 2018-04-12 | 2023-10-17 | Precision Biosciences, Inc. | Polynucleotides encoding optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome |
WO2019200247A1 (en) | 2018-04-12 | 2019-10-17 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome |
WO2019211799A1 (en) | 2018-05-03 | 2019-11-07 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide |
WO2020028097A1 (en) | 2018-08-01 | 2020-02-06 | Gilead Sciences, Inc. | Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid |
US10865211B2 (en) | 2018-09-21 | 2020-12-15 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
US11377450B2 (en) | 2018-09-21 | 2022-07-05 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2020061435A1 (en) | 2018-09-21 | 2020-03-26 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2020092621A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
WO2020092528A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
EP4371987A1 (en) | 2018-10-31 | 2024-05-22 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
US11891393B2 (en) | 2018-11-21 | 2024-02-06 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
US11198693B2 (en) | 2018-11-21 | 2021-12-14 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2020178769A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides and prodrugs thereof |
WO2020178768A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
US11766447B2 (en) | 2019-03-07 | 2023-09-26 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
WO2020178770A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides and prodrugs thereof |
WO2020214663A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020214652A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020237025A1 (en) | 2019-05-23 | 2020-11-26 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
US11236111B2 (en) | 2019-06-03 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11760755B2 (en) | 2019-06-04 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11472808B2 (en) | 2019-06-04 | 2022-10-18 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents |
WO2020263830A1 (en) | 2019-06-25 | 2020-12-30 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
US11236108B2 (en) | 2019-09-17 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2021067181A1 (en) | 2019-09-30 | 2021-04-08 | Gilead Sciences, Inc. | Hbv vaccines and methods treating hbv |
WO2021113765A1 (en) | 2019-12-06 | 2021-06-10 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome |
US11802125B2 (en) | 2020-03-16 | 2023-10-31 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
WO2021188959A1 (en) | 2020-03-20 | 2021-09-23 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
WO2022031894A1 (en) | 2020-08-07 | 2022-02-10 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
WO2022087149A2 (en) | 2020-10-22 | 2022-04-28 | Gilead Sciences, Inc. | Interleukin-2-fc fusion proteins and methods of use |
WO2022241134A1 (en) | 2021-05-13 | 2022-11-17 | Gilead Sciences, Inc. | COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS |
WO2022271659A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271677A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271650A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271684A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
Also Published As
Publication number | Publication date |
---|---|
US10308642B2 (en) | 2019-06-04 |
JP6723254B2 (ja) | 2020-07-15 |
CN108135891A (zh) | 2018-06-08 |
EP3360554A4 (en) | 2019-05-22 |
EP3360554B1 (en) | 2021-07-28 |
CN108135891B (zh) | 2021-07-20 |
US20180291011A1 (en) | 2018-10-11 |
EP3360554A1 (en) | 2018-08-15 |
JPWO2017061466A1 (ja) | 2018-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6723254B2 (ja) | 抗b型肝炎ウイルス剤 | |
CN110475775B (zh) | 4-吡啶酮化合物或其盐、包含4-吡啶酮化合物的药物组合物及剂 | |
EP2086966B1 (en) | 2-carboxy thiophene derivatives as anti viral agents | |
EP2097419B1 (en) | Benzofuropyrimidinones as protein kinase inhibitors | |
AU2002220195B2 (en) | Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto | |
US20180085365A1 (en) | Amino-quinolines as kinase inhibitors | |
EP2744812B1 (en) | Therapeutically active fused pyrimidine derivatives | |
CN103930399A (zh) | 包含亚氨基亚磺酰基的二取代的5-氟嘧啶衍生物 | |
JPWO2002051849A1 (ja) | Cdk4活性阻害剤 | |
JP2001261663A (ja) | Impdh阻害剤としてのオキサミド類 | |
WO2005118579A2 (en) | Thiazole derivatives as chemokine receptor antagonists | |
TW202106685A (zh) | 抗b型肝炎病毒(hbv)之新穎苯基及吡啶基脲活性劑 | |
AU2019373677B2 (en) | Novel urea 6,7-dihydro-4H-pyrazolo(4,3-c)pyridines active against the hepatitis B virus (HBV) | |
CN113527296A (zh) | 一种流感病毒抑制剂 | |
ES2742309T3 (es) | Derivados de piperazina-imidazol y métodos de uso de los mismos para mejorar la farmacocinética de un fármaco | |
KR100661081B1 (ko) | 항바이러스제로 유용한 6-메틸니코틴아미드 유도체 | |
CA3220874A1 (en) | Parp7 inhibitor and use thereof | |
CA3118339A1 (en) | Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16853620 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017544524 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15765011 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2016853620 Country of ref document: EP |